bluuebunny/crossref_metadata_2025 huggingface dataset:
OS08.4.A Retrospective analysis of in vivo 1H-magnetic resonance spectroscopy based on a machine learning approach enables reliable prediction of IDH mutation in patients with glioma
Authors: Bumes E , Fellner C , Lenz S , Linker R , Weis S , Wendl C , Wimmer S , Hau P , Gronwald W , Hutterer M
Published: September 2021

BACKGROUND

Mutation of isocitrate dehydrogenase (IDH) is not only an important landmark in the development of low-grade gliomas, but also has prognostic significance and is a potential therapeutic target. There is a high need to determinate IDH mutation status at diagnosis and during the course of therapy in a non-invasive and reliable manner. We established a machine learning approach based on a support vector machine to detect IDH mutation status in in vivo standard 1H-magnetic resonance spectroscopy (1H-MRS) at 3T with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2–99.9%), and a specificity of 75% (95% CI, 42.85–94.5%) in a prospective monocentric clinical trial. Here, the same method is applied in a retrospective cohort at 1.5T and tested for transferability.

MATERIAL AND METHODS

Validation cohort. The validation cohort comprised 100 patients with glioma for which standard in vivo 1H-MRS spectra had been acquired between 2002 and 2007. Standard single voxel spectroscopy had been measured at 1.5T using a PRESS sequence with a TR of 1500ms and a TE of 30ms. One sample had to be excluded due to non-malignant histology and for 15 samples the IDH mutation status was not available. Therefore, the validation cohort comprised 84 samples, of which 35 were bearing an IDH mutation in immunohistochemistry (sequencing for confirmation is outstanding). Machine learning. To transfer our method to an independent validation cohort our previously established machine learning approach was first trained on all samples of the 3T group. The trained algorithm was then applied to the data of the validation cohort. Here, among other factors the different field strengths, with which the spectra were acquired (3T vs. 1.5T) had to be considered.

RESULTS

27 samples of the validation cohort had to be excluded due to poor spectra quality. Our approach correctly detected IDH mutation status in 47 of 62 patients (75.8%), although the technical conditions were significantly different from our published prospective cohort. 17 of 30 patients bearing an IDH mutation were correctly identified, while 30 of 32 wild type patients were determined successfully.

CONCLUSION

Our approach to detect IDH mutation status has promising application in an unselected retrospective cohort, demonstrating transferability across different technical conditions. Further investigations to improve our technique and an advanced neuropathological processing of the samples are planned.
OS08.5.A Proteomic analysis of meningioma
Authors: Hanemann C O , Dunn J , Akther Y , Ercolano E , Adams C , Banton M , Sharma V , Hilton D
Published: September 2021

BACKGROUND

Meningioma is the most common primary intracranial tumor. Although ~80% are benign some WHO grade I are clinically aggressive. Chemotherapies are ineffective and biomarkers for clinical management are lacking. Approximately 60% sporadic meningiomas harbor mutations in the NF2 gene andutations in TRAF7, KLF4, AKT1, SMO and PIK3CA have been identified in the majority NF2-positive tumors esp lower grade. However, the molecular mechanisms behind meningioma tumourigenesis is still unclear. We aim to identify novel biomarkers and therapeutic targets of meningioma by characterizing the proteomic landscape.

MATERIAL AND METHODS

We analysed grade I, II and III frozen meningioma specimens and three different mutational groups: AKT1/TRAF7, KLF4/TRAF7 and NF2 -/- using LC-MS/MS to analyse global proteins, enriched phosphoproteins and phosphopeptides. Differential expression and functional annotation of proteins was completed using Perseus, IPA® and DAVID. For mutational subtypes quantitative phosphoproteomics was performed using TMT 10plex labeling approach followed by motif analysis using motif-X algorithm. We validated differential expression of proteins and phosphoproteins by Western blot and immunohistochemistry.

RESULTS

We quantified 3888 proteins and 3074 phosphoproteins across all meningioma grades. Bioinformatics analysis revealed commonly upregulated (phospho)proteins to be enriched in Gene Ontology terms associated with RNA metabolism. Validation confirmed significant overexpression of proteins such as EGFR, CKAP4, the nuclear proto-oncogene SET, the splicing factor SF2/ASF as well as total and activated phosphorylated form of the NIMA-related kinase, NEK9, involved in mitotic progression. Hexokinase 2 was overexpressed in higher grades. For the mutation subtypes we have quantified 4162 proteins across all mutational meningioma subgroups. Analysis showed distinct proteomic profiles of mutational subgroups. Comparative analysis showed 10 proteins were commonly significantly upregulated among all mutational subtypes vs. normal meninges. 257 proteins were commonly significantly downregulated and enriched with molecular functions including aldehyde dehydrogenase and oxido-reductase. Mutational subtype-specific analysis identified 162 proteins significantly upregulated in AKT1/TRAF7 vs. remaining sample groups to be enriched in the oxidative phosphorylation pathway. 14 and 7 proteins were commonly significantly upregulated in KLF4/TRAF7 and NF2 -/- mutant meningioma subtypes respectively. Several of these up-regulated proteins including ANNEXIN-3, CRABP2, CLIC3 and Endoglin were verified via WB. Lastly, analyses of 6600 phosphosites predicted regulatory kinases

