bluuebunny/crossref_metadata_2025 huggingface dataset:
P10.18.B JUGLONE AS A NOVEL EPIGENETIC DRUG FOR GLIOBLASTOMA
Authors: Barciszewska A , Belter A , Gawrońska I , Giel-Pietraszuk M , Naskręt-Barciszewska M Z
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is the most common and aggressive primary brain tumor and one of the human malignancies with the highest mortality. Standard approaches for GBM, including, gross total resection, radiotherapy, and chemotherapy, cannot destroy all the cancer cells and, despite advances in its treatment, the prognosis for GBM remains poor. The, until now, the most successful chemotherapy with temozolomide (TMZ) for brain gliomas is not fully effective, and therefore new therapeutic strategies for GBM are needed. We found that juglone (J), which exhibits cytotoxic, anti-proliferative, and anti-invasive effects on various cells could be a promising agent for GBM therapy.

MATERIAL AND METHODS

We analyzed the effects of juglone alone and in combination with temozolomide on glioblastoma cell lines. In addition to the analysis of cell viability and cell cycle, we looked at the epigenetic effects of these compounds on cancer cells. We estimated the total DNA methylation in T98G, U138, U118, and HaCaT lines after treatment with different J and J/TMZ concentrations and incubation time using TLC separation of radioactively labeled nucleotides. The combination treatment with J and TMZ was evaluated with total DNA methylation analysis and 8-oxo-dG (oxidative stress marker) estimation using EC detection.

RESULTS

We noticed concentration and time-dependent changes in total DNA methylation. The highest increase was observed for the T98G cell line at the incubation time of 24hrs. Normal cell line (HaCaT) did not present significant changes. TMZ alone induced a lowering of DNA methylation, but juglone diminished that effect. J induces minute oxidative stress in low concentrations, but is quite high and rapid at concentrations over 50uM, concomitantly with none/slight decrease in DNA methylation. However, the combination of J/TMZ in increasing concentrations diminished the oxidative stress effect.

CONCLUSION

Our results strongly suggest that a combination of juglone and temozolomide can be applied for better GBM treatment. At certain incubation times and concentrations, juglone increases DNA methylation, which is a positive therapeutic effect in oncogenesis. Small doses of J keep a low level of 8-oxo-dG with an increase in DNA methylation. The combination of J/TMZ in high concentrations of both drugs decreases the oxidative stress effect of chemotherapy. The study was supported by OPUS 19 (2020/37/B/NZ5/03249) grant from the National Science Center, Poland.
P10.22.B COMBINATION OF ARTS MIMETICS WITH AUTOPHAGY INHIBITORS AS A NOVEL THERAPEUTIC STRATEGY TO OVERCOME APOPTOSIS RESISTANCE IN GLIOBLASTOMA
Authors: Kuzmychova H , Martell E , Yathindranath V , Senthil H , Kaul E , Miller D , Singh S K , Sharif T
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is the most common malignant brain tumour in adults. The current standard of care for GBM patients consists of maximal surgical resection followed by chemotherapy and radiation. Despite such an aggressive treatment approach, the average 5-year survival rate for GBM patients is approximately 5%. One of the main reasons for poor therapy response in the GBM is resistance to programmed cell death, otherwise known as apoptosis. One of the mechanisms behind apoptosis resistance relies on the upregulation of inhibitor of apoptosis proteins (IAPs) which are known to hinder pro-apoptotic proteins and allow cell survival under abnormal conditions such as severe DNA damage. However, there are natural IAP antagonists such as ARTS which are capable of stimulating cell death by promoting the degradation of IAPs. To harness the pro-apoptotic function of IAP antagonists, small peptide mimetics of ARTS have been developed. This project investigates the efficacy of utilizing ARTS mimetics as a novel strategy to overcome apoptosis resistance in the GBM treatment.

MATERIAL AND METHODS

This study utilizes patient-derived cells with exogenous gain-of-function (GOF) overexpression to introduce full-length ARTS protein as well as pharmacological small peptide mimetics of ARTS to evaluate the response of GBM cells following the promotion of ARTS activity. We also employ a patient-derived orthotopic xenograft mouse model to test novel combinatorial strategies in vivo, where we used a nanoparticle drug delivery system to ensure treatment delivery across the blood-brain barrier (BBB).

RESULTS

We found that patient-derived GBM cells were highly resistant to ARTS-induced apoptosis. Further molecular investigation unveiled a novel role of ARTS in the upregulation of autophagy as a resistance mechanism. A combination of ARTS GOF or mimetic peptides with autophagy inhibitors mitigated resistance to ARTS-mediated apoptosis and drastically decreased GBM cell proliferation. This combination was further tested in the patient-derived xenograft mouse model, which demonstrated the successful delivery of ARTS mimetic peptides and autophagy inhibitors through the BBB via nanoparticle lipid carriers. Animals treated with a combination of the autophagy inhibitor Spautin-1 and ARTS mimetic peptides demonstrated significantly prolonged survival, confirming the therapeutic potential of such combinatorial approach for GBM treatment.

CONCLUSION

Altogether, these findings uncover a previously unknown role of ARTS in autophagy regulation and provide evidence that the combination of IAP-antagonist mimetics with autophagy inhibitors can be an effective strategy against highly aggressive GBM brain tumours. This work was supported by the Health Sciences Centre Foundation (HSCF).
P10.36.B ROLE OF AMPK IN GLIOBLASTOMA BIOENERGETICS
Authors: Caamaño-Teixeira S , Iglesias C , Gonzalez-Alvarez V , Arce V , Costoya J , Señaris R
Published: September 2023

BACKGROUND

Glioblastoma is the most prevalent and aggressive primary brain tumor. AMP-activated kinase (AMPK), the main energy sensor of the cell, has been previously described by our group as a key factor in glioblastoma oncogenesis and proliferation and is known for taking part in tumoral metabolic transformation. Our group has also formerly reported how AMPK regulates the expression of lipoprotein receptors and alters lipid reliance of glioblastoma cells, suggesting AMPK orchestrates nutrient dependency and flexibility on glioblastoma. Overall, this evidence positions AMPK inhibition as a promising antitumoral therapy for glioblastoma.

