bluuebunny/crossref_metadata_2025 huggingface dataset:
P01.03.B A quantitative comparison of cognitive performance and patient-reported symptoms in preoperative lower-grade glioma patients from two Dutch Hospitals
Authors: Belgers V , van Buijtene W , Butterbrod E , Röttgering J G , Douw L , De Witt Hamer P C , Rutten G M , Klein M , De Baene W , Kouwenhoven M C M , Gehring K
Published: September 2022

Background

Protocols for assessment of (neuro)psychological outcomes in lower-grade glioma patients vary between hospitals. This potentially complicates generalization of these outcomes. We compared standardized scores on tests of two frequently impaired cognitive domains (attention and executive functioning (EF)), and two relevant patient-reported outcomes (PROs; depression and fatigue) of two neuro-oncological hospitals that use different measurement instruments.

Material and Methods

Data were used from preoperative assessments of patients with (IDH-mut) WHO grade II/III glioma tested between 2007 and 2021 at Amsterdam UMC (AMS) or at Elisabeth-Tweesteden Hospital Tilburg (ETZ). AMS patients were referred for (neuro)psychological assessment based on physician and patient preference (paper and pencil tests), whereas all ETZ patients routinely undergo screening (computerized tests). To compare scores of the different attention and EF tests we converted patients’ performances to z-scores based on normative data. For cognitive performance, we compared scores of different cognitive flexibility tests (CST vs SAT), processing speed tests (SDC vs LDMT), and Stroop tests (Stroop I and Stroop III). PROs included the CES-D vs HADS-D and the CIS-fatigue vs MVI-general fatigue (AMS vs ETZ, resp.). Differences were tested using Fisher's, χ 2, and Mann-Whitney U tests.

Results

Assessments were done median 4 weeks (AMS, n=97, range 19-0 weeks) and 1 day (ETZ, n=106; range 14-0 days) preoperatively. Age, sex, tumor location and histology were comparable between cohorts (p>0.05), but the AMS cohort showed significantly more grade III tumors (36% vs 16%) and more awake surgeries (84% vs 46%). Z-scores measuring attention and EF (n=94 and n=95, AMS vs ETZ) were not significantly different (CST vs SAT, percentage with a disorder (z <-1.5SD) 15% vs 13%; SDC vs LDMT 13% vs 14%; Stroop I 11% vs 18%; Stroop III 13% vs 16% at AMS and ETZ, resp.). Percentages of patients with possible depression (CES-D≥16, n=88 and HADS-D≥8, n=106) did not differ significantly between hospitals (28% vs 26%), nor did percentages of patients with severe fatigue (CIS-fatigue≥35, n=88 and MVI-general fatigue (z <-1.5SD), n=38, 42% vs 24% at AMS and ETZ, resp.).

Conclusion

Standardized scores of glioma patients on cognitive domains (attention and EF) and PROs (depression and fatigue) did not differ between two centers with slightly different samples using different testing protocols. This cautiously suggests that study findings on cognitive functioning and symptoms could be generalized. For research purposes, conjoint use of pooled populations for outcome evaluation could be explored with different samples from other centers using different instruments.
P01.05.A Working memory performance is associated with functional connectivity between the right dlPFC and DMN in glioma patients
Authors: Smolders L , de Baene W , Rutten G , van der Hofstad R , Florack L
Published: September 2022

Background

Patients with primary brain tumors frequently suffer from cognitive impairments in multiple domains, leading to serious consequences for socio-professional functioning and quality of life. The functional-anatomical basis of these impairments is still poorly understood.

The study of correlated BOLD activity in the brain (i.e. functional connectivity) has greatly contributed to our understanding of how brain activity supports cognitive function. In particular, activity observed during the execution of specific tasks can be related to various distributed functional networks, stressing the importance of interactions between remote brain regions. Among these networks, the Default Mode Network (DMN) and the Fronto-Parietal Network (FPN) have consistently been associated with working memory performance.

Recently, using task-fMRI in glioma patients, poor performance in a working memory task was associated with less deactivation of the DMN during this task and to a lack of task-evoked changes in the DMN-FPN structure. In this study, we investigated whether these effects are reflected in the resting-state (RS) functional connectivity of the same patient group, i.e. when no task was performed during fMRI. We additionally zoomed in on the part of the FPN located in the dorsolateral Prefrontal Cortex (dlPFC), since this region is believed to be mainly responsible for DMN deactivation.