CONCLUSION

We show extensive proteomic and phospophoproteomics analysis of meningioma and suggest new therapeutic and biomarker candidates.
OS09.4.A Health-related quality of life in low-grade glioma survivors 26 years after diagnosis
Authors: Boele F W , Reijneveld J C , de Witt Hamer P C , van Thuijl H F , Wesseling P , Lagerwaard F J , Taphoorn M J B , Kouwenhoven M C M , Snijders T J , Douw L , Klein M
Published: September 2021

BACKGROUND

Many patients with low-grade gliomas (LGGs) continue to survive for many years, yet little is known about patients’ health-related quality of life (HRQOL) in long-term survivorship. We previously investigated HRQOL in LGG patients diagnosed on average 6 years prior to assessment (T1, N=195) with a follow-up in stable patients on average 12 years after diagnosis (T2, N=65). We present a final follow-up of LGG survivors (T3), now decades after diagnosis.

MATERIAL AND METHODS

We invited patients who participated in our previous assessment (N=65), regardless of disease status. Patients completed questionnaires to assess HRQOL, fatigue, and depressive symptoms: Short Form-36 Health Survey (SF-36), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Brain Tumour Module (EORTC BN20), Checklist Individual Strength (CIS), and the Center for Epidemiological Studies Depression Scale (CES-D). Changes over time (T1-T2-T3) on group level and participant level were assessed.

RESULTS

Of the 65 patients, 18 (27.7%) were deceased, 3 (4.6%) experienced tumour progression to WHO III, 7 (10.8%) declined, and 3 (4.6%) could not be contacted. Thirty-four patients (52.3%) participated. Of these, 2 had missing HRQOL data, with 32 patients included in analysis. Survivors were M=52.0 (sd=11.3) years old and diagnosed M=26.2 (sd=3.7, range 19–35) years prior. On group level, a statistically significant (but not clinically relevant) improvement in mental health (p=0.049), and a clinically relevant (but not statistically significant) decline in emotional role functioning was found. No other group-level changes over time in HRQOL were found. Minimal detectable change in HRQOL scale scores over time was observed in individual participants (28.1% only improvement; 25.0% only decline; 21.9% both improvement and decline) with 25.0% remaining completely stable. At T3, 25.0% of survivors scored above the cut-off for high risk of clinical depression (≥16 CES-D), and 53.1% of survivors classed as severely fatigued (≥35 CIS).

CONCLUSION

In this cohort of LGG survivors, assessed decades after diagnosis and treatment, HRQOL does not appear to be greatly impacted during survivorship. However, depressive symptoms and fatigue remain relatively common. Findings can help inform patients, their families, and clinicians and can serve as a benchmark for treatment trials evaluating interventions that can have very long-term effects.
OS09.6.A Cognition and health-related quality of life in long time survivors of high-grade glioma
Authors: Spoor J K H , Donders-Kamphuis M , Veenstra W S , van Dijk S A , Dirven C M F , Sillevis Smit P A E , van den Bent M J , Leenstra S , Satoer D D
Published: September 2021

BACKGROUND

Although prognosis is poor in high-grade glioma (HGG) patients, some become a long-term survivor (LTS). Health-related quality of life (HRQOL) and cognition are seen as indicators for quality of survival in HGG but data in LTS and their caregivers are scarce. We aim to investigate cognition and HRQOL in LTS with evaluation by their proxies.

MATERIAL AND METHODS

We included LTS with initial HGG-diagnosis between 1999–2014. Cognition was assessed with: Boston Naming Test, shortened Token Test, verbal (Category and Letter) Fluency, Diagnostic Instrument of Mild Aphasia, Hopkins Verbal Learning Test and Trail Making Test (A, B, B/A) and HRQOL with: EORTC Quality of Life Questionnaire (C30) and Brain Cancer Module (BN20). 15 Proxies evaluated patients’ HRQOL with: C30, BN20 and they filled in a burden scale: Caregiver Strain Index (CSI).

RESULTS

21 patients with grade III or IV glioma and 7 years (range 5–20 years) median survival after diagnosis participated. Compared to normative data patients deviated significantly on HVLT (direct recall, delayed recall, recognition true positives), TMT (A, B and B/A), BNT and CF (p<0.05) which was not affected by hemispheric localization (left/right) or tumor grade (III/IV). HVLT delayed recall was significantly worse in patients with >12 years survival compared to patients with <12 years survival. Average QoL rating in patients was 75%, proxy’s evaluation about patients’ QoL was similar. Moderate correlations (p<0.05) were found between impaired scores on TMT and CF and C30 cognition subscale and between impaired scores on CF, HVLT delayed recall and BNT and BN20 language subscale. At individual level only one patient had intact scores on all administered tests. Other patients had mild impairments on 1–5 subtests and severe impairment on 1–8 subtests. Five out of 14 (36%) proxies reported a great level of caregiver strain on CSI.