MATERIAL AND METHODS

To further study the role of AMPK in glioblastoma bioenergetics, we used the human glioblastoma cell lines U87 and U373 and silenced AMPK by transfecting the cells with a siRNA for AMPKα1/2. To assess mitochondrial function (OCR), fuel oxidation, and glycolytic parameters (ECAR), we carried out Seahorse metabolic analyses. This technology provides non-invasive and real-time monitoring of glycolytic and mitochondrial metabolic profiles. The expression of genes related to mitochondrial energetics (CPT1C, PPARGC1A, and PPARA) in these cells was studied using RT-qPCR. We are also currently studying lactate dehydrogenase (LDH) function and expression, as well as glutamine metabolism.

RESULTS

Our data show that silencing of AMPKα1/2 reduces basal and maximum mitochondrial respiration, as well as decreases the expression of CPT1C, PPARGC1A, and PPARA. Altogether, these results suggest alterations in mitochondrial energetic pathways. Our results do not reveal a significant effect of AMPK on the glycolytic activity of these glioblastoma cell lines. Finally, we found a great capacity of these cells to use glucose, but also fatty acids and glutamine as energy substrates, although with a very high dependency on glucose.

CONCLUSION

Even though in glioblastoma cells there is an increment in aerobic glycolysis (Warburg effect), these tumoral cells still maintain an elevated mitochondrial activity and a great capacity to use lipids as a fuel. AMPK plays an important role in regulating glioblastoma mitochondrial activity and bioenergetics. The authors would like to acknowledge the Funding for the Consolidation of Competitive Groups of Research (ED431B 2020/26, Xunta de Galicia, 2020-2022).
P11.23.A GLIOBLASTOMA MOLECULAR CORRELATES OF SEIZURE OCCURRENCE/RECURRENCE AFTER SURGERY: THE ROLE OF P53 MUTATION
Authors: Mattioli P , Cella E , Donniaquio A , Aloisio R , Mancini R , Calizzano F , Costa V , Villani F , Dellepiane C , Genova C , Vecchio S , Zona G , Fiaschi P , Truffelli M , Giannelli F , Barra S , Satragno C , Barletta L , Donegani M , Caneva S , Nozza P , Bennicelli E , Arnaldi D
Published: September 2023

BACKGROUND

The integration of molecular data and histology changed the diagnostic approach and prognostic characterization for patients with brain tumors. The aim of this study is identify molecular risk factors associated with seizure occurrence and/or recurrence after surgery in patients with brain glioblastoma.

MATERIAL AND METHODS

Patients with brain glioblastoma were consecutively enrolled and underwent brain surgery, followed by histopathological and molecular evaluation. Immuno-histochemical, molecular (synaptophysin, GFAP, ATRX, p53, ki67 index and MGMT gene promoter methylation) and clinical (age, sex and seizure occurrence/recurrence before and/or after surgery) data were collected. Histopathological and molecular features were compared between patients with and without seizure occurrence/recurrence after surgery. A step-backward logistic regression was performed to investigate the association between molecular features and seizure occurrence/recurrence.

RESULTS

100 patients (age 59.51±1.23, 65 males) were enrolled. Forty-nine patients had seizures before surgery. After surgery, 40 patients (age 59.43±1.64, 27 males) had seizure occurrence/recurrence, while 60 (age 59.57±1.75, 38 males) had not. Patients with epilepsy (i.e., seizures before and/or after surgery) had lower synaptophysin (33.33%, p=0.008) and higher p53 (85%, p=0.038) mutation rate compared with patients without epilepsy. In the whole sample, seizure occurrence/recurrence after surgery was significantly associated with p53 mutation (OR: 3.9, CI 1.12-13.50, p=0.032) and seizure occurrence before surgery (OR: 5.3, CI 2.15-13.08, p<0.001). In patients without seizures before surgery, p53 mutation perfectly predicted seizure occurrence, therefore the OR was not computable. In fact, all patients without p53 mutation didn’t have seizure after surgery, while all patients that had seizure after surgery, also had p53 mutation (p=0.028). However, to note 71% patients with p53 mutation didn’t have seizure after surgery.

CONCLUSION

The p53 mutation is related with a high risk of seizure occurrence/recurrence after surgery in brain glioblastoma, even in patients that didn’t have seizures before surgery. Conversely, the absence of p53 mutation appears to protect against the occurrence of seizures. If confirmed, this result may help in the management of anti-seizure treatment after surgery in brain glioblastoma patients.
P11.24.B PRELIMINARY RESULTS OF THE TRAIN STUDY: TRAMETINIB IN NEUROFIBROMATOSIS TYPE 1 RELATED SYMPTOMATIC PLEXIFORM NEUROFIBROMAS
Authors: Noordhoek D C , van Dijk S A , French P J , Wiemer E A C , Visser J , Moelker A , Manintveld O C , van den Bent M J , Taal W
Published: September 2023

BACKGROUND

About half of the patients with neurofibromatosis type 1 (NF1) have plexiform neurofibromas (PN). PNs can cause pain, neurological deficit and cosmetic problems. The current standard treatment of PN is surgery, which is often difficult due to invasive growth and vascularisation. Recent data suggests promising effect of MEK inhibition on symptomatic PN in NF1.

MATERIAL AND METHODS

We started an open-label, single arm, phase 2 trial of trametinib 2 mg daily in 30 adults with NF1 and at least one symptomatic inoperable PN. The primary outcome measure is decrease in tumor volume of the PN target lesion, as measured on MRI every 6 months. A decrease of ≥20% will be considered as treatment response. The secondary outcome measures are pain, disfigurement, safety and toxicity.

