bluuebunny/crossref_metadata_2025 huggingface dataset:
P13.17.A THE EFFECTS OF RADIOTHERAPY ON GREY AND WHITE MATTER VOLUME IN THE BRAINS OF PATIENTS WITH HEAD AND NECK CANCER
Authors: van der Weijden C W J , Wickborn K , Kramer M C A , Buunk A M , Spikman J M , Langendijk J A , van Zon-Meijer T W H , de Vries E F J , van der Hoorn A
Published: October 2024

BACKGROUND

Patients with head-and neck-cancer (HNC) often receive radiotherapy as part of their treatment. Due to the tumour location, exposure of the brain to irradiation is inevitable, but the brain is not confounded by effects of having an intracranial brain tumour. Detailed knowledge of radiotherapy-induced effects on the brain can help to improve treatment planning by optimizing radiation doses and avoiding critical brain structures, thereby reducing the risk of neurotoxicity while effectively treating the tumour and thus improving quality of life. As T1w MRI allows the quantification of grey matter and white matter volumes, it can be used as proxies to assess tissue alterations. Therefore, this study aims to evaluate whether changes in grey and/or white matter volume could be detected in patients with HNC treated with radiotherapy.

MATERIAL AND METHODS

Patients with HNC that received radiotherapy (>50 Gy) as part of their regular treatment were subjected to T1w (MP2RAGE) MRI at the start of radiotherapy and at the end of radiotherapy (0-14 days). Differences in grey and white matter volume of various brain regions in the posterior fossa, inferior temporal lobe, and medial temporal lobe (total 24 ROIs) between start and end of radiotherapy was determined. These brain regions were chosen, as they are closest to the tumour location. Differences in brain volumes were correlated to the radiation dose using Spearman correlations.

RESULTS

So far, 9 of 40 patients have been enrolled. They had a mean age of 50±15 years. Two were female and 7 male and 2 received photon radiotherapy and 7 proton radiotherapy. From evaluated brain regions, grey matter volume of the right middle and inferior temporal gyrus was significantly lower (p=0.043) after radiotherapy (8.39±0.87 mL) than before radiotherapy (8.87±1.01 mL). For other regions, no significant differences were observed. Only non-significant increases in white matter ROI volumes between start and end of radiotherapy were observed. Differences in brain region volumes between start and end of radiotherapy were not significantly correlated with the radiation dose, neither for grey matter (-0.30±0.30 ρ) for white matter (0.19±0.30 ρ).

CONCLUSION

With an inclusion of 9 out of 40 subjects, we mainly found non-significant changes in grey and white matter volumes after radiotherapy in HNC patients, although reductions in temporal grey matter reached significance. More inclusions are necessary to reach proper power and to determine whether changes in brain volumes can be used for early detection radiotherapy induced brain alterations and if they correlate with radiotherapy dose.

FUNDING

This study is supported by a VENI grant to Anouk van der Hoorn (no: 09150161910041).
P14.11.B DISTINGUISHING RESPONDERS FROM NON-RESPONDERS IN PATIENTS WITH GLIOBLASTOMA AFTER FIRST LINE THERAPY USING GRASP DCE-MRI
Authors: Vankan B , Rommers N , Psychogios M N , Todea R A
Published: October 2024

BACKGROUND

After completion of radiochemotherapy distinguishing responders from non-responders in glioblastoma patients with conventional sequences is still challenging. The purpose of this study is to investigate whether Golden Angle Radial Sparse Parallel Dynamic Contrast-Enhanced (GRASP DCE) MRI can aid in making this differentiation.

METHODS

In total, 66 patients with glioblastoma, diagnosed between 01/2017-12/2021 who had undergone first line therapy and developed new or enlarging contrast-enhancing lesions suspicious of tumor progression and had GRASP DCE-MRI, were analyzed. Using MRI follow-up, PET CT, histology as gold standard the scans were classified into two groups: responders and non-responders to first line therapy. The scans were then analyzed based on the time window after the completion of radiochemotherapy during which they had been completed (1-2, 3-4, 5-6, >6 months) and then all together independent of the time window. To evaluate the accuracy of the DCE-MRI kinetics parameters in differentiating responders from non-responders, a descriptive analysis and a diagnostic accuracy analysis were performed using the area under the receiver operating characteristic curve.