CONCLUSION

Most LTS suffer from cognitive impairments. Despite worse prognosis and cognitive impairments, at group level patients report relatively intact QoL, which is supported by their proxies. However, at the individual level severity of impairments is variable and high caregiver strain is reported in one-third of the proxies. Objective cognitive functioning was only modestly associated with subjective experience in patients. A patient-tailored approach is recommended to investigate individual impairments and needs for rehabilitation and support for patients and also for their carers.
OS10.4.A The effects of SmartCare on neuro-oncology family caregivers’ distress: a randomized controlled trial
Authors: Boele F W , Weimer J M , Proudfoot J , Marsland A L , Armstrong T S , Given C W , Drappatz J , Donovan H S , Sherwood P R
Published: September 2021

BACKGROUND

Patients with primary malignant brain tumors have high symptom burden and commonly rely on family caregivers for practical and emotional support. This can lead to negative mental and physical consequences for caregivers. We investigated effectiveness of an 8-week nurse-led online needs-based support program (SmartCare©) with and without online self-guided cognitive behavioral therapy (CBT) for depression compared to enhanced care as usual (ECAU) on depressive symptoms, caregiving-specific distress, anxiety, mastery, and burden.

MATERIAL AND METHODS

Family caregivers with depressive symptoms were randomized to three groups: SmartCare© plus/minus self-guided CBT, or ECAU. Primary outcomes (depressive symptoms (CES-D); caregiving-specific distress (Caregiver Needs Screen)) and secondary outcomes (anxiety (POMS-A), caregiver mastery (Caregiver Mastery Scale), and caregiver burden (Caregiver Reactions Assessment)) were assessed online. Intention to treat analyses of covariance corrected for baseline scores were performed for outcomes at four months.

RESULTS

In total, 120 family caregivers participated. Accrual and CBT engagement were lower than expected, therefore intervention groups were combined (n=80) and compared to ECAU (n=40). For depressive symptoms, no statistically significant group differences were found. Caregiving-specific distress decreased in the intervention group compared with ECAU (p=0.01, partial ɳ 2=0.08). Among secondary outcomes, there was a trend towards improvement in mastery for the intervention group compared with ECAU (p=0.08, partial ɳ 2=0.04).

CONCLUSION

SmartCare©, with or without self-guided CBT, reduced caregiving-specific distress with a trend towards improving mastery. SmartCare© has the potential to improve the lives of families coping with a brain tumor diagnosis.
P03.04 Primary CNS lymphoma of the corpus callosum: presentation and neurocognitive prognosis. Study of a monocentric cohort of 27 patients
Authors: Nilles C , Delgadillo D , Martin Duverneuil N , Mokhtari K , Mathon B , Hoang-Xuan K , Duran-Pena A , Morales A , Houillier C
Published: September 2021

BACKGROUND

The corpus callosum (CC) is frequently involved in primary central nervous system lymphomas (PCNSL). The aim of our study was to describe the impact of these lesions on neurocognition of patients presenting with PCNSL of the CC (PCNSL-CC) and their post-therapeutic evolution.

MATERIAL AND METHODS

This is a retrospective single-center study. Patients newly diagnosed at Pitié Salpêtrière Hospital from (1999–2018) were included in this study according to the following criteria: age >18, immunocompetent patient, pathological confirmation (Diffuse Large B cell lymphoma) and CC as main location of the tumor on MRI. Clinical, neuroradiological and neuropsychological data of the patients were collected. In addition, prognostic factors for the neurocognitive outcome of the patients were investigated.

RESULTS

27 patients were included (median age: 67 years, median KPS: 70). At the time of diagnosis, 74% of patients had cognitive impairment and 59% of patients had balance disorders. The cognitive functions most frequently affected were memory and executive functions. Tumor lesions in the CC had a median maximum diameter of 5 cm with a so called “butterfly pattern” in 92% of cases. All patients received a high dose methotrexate based polychemotherapy, including one with radiation therapy, and 67% of patients achieved a complete remission (CR). Median PFS and OS were 33.3 months and 177.9 months respectively. With a median follow-up of 48 months (range 6–156), despite CR, there were still abnormal values in 17% of patients on overall efficiency, 17–55% of patients on executive function tests, 45–55% of patients on memory tests. No significant impaired values were found for visuo-spatial and language tests. Splenial location and age ≥ 60 years were significantly associated with worse episodic memory scores throughout the follow-up.

CONCLUSION

PCNSL-CC are associated with frequent cognitive dysfunctions, especially memory impairment, which may recover only partially despite CR, that warrant specific rehabilitation. Older age (≥ 60) and splenial location have worse neurocognition outcome.
P04.10 CDKN2A mutational status is associated with venous thromboembolism in patients with glioblastoma
Authors: Kapteijn M Y , Kaptein F H J , Stals M A M , van Duinen S G , Taphoorn M J B , Dirven L , Koekoek J A F , Klok F A , Versteeg H H , Buijs J T
Published: September 2021

BACKGROUND

Patients with glioblastoma have a high risk of developing venous thromboembolism (VTE). However, the underlying genetic risk factors remain largely unknown. Therefore, the aim of our study was to discover whether genetic aberrations in glioblastoma associate with VTE.

MATERIAL AND METHODS

In this retrospective cohort study, all patients diagnosed with glioblastoma between February 2017 and August 2020 in two hospitals (Leiden University Medical Center and Haaglanden Medical Center) were included (n=341). Targeted DNA next-generation sequencing (NGS) had been performed of all glioblastomas for diagnostic purposes and included tumor mutational status of the genes ATRX, BRAF, CIC, FUBP1, H3F3A, IDH1, IDH2, PIK3CA, PTEN and TP53 and amplification/gain or deletion of BRAF, CDKN2A, EGFR, NOTCH1 and PTEN. Through extensive chart review, we collected data on VTE events (deep vein thrombosis and/or pulmonary embolism) three months before until two years after glioblastoma diagnosis, which were adjudicated by an independent investigator. Patients with cerebral vein thrombosis (n=3) and low quality NGS data (n=1; minimum reads/samples: <1.5M and/or minimum depth: <100 reads) were excluded. Cox regression analysis and competing risk analysis (CICR) were performed to compare patients that developed VTE with patients that did not.