RESULTS

Seventeen patients have been enrolled between July 2020 and July 2022 with an average follow-up duration of 16 months. In the 15 patients with at least 6 months follow-up, the average numeric pain rating scale (NRS-11) was reduced in 10/15 patients (67%) and a reduction of at least 3 points on the NRS-11 was achieved in 6/15 patients (40%). Tumor volume measurements have been completed in one patient with a PN in the left shoulder region. Tumor volume decreased from 160 cm3 to 100 cm3 (38%) after 18 months of treatment. The most common side effect was acneiform rash, which was present in 11/17 patients (65%). Four patients discontinued treatment permanently, 3 because of toxicity (acneiform rash (2) and CPK increase (1)) and one because of increased pain. Four cases of grade 3 adverse events have been reported: acneiform rash (2), hypertension (1) and asparatate aminotransferase increase (1). The only severe adverse event related to treatment was CPK increase grade 4, for which the patient was hospitalised for diagnostic work-up. Toxicity resolved completely in all patients after discontinuation of treatment.

CONCLUSION

From these preliminary results we can conclude that trametinib has a beneficial effect on PN related pain. Side effects are mild and toxicity resolved after discontinuation of treatment. At least one patient had a decrease in tumor volume of ≥20%.
P11.35.B STEREOTACTIC RADIOTHERAPY FOR VESTIBULAR SCHWANOMMAS: THE WESSEX EXPERIENCE
Authors: Main S , Yeo H , Caamina L , Ching J , Kaylan J , Sinclair G , Shanmugasundaram R , Clarke E
Published: September 2023

BACKGROUND

Review of SRT for vestibular schwannoma (VS) within Wessex region led by University Hospital Southampton (UHS). UHS treat tumour volumes max 2.5cm in diameter without brainstem compression with 21Gy/3#. We reviewed the experience of local control and toxicity profile in our centre comparing with 1 and 5 fraction SRT schedules. We present three fraction SRT as an appropriate fractionation schedule.

MATERIAL AND METHODS

This is a retrospective analysis of patients treated for radiologically diagnosed vestibular schwannoma from 2019 to present. Patient notes, audiograms, imaging and radiotherapy planning system were reviewed for data collection. No patients were removed from analysis due to missing data.

RESULTS

84 patients have been treated with SRT for VS. Median age 66 (39-94). 12Gy/1# (1#) in 36 patients, 21Gy/3# (3#) in 36 patients, 25Gy/5# (5#) in 12 patients. In the 1# group PTV volume 0.31cm3-4.44cm3 (median 1.12cm3), in the 3# group PTV volume from 1.03cm3 to 5.52cm3 (median 2.37cm3), in the 5# group 2.05cm3-5.44cm3 (median 4.12cm3). All patients have radiologically stable disease to date. Objective radiological response noted in 14 patients (38.9%) in 3# group this is higher than any other group and statistically significant (p=0.016). Pre-treatment serviceable hearing only in a minority of patients. Treatment related toxicity was seen in 27% in the 1# group, 19% of patients within the 3# group, and 33% in the 5# group. This was mostly mild and self-limiting. Facial nerve toxicity was seen in 8.3% of the 1# group, 16.7% of 3# group, and 33.3% of the 5# group. However, this was only persistent in 2 patients in 1# group (5.6%), 2 patients in the 3# group (5.6%), and 1 (8.3%) in the 5# group. There is no statistical difference in toxicity between any group using Chi squared test. In 3# group, when Dmax limited to <26Gy (n=15), the frequency of facial nerve toxicity reduces to 1 (2.78%).

CONCLUSION

Three fraction SRT provides excellent local control with high levels of objective radiological response in tumours up to 4cm3, however, long term follow-up is required. This treatment has acceptable toxicity which is not significantly different from alternative fractionation schedules and is improved by limiting Dmax to <26Gy.
P11.53.B MOLECULAR PROFILING AND ACTIONABLE MUTATIONS IN ADULT PATIENTS WITH IDH WILD TYPE GLIOMAS AND GLIONEURONAL AND NEURONAL TUMORS
Authors: Pellerino A , Marchesani E , Bertero L , Ricci A , Mangherini L , Bruno F , Soffietti R , Rudà R
Published: September 2023

BACKGROUND

Next generation sequencing (NGS) assays enable the identification of genetic alterations that may guide a personalized treatment in glioma patients.

MATERIAL AND METHODS

From July 2021 to March 2023 a NGS analysis (Myriapod® NGS Cancer DNA and RNA panels) was performed in a large prospective cohort of adults with an histological diagnosis of IDH wild type glioma or circumscribed astrocytoma or glioneuronal and neuronal tumor at the Division of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy. The aim was to identify potential actionable molecular alterations and provide targeted therapy at recurrence accordingly.

RESULTS

We collected tumor samples from 221 patients. NGS analysis was available in 211 patients (95.5%), while NGS was not feasible in 10 patients (4.5%). 188 patients out of 211 (89.1%) had an IDH wild type glioblastoma (GBM) (median age 61 years, range 24-84; F/M: 97/91), 6 patients (2.8%) had IDH wild type lower grade gliomas (LGG) (median age 63 years, range 43-78; F/M: 3/3), and 17 patients (8.1%) had circumscribed astrocytoma or glioneuronal and neuronal tumor (median age 37 years, range 18-67; F/M: 13/4). Overall, actionable molecular alterations were found in 13/211 patients (6.2%). In this regard, 7/211 patients (3.3%) had BRAF V600E mutation (3 IDH wild type GBM, 1 IDH wild type LGG, and 3 circumscribed/glioneuronal and neuronal tumor), 4/211 patients (1.9%) had FGFR3-TACC3 fusion (all GBM), 1/211 patients (0.5%) had PIK3CA mutation (GBM), and 1/211 patients (0.5%) had NTRK1 fusion (glioneuronal tumor). Other molecular mutations, including ALK, ERBB2, MET, KIT, KRAS, PDGFRA, and RET have not been detected in our cohort. Three patients with druggable mutations recurred after first-line therapy: 1 patient with BRAF mutated GBM, 1 patient with GBM harboring FGFR3-TACC3 fusion, and 1 patient with NTRK1 fusion positive glioneuronal tumor received specific BRAF/MEK inhibitor (dabrafenib/trametinib), FGFR inhibitor (pemigatinib), and NTRK inhibitor (larotrectinib), respectively. A remarkable activity of BRAF/MEK and NTRK inhibitors was observed (8 months and 5 months, respectively *), while FGFR inhibitor did not display a significant activity to control disease (9 weeks). * ongoing