RESULTS

In total, 138 GRASP DCE-MRI scans were analyzed. The peak enhancement (PE%) and the initial area under the curve for 30 seconds (IAUC 30) 60 seconds (IAUC 60), were consistently lower in the responders (n=63) than in the non-responders (n=75). Considering the scans independent of their time window, the PE% for responders vs non-responders was 29% IQR [26, 35] vs. 53% IQR [45, 69] respectively. The best threshold to differentiate the responders from non-responders was 41% (Sensitivity 89% (95% CI [83, 96]), Specificity 87% (95% CI [78, 95]), AUC 0.94 (95% CI [0.89, 0.98])). The IAUC 30 for responders vs. non-responders was 949 IQR [756, 1196] vs. 1627 IQR [1358, 2058] respectively. The best threshold to differentiate the responders from non-responders was 1079 (Sensitivity 93% (95% CI [87, 99]), Specificity 68% (95% CI [57, 79]), AUC 0.90 (95% CI [0.85, 0.94])). The IAUC 60 for responders vs. non-responders was 1847 IQR [1439, 2386] vs. 3337 IQR [2670, 3965] respectively. The best threshold to differentiate the responders from non-responders was 2614 (Sensitivity 79% (95% CI [69, 88]), Specificity 83% (95% CI [75, 92]), AUC 0.89 (95% CI [0.84, 0.94])).

CONCLUSION

The peak enhancement and the initial area under the curve (30 seconds), extracted from GRASP DCE MRI, considering all scans independent of their time window, had the best diagnostic accuracy to differentiate responders from non-responders in glioblastoma patients with a threshold of 41% vs 1079 respectively.
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

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<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

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

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

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

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

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< 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

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

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

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 >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 >70 years, and encouraging survival times were observed. Future prospective analyses involving CCNU/TMZ for MGMT-methylated glioblastoma might consider including elderly patients.
P18.16.A DTI FIBER-TRACKING PARAMETERS ADJACENT TO GLIOMAS: THE ROLE OF TRACT IRREGULARITY VALUE IN OPERATIVE PLANNING, RESECTION, AND OUTCOME
Authors: Armocida D , Pesce A , Salvati M , Cofano F , Frati A , Garbossa D , Santoro A
Published: October 2024

BACKGROUND

The goal of glioma surgery is maximal tumor resection associated with minimal post-operative morbidity. Diffusion tensor imaging-tractography/fiber tracking (DTI-FT) is a valuable white-matter (WM) visualization tool for diagnosis and surgical planning. Still, it assumes a descriptive role since the main DTI metrics and parameters showed several limitations in clinical use. New applications and quantitative measurements were recently applied to describe WM architecture adjacent to the tumor area (BAT), which can be adopted as predictive values and a guide for safe tumor resection.

MATERIAL AND METHODS

This is an observational prospective study on an extensive series of glioma patients who performed magnetic resonance imaging (MRI) with pre-operative DTI-FT analyzed on the BAT by two different software. We examined DTI parameters of Fractional anisotropy (FA mean, min-max), Mean diffusivity (MD), and the shape-metric “tracti irregularity” (TI) grade, comparing it with the surgical series’ clinical, radiological, and outcome data.

RESULTS

The population consisted of 118 patients, with a mean age of 60.6 years. 82 patients suffering from high-grade gliomas (69.5%), and 36 from low-grade gliomas (30.5%). A significant inverse relationship exists between the FA mean value and grading (p=0.001). The relationship appears directly proportional regarding MD values (p=0.003) and TI values (p=0.005). FA mean and MD values are susceptible to significant variations with tumor and edema volume (p=0.05). TI showed an independent relationship with grading regardless of tumor radiological features and dimensions, with a direct relationship with grading, ki67% (p=0,05), PFS (p<0.001), and EOR (p<0.01).