RESULTS

Of the 337 patients, 215 had died, 26 were diagnosed with VTE and 37 were lost to follow-up. CDKN2A deletion was found to associate most significantly with VTE (HR: 2.65, 95%CI: 1.18–5.94, p=0.018). Competing risk analysis confirmed this finding, demonstrating a 12-month adjusted cumulative incidence of 12.7% (95%CI: 7.5–19.3) compared to 5.2% (95%CI: 2.5–9.2) in patients with CDKN2A wild-type (p=0.013). No significant association was found between any of the investigated genes, including CDKN2A deletion, and death.

CONCLUSION

This study demonstrates that CDKN2A deletion is associated with VTE in glioblastoma patients. Therefore, CDKN2A mutational status may be a promising predictor to identify patients with glioblastoma at high risk of VTE, who may benefit from thromboprophylaxis.
P07.03 Fluorescence navigation in glioma surgery using 5 ALA and chlorin E6
Authors: Rynda A , Olyushin V , Rostovtsev D
Published: September 2021

BACKGROUND

Metabolic navigation in the surgery of malignant gliomas is the most effective way to distinguish the border of the tumor during surgery and achieve a more radical resection, and as a result, to increase the recurrence interval and increase the life expectancy.

MATERIAL AND METHODS

A comparative analysis of fluorescent navigation was carried out in 50 patients (group 2) with glioma of a high degree of anaplasia, who were treated at the Department of Neurooncology of the A.L. prof. A.L. Polenov. In 25 patients (group 1), chlorin E6 1 mg / kg intravenously was used as a fluorescence inducer, the other 25 patients (group 2) received 5 ALA 20 mg / kg orally. Each group included 10 patients with Grade III anaplasia and 15 patients with Grade IV anaplasia. Both groups were statistically representative (p> 0.05).

RESULTS

For surgery of grade III glioma, the sensitivity of the method was 83.3% (chlorin E6), 82.9% (5ALA); specificity 66.7% (chlorin E6), 65.4% (5ALA). For grade IV glioma surgery, the sensitivity of the method is 87.5% (chlorin E6), 87.7% (5ALA); specificity - 85.7% (chlorin E6), 85.3% (5ALA).

CONCLUSION

Statistical analysis showed comparable high efficacy of the drugs in the surgery of malignant gliomas. The sensitivity and specificity of the method for fluorescent preparations of chlorin E6 and 5 ALA showed no statistically significant difference in the achievement of the result (p> 0.05)
P10.02 Combined methods of a micropump system and a chronic cranial window allows tumor observation with multi photon laser scanning microscopy under continuous treatment
Authors: Weil S , Jung E , Domínguez Azorín D , Higgins J , Reckless J , Ramsden N , Keller P , Grainger D , Wick W , Winkler F
Published: September 2021

BACKGROUND

Glioblastomas are notoriously therapy resistant tumors. As opposed to other tumor entities, no major advances in therapeutic success have been made in the past decades. This has been calling for a deeper biological understanding of the tumor, its growth and resistance patterns. We have been using a xenograft glioma model, where human glioblastoma cells are implanted under chronic cranial windows and studied longitudinally over many weeks and months using multi photon laser scanning microscopy (MPLSM). To test the effect of (new) drugs, a stable and direct delivery system avoiding the blood-brain-barrier has come into our interest.

MATERIAL AND METHODS

We implanted cranial windows and fluorescently labeled human glioblastoma stem-like cells into NMRI nude mice to follow up on the tumor development in our MPLSM model. After tumor establishment, an Alzet® micropump was implanted to directly deliver agents via a catheter system continuously over 28 days directly under the cranial window onto the brain surface. Using the MPLSM technique, the continuous delivery and infusion of drugs onto the brain and into the tumor was measured over many weeks in detail using MPLSM.

RESULTS

The establishment of the combined methods allowed reliable concurrent drug delivery over 28 days bypassing the blood-brain-barrier. Individual regions and tumor cells could be measured and followed up before, and after the beginning of the treatment, as well as after the end of the pump activity. Fluorescently labelled drugs were detectable in the MPLSM and its distribution into the brain parenchyma could be quantified. After the end of the micropump activity, further MPLSM measurements offer the possibility to observe long term effects of the applied drug on the tumor.

CONCLUSION

The combination of tumor observation in the MPSLM and concurrent continuous drug delivery is a feasible and reliable method for the investigation of (novel) anti-tumor agents, especially drugs that are not blood-brain-barrier penetrant. Morphological or even functional changes of individual tumor cells can be measured under and after treatment. These techniques can be used to test new drugs targeting the tumor, its tumor microtubes and tumor cells networks, and measure the effects longitudinally.
P12.03 A Delphi survey to inform core ‘red flag’ symptoms for an electronic patient reported outcome system in glioblastoma follow up
Authors: Luis A , Boele F , Booth T
Published: September 2021

BACKGROUND

Glioblastoma is a common and aggressive primary malignant brain tumour in adults associated with a poor prognosis and considerable symptom burden. Clinical review and serial neuroimaging remain the primary monitoring tools to assess for disease status. However, the evidence base for the existing surveillance imaging schedule is yet to be established. New models of follow up care are needed to demonstrate better patient outcomes in this patient cohort. There are indications that patient-reported outcome measures (PROMs) can contribute to improved survival and maintaining an optimal quality of life in other oncology populations.