CONCLUSION

The incidence of actionable molecular alterations in IDH wild type gliomas and glioneuronal and neuronal tumors was low. However, the possibility of using targeted therapies may lead to an important impact on the outcome.
P11.74.A EXPERIENCE OF PREOPERATIVE GAMMA KNIFE RADIOSURGERY FOR RECURRENT BRAIN METASTASES
Authors: Verhaak E , van Seeters T , Ardon H , Brouwers B , Hanssens P
Published: September 2023

BACKGROUND

Resection of brain metastases (BM) without additional radiation therapy yields a high local failure rate. Surgical resection of newly diagnosed BM combined with post-operative stereotactic radiosurgery (SRS) to reduce the risk of a local recurrence is an accepted and effective treatment option. Drawbacks of postoperative SRS include uncertainty in target delineation, potential delay in the administration of SRS and intraoperative risk of tumor spillage. Preoperative SRS might address these potential drawbacks. We present our experience with preoperative Gamma Knife radiosurgery (GKRS) for recurrent BM.

MATERIAL AND METHODS

Data of patients with recurrent BM treated with GKRS followed by surgical resection between June 2019 and June 2021 at the Elisabeth-TweeSteden Hospital Tilburg were retrospectively collected. Surgery was necessary according to the multidisciplinary team because of mass effect, a symptomatic lesion or a large tumor volume not eligible for salvage stereotactic radiosurgery. Pre-operative SRS was performed with GKRS followed by surgery within 24 hours. All patients had follow-up appointments with MRI scan as long as clinical meaningful. In case of new intracranial disease new treatment was offered if appropriate. Descriptive analyses were used to give an overview of the patient characteristics. Kaplan-Meier curves were used to analyze overall survival.

RESULTS

25 patients (male 8, female 17; median age 64 years (range 20-79 years)) underwent preoperative GKRS for recurrent brain metastases. Most patients were previously treated with GKRS (76%) or SRS (24%). Most patients had non-small cell lung cancer (44%), followed by breast (12%), small cell lung cancer (12%), and melanoma (12%). The median overall survival was 18.5 months (95% CI, 4.9 to 32.1 months). Eight patients (32%) had (multiple) surgical complications, three of these patients died due to the postoperative complications. Twelve patients (48%) developed a local recurrence. The median time to local recurrence was 6.9 months (95% CI, 4.7 to 9.1months). Of the 16 patients with a subtotal resection, 10 patients developed a local recurrence, with 6 recurrences at the site of the macroscopic residual tumor. Two patients (8%) developed leptomeningeal disease at 2.8 months and 3.9 months. Two patients (8%) developed new brain metastases (distant failure) at 5.4 months and 23.8 months.

CONCLUSION

Pre-operative radiosurgery was well tolerated in a group of patients with recurrent BM who were eligible for surgery. Larger series are needed to perform multivariate analyses on predictors of local recurrence in order to evaluate for which patients this treatment option is best suited.
P12.12.A DISTRIBUTION AND TUMOR CELL PROXIMITY OF IMMUNE CELLS IN THE TUMOR CORE, TRANSITION ZONE AND PERIPHERY OF GLIOBLASTOMAS
Authors: Pedersen V , Møldrup Knudsen A , Regner Michaelsen S , Winther Kristensen B
Published: September 2023

BACKGROUND

Glioblastoma is the most frequent and malignant brain tumor. Immune therapies have had limited effect but not much is known about the frequency and type of immune cells in the transition zone and periphery of the tumors. In these areas, tumor cells migrate into the brain parenchyma and prevent total tumor resection thereby leading to recurrence. This study aims to quantify the type and distribution of immune cells in glioblastomas.

MATERIAL AND METHODS

A cohort of 67 glioblastomas with strong P53 immunoreactivity in the tumor cells was established. Slides contained tissue from central tumor and/or transition zone and/or tumor periphery. A chromogenic multiplex was established, where tissue sections were stained with P53 (tumor cells), FOXP3 (FOXP3+ regulatory T cells), CD8 (CD8+ cytotoxic T cells) and IBA1 (microglia/macrophages). Cells were counted in tumor core, transition zone and periphery using Visiopharm software based on training of convolutional neural networks. Moreover, the number of tumor cells with immune cells in proximity (30 µm) was quantified, and the distance from a reference cell to another cell type within 30 µm was calculated.

RESULTS

The densities of CD8+, FOXP3+ and IBA1+ cells were significantly higher in the core (10, 1 and 473 cells/mm2) than in the periphery (3, 0,2 and 179 cells/mm2) (P < 0.001), and in the transition zone (10, 1 and 396 cells/mm2) than in the periphery (P < 0.001). However, the CD8+ and IBA1+ cells/tumor cell ratio increased from core (0,004 and 0,18) to transition zone (0,01 and 0,36) and to periphery (0,015 and 0,8) (P < 0.001). The highest density of tumor cells with CD8+ cells in proximity was in the tumor core (55 cells/mm2 in core, 22 cells/mm2 in transition zone, 3 cells/mm2 in periphery) (P < 0.001), whereas the highest density of tumor cells with IBA1+ cells (1412 cells/mm2 in core, 7412 cells/mm2 in transition zone, 98 cells/mm2 in periphery) and FOXP3+ cells (0 cells/mm2 in core, 3 cells/mm2 in transition zone, and 0 cells/mm2 in periphery) in proximity was in the transition zone (P < 0.001).

