bluuebunny/crossref_metadata_2025_split huggingface dataset:
P14.15.A INTRAOPERATIVE ASPIRATE TISSUE MONITORING DURING 5-ALA GUIDED HIGH-GRADE GLIOMA SURGERY
Authors: Elomaa A , Lehtonen S , von und zu Fraunberg M , Charbel F , Luoma J , Visuri M , Haapala I , Haapasalo J , Vik-Mo E , Puustinen S 
Published: October 2024

Abstract

BACKGROUND
The first-line treatment for high-grade gliomas (HGG) is maximal safe resection, which is limited by diffuse tumor margins and nearby eloquent areas. Intraoperative detection of tumor cells is improved with fluorescence-guided surgery using 5-ALA, but its visual detection is limited by blood, obstacles and weakness of the fluorescence. Aspirate tissue monitoring (ATM) of fluorescence from surgical suction waste could improve surgical performance by providing objective feedback while maintaining a natural white light anatomical view. This observational study compared the visual detection of 5-ALA fluorescence to feedback from an ATM device.

MATERIALS AND METHODS
Twelve (n=12) patients’ suspected HGG resection with (n=9) and without (n=3) prescribed 5-ALA were recorded while a prototype ATM, was attached to the tube of an ultrasonic aspirator. Seven (7) neurosurgeons viewed the white and blue light operation videos with and without ATM feedback and responded to a questionnaire assessing the safety and benefit-risk ratio of ATM. According to the averaged experts’ analysis, the resected tissues were categorized to visually perceivable fluorescence (yes/no) and compared to the ATM signals.

RESULTS
In total 42 video sequences were analyzed. The sensitivity and specificity of ATM in comparison to visual analysis was 100% and 80%, respectively. The positive predictive value (PPV) of ATM was 92% and the negative predictive value (NPV) was 100%. The ATM detected fluorescence under white light in 11 of the resected areas, whereas experts in 0 areas (p&lt;0.001). 10/11 of these areas were verified to include strong visual fluorescence under blue light according to experts’ analysis. The neurosurgeons agreed that ATM appears safe and adds value to contemporary navigation techniques with good agreement (averaged overall agreement rate = 96,7%).

CONCLUSIONS
The ATM improved intraoperative detection of fluorescence compared to visual analysis. The safety and benefit-risk assessment depicts non-inferiority compared to visual analysis for detecting fluorescence during HGG surgery.
P14.19.A PRE-CLINICAL SAFETY AND EFFICACY OF AN INNOVATIVE SURGICALLY IMPLANTABLE MEDICAL DEVICE TO DELIVER ELECTRIC FIELD THERAPY IN GLIOBLASTOMA
Authors: Narayanan A , Venters D , Olukoga T , Purdy R , Munir N , Zhao J , Treen J , Bullock C , Fu R 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. Current standard of care (SOC) involves maximal surgical resection and adjuvant chemoradiotherapy but clinical outcomes remain poor. Electric field therapy (EFT) is one of few developments in recent decades to demonstrate robust survival benefit in GBM, but is currently only available as an external system. Fully implantable EFT would allow continuous and immediate treatment following surgery thereby maximizing therapeutic efficacy. It would also preserve the quality of life of patients and caregivers.

MATERIAL AND METHODS
QV Bioelectronics (Manchester, UK) is developing a fully implantable system to deliver EFT in GBM, called GRACE. The first generation includes industry-standard, GBM-targeted electrodes, a custom cranioplasty for skull fixation, and an implantable pulse generator (IPG) to deliver proprietary stimulation regimes. Optimized stimulation regimes were applied to patient-derived 3D GBM cell lines (n=5) and human iPSC-derived neuronal cultures (n=4) to demonstrate treatment efficacy and selectivity. EFT was tested independently and alongside SOC options. Implanted EFT technology has progressed through formative usability and initial large animal studies. In silico modeling of GRACE was conducted to simulate electric field distributions around implanted electrodes and resultant heat dynamics in surrounding brain tissue with continuous device operation.

RESULTS
Proprietary stimulation regimes demonstrate at least 80% reduction in cancer cell viability across cell lines (L0627 p=0.0005, L160315 p=0.0020) - greater efficacy than currently used regimes described in the literature. Dosing compliance studies demonstrate the importance of continuous stimulation, with 2.7x greater reduction in cancer cell viability with 24hr/day stimulation vs. 18hr/day. Studies of EFT safety with neuronal cultures are underway with estimated completion later in 2024. QV Bioelectronics will also be undertaking further biological replicates with several patient-derived glioma stem cell lines. No gross abnormalities or adverse events related to EFT in pre-clinical health large animal models were noted. Initial in silico results demonstrate that therapeutically effective field strengths can be achieved in clinically relevant target volumes and can rapidly reach safe thermal equilibrium in continuous device operation.