MATERIALS AND METHODS

There are no standardised PROMs for the priority symptoms in glioblastoma patients, which can be used for evaluation in clinical care as a surrogate marker for disease progression. A broad set of symptoms were therefore initially identified in a targeted literature search and were further refined via Delphi methodology, with the aim to obtain consensus amongst a small expert panel involved in the care of glioblastoma patients. A three round Delphi email survey was conducted. Consensus was defined as 70% agreement.

RESULTS

Symptom and function constructs were assessed for relevance, relationship to disease and treatment, sensitivity to change, psychometric properties and patient acceptability. Consensus was reached on the red flag symptoms and symptom clusters to monitor, as well as the minimum severity thresholds needed to trigger an alert on an electronic symptom reporting system, which has been developed to allow patient self-reporting of symptoms during treatment.

CONCLUSION

The red flag symptoms to monitor, along with the symptom severity thresholds, informed an app-based symptom reporting system, which is currently being piloted in a feasibility study exploring triggered imaging using ePROMs. This has the potential to inform future clinical practice through development of patient reported biomarkers.
P13.03 Sex-specific influence of androgen receptor gene expression on survival of glioblastoma patients
Authors: Łysiak M , Trybuła M , Malmström A , Mudaisi M , Bratthäll C , Strandeus M , Milos P , Hallbeck M , Söderkvist P
Published: September 2021

BACKGROUND

The mRNA and protein expression of androgen receptor (AR) are upregulated in glioblastoma (GBM) and studies show that use of AR antagonists leads to apoptosis of GBM cells in vitro and reduction of tumor volume in a mouse model. With increased prevalence of GBM among males, the role and genetic alterations of AR are worth investigating, especially taking into account the location of AR on chromosome X and possible sex differences associated with it.

MATERIAL AND METHODS

Copy number (CN) and mRNA expression of AR were tested with droplet digital PCR in 106 fresh frozen GBM samples (34 females and 72 males) collected at Linköping University Hospital. This cohort was also subjected to AR promoter methylation analysis, where 17 CpG sites were the target of pyrosequencing. Methylation levels were then correlated with mRNA gene expression, independently for each sex, using Pearson correlation coefficient. Gene expression of AR was also analyzed in The Cancer Genome Atlas cohort of primary IDH wild type GBM (135 females and 219 males) and association of AR expression and overall survival (OS) was tested with Kaplan-Meier log rank analysis after dichotomization by maximally selected rank statistics.

RESULTS

DNA amplifications, as well as deletions of the AR were detected, with a higher frequency of alterations found in females (26.4% vs. 8.3%). AR gene expression correlated with methylation levels of two CpG sites in females (chrX:67543271, chrX:67543762) and three different CpG sites in males (chrX:67543889, chrX:67543895, chrX:67543899). There was no difference in the AR expression between males and females in neither of the cohorts, but significantly higher AR expression was found in the classical subtype of GBM in TCGA. Survival analysis of the TCGA cohort revealed the opposite effect of AR expression on OS of males and females, with high AR expression correlating with shorter OS in females (13.6 vs.15.7 months, p=0.035) and longer OS in males (16.6 vs. 12.2 months, p=0.04). Additional gene set enrichment analysis of these samples showed that high AR expression was strongly correlated with DNA repair but only in the male group.

CONCLUSION

Our results show that high AR mRNA expression in GBM exhibits different effects on patients’ survival depending on their sex, despite common occurrence of high AR expression and CN changes in males and females. The reasons for potential protective influence of AR in males remain unclear and require further investigations.
P13.14 Inhibition of extracellular carbonic anhydrases reduces glioblastoma cell invasion
Authors: Proescholdt M , Qiu Z , Falter J , Schmidt N
Published: September 2021

BACKGROUND

Malignant gliomas metabolize glucose preferably by glycolysis which is in accordance with the Warburg effect. This induces a high demand of glucose combined with a significant lactic acid load. The hypoxia-inducible carbonic anhydrase (CA) IX has been shown to moderate the extrusion of hydrogen ions into the extracellular space. Since the acidification of the extracellular environment contributes to host tissue invasion due to activation of proteolytic enzymes, we hypothesized that CA IX plays an important role in malignant glioma Recently, specific small molecule inhibitors of this enzyme have been developed and may provide an innovative strategy for anti - invasive treatment.

MATERIAL AND METHODS

Two established and 4 primary GBM cell lines (2 with mesenchymal and 2 with proneural transcriptional profile) were exposed to the CAIX inhibitor U104 under normoxic and hypoxic conditions. Cell toxicity was measured by ATP and crystal violet assay. For invasion assessment, a matrigel invasion chamber system with 8 µm pore size polycarbonate filter was used. CAIX expression was analyzed by quantitative RTPCR and Western Blot.