CONCLUSION

Although levels of immune cells are highest in the tumor core - the higher proximity and ratio of immune cells to tumor cells in the transition zone/periphery suggest immune-suppressive mechanisms to be active in these areas.
P13.03.B PREDICTING FUNCTIONAL CONNECTIVITY FROM STRUCTURAL CONNECTIVITY IN GLIOMA PATIENTS
Authors: Smolders L , De Baene W , Florack L , van der Hofstad R , Rutten G
Published: September 2023

BACKGROUND

The mechanism by which activity in the brain relates to its anatomical structure is a central topic of research in neuroscience. In recent years, this relation has been studied in the context of network science, where anatomical white-matter connections are captured in Structural Connectivity (SC) and statistical dependence between grey-matter activity in Functional Connectivity (FC). The relation between SC and FC is poorly understood at an individual level, especially in glioma patients. Developing methods to predict FC from SC in these patients could improve our understanding of how gliomas affect brain function, and consequently cognition. Furthermore, a model accurate at individual patient level could aid in clinical decision-making by identifying eloquent areas and connections in individuals.

MATERIAL AND METHODS

Building on earlier work predicting FC from SC in healthy subjects, we trained a deep learning model on tractography and resting-state fMRI data of 288 glioma patients to predict FC at an individual level. Since our sample size is modest in the context of deep learning, we attempted to improve accuracy by pre-training the model on a large set of healthy subjects. This way, the model should learn baseline patterns in SC and FC before learning the specific patterns associated with glioma patients. We used data from 1052 subjects of the Human Connectome Project and 633 subjects of the Cambridge Centre for Ageing and Neuroscience. Finally, we analyzed the effect of several factors on prediction accuracy: tumor volume, location and grade and patient age.

RESULTS

Training on only the patient set, the prediction model achieved an accuracy, measured as correlation between predicted and empirical FC, of 0.53 ± 0.03 at individual patient level. This is comparable with accuracy achieved in studies on healthy subjects. Pre-trained models did not improve accuracy. The model had more difficulty predicting FC in patients with a glioma in the insular region (p = 0.0014). No other factors were associated with accuracy.

CONCLUSION

Although further research is required to investigate the utility of FC predictions made by our model, our work is a first step towards predicting activity from brain structure in glioma patients at an individual level, since earlier research in patient populations has focused on group-level effects. We observed that predictions are less accurate in patients with a glioma in the insular region, which indicates that the relation between the structural and functional organization of the brain in this group is different from that in patients with tumors in other locations. Improving our methods to achieve higher accuracy could provide us, as a next step, with a tool to predict functional consequences of resective surgery on glioma patients, and consequently improve decision making by more accurately identifying eloquent regions at an individual level.
P13.07.B IMMUNE AND CELL PROLIFERATION PATHWAYS CONTRIBUTE TO THE SEX DIFFERENCES IN A-TO-I RNA EDITING-BASED SUBTYPING OF GLIOBLASTOMA
Authors: Chen S , Wong S
Published: September 2023

BACKGROUND

A-to-I RNA editing has been recently identified as a sex-specific prognostic factor for glioblastoma (GBM). However, the underlying molecular mechanisms of sexual dimorphism are still understudied. We aimed to identify genes displaying sexual dimorphism in patient survival and investigate their involvement in the pathogenesis of GBM.

METHODS

We performed differential expression analyses on bulk RNA-Seq data between GBM patients with distinct survival rates, controlling for sex and the sex-survival interaction. Two principal components that captured the effects of both survival and the sex-survival interaction were constructed to rank genes for gene set enrichment analysis (GSEA). We also analyzed single-cell RNA-Seq data to evaluate the interactions of sexually dimorphic genes between different cell types.

RESULTS

A negative correlation was found between survival and the sex-survival interaction, indicating a substantial proportion of DEGs with sexually dimorphic prognostic value. GSEA revealed that immune-related pathways exhibited higher expression in males with a favorable prognosis, while females with a poor prognosis showed elevated expression levels in these pathways. Conversely, cell proliferation and stemness pathways were more highly expressed in males with a poor prognosis, whereas females with a favorable prognosis displayed higher expression levels in these pathways. Additionally, we found 22 DEG-associated cell-cell interactions, many of which were between macrophage/microglia and tumors.

CONCLUSION

Our findings suggest that sexual dimorphism of RNA editing may be attributed to cell proliferation and immune-related pathways. Moreover, our results provide valuable insights into the underlying mechanisms of cellular communication during the pathogenesis of GBM.
P13.16.A MACHINE LEARNING-BASED RADIOMIC MODEL USING MULTIPARAMETRIC MAGNETIC RESONANCE IMAGING FOR PREDICTION OF POSTOPERATIVE VISUAL RECOVERY OF PITUITARY ADENOMA PATIENTS
Authors: Zhang Y , Chen C , Xu J
Published: September 2023

BACKGROUND

Preoperative prediction of the visual outcome after pituitary adenoma surgery is crucial to clinical decision-making but remains challenging. We aimed to develop radiomic models based on multiparametric magnetic resonance imaging (MRI) to predict the postoperative visual outcome for pituitary adenoma patients using machine learning approaches.

MATERIAL AND METHODS

A cohort of 152 patients who underwent endoscopic endonasal transsphenoidal surgery of pituitary adenomas were retrospectively enrolled and divided into the recovery group and the non-recovery group based on the six-month postoperative visual examinations. Radiomic features of the optic chiasm were extracted from preoperative T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) and contrast-enhanced T1-weighted imaging (T1CE), respectively. Predictive models were constructed by least absolute shrinkage and selection operator wrapped with support vector machine through the five-fold cross-validation in the development cohort, and then evaluated in the independent test cohort. Area under the receiver operating characteristic curve (AUC), accuracy, specificity and sensitivity were used to assess the predictive performance of models.

