bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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&lt;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

Abstract

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

Abstract

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 &lt;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 &lt;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

Abstract

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

Abstract

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

Abstract

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 &lt; 0.001), and in the transition zone (10, 1 and 396 cells/mm2) than in the periphery (P &lt; 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 &lt; 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 &lt; 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 &lt; 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.