CONCLUSION
QV Bioelectronics demonstrates novel, highly effective EFT regimes; studies to confirm GBM selectivity are underway. Simulation has demonstrated the feasibility of implantable EFT achieving therapeutic field strengths. Further work will combine optimized current delivery sequencing with MRI-derived GBM patient models to define a framework for clinical electrode trajectory planning.
P14.23.B USE OF BIOPSY-DERIVED TUMOR ORGANOIDS FOR PERSONALIZED DRUG TESTING IN RECURRENT GLIOBLASTOMA
Authors: Wöllner A , Warta R , Cao J , Paul A , Arquilla M , Jungwirth G , Wick W , von Deimling A , Krieg S , Unterberg A , Jakobs M , Herold-Mende C 
Published: October 2024

Abstract

BACKGROUND
To date, there are no systemic treatment options for patients suffering from recurrent glioblastoma with a proven efficacy. Furthermore, often surgical resection is not any more possible and patient tumors have acquired an increased chemo- and radioresistance. Patient-derived tumor organoids (TOs) provide a new exciting tool to test individual treatment responses. Aim of this study was to develop a protocol and to test the feasibility to perform personalized TO-based drug testing using the rare material from stereotactic biopsies.

MATERIAL AND METHODS
Patient-derived TOs were prepared based on single cell suspensions from tumor material obtained either from open glioblastoma resections serving as a reference data set (n=37) or from stereotactic biopsies of 8 patients. Drug response curves (6-9 dose points) were performed for nine selected drugs including temozolomide, lomustine, etoposide and temsirolimus, which are commonly used in clinical practice. Viability and metabolic activity were measured using CellTiterGlo (Promega). Half-maximal inhibitory concentrations (IC50) were calculated by GraphPad Prism software. Medical records were reviewed for survival and routine molecular information such as the MGMT promoter methylation status.

RESULTS
Drug testing performed on TOs derived from open resections allowed to adjust the concentration test range for each drug, as well as to determine the range of drug vulnerability. Additionally, we found a significant association between increased temozolomide sensitivity of TOs and both, MGMT methylation and increased survival. However, in 59% of the cases, no high sensitivity to any of the drugs was observed, and only 17% were highly sensitive to more than one drug. Subsequent drug testing on TOs derived from biopsies of recurrent glioblastoma revealed sensitivity in 3/8 cases against one (n=2) or two (n=1) of the drugs. However, sensitivity against drugs varied substantially in a patient-individual manner.

CONCLUSION
Taken together, we successfully developed a workflow to test drug sensitivity on glioblastoma-derived tumor organoids even from the low starting material obtained from stereotactic biopsies. Association of clinical outcome and MGMT methylation with temozolomide sensitivity corroborated the strength of this approach. Furthermore, patient-individual treatment responses strongly suggest for a future personalized drug testing.
P16.03.A GEMOX ADD-ON AFTER THE ITALIAN INDUCTION CHEMOTHERAPY SCHEME IN MALIGNANT BRAIN TUMORS UNDER 3 YEARS
Authors: Castelli B , Fonte C , Tellini M , Di Nicola M , Guidi M , Giunti L , Marzano C , Tirinnanzi B , La Torre C E , Buccoliero A M , Caporalini C , Giordano F , Tintori V , D’Incerti L , Scagnet M , Genitori L , Sardi I 
Published: October 2024

Abstract

BACKGROUND
Gemcitabine plus oxaliplatin chemotherapy (GemOx) represents a possible option in advanced hepatocholangiocarcinoma and pancreatic cancer of adulthood. Considering the pediatric population, it was evaluated in recurrent solid tumors and in children with non-Hodgkin lymphoma unable to tolerate intensive therapy. We report our single-center experience on the applicability of GemOx in infant type brain tumors.

MATERIAL AND METHODS
At the Meyer Children’s Hospital IRCCS in Florence (Italy), from May 2017 to April 2024, seven children received GemOx after induction chemotherapy delivered according to Italian program for malignant brain tumors under 3 years (AIEOP SNC INFANT). The median age at diagnosis was 14 months, the female/male ratio was 1.3, histology was: three high-grade gliomas, a metastatic medulloblastoma MM, a pineoblastoma, a choroid plexus carcinoma CPC, a pilomyxoid astrocytoma progressed during first line chemotherapy. GemOx was administered to ascertain a more stable disease control and to allow a better recovery from the induction chemotherapy, especially in prevision of high-dose chemotherapy, but also to consider the possibility of a second look neurosurgery. Response was evaluated maximum every four cycles and assessed according to RECIST criteria.