CONCLUSION

FA, MD, and TI are useful predictive measures of the clinical behavior of glioma, and TI could be helpful for tumor grading identification and surgical planning.
P18.18.B EFFICACY AND FAILURE PATTERNS OF SIMULTANEOUS INTEGRATED BOOST INTENSITY- MODULATED RADIOTHERAPY FOR WHO GRADE IV GLIOMAS
Authors: Du X , Huo L , Deng M , Chen Y , Wu S
Published: October 2024

BACKGROUND

We analyzed the efficacy and failure patterns of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) in patients with WHO grade IV gliomas.

MATERIAL AND METHODS

From June 2016 to December 2020, 246 newly diagnosed patients with histologically-proven WHO grade IV gliomas were retrospectively analyzed. All patients were treated with post-operative SIB-IMRT at a total planned dose of 60 Gy for gross tumor volume (PGTV) and 50 Gy for clinical target volume (PCTV), to be given in 28-30 fractions. On progression, recurrent tumors were classified as in-field, marginal, or distant, relative to the 95% isodose line of PGTV.

RESULTS

Median OS and PFS was 23.5 (95% CI 19.9-27.1) and 13.4 (95%CI 11.6-15.2) months, respectively. One-year OS and PFS was 86.4% and 56.1%, respectively. Multivariate analysis identified female sex, gross tumor resection and MGMT promotor methylation as independent predictive factors for better PFS and OS. Of the 98 patients with documented recurrences, 83 patients (84.7%) had an in-field component of treatment failure, 7 (7.1%) had a marginal component, and 18 (18.4%) had a distant component. Seventy-four patients (75.5%) had in-field only recurrence. Of the 100 documented local recurrent lesions, 87% lesions were located within 2 cm-margins of the original GTVs. Patients with multifocal disease were more likely to experience marginal failures (P = 0.041).

CONCLUSION

Post-operative SIB-IMRT is a feasible and safe treatment option for WHO grade IV gliomas with a low rate of marginal recurrence and good survival outcomes.
P18.31.A NIRAPARIB EFFICACY IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA: CLINICAL READOUT OF A PHASE 0/2 ‘TRIGGER’ TRIAL
Authors: Sanai N , Umemura Y , Margaryan T , Molloy J , Zhang H , Knight W , Harmon J , Hong A , Wanebo J , Braun K , Kennedy W , Garcia M , Barani I , Yoo W , Tien A , Tovmasyan A , Mehta S
Published: October 2024

BACKGROUND

Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when a PK threshold is met.

METHODS

Presumed newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 (cohort 1) or 8-10 hours (cohort2) following the last dose. Tumor tissue (Gadolinium enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation of surgical vs non-irradiated tissue. A PK ‘trigger’ determined eligibility for the Phase 2 component of the study and was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors in excess of the PK threshold were eligible for Phase 2 dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib monotherapy.

RESULTS

All patients in the Phase 0 analysis population (n=46) met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 335.1 nM (n=43) for cohort 1 and 331.9 nM (n=3) for cohort 2. PAR suppression after ex vivo radiation was observed in 73% of the patients (24/33). Twenty of 28 (71.4%) patients with unmethylated tumors were enrolled into Phase 2. Five patients in Phase 2 experienced Grade 4 thrombocytopenia related to niraparib. All adverse events resolved without sequelae. Median progression-free survival was 14.9 months and median overall survival was 20.3 months.