RESULTS

Hypoxia significantly induced CAIX expression in all cell lines. Invasiveness increased significantly under hypoxic conditions in the mesenchymal cells (p < 0.01). Regardless of oxygenation status, the mesenchymal group displayed significantly higher invasiveness compared to the proneural group (p = 0.006). Looking at all cell lines, invasion is significantly inhibited by U104, both under normoxic and hypoxic conditions (p < 0.01). However, while the mesenchymal group showed the highest susceptibility to CAIX inhibition followed by the proneurally differentiated group, the established cell lines were entirely refractory to CAIX inhibition.

CONCLUSION

Our data demonstrate that CAIX inhibition can effectively inhibit invasion in malignant glioma cells independent from oxygenation status, however the effects are significantly influenced by cell type specific biological features.
P13.16 Metastatic potential of systemic glioblastoma stem cell lines in vivo
Authors: Schwab S G , Sarnow K , Thorsen F A , Hossain J A , Goldbrunner R , Miletic H , Bjerkvig R
Published: September 2021

BACKGROUND

Despite aggressive tumor behavior, extracranial metastases rarely develop in glioblastoma (GBM) patients. Two potential explanations have been suggested: 1) The blood-brain-barrier functions as a physical barrier that prevents the dissemination of GBM cells out of the central nervous system (CNS) or 2) that extracranial metastasis do occur, but the patients die before extracranial metastases manifest themselves. The first theory has been questioned based on the fact that circulating tumor cells (CTC) were found in blood samples of GBM patients without systemic metastases. To date it has not been proven if CTCs are able to reenter the brain and to what extent they are able to form systemic extracranial metastatic lesions. Therefore, the current study aimed at analyzing the dissemination patterns and the underlying mechanisms associated with the ability of GBM CTCs to form extracranial metastases.

MATERIAL AND METHODS

Five highly characterized human GBM stem cell (GSC) lines (P3, BG5, BG7, GG6, GG16), displaying GBM CNV patterns, were intracranially implanted in a first cohort, then transduced with a lentiviral Firefly Luciferase-eGFP vector and injected into the left cardiac ventricle of NOD/SCID mice in a second cohort. Mice were observed closely and tumor burden was assessed using in vivo as well as ex vivo bioluminescence imaging, MRI and PET. Mice were euthanized when the objective endpoint criteria (tumor burden) was met, then organs were harvested and fixed for further analysis.

RESULTS

First, a detailed characterization of the GSC line invasion patterns were assessed when grown as orthotopic xenografts in vivo dividing them into three categories: 1) Highly invasive without apparent angiogenesis (BG5) 2) Invasive with perivascular infiltration and angiogenesis (P3, BG7 and GG16) and 3) Angiogenic and highly circumscribed (GG6). Following intracardial injection, (7 out of 8) P3 animals developed extracranial and intracranial tumors with a distinctive pattern. Brain, adrenal gland, ovary and liver were amongst the organs most susceptible for tumor growth in the P3 group. For the BG5 and BG7 cell lines, no metastases were observed whereas only 1 animal out of 10 developed metastases in both groups GG16 and GG6.

CONCLUSION

Only one out of 5 GSC lines exhibited a strong metastatic potential when injected into the left cardiac ventricle. Compared to other tumors which exhibit a strong metastatic potential from the circulation, GSC lines do only to a very limited extent show this potential reflecting observations made in the clinic.
P14.14 Adjuvant treatment versus initial observation in newly diagnosed WHO grade II and grade III oligodendroglioma: real-life data from two academic, tertiary care centers in Austria
Authors: Mair M J , Leibetseder A , Wöhrer A , Widhalm G , Dieckmann K , Aichholzer M , Weis S , von Oertzen T , Pichler J , Preusser M , Berghoff A S
Published: September 2021

BACKGROUND

Oligodendrogliomas are rare, slow-growing brain tumors with a survival prognosis of >10 years. Although adjuvant radio-chemotherapy has been shown to prolong survival, aggressive treatment comes at the cost of increased toxicity. Systematic data on the optimal timing of adjuvant treatment in oligodendroglioma are lacking.

MATERIAL AND METHODS

Patients treated for a newly diagnosed IDH-mutated, 1p/19q-codeleted oligodendroglioma (WHO grades II/III) in 2000 - 2018 at the Medical University of Vienna or the Kepler University Hospital Linz (Austria) were included in this retrospective study. Adjuvant treatment was defined as radiotherapy (RT), chemotherapy (CHT) or radio-chemotherapy (R-CHT) within 6 months after resection in the absence of progression. “Wait and see” was defined as regular follow up with magnetic resonance imaging and treatment at progression.

RESULTS

185 patients were identified, comprising 123/185 (66.5%) WHO grade II and 62/185 (33.5%) WHO grade III oligodendrogliomas. Median age at diagnosis was 42 years (range: 20–82). Gross total resection (GTR) could be achieved in 77/178 (42.3%) evaluable patients. Adjuvant treatment was applied in 63/185 (38.2%) patients, of whom 43/63 (68.3%) underwent R-CHT, 9/63 (14.3%) CHT only and 11/63 (17.5%) RT only. 43/52 (82.7%) received temozolomide-based treatment, 1/52 (1.9%) procarbazine, lomustine and vincristine (PCV), 1/52 dacarbazine/fotemustine and in 7/52 (13.5%) patients, no data on used regimens was available. Adjuvant treatment was more frequently applied in WHO grade 3 tumors (p<0.001), while there was no association of adjuvant treatment with extent of resection (p=0.24). Patients after GTR who underwent adjuvant therapy presented with longer progression-free survival (PFS) compared to patients initially managed with observation (median: 150 months, 95%CI: 100 - not reached (n.r.) vs. median: 101 months, 95%CI: 73.2–115; p=0.053). In non-GTR tumors, patients with adjuvant therapy presented with a significantly longer median PFS of 107.5 months (95%CI: 62.8-n.r.) as compared to patients initially managed with observation (45.3 months, 95%CI: 41.2–78.8; p=0.025).