Material and Methods

Resting-state functional MRI data were acquired pre-operatively from 45 brain tumor patients (20 low- and 25 high-grade glioma patients). Results of a pre-operative in-scanner N-back working memory fMRI task were used to assess working memory performance.

Patient brains were parcellated into ROIs using both the Gordon and Yeo atlas, which have the FPN and DMN network identities readily available. The dlPFC was defined based on masks retrieved from NeuroSynth.

To measure DMN-FPN functional connectivity the average Pearson correlation between the activation time series in the regions belonging to the FPN and the DMN was calculated. Functional connectivity between the DMN and the dlPFC was calculated in a similar way.

Results

The average correlation between the resting-state fMRI activity in the right dlPFC and in the DMN was negatively associated with working memory performance for both the Gordon atlas (p < 0.003) and Yeo atlas (p < 0.007). No association was found for the correlation between activity in the left dlPFC and the DMN, nor for the correlation between the activity in the whole FPN and the DMN.

Conclusion

Our findings show that working memory performance of glioma patients is related to interactions between networks that can be measured with resting-state fMRI. Furthermore, the results provide further evidence that not only specific brain regions are important for cognitive performance, but that also the interactions between large-scale networks should be considered.
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

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

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<.01, β= -.473), Stroop (p<.01, β= -.519), and SDC (p<.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<.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

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

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 < .05) and the number of peritumoral cortical eloquent spots (p < .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

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

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% <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 <17 (5.32%) compared with one with a SVFT >=17. The median SVFT in cases with cancer was 10 animals. Other possible causes of SVFT <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 <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 >=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

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

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

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.
P02.06.B Calvarial metastases: overview of the different entities and the pre-, intra- and postoperative course
Authors: Hunziker S , Nasi-Kordishti I , Tatagiba M
Published: September 2022

Background

Calvarial metastases are most often in cancer with systematic bony metastatic disease. Calvarial metastases occur via hematogenous spread, retrograde seeding through Batson’s venous plexus, or direct extension. A variety of different primary tumours can cause calvarial metastases. The lesions can be palpable on the skin, cause local swelling and, depending on the location, neurological deficits can also occur. The aim of this research is to present an overview of the different entities and the neurosurgical management.

Material and Methods

Retrospectively, all patients who underwent surgery on a calvarial metastasis in our department between 2004 and 2021 (n=22) were identified. Data on the morphological and histological findings as well as the pre-, intra- and postoperative course were gathered and analysed.

Results

Swelling (n=14), cosmetically disturbing (n=9), pain (n=6), neurological deficits (n=4), epilepsy (n=3) and B-symptoms (n=1) were the main complaints. 7 had no symptoms at the time of diagnosis. There was a side preference with most of the lesions occurring on the right (n=13), less on the left (n=5) or bilateral (n=4). Calvarial metastases are divided in primary lesions, originating in the bone and secondary lesions infiltrating the bone. The majority of lesions originated from the bone except two, which wer secondary infiltrating the bone. 20 were not limited to the bone, infiltrating adjacent tissue (skin 70%, dura 85%, brain 35%). 18 lesions were osteolytic except four, where no further description was provided. Intraoperatively, craniectomy or in case of biopsy a craniotomy was performed. 70% of cases required Dural plastic. Depending on history and location the operative approach was biopsy (n=1), extended (n=6), subtotal (n=1) or complete (n=14) resection. Intraoperative major bleeding occurred in 15 % of cases, all with macroscopic high vascularization; hemodynamically relevant (n=1), requiring LAE (n=1). Histologically most common were adenocarcinoma of the lung (n=5), mamma (n=3), prostate (n=2), sigma (n=1), rectum (n=1) and gastric (n=1). Melanoma (n=3), neuroblastoma (n=1) and clear cell renal carcinoma (n=2) were less common. Other rare primaries were carcinoma of the parotid (n=1), SCLC (n=1) and follicular thyroidal cancer (n=1). Postoperatively, further treatment was initiated depending on the primary tumour.

Conclusion:

Above mentioned clinical symptoms or the staging of a cancer leads to the diagnosis of calvarial metastasis. Preoperative imaging shows localisation and the degree of infiltration into adjacent tissues. Imaging results and the clinical symptoms determine the surgical strategy. But definitive diagnosis can only be made by histological analysis. After surgery, the histology, the extension of the primary tumour and the clinical condition of the person influence the kind of further treatment initiated.
P02.07.B Patient-derived glioblastoma organoids: Elucidating the mechanisms of glioblastoma therapeutic resistance in the context of tumor microenvironment
Authors: Habič A , Majc B , Porčnik A , Bošnjak R , Mlakar J , Lah Turnšek T , Breznik B , Novak M
Published: September 2022

Background

Intratumoral heterogeneity plays an important role in glioblastoma (GB) resistance to standard therapy consisting of irradiation and chemotherapy with temozolomide (TMZ). However, classical in vitro GB models fail to represent the complex cellular composition of tumors in vivo, which hinders relevant examination of GB therapeutic response. To overcome these limitations, we studied the effects of irradiation and TMZ in a novel patient-derived organoid model.