RESULTS
Gemcitabine 1000 mg/m2 and Oxaliplatin 100 mg/m2 were administered every 14-28 days for 1-11 cycles. Five patients presented stable diseases and two partial responses. GemOx treatment allowed further neurosurgery in one patient (MM). The treatment was overall well tolerated. The most common toxicities were hematological (reaching neutropenia and thrombocytopenia Common Terminology Criteria for Adverse Events grade 4). Six patients were safely exposed to HDC (1-2 courses), another patient is on GemOx treatment. Two patients (MM and CPC) progressed respectively 4 ad 19 months after the end of GemOx: considering the achievement of permissive age also through the bridge therapy, it was possible to expose both to radiotherapy (the latter after a second look neurosurgery). To date all patients are alive and in good clinical condition.

CONCLUSION
Infant brain tumors represent an extremely challenging subgroup, due to the vulnerable age, with subsequently major risk of therapy-related sequelae and limitation of therapeutic instruments. In the event that a bridge strategy is temporarily warranted, GemOx add on should be considered as a safe option. In our limited and heterogenous cohort, it permitted disease control during the awaiting period, and it was crucial for the patients’ course, especially when a palliative perspective emerged to the lack of other feasible strategies expecting induction therapy recovery.
P16.09.A TGFB1 INDUCED TET3 DEPENDENT REGULATION OF OTX2 SUPER ENHANCER HYPOMETHYLATION PROMOTES GROUP3 MEDULLOBLASTOMA PROGRESSION
Authors: Xuan C , Jiankang L , Tao J , Hailong L 
Published: October 2024

Abstract

BACKGROUND
DNA methylation patterns have been extensively utilized for medulloblastoma (MB) classification. However, the functional implications of enhancer methylation in MB remain poorly understood.

METHODS
We conducted bisulfite-based genome-wide sequencing on 189 human MB cases. Upon molecular classification, 80 cases was compared against 8 normal cerebellums, revealing differentially methylated regions (DMRs). Integration with gene expression data facilitated the identification of DMR target genes, subsequently validated in the 109 cases. Further, leveraging sn-ATACseq, we evaluated the association between DMRs in chromatin accessibility regions and tumorigenesis. Finally, we investigatedd the impact of upstream epigenetic events involving aberrant methylation on tumor development.

RESULTS
We observed a negative correlation between the methylation levels of DMR overlapping super enhancers (seDMRs) and the expression of targeted genes, particularly in Group_3 MB (G3-MB), the most aggressive subgroup. Genes targeted by hypomethylated seDMRs were significantly enriched in early-stage cerebellum development hallmarks, specifically the rhombic lip subventricular zone (RLSVZ), but not in the late stage. Hypomethylated seDMRs of OTX2 were associated with elevated chromatin accessibility and oncogenic activation of progenitor-like MB tumor cells, leading to worse prognosis. Integrative epigenetic analysis revealed highly active OTX2 binding sites within its own hypomethylated seDMRs, indicating feedback auto-regulation. Deletion of motif at this enhancer region reduced OTX2 expression and attenuated tumor progression. Further, we found that ten-eleven translocation 3 (TET3), a DNA methylation eraser, was recruited by OTX2 to catalyze active DNA demethylation at binding motifs, thereby organizing chromatin and stimulating gene expression. TET3 was upregulated by TGF-β1/Smad2 signaling. Based on these findings, nanoparticle-coated small interfering RNAs (siRNA) targeting TET3 were designed, effectively suppressing xenograft progression.

CONCLUSION
Our study highlights the increased transcriptional activity of OTX2 through cell-type-specific super enhancer demethylation, which is dependent on TGF-β1/Smad-induced TET3. This identifies a potential therapeutic strategy for G3-MB.
P16.11.B UTILITY OF DNA METHYLATION PROFILING AGAINST UNRESOLVED PEDIATRIC HIGH-GRADE BRAIN TUMOR IN ROUTINE DIAGNOSTICS
Authors: Hou Y , Zhu J , Yu Q , Wu J , Zhao J , Cao Y 
Published: October 2024

Abstract

BACKGROUND
Recent advances in genetics and epigenetics research have underscored the heterogeneity of pediatric brain tumors, characterized by overlapping morphological and molecular features across various tumor types. This complexity presents substantial challenges for precision diagnosis in routine diagnostics. In this study, we collected a cohort of pediatric high-grade brain tumors that remain unresolved after next-generation sequencing (NGS). Our goal is try to refine diagnosis by DNA methylation profiling, thereby evaluating the utility of this new diagnostic tool against unresolved and challenging cases in standard clinical practice.