CONCLUSION

The application of adjuvant therapy was associated with favorable PFS in patients who underwent resection of newly diagnosed oligodendroglioma in this retrospective study. Prospective clinical trials should investigate the risks and benefits of adjuvant treatment versus initial observation in patients with oligodendroglioma.
P14.17 Conventional MRI criteria differentiate true tumour progression from treatment-induced effects in irradiated WHO grade 3 and 4 gliomas
Authors: Flies C M , van Leuken K H , Verhoeff J J C , de Vos F Y F , Seute T , Robe P A , Hendrikse J , Witkamp T D , Dankbaar J W , Snijders T J
Published: September 2021

BACKGROUND

Post-treatment radiological deterioration of patients with an irradiated high-grade (WHO grade 3 and 4) glioma (HGG) may be the result of true progressive disease (PD) or treatment-induced effects (TIE). Differentiation between these two entities is of great importance, but remains a diagnostic challenge. This study assesses the diagnostic value of conventional MRI characteristics to differentiate PD from TIE in treated HGGs.

MATERIAL AND METHODS

In this single-centre, retrospective cohort study, we included adult patients with a HGG, who were treated with radiotherapy and subsequently developed a new or increasing contrast-enhancing lesion on conventional follow-up MRI. TIE and PD were defined radiologically as stable/decreased for a minimum of six weeks or progressive according to the RANO criteria, and histologically as predominantly TIE without viable tumour or PD. Demographic and clinical data were retrieved. Twenty-one preselected MRI characteristics of the progressive lesions were assessed by two neuroradiologists. The statistical analysis included logistic regression to develop a) a full multivariable model b) a diagnostic model with model reduction, and a Cohen’s Kappa interrater reliability coefficient.

RESULTS

210 patients (median age 61, IQR=54–68, 189 males) with 284 lesions were included, of which 141 (50%) had PD. Median time to PD was 2 (0.7–6.1) and to TIE 0.9 (0.7–3.5) months after RT. In multivariable modelling and after model reduction, the following determinants were significant diagnostic factors: Radiation dose (Odds ratio (OR)=0.68, p=0.017), longer time since radiotherapy (OR=3.56, p<0.0005), certain enhancement patterns (soap bubble enhancement: OR=2.63, p=0.003), isointense apparent diffusion coefficient-signal (OR=2.11, p=0.036), development of multiple new lesions (OR=1.68, p=0.088) and increased marginal enhancement (OR=2.04, p=0.027). ORs of >1 indicate higher odds of PD. The Hosmer & Lemeshow test showed a good calibration (p=0.947) and the area under the ROC-curve was 0.722 (95%-CI=0.66–0.78). Interrater reliability analysis between neuroradiologists revealed moderate to near-perfect agreement for the significantly predictive items, but poor agreement for others.

CONCLUSION

In patients with irradiated high-grade gliomas, several characteristics from conventional MRI are significant predictors for the discrimination between true progression and treatment-induced effects. Interrater reliability for these characteristics was variable. Conventional MRI characteristics from this study should be incorporated into a multimodal diagnostic model that includes advanced imaging techniques.

FUNDING INFORMATION

Foundation Vrienden UMC Utrecht and The StophersenkankerNU Foundation.
P14.19 Regorafenib in recurrent glioblastoma patients: a large real-life experience
Authors: Caccese M , Cerretti G , Padovan M , Zagonel V , Lombardi G
Published: September 2021

BACKGROUND

Regorafenib (REG), an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases showed encouraging benefit in recurrent GBM patients enrolled in the randomized, phase 2 REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recurrent glioblastoma patients treated at Veneto Institute of Oncology as off-label use.

MATERIAL AND METHODS

Patients receiving REG at Veneto Institute of Oncology (Padua, Italy) were entered prospectively on a clinical database. Data were retrospectively analyzed. The primary endpoints of the study were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression as defined by RANO criteria after surgery followed by radiochemotherapy with temozolomide, ECOG PS ≤ 2; PTS with ≥ 2 prior lines of therapy were excluded. According to original schedule, patients received REG 160 mg once daily for the first 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity, or consent withdrawal. Kaplan-Meier method was used to estimate the survival curves, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events.

RESULTS

From February 2018 to September 2020, 54 consecutive patients were treated with REG and enrolled in this study: median age was 56, ECOG PS 0–1 in 91% of patients, MGMTmet in 53%, second surgery at the time of relapse were performed in 30% of enrolled patient, 41% of patients underwent steroids at baseline. At the time of analysis, median follow-up was 11.1 ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. Median OS was 10.2 ms (95%CI, 6.4–13.9), 12m-OS was 43%; median PFS was 2.3ms (95%CI, 1.3–3.3) and 6m-PFS was 18%. All patients were evaluable for response: disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT status and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT (2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%. No death was considered to be drug-related.