Material and Methods

We established a patient-derived GB organoid model by a protocol recently published by Jacob et al. Original tumor tissue and tissue-derived organoids were compared by immunofluorescence staining of selected cell type markers and qPCR analysis of expression levels of a panel of selected target genes, including 15 genes defining GB subtypes. To analyze GB therapeutic response, organoids from 11 patients were exposed to a single dose of irradiation (10 Gy), one-week treatment with TMZ (50 µM) or their combination. The effects of therapy were assessed by viability and invasion assays. Expression levels of a number of genes related to GB subtypes, epithelial-mesenchymal transition, stemness, DNA damage responses, cell cycle, cytokines, and cell markers of the tumor microenvironment (TME) were compared between treated organoids and untreated controls. In addition, the heterogeneity of the TME and its responses to treatment were investigated by spatially resolved transcriptomics with in situ sequencing (ISS) methodology.

Results

Organoids recapitulate inter-patient variability and reflect the cellular composition and gene expression levels of the tumor tissue from which they were derived. GB stem cells and differentiated cancer cells are present in organoids along with various cells of the TME, e.g., macrophages and microglia, lymphocytes, and endothelial cells. Irradiation and TMZ showed no significant effects on organoid viability and invasion. However, some target genes were differentially expressed in the treated organoids, such as E3 ubiquitin-protein ligase MDM2 and cyclin-dependent kinase inhibitor 1A (CDKN1A). To our knowledge, we are the first to apply spatially resolved transcriptomics (ISS) to formalin-fixed, paraffin-embedded sections of (un)treated GB organoids. Our results elucidate the role of the TME in GB therapeutic response and shed light on potential mechanism underlying GB therapy resistance.

Conclusion

Patient-derived GB organoids recapitulate the key characteristics and complex composition of patient’s tumor tissue, providing a valuable platform for studies of GB therapeutic response and resistance.
P02.10.A CRISPR/Cas9 deletion of SOX2 Regulatory Region 2 (SRR2) decreases SOX2 malignant activity in glioblastoma
Authors: Saenz-Antoñanzas A , Moncho-Amor V , Elúa-Pinín A , Rizzoti K , Lovell-Badge R , Matheu A
Published: September 2022

Background

SOX2 is a transcription factor associated with stem cell activity in several tissues. SOX2 expression is elevated in a large proportion of cancers, such as glioblastoma (GB), the most common malignant primary brain tumor in adults. SOX2 acts as a relevant driver of GB progression and high levels are associated with the population of tumor initiating cells and poor patient outcome. Transcriptional regulation of SOX2 is complex and not fully understood. The SOX2 regulatory region 2 (SRR2) is located downstream of the SOX2 coding region and mediates SOX2 expression by the association of p21CIP1 and p27KIP1 to SRR2. In this study we dissected the role of SRR2 on SOX2 activity in GB.

Material and Methods

We deleted SRR2 (SRR2del) by CRISPR/Cas9 technology in U373 GB cells. We analyzed the expression of SOX2 and performed in vitro functional experiments. We accomplished rescue experiments overexpressing SOX2 in SRR2del cells and we studied the link between SOX2, p21CIP1 and p27KIP1. Finally, we carried out an in vivo carcinogenesis assay by the injection of SRR2del cells in immunodeficient mice.

Results

We report that the deletion of SRR2 in GB cells leads to a reduction of SOX2 expression, which was accompanied with an impairment of cell growth and proliferation as well as with a reduction of self-renewal capacity in vitro. These data reveal that SRR2 is required for SOX2 expression and that its deletion results in impaired tumorigenic capacity of GB cells. These effects correlated with an increased expression of p21CIP1 and p27KIP1 together with high levels of p53 in SRR2del cells. On the contrary, SRR2del cells presented decreased levels of stem cell markers, supporting the idea that SRR2 is necessary for the SOX2-mediated regulation of stemness pathways. Furthermore, ectopic overexpression of SOX2 in SRR2del cells restored SOX2 expression as well as proliferation and stem cell properties, indicating that the expression and the oncogenic activity of SOX2 is regulated by SRR2. Additionally, our xenograft models revealed that the lack of SRR2 impairs tumor initiation and growth in vivo. Tumors derived from SRR2del cells were significantly smaller compared to controls and exhibit low levels of SOX2, Ki67 and BMI1 but high levels of p21CIP1 and p27KIP1.