METHODS
In this retrospective analysis, we selected 10 cases from local pathology archives based on the following criteria: (1) age at diagnosis&lt; 18 years; (2) brain tumor with high-grade evidence; (3) NGS was employed but failed to provide a definitive diagnosis or not aligned to WHO CNS tumor classification. All cases were subjected to the Illumina Infinium MethylationEPIC v2.0 BeadChip, DNA methylation profiling was conducted by using an customized pipeline alongside the DKFZ brain tumor classifier. NGS was previously done by utilizing a DNA-panel targeting over 500 genes associated with tumor-related genetic variations. The collection of tumor samples and clinical data was processed in accordance with standards approved by the local ethical committees.

RESULT
All cases were supratentorial high-grade tumors, aged 1 to 16 years (n=10). Utilizing DNA methylation profiling, definitive diagnoses were established in 60% of cases: two cases of embryonal tumor with multilayered rosettes (ETMR), one pediatric diffuse high-grade glioma MYCN subtype, one pleomorphic xanthoastrocytoma (PXA), one medulloblastoma non-WNT/non-SHH subgroup 7, and one alveolar rhabdomyosarcoma. The remaining cases (n=4) neither yielded convincing calibrated scores from the DKFZ brain tumor classifier (v12.8) nor provided valuable insights from methylation based t-SNE clustering or copy-number profiling analysis. These 4 cases includes: a pediatric high grade glioma (pHGG) harboring CDK12, DICER1, JAK3, NF1, NTRK2, RB1 and SPEN mutation; a pHGG harboring PIK3CA, NF1 and TP53 mutation; a malignant embryonal tumor in the pineal gland harboring ATRX, BCL2, BLM, CYSLTER2, GPR101, HIF1A and SHOC2 mutation; and a malignant embryonal tumor with TERT, SMARCA4 mutation and EML4-ALK fusion.

CONCLUSION
In confronting the diagnostic complexities of pediatric high-grade brain tumors, DNA methylation profiling may provide more critical evidence that can address and unravel intricate clinical diagnostic challenges.

SUPPORT/DISCLOSURE
This research was supported by Natural Science Foundation of Chongqing (No.CSTB2023NSCQ-BHX0105).
P17.21.B SEIZURE OUTCOMES IN PATIENTS WITH BRAIN METASTASES: A SYSTEMATIC REVIEW ON THE EFFICACY OF ANTITUMOR TREATMENT AND ANTISEIZURE MEDICATION
Authors: Scheepens J C C , van der Meer P B , Dirven L , Vos M J , Taphoorn M J B , Koekkoek J A F 
Published: October 2024

Abstract

BACKGROUND
Brain metastases (BMs) are the most common type of malignant brain tumor and their incidence is rising. As many patients with BMs develop epileptic seizures, adequate seizure management is warranted. However, most research has focused on patients with primary malignant brain tumors instead of BMs. We conducted a systematic review on seizure outcomes after antitumor treatment and antiseizure medication (ASM) in patients with BMs from solid tumors.

MATERIAL AND METHODS
We performed a systematic literature search in six databases up to February 2024. The endpoints of interest were efficacy (i.e., the ability to achieve seizure freedom) and tolerability (for ASM only) (i.e., the incidence, severity, and impact of ASM-related adverse events). Extracted outcomes included rates for: (1) seizure freedom; (2) ≥50% seizure reduction; and (3) ASM treatment failure. If possible, we calculated a weighted average (WA) of each seizure outcome. The Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool was used to systematically judge the overall risk of bias of each study as low, moderate, serious, or critical based on seven bias domains. The ROBINS-I tool recommends to exclude studies at critical risk of bias.

RESULTS
Our search yielded 2244 references, of which 16 studies were included. Eight studies were at critical, and 8 at serious risk of bias. The WAs of seizure freedom at 3 and 6 months after surgical resection were 84% and 67% (n=145 and n=164 patients), respectively. When excluding studies at critical risk of bias, seizure freedom at 3 months was 88% and at 6 months 64% (n=59 and n=151 patients). For other treatments and outcomes, no WAs could be calculated because of a limited number of studies with varying follow-up times. Based on 3 studies (n=85 patients total), seizure freedom with ASM ranged from 77% to 57%, and treatment failure from 0% to 50% after 1 month to a median of 11 months of follow-up. However, these results on the efficacy and tolerability of ASM were unreliable, as all 3 studies were at critical risk of bias.