RESULTS

A total of four predictive models were established based on selected radiomic features from three sequences individually or in combinations. Three features from T1WI, two features from T2WI and nine features from T1CE were selected in the multiparametric radiomic model that represented the best performances among the four models, with AUC values of 0.851 (95% CI: 0.768 - 0.933) in the development cohort and 0.847 (95% CI: 0.722 - 0.971) in the independent test cohort.

CONCLUSION

Our proposed machine learning-based radiomic model using multiparametric MRI can be utilized to assist in predicting the postoperative visual recovery of pituitary adenoma patients in clinical practice.
P13.17.B PREDICTING KI-67 PROLIFERATION INDEX OF MENINGIOMAS ON MRI: A DEEP LEARNING METHOD BASED ON MULTI-MODAL INFORMATION
Authors: Chen C , Xu J
Published: September 2023

BACKGROUND

A high Ki-67 index usually suggests accelerated cell proliferation of meningioma related to significant tumor growth as well as increased recurrent risk. This study aimed to explore the feasibility of deep learning method in predicting Ki-67 index of meningiomas with multi-modal information.

MATERIAL AND METHODS

Pre-treatment magnetic resonance images were retrospectively curated from 521 patients with surgically resected, pathologically confirmed meningiomas from three institutions. The cases were classified into low-expressed or high-expressed groups with a threshold of 5% of Ki-67 index. Predictive models were developed with multi-modal deep learning network by using traditional radiological findings, radiomics features extracted from tumors, and MRIs of meningiomas. The performance of the models was evaluated with area under curve (AUC), accuracy (ACC), sensitivity, and specificity. In addition, 127 cases with incidental small meningioma were recruited and followed up in 2 years, to investigate if the model could be used for predicting the tumor growth to assist in patient management.

RESULTS

Overall, 371 patients were enrolled for model development and primary analysis. The predictive model showed good performance with AUC of 0.798, ACC of 0.710, sensitivity of 0.613, and specificity of 0.806 in the internal test. It also achieved robustness in the external test cohort consisted of 150 cases, with AUC of 0.758, ACC of 0.661, sensitivity of 0.677, and specificity of 0.645. Moreover, model-predicted high Ki-67 tumor was associated with significant tumor volume growth happened in two years.

CONCLUSION

The predictive model can efficiently predict the Ki-67 index in meningioma patients, and showed good potential in facilitating the therapeutic decisions.
P14.09.B IS BLOOD-DERIVED EXOSOMAL HTERT TRANSCRIPT A MARKER OF ONCOGENIC ACTIVITY IN PRIMARY BRAIN TUMORS? AN EXPLORATORY STUDY
Authors: Uziel O , Kanner A , Beery E , Lev S , Lahav M , Horn-Fichman S , Har Nof S , Laviv Y , Yust Katz S , Amiel A , Levi-Barda A , Raanani P , Sela Y , Cohen Z , Siegal T
Published: September 2023

BACKGROUND

In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism. The expression of human telomerase reverse transcriptase (hTERT) enables telomere maintenance and provides cancer cells with limitless replicative potential. As such, it may serve as an attractive biomarker for oncogenic activity. This study explored whether a liquid biopsy that analyses blood derived exosomal hTERT transcript (e-hTERT-trans) may serve as such a biomarker in gliomas and meningiomas when compared to healthy controls.

MATERIAL AND METHODS

Exosomes were isolated from the pre-operative sera of patients’ samples stored in the biobank of both Rabin and Sheba Medical Centers. The levels of e-hTERT-trans were measured in 81 healthy controls, 117 meningiomas, 17 low-grade gliomas, and 61 glioblastomas. Clinical parameters of the patients were collected retrospectively and compared to the levels of the e- hTERT-trans.

RESULTS

The Upper normal limit of controls e-hTERT-trans was 1.85 relative quantitation (RQ). The rate of detection increased with rising tumor grade and correlated with tumor recurrence in meningiomas: mean RQ without recurrence (2.17+11.7) vs. with recurrence (3.59+4.42; p=0.002). In glioblastomas, pre-operative measurements correlated with tumor volume and with the disease course on serial sampling.

CONCLUSION

We demonstrated for the first time that the expression of e-hTERT-trans transcript can be measured in the serum of primary brain tumors. This exosomal marker carries the potential to serve as a biomarker once used in conjunction with other clinical and radiological parameters. Future studies are required to investigate whether the sensitivity could be augmented and whether it can be implemented into routine patients care.
P15.03.B MOLECULARLY TARGETED PROTEASE-ACTIVATED PROBES FOR THE VISUALIZATION OF GLIOBLASTOMA: A COMPARISON WITH 5-ALA
Authors: Konecna D , Vymola P , Ternerova N , Vymolova B , Garcia-Borja E , Mateu R , Sroubek F , Pankrac J , Widen J , Bogyo M , Netuka D , Sedo A , Busek P
Published: September 2023

BACKGROUND

Surgery is the main treatment option for glioblastoma. However, due to its highly infiltrative growth, it is difficult to distinguish the tumor from normal brain tissue. The aim of this work was to evaluate the ability of recently developed molecularly targeted near-infrared (NIR) protease-activated probes to be specifically activated in brain tumor tissue and to compare the most promising candidate with the FDA approved 5-aminolevulinic acid (5-ALA).