CONCLUSIONS

Niraparib achieves pharmacologically relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. Accompanying PD effects were observed in patient tumor tissue and long-term clinical efficacy data is promising. A global Phase 3, open-label, randomized 2-arm study comparing niraparib versus temozolomide in adult patients with newly diagnosed, MGMT unmethylated glioblastoma is underway.
P18.48.B THE TRANSFORMATION AND RECURRENCE PATTERN OF TARGET VOLUME FOR GLIOMA ON THE MR-LINAC
Authors: Chen Y , Yin X , Guo L , Ding S , Wang Y , Deng M , Liu Z , Mu Y
Published: October 2024

BACKGROUND

Glioma, which carries a poor prognosis, stands as the most prevalent primary tumor of the central nervous system. The magnetic resonance (MR) linear accelerator (Linac) was increasingly used in the treatment of glioma, allowing for the collection of MRI images before each radiotherapy session, facilitating real-time adjustments to target volume.

MATERIAL AND METHODS

The authors retrospectively reviewed the patients with newly diagnosed glioma who underwent adaptive radiotherapy by means of 1.5 T MR-linac between August 2021 and December 2022 at Sun Yat-sen University Cancer Center, and analyzed changes in target volume (GTV), Dice Similarity Coefficient, Hausdorff distance (HD), relative GTV volume, and recurrence pattern.

RESULTS

A total of 20 patients were treated, including 18 with high-grade glioma and 2 with low-grade glioma. In 18 high-grade gloma patients, 10 had a recurrence, with 50% (5/10) exhibiting in-field recurrence, 40% (4/10) ex-field, and 10% (1/10) in/ex-field recurrence. The median progression-free survival (PFS) was 6 months (range, 2-13 months). Among 3 patients with initial GTV HD greater than first radiation therapy session for 15mm, all had ex-field recurrence. Of 9 patients who underwent complete resection, 44.4% (4/9) experienced recurrence (3 in-field, 1 ex-field), while 66.7% (6/9) experienced recurrence (2 in-field, 4 in/ex-field) in the other 9 patients. In 17 patients, MGMT methylation IDH1/2 mutation status was evaluated. 50% (4/8) of the MGMT methylated population occurred recurrence (3 in-field, 1 ex-field); 66.7% (6/9) of the MGMT unmethylated population occurred recurrence (2 in-field, 3 ex-field, 1 in/ex-field). 75% (9/12) IDH1/2wt patients developed recurrence (4 in-field, 4 ex-field, 1 in/ex-field), whereas only 20% (1/5) IDH1/2mut patients developed in-field recurrence. All patients tolerated MR-linac radiotherapy well, with minimal complications or toxicity. Notably, while preparing for radiotherapy of one patient, whose radiotherapy was scheduled after reoperation due to recurrence. During the radiotherapy, 3 patients occurred recurrence, then received prompting adjustments to target volume and drug treatments, resulting in successful recovery.

CONCLUSION

The implementation of MR-linac offers a novel approach for precise radiotherapy to glioma. Among patients who received adaptive radiotherapy on the MR-linac, the incidence of in-field recurrence decreased compared to previous research, likely attributable to precise irradiation of GTV. Nevertheless, longer follow-up is necessary to determine survival benefits. Future research should focus on increasing sample sizes to explore the relationship between target volume deformation and recurrence pattern in radiotherapy, as well as developing new modes of target volume delineation and optimizing target volume dosages.
P19.16.A THE EFFECT OF TARGETING CCNB1 ON THE RADIOSENSITIVITY OF MALIGNANT MENINGIOMA
Authors: Gong Z , Ma P , Zhou D , Xu T , Fang Y
Published: October 2024

BACKGROUND

While most meningiomas are benign with favorable outcomes, malignant meningiomas are challenging due to high recurrence rates. The standard treatment involves surgical resection followed by radiotherapy. However, radiotherapy resistance is common, underscoring the need for novel targets to improve radiotherapy outcomes. Cyclin B1 (CCNB1) serves as a key regulator at the G2/M checkpoint of the cell cycle. It plays a significant role in DNA damage repair pathways, intimately linked to various cancers’ development and radiosensitivity.