Conclusion

Our data confirm that the SRR2 regulates SOX2 expression and reveal that SRR2 deletion reduces SOX2 levels and halts malignant activity driven by SOX2 in GB.
P02.11.B An hypothesis generating study of MRI-Derived Radiomics on tumor and microenvironment tissue heterogeneity to guide post-operative management of glioblastoma: toward personalized radiation treatment volume delineation
Authors: Cannatà M , Russo R , Beghella Bartoli F , Palumbo I , Tran H , Votta C , Lupattelli M , Boldrini L , Dinapoli N , Camilli F , Balducci M , Gambacorta M , Valentini V , Aristei C , Sabatino G , Pignotti F , Gaudino S , Chiesa S
Published: September 2022

Background

The glioblastoma’s bad prognosis is primarily due to intra-tumor heterogeneity, demonstrated from several studies that collected molecular biology, cytogenetic data and more recently radiomic features for a better prognostic stratification.The GLIFA project (GLIoblastoma Feature Analysis) is a multicentric project planned to investigated the role of radiomic analysis in GBM management, to verify if radiomic features in the tissue around the resection cavity which may guide the radiation target volume delineation.

Material and Methods

We retrospectively analyze from three centers radiomic features extracted from 90 patients with total or near total resection, who completed the standard adjuvant treatment and for whom we had post-operative images available for features extraction.The Manual segmentation was performed on post gadolinium T1w MRI sequence by 2 radiation oncologist reviewed by a neuroradiologist, both with at least 10 years of experience. The Region of interest (ROI) considered for the analysis were: the surgical cavity +/- post-surgical residual mass (CTV_cavity); the CTV a margin of 1.5 cm added to CTV_cavity and the volume resulting from subtracting the CTV_cavity from the CTV was defined as CTV_Ring. Radiomic analysis and modelling were conducted in RStudio. Z-score normalization was applied to each radiomic feature. A radiomic model was generated using the 226 features extracted from the Ring to perform a binary classification and predict the PFS at 6 months (statistical, morphological and textural features). A 3-fold cross-validation repeated five times was implemented for internal validation of the model.

Results

Two-hundred and seventy ROIs were contoured. The proposed radiomic model was given by the best fitting logistic regression model, and included the following 3 features: F_cm_merged.contrast, F_cm_merged.info.corr.2, F_rlm_merged.rlnu. A good agreement between model predicted probabilities and observed outcome probabilities was obtained (p-value of 0.49 by Hosmer and Lemeshow statistical test). The ROC curve of the model reported an AUC of 0.78 (95% CI: 0.68 - 0.88).

Conclusion

This is the first hypothesis-generating study who applies a radiomic analysis focusing on healthy tissue ring around the surgical cavity on post-operative MRI. This study provides a preliminary model for a decision support tool for a customization of the radiation target volume in GBM patients in order to achieve a margin reduction strategy.
P03.03.A STEREOBRAIN: Stereotactic radiosurgery versus whole-brain radiotherapy in patients with 4-10 brain metastases - a non-randomized controlled trial
Authors: Niyazi M , Bodensohn R , Kaempfel A , Forbrig R , Garny S , Corradini S , Belka C
Published: September 2022

Background

Since the JLGK0901 study described non-inferiority of stereotactic radiosurgery (SRS) of 5-10 compared to 2-4 brain metastases in 2014, it has been widely discussed if SRS should replace whole brain radiotherapy (WBRT) in 5 - 10 brain metastases though lacking randomized evidence. At our department, WBRT has been the treatment of choice in 4-10 brain metastases until 2017. This paradigm was entirely changed to include patients within the STEREOBRAIN trial (DRKS00014694). We designed this prospective controlled single arm trial to systematically introduce SRS to 4 to 10 brain metastases comparing this new treatment regimen with the former approach. We aimed at showing a survival benefit of this novel treatment paradigm.