CONCLUSION
Limited available evidence demonstrated that in most patients with epilepsy due to BMs seizure freedom is achieved within 6 months after surgical resection. Due to the high risk of bias of available studies, the efficacy and tolerability of ASM in patients with epilepsy due to BMs remains to be elucidated.
P18.02.B ANALYSIS OF TUMOR RELAPSE PROBABILITY AND OVERALL SURVIVAL PREDICTION FOLLOWING CONCOMITANT RADIOTHERAPY WITH TEMOZOLOMIDE USING FET PET IN PATIENTS WITH GLIOBLASTOMA
Authors: Stetter I , Werner J , Wollring M , Ceccon G , Lohmann P , Stoffels G , Mottaghy F M , Fink G R , Langen K , Galldiks N 
Published: October 2024

Abstract

BACKGROUND
Early after surgery and completion of concomitant radiotherapy with temozolomide, the evaluation of tumor relapse probability and overall survival prediction is of considerable interest for the management of patients with glioblastoma.

MATERIAL AND METHODS
Sixty-three adult glioblastoma patients (mean age 55.4 years, SD ± 14.6) who received dynamic PET imaging using the radiolabeled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) after surgery or biopsy and completion of concomitant radiotherapy with temozolomide, were retrospectively included in the study. Static FET PET parameters such as maximum and mean tumor-to-brain ratios (TBRmax/TBRmean) and metabolic tumor volumes (MTV) and the dynamic FET PET parameter time-to-peak (TTP) were obtained. The prognostic value of FET PET parameters was evaluated concerning the progression-free and overall survival (PFS, OS). Using receiver-operating-characteristic (ROC) analyses, threshold values for FET PET parameters were acquired. Subsequently, univariate and multivariate survival estimates were performed to assess the prognostic value of these parameters to predict a significantly longer PFS (as a surrogate for tumor relapse probability) and OS.

RESULTS
ROC analysis revealed that the parameter TBRmax was the most powerful parameter to predict both a significantly longer PFS (17.8 vs. 9.0 months; P=0.003; threshold, 2.85) and OS (33.2 vs. 18.4 months; P=0.002; threshold, 2.75). MTV had a similar prognostic value for both PFS (15.9 vs. 7.2 months; P=0.002; threshold, 34.0 mL) and OS (28.2 vs. 14.4 months; P=0.003; threshold, 32.6 mL). At a lower level of significance, TTP was only prognostic for a significantly longer OS (27.7 vs. 17.5 months; P=0.037; threshold, 25 minutes). TBRmax and MTV remained significant in multivariate survival analysis, indicating independent predictors for both a significantly longer PFS and OS (all P≤0.04).

CONCLUSION
Our results suggest that FET PET parameters were highly prognostic in patients with newly diagnosed glioblastomas at an early stage of first-line therapy for predicting favourable PFS and OS.
P18.08.A CCNU/TMZ IN ELDERLY PATIENTS WITH MGMT-METHYLATED GLIOBLASTOMA: A MULTICENTRIC RETROSPECTIVE COHORT
Authors: Weller J , Zeyen T , Schäfer N , Hau P , Glas M , Werner J , Galldiks N , Seidel C , Kowalski T , Schaub C , Sabel M , Drexler R , Schneider M , Herrlinger U 
Published: October 2024

Abstract

BACKGROUND
Lomustine-temozolomide combination therapy (CCNU/TMZ), in addition to standard radiotherapy, improves survival in MGMT-methylated newly diagnosed glioblastoma. As the CeTeG/NOA-09 trial included patients aged up to 70 years, the feasibility of CCNU/TMZ in older patients remains unknown.

MATERIAL AND METHODS
Retrospective multicentric analysis of patients aged &gt;70 years with newly diagnosed MGMT-methylated glioblastoma, IDH-wildtype, receiving at least one dose of CCNU/TMZ according to the CeTeG/NOA-09 protocol.

RESULTS
Seventeen patients with a median age of 72 years (range, 71-78) were included. 71% (n=12) were male, the median KPS was 80% (IQR, 80-90), and the extent of resection was biopsy in 18% (n=3), partial resection in 24% (n=4), and gross total resection in 59% of cases (n=10). The median number of chemotherapy courses was five (IQR, 2-6). After a median follow-up of 19.1 months (IQR, 11.2-29.8), the median progression-free survival was 13.5 months (95%CI, 7.9-not reached) and the median overall survival was 20.7 months (95%CI, 17.6-not reached). Updated data will be presented at the meeting.

CONCLUSION
Combined radiochemotherapy with CCNU/TMZ is feasible in glioblastoma patients aged &gt;70 years, and encouraging survival times were observed. Future prospective analyses involving CCNU/TMZ for MGMT-methylated glioblastoma might consider including elderly patients.