MATERIAL AND METHODS

87 meningiomas (15 WHO Grade I, 63 WHO Grade II, 9 WHO Grade III) and 9 normal dural tissue microarrays were constructed for immunohistochemical and subsequent survival analyses. The malignant meningioma cell line IOMM-Lee was used to develop CCNB1 knockdown and overexpression models. In vitro assays included cell migration, proliferation, clonogenicity, apoptosis, cell cycle analysis, and DNA damage repair pathway assessments. In vivo, CCNB1’s impact on radiosensitivity was evaluated using an orthotopic meningioma model in nude mice, assessing post-irradiation tumor growth through bioluminescence imaging, and survival rates were analyzed.

RESULTS

Immunohistochemical analysis on tissue microarrays revealed that CCNB1 expression was minimal in normal dural tissues but significantly elevated in meningioma tissues, with higher expression particularly noted in high-grade tumors compared to low-grades. Survival analysis indicated that high CCNB1 expression correlates with a shorter progression-free survival (PFS) in patients. In vitro, CCNB1 knockdown in IOMM-Lee cells markedly reduced migration and proliferation compared to controls. Conversely, CCNB1 overexpression led to increased migration and proliferation compared to controls. The apoptotic rate in knockdown cells increased significantly post-irradiation to 11.43±0.40% from 6.27±0.34% in controls (p < 0.01). Additionally, a pronounced increase in G2/M phase arrest was observed, with cells exhibiting 66% in G2/M phase at 8 hours post-irradiation, compared to 48% in controls, indicating enhanced radiosensitivity. In vivo studies further confirmed these findings, demonstrating significant tumor growth suppression and prolonged survival in xenografted nude mice with CCNB1 knockdown tumors. These comprehensive results underline the significant role of CCNB1 in modulating DNA damage response pathways, particularly the ATR-Chk1 pathway, and its potential as a prognostic marker and therapeutic target in high-grade meningiomas.

CONCLUSION

CCNB1 is a pivotal factor in the radiosensitivity of malignant meningiomas. Targeting CCNB1 may improve the efficacy of radiotherapy, providing a potential therapeutic avenue to combat the high recurrence and mortality rates of these tumors.
P20.05.B BELZUTIFAN TREATMENT OF VON HIPPEL-LINDAU-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA
Authors: Thomsen A , Valerius A , Uhm J H , Ruff M , Baykal D , Caron S , White J D , Neth B J , Webb M J , Pichurin P N , Sener U
Published: October 2024

BACKGROUND

Von Hippel-Lindau (VHL) disease is a rare autosomal-dominant hereditary disease associated with tumors in multiple organs. VHL is characterized by mutation of the VHL gene which leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. Conventional management of VHL-associated tumors involves surgical resection and radiation therapy. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). Belzutifan was approved by the United States Food and Drug Administration (FDA) in August 2021 as a targeted therapy option for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Our objective here is to report on our clinical experience with use of belzutifan for VHL-associated CNS hemangioblastomas.

MATERIAL AND METHODS

We retrospectively chart reviewed our institutional (Mayo Clinic Rochester) experience of belzutifan in adults (18 years or older) with VHL and craniospinal hemangioblastomas not amenable to surgery. The study period was October 2021 to March 2024.

RESULTS

Nine adults (5 female, 4 male) were included in the study. Of those able to continue the therapy without interruption (6 patients), the median duration of therapy at last follow-up was 11.5 months (range 3-22 months). Seven had radiographic response to therapy after a median of 3 months (1-5 months), with a maximal response to therapy after a median of 13 months (3-29 months). One patient had a mixed radiographic response, and 1 patient had tumor progression while on belzutifan noted at 5 months. The most common adverse effect was fatigue. Seven patients reported fatigue, 4 patients experienced anemia, and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects, specifically fatigue and hypoxia. One patient had to take multiple medication pauses, once due to seizure and once due to kidney injury, but resumed treatment with dose reduction.