Material and Methods

Inclusion criteria were 4-10 brain metastases, largest diameter 2.5 cm, all histologies except SCLC, germ cell tumors, lymphoma, and ECOG ≤ 2. The retrospective WBRT cohort was identically selected from consecutive patients from 2012 to 2017 in a 1:2 fashion. At a significance level of 5%, a total number of 99 events (deaths) across the two groups allows to detect an increase in median OS from 6 months (retrospective WBRT cohort) to 11 months (SRS) considered clinically relevant (and corresponding to a hazard ratio of 0.55 assuming exponential distributions of survival times within groups) with a power of 80%. Propensity-score matching was performed to take confounders into account given the inherent bias caused by different treatment periods. Multiple brain mets SRS was performed using a single-isocenter technique.

Results

Patients were recruited from 2017 - 2020 and end of F/U was July 1st 2021. Forty patients were recruited to the SRS cohort and 70 patients were eligible within the WBRT cohort (81 events altogether). Median follow-up, OS and intracranial progression free survival were 21.6 months (95%-CI 19.8-NA), 10.4 months (95%-CI 9.3-NA) and 7.1 months (95%-CI 3.9-14.2) for the SRS-cohort, and 61.4 months (95% 54.6-NA), 6.5 months (95%-CI 4.9-10.4) and 5.9 months (95%-CI 4.1-8.8) for the WBRT-cohort, respectively. The Cox-model yielded a trend for improved survival within the SRS-cohort, HR 0.65 (95%-CI 0.4-1.1); p=0.076. After optimal propensity score matching, OS was significantly superior for the SRS-cohort (HR 0.53 (95%-CI 0.32-0.86), p=0.01). No grade III toxicities were observed in the SRS-cohort.

Conclusion

Despite all limitations of a historical control and missing the target number of events, there was a clear signal of improved survival with SRS compared to WBRT for patients with 4-10 metastases. Whether adapted WBRT (hippocampal sparing, simultaneous integrated boost) or SRS is to be preferred needs to be investigated in the future.
P03.05.A Radiation-induced leukoencephalopathy (RIL) in glioma: unique injury dynamics following proton vs photon beam radiotherapy
Authors: Winter S F , Gardner M , Parsons M W , Grassberger C , Bussière M , Kaul D , Boehmerle W , Endres M , Shih H A , Dietrich J
Published: September 2022

Background

White matter injury after brain-directed radiotherapy (RT), aka radiation-induced leukoencephalopathy (RIL), is common in brain tumor patients. Differentiation from progressive disease can be challenging. Dosimetric advantages of protons (PRT) over photons (XRT) minimize radiation to healthy brain tissue, potentially limiting radiotoxic sequelae including RIL. We characterized RIL during periods of progression-free survival (PFS) in glioma patients irradiated with either PRT or XRT, hypothesizing that PRT would result in reduced RIL outside of the target field.

Material and Methods

34 patients (19 male; mean age = 40.10y) with grade 2/3 gliomas and a history of partial cranial RT were stratified by RT modality [XRT (n=17) vs PRT (n=17)] and matched on 11 criteria [age, sex, tumor type/location/laterality, mutational status (IDH; 1p19q deletion), concurrent/adjuvant chemotherapy, radiation dose/fractions] for retrospective analysis. RIL development was characterized longitudinally for up to 3 years post-RT via analysis of serial MRI T2/FLAIR sequences. A novel RIL scoring system with embedded Fazekas scale was designed to quantify injury severity at both global (whole brain) and hemispheric levels.

Results

Matched groups did not differ significantly on any demographic or clinical characteristics. Median PFS post-RT was 4.7 (XRT) and 5.1 (PRT) years. The novel RIL scoring system was reliable (intraclass correlation coefficient >0.9). There was a significant increase in global RIL in both XRT [F(3, 57)=8.63, p< .001] and PRT [F(3, 61)=4.69, p< .005] groups over time, relative to baseline (1-month post-RT). A majority [62% (XRT) and 72% (PRT)] developed moderate or severe RIL within 3 years, with the ipsilesional hemisphere more severely affected. Analysis of RIL injury dynamics (i.e., average % change between 1 and 3 years post-RT) at hemispheric level identified radiation modality-specific differences: XRT resulted in greater contralesional hemispheric injury than PRT [F(1, 31)=4.32, p<.05]. This effect was not observed in ipsilesional hemispheres.

Conclusion

RIL is common in glioma patients and quantifiable by characteristic imaging features, including early onset post-RT, greater ipsilesional injury burden, and progression over time. RIL injury dynamics appear to be radiation modality-specific, whereby XRT causes greater delayed injury in the remote, contralesional hemisphere. These findings may reflect dosimetric differences between protons and photons. The impact of such sequelae on cognitive function is subject of current investigation.