MATERIAL AND METHODS

The cysteine cathepsin-cleavable probes 6QC-ICG and 6QC-Cy5 (single-substrate), the cysteine cathepsin and caspase 3-cleavable dual, AND-GATE substrate probes AG2-FNIR and AG2-Cy5 (double-substrate) were administered intravenously to mice with orthotopic tumors. Activation of the probes was further evaluated in glioma cell lines, patient-derived glioma stem-like cells, M2-polarized macrophages in vitro, and biopsy material from patients with glioblastoma ex vivo. Tumor to normal brain tissue fluorescence ratio (TNR) was quantified in tissue sections using preclinical and clinical visualization platforms. Fluorescence in tissue homogenates and cell suspensions was quantified by spectrofluorimetry.

RESULTS

6QC-ICG was activated in glioma cells and macrophages in vitro and the resulting fluorophore accumulated intracellularly. In experimental glioblastomas, single- and double-substrate probes visualized tumor tissue with a minimum signal generated in healthy brain. TNR was highest for 6QC-ICG and AG2-FNIR. Nevertheless, the signal intensity was higher for 6QC-ICG. Using xenograft and syngeneic mouse models, we confirmed the ability of 6QC-ICG to specifically visualize glioma tissue based on image analysis and spectrofluorimetric measurement. Furthermore, we confirmed that 6QC-ICG was activated in human glioblastoma tissue using ex vivo biopsy material and could be visualized on a clinical visualization platform. Finally, a comparison with 5-ALA in animals co-administered with both compounds revealed a higher TNR for 6QC-ICG in experimental glioblastomas.

CONCLUSION

6QC-ICG is activated by glioma cells and tumor-associated macrophages leading to a high contrast between tumor and non-tumorous brain tissue that is superior to that of the current standard 5-ALA. In addition to their well-defined mechanism of action, the protease-activated probes using NIR fluorophores such as ICG offer the advantage of low absorption and scattering of the NIR light and lower tissue autofluorescence. Our results thus suggest the potential of 6QC-ICG to become a targeted agent for the intraoperative detection of glioblastoma.

Supported by National Institute for Cancer Research (LX22NPO5102), Centre for Tumour Ecology (CZ.02.1.01/0.0/0.0/16_019/0000785), EATRIS-CZ (LM2023053), Cooperatio Program-,,Oncology and Haematology", Ministry of Health of the Czech Republic (NV190300501).
P17.05.A TUMOR-TREATING FIELDS COMBINED WITH SECOND-LINE CHEMOTHERAPY REACHED PROGRESSION FREE SURVIVAL OF 8.33 MONTHS IN CHINESE RECURRENT GLIOBLASTOMA
Authors: Guo C , Yang Q , He Z , Duan H , Liu R , Mu Y
Published: September 2023

BACKGROUND

Tumor-treating Fields (TTFields) monotherapy has been approved for recurrent glioblastoma. However, TTFields combined with second-line chemotherapy has not been well studied in China. This study aims to explore the efficacy and safety of such combination therapy for recurrent GBM.

MATERIAL AND METHODS

This study is a prospective, single-arm, open-label clinical trial (NCT04689087) planning to enroll 40 recurrent supratentorial GBM and use TTFields combined with physician choose second-line chemotherapy. Kaplan-Meier survival curve was used to estimate PFS, OS and survival rate. Safety of the combined treatment was assessed by AE incidence.

RESULTS

Thirty-four recurrent supratentorial GBM patients was enrolled from April 2019 to February 2023. The average age was 51.9 and median KPS score was 80. Seventy-seven percent (26/34) of them underwent total resection surgery and 2.9% (1/34) only experienced biopsy. Eighty-eight percent (30/34) of patients started TTFields when they were first diagnosed as recurrence, while 12% (4/34) patients started TTFields at their second time recurrence or latter, and average compliance of TTFields was 85.5%. As for molecular biomarkers, 47.1% (16/34) patients were MGMT methylated and 38.2% (13/34) were TERT mutant. Since the study initiated in 2019, one IDH-mutant patients were also enrolled. Second-line chemotherapy was combined with antiangiogenic therapy in 47.1% (16/34) patients. The median follow-up period was 8.33 months. Median PFS of these 34 recurrent GBM patients was 8.33(95% CI 4.72-11.95) months, but median OS was not reached. Six months PFS rate was 56.8% (EF-11 historical data of physicians choose chemotherapy was 15.1%) and 6 months OS rate was 74.8%. Two thirds of patients experienced grade 1 or 2 skin adverse events which can be relieved by topical corticosteroids.

CONCLUSION

TTFields combined with second-line chemotherapy showed favorable efficacy and safety in Chinese recurrent GBM patients.
P17.08.A CLINICAL AND MOLECULAR CHARACTERIZATION OF EXTRACRANIAL METASTASES IN GLIOBLASTOMAS
Authors: Jacobsen J , O'Rourke C , Locallo A , Carlsen J , Ewald J , Scheie D , Grunnet K , Schmidt A , Melchior L , Weischenfeldt J , Larsen V , Andersen J , Poulsen H , Broholm H , Michaelsen S , Kristensen B
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults, but in contrast to many other malignancies they rarely metastasize. Metastasizing GBMs cause both diagnostic and therapeutic challenges and are generally poorly investigated. Therefore, our aim was to characterize these tumors clinically and molecularly.

MATERIAL AND METHODS

We collected and examined the largest cohort to date of tissue from 16 glioma patients (14 GBMs and 2 lower-grade gliomas) with extracranial metastases, including metastases to scalp (7) lymph nodes (5), bone (2), liver (1), and upper neck (1). After histopathological re-evaluation of the tumors, we assessed the associated magnetic resonance imaging (MRI) scans. Paired samples from the primary tumors, recurrences and metastases were investigated by next-generation sequencing (NGS) analysis with the TSO500 panel, genome-wide 850 K methylation profiling and immunohistochemistry followed by artificial intelligence-based quantification of markers of stemness and immune cells in the tumor microenvironment (TME).