CONCLUSION

Among patients with VHL-associated CNS hemangioblastomas, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to FDA approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, duration of treatment, and effects of cessation after long-term use.
P20.09.A CLINICAL, PATHOLOGICAL AND MOLECULAR DISEASE CHARACTERISTICS OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Le Rhun E , Bink A , Felsberg J , Gramatzki D , Brandner S , Benhamida J K , Wick A , Tonn J C , Mohme M , Tabatabai G , Capper D , Snuderl M , Razis E , Ronellenfitsch M , Neidert N , Ng H , Pohl U , Bale T A , Quach S , Rieger D , Schüller U , Drüschler K , Healy E , Graham M , Paine S M L , Medici V , Sievers P , Schrimpf D , Wick W , Sahm F , Reifenberger G , von Deimling A , Weller M
Published: October 2024

BACKGROUND

Diffuse hemispheric glioma, histone 3 (H3) G34-mutant, is a pediatric-type diffuse high-grade glioma newly defined in the World Health Organization (WHO) classification of central nervous system tumors 2021. Here we sought to define the prognostic roles of clinical, neuroimaging, pathological and molecular features of these tumors.

MATERIAL AND METHODS

We retrospectively assembled a cohort of 114 patients with diffuse hemispheric glioma, H3 G34-mutant and profiled the imaging presentation and the molecular landscape of their tumors.

RESULTS

Compared with glioblastoma, H3 G34-mutant tumors exhibited less avid contrast enhancement, less necrosis and less edema on magnetic resonance imaging (MRI). Comprehensive analyses of mutational and DNA copy number profiles revealed recurrent mutations in TP53 and ATRX, homozygous deletions of CDKN2A/B, and amplifications of PDGFRA, EGFR, CCND2 and MYCN. MGMT promoter methylation was detected in 79 tumors (75%). Median survival was 21.5 months (95% CI 15.3-27.7) and 8 patients (7.0%) survived for ≥ 5 years. Female sex, gross total resection, and MGMT promoter methylation were prognostic factors on univariate analysis. Among pathological and radiological features, presence of microvascular proliferation and absence of pial invasion were prognostic factors on univariate analyses.

CONCLUSION

This study refines the clinical and molecular landscape of H3 G34-mutant diffuse hemispheric gliomas. Dedicated trials for this novel tumor type are urgently needed.
P20.10.B CLINICAL, PATHOLOGICAL, AND GENOMIC FEATURES OF INFRATENTORIAL IDH-MUTANT GLIOMAS
Authors: WANG L
Published: October 2024

BACKGROUND

Isocitrate dehydrogenase (IDH) 1/2 mutations are rare in infratentorial gliomas, which of clinico-molecular characteristics of infratentorial IDH-mutant gliomas have not been well characterized.

MATERIAL AND METHODS

In the current study, a series of 12 cases of infratentorial IDH-mutant gliomas were described for clinical, pathological, and genomic characteristics.

RESULTS

The median age of this cohort at diagnosis was 41-year-old (range: 10-67). 9 tumors were located in posterior fossa, including 5 (41.7%) were only in the brainstem and 4 (33.3%) were present in both brainstem and cerebellum, and 3 (25%) in spinal cord. Histopathologic diagnosis of twelve cases are all diffuse astrocytoma. Eight cases were low-grade astrocytoma (WHO grade 2) including one with concomitant KIAA1549-BRAF fusion and IDH mutation in pediatric spinal cord astrocytoma, and four high-grade astrocytoma (WHO grade 3). Comprehensive genomic profiling revealed that Non-canonical IDH (50%, 6/12) and TP53 (75%, 9/12) mutations were more frequent in infratentorial IDH-mutant astrocytomas than supratentorial cases. While ATRX mutation (33.3%, 4/12) and MGMT promoter methylation (41.7%, 5/12) were less frequent (p<0.005). No mutations of H3.1, H3.3, TERT, homozygous deletion of CDKN2A/B, or co-deletion of 1p/19q were detected.

CONCLUSION

Our data revealed infratentorial IDH-mutant gliomas have distinct clinical, pathological, molecular, and prognostic characteristics, differed from supratentorial cases.