CONCLUSION

We reported a large, mono-institutional “real world” experience of REG in recurrent glioblastoma patients. Overall, results are close to those reported in REGOMA trial although, we showed a longer OS. Toxicity was moderate and manageable. Encouraging clinical benefits of REG in recurrent GBM population were confirmed.
P14.22 Quality indicators in neuro-oncology: modified Delphi process for the development of a quality indicator set for assessment of glioma care
Authors: Vanhauwaert D J , Pinson H , De Schutter H , Van Eycken E , De Vleeschouwer S , Boterberg T
Published: September 2021

BACKGROUND

Quality Indicators (QIs) are important tools to assess the quality and variability of oncological care. However, their application in neuro-oncology is limited. The objective of this study was to develop a set of QIs for glioma, covering process and outcome indicators.

METHODS

First a systematic literature search was performed in peer-reviewed papers and grey literature to identify existing QIs in neuro-oncology and guidelines or recommendations that could be translated into new QIs. The PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) checklist and flow diagram were taken into account. The search strategy focused on diagnostics, treatment, follow-up and survival. For each (set of similar) recommendation(s) a QI was created that could easily be translated into a measurable proportion. Concordant QIs were rationalized to further reduce redundancy. Secondly a two round Delphi survey was organized amongst a multidisciplinary expert panel that was asked to score relevance for all proposed QIs. The panel consisted of neurosurgeons(4), radiation(3) and medical(3) oncologists, pathologists(3), radiologists(2), neurologists(1), nuclear medicine physicians(2) from university and non-university centers, and representatives of the Belgian Cancer Registry.

RESULTS

The conducted literature search in PubMed and Embase yielded 2392 abstracts. After screening and duplicate removal, 221 full text articles were assessed of which 79 were retained. In addition 28 references from the Grey literature were added. In total 240 recommendations and 30 QIs could be identified in this way. After translation of these recommendations into a measurable proportion, merging with the QIs found as such in the literature and rationalization, 148 QIs were presented to the expert panel. In the Delphi survey 15 of the 19 (79%) invited experts responded and eventually consensus was reached on 46 QIs that were considered relevant for the assessment of 6 different domains of neuro-oncological care: diagnosis and imaging (10), surgery (4), pathology (6), radio/chemotherapy (14), recurrence (5) and supportive treatment (7).

CONCLUSION

A set of 46 QIs grouped in 6 categories to assess the quality of care of glioma patients was developed. These QI’s are readily applicable dependent on the availability of population-based health care data
P14.30 Voxelwise analysis of spatial distribution of postoperative ischemia in diffuse glioma
Authors: van der Boog A T J , David S , Steennis A M M , Snijders T J , Dankbaar J W , Robe P A , Verhoeff J J C
Published: September 2021

BACKGROUND

Surgical treatment of diffuse glioma is performed to reduce tumor mass effect and to pave the way for adjuvant (chemo)radiotherapy. As a complication of surgery, ischemic lesions are often found in the postoperative setting. Not only can these lesion induce neurological deficits, but their volume has also been associated with reduced survival time. Prior studies suggest areas with a singular vascular supply to be more prone to postoperative ischemic lesions, although the precise cause is yet unknown. The aim of this study was to explore the volumetric and spatial distributions of postoperative ischemic lesions and their relation to arterial territories in glioma patients.

MATERIAL AND METHODS

We accessed a retrospective database of 144 adult cases with WHO grade II-IV supratentorial gliomas, who received surgery and postoperative MRI within 3 days in 2012–2014. We identified 93 patients with postoperative ischemia, defined as new confluent diffusion restriction on DWI. Ischemic lesions were manually delineated and spatially normalized to stereotaxic MNI space. Voxel-based analysis (VBA) was performed to compare presence and absence of postoperative ischemia. False positive results were eliminated by family-wise error correction. Areas of ischemia were labeled using an arterial territory map, the Harvard-Oxford cortical and subcortical atlases and the XTRACT white matter atlas.

RESULTS

Median volume of confluent ischemia was 3.52cc (IQR 2.15–5.94). 23 cases had only ischemic lesion in the left hemisphere, 46 in the right hemisphere and 24 bilateral. Median volume was 3.08cc (IQR 1.35–5.72) in left-sided lesions and 2.47cc (1.01–4.24) in right-sided lesions. Volume of ischemic lesions was not associated with survival after 1, 2 or 5 years. A cluster of 125.18cc was found to be significantly associated with development of postoperative ischemia. 73% of this cluster was situated in the arterial territory of the right middle cerebral artery (MCA), limited by the border of the posterior cerebral artery (PCA), and the watershed area between the right MCA and the right anterior cerebral artery (ACA). Significant areas were located in the frontal lobes, spanning into the right temporo-occipital region, and predominantly included right and left thalamus, caudate nucleus, putamen, pallidum, as well as right temporal gyri and insular cortex, and parts of the right corticospinal tract, longitudinal fasciculi and superior thalamic radiation.

CONCLUSION

We found slightly more and larger ischemic lesions in the right than left hemisphere after glioma resection. A statistically significant cluster of voxels of postoperative ischemia was found in the territory of the right MCA and watershed area of the right ACA. Exploration of the spatial distribution of these lesions could help elucidate their etiology and form the basis for predicting clinically relevant postoperative ischemia.