RESULTS

Clinically, the patients were comparable to other GBM patients (gender, age, treatment, and survival). 12/16 patients developed one or more intracranial recurrence(s). MRI scans revealed proximity of the brain tumors to dura, large vessels, and ventricles in a high proportion of the patients. Moreover, we found that (6/7) scalp lesions were in fact extracranial extensions of the brain tumors. NGS data showed that the metastases were clonally derived from the primary tumors and not from the brain recurrences. Methylation- and copy number analysis overall confirmed the initial diagnoses and revealed a patient-specific signature across paired samples in a majority of the patients. Additionally, we observed methylation subclass switch during tumor progression and identified differentially methylated regions enriched in the olfactory transduction pathway when comparing metastases to primary tumors. Levels of tumor stemness were generally preserved according to methylation-based stemness index and OLIG2 and SOX2 protein expression. Similarly, the composition of immune cells in the TME did not change significantly, as shown by cell-type deconvolution and immune cell quantification.

CONCLUSION

Extracranial metastases occurred as early events and overall preserved the tumor- and TME characteristics of the primary brain tumors. Factor such as brain tumor location, neurosurgery and epigenetic regulation of genes associated with olfactory transduction could be involved in glioblastoma metastasis.
P19.02.A FUNCTIONAL CONSEQUENCES OF IDH1 AND CIC MUTATIONS ON OLIGODENDROGLIOMA CELLS OF ORIGIN
Authors: Pottier N , Joppé S , Magne N , Paris S , Delannoy L , Bardella C , Huillard E
Published: September 2023

BACKGROUND

Oligodendrogliomas are primitive tumors of the central nervous system characterized by mutations in isocitrate dehydrogenase 1 (IDH1R132H) gene, codeletion of 1p and 19q chromosomic arms and mutations in Capicua (CIC) gene. Oligodendrocyte precursor cells (OPCs) are potential cells of origin for oligodendrogliomas and OPC-like tumor cells are responsible for tumor amplification at early stages of gliomagenesis. Although genetic alterations are well characterized for these tumors, little is known about the roles of IDH1 and CIC in oligodendroglioma initiation and development. Individually, IDH1 and CIC mutations can induce neoplastic characteristics but are not sufficient for tumoral development. We aim to understand how IDH1 and CIC mutations impact OPC development and whether these alterations are sufficient for tumoral initiation.

METHODS

We have generated an inducible mouse model allowing endogenous expression of IDH1R132H and inactivation of CIC in postnatal OPCs. We analyzed by immunofluorescence the proliferation and differentiation status of mutated oligodendroglial cells and other brain cells, at postnatal and adult stages.

RESULTS

We describe distinct effects of these mutations on oligodendroglial cell number and proliferation, at early and late time points. In addition, we found that IDH1R132H increases the proliferation of other brain cell types, suggesting paracrine effects of this mutation in the brain. We find no evidence of tumor in the brain of mice mutated for both IDH1 and CIC at late time points.

CONCLUSION

Our study describes for the first time the phenotypic impact of the combined expression of IDH1 and CIC mutations on oligodendroglial lineage cells and other brain cells, leading to a better understanding of oligodendroglioma development.
P20.14.B SYSTEMIC THERAPY FOR RECURRENT ADULT INTRACRANIAL AND SPINAL EPENDYMOMAS: A MONO-INSTITUTIONAL EXPERIENCE
Authors: Maccari M , Padovan M , Caccese M , Cerretti G , Lombardi G
Published: September 2023

BACKGROUND

Ependymoma is a rare disease in adult patients (pts) and there is no standard systemic treatment in recurrent disease after surgery and radiotherapy. We reviewed our cases of confirmed intracranial and spinal ependymomas and described experience of pts treated with systemic therapies at disease recurrence.

MATERIAL AND METHODS

We retrospectively collected data of pts with histopathologically confirmed intracranial and spinal ependymomas from Veneto Institute of Oncology IOV in Padua, Italy from April 2018 to April 2023 and identified a subgroup of pts that received at least one line of systemic therapy at disease recurrence. All ependymomas were classified according to WHO 2016. As local protocol, brain and spinal MRI was performed every 2-3 months or when clinically indicated. RANO criteria were used to neuroradiological response. Primary endpoints were disease control rate and progression-free survival.

RESULTS

A total of 36 adult pts with ependymoma were identified, 18 males, median age at diagnosis 43. Tumor locations were spine (n=6), infratentorial (n=6), supratentorial (n=24). The majority were grade 3 (n=15), the others grade 2 (n=11) and grade 1 ependymoma (n=10).9 selected pts received at least one line of systemic treatments at disease recurrence (6 female, 3 male, median age at diagnosis 42 years). The majority were grade 3 (n=7), the others grade 2 (n=2). All 9 pts had undergone surgery and adjuvant radiotherapy. In this subgroup, the median time to recurrence from diagnosis was 12.4 months (range 3-32). At disease recurrence surgery was re-performed in 3 pts. Median number of lines of systemic therapies was 2, with a range from 1 to 6. TMZ alone in 4 pts with a DCR 40% and mPFS 4ms; TMZ+ cisplatin in 2 pts (DCR 50%, mPFS 4ms); TMZ+lapatinib in 3 pts (DCR 33%, mPFS 3.5ms); TMZ+bevacizumab in 1 pt (DCR 0%, mPFS 2ms); bevacizumab alone in 2 pts (DCR 0%, mPFS 2ms); bevacizumab+fotemustine in 1 pts (DCR 100%, mPFS 14ms), fotemustine alone in 2 pts (DCR 50%, mPFS 7.5ms); carboplatin 1 pts (DCR 0%, mPFS 2ms). At the data cut-off (April 2023), median overall survival from the date of diagnosis was 18.5 months (range 2-50).

CONCLUSION

The management of recurrent ependymoma in adults remains a therapeutic challenge. Our experience reflects heterogeneity regarding systemic treatments for patients with more aggressive ependymomas. Even if it was a small population, TMZ plus cisplatin ,fotemustine alone or in association with bevacizumab might represent promising treatments. However, other larger and prospective studies are needed.