bluuebunny/crossref_metadata_2025 huggingface dataset:
P11.63.B VALIDATING THE NEUROLOGIC ASSESSMENT IN NEURO-ONCOLOGY (NANO) SCALE IN CLINICAL PRACTICE: A MULTI-CENTER PROSPECTIVE STUDY IN PATIENTS WITH GLIOBLASTOMA
Authors: Lim Fat M , Fox R , Allen M , Roberto K , Machado M , Chen H , Melhem J , Gonzalez Castro L , Youssef G , Chukwueke U , McFaline-Figueroa J , Lee E , Wen P , Perry J , Reardon D , Nayak L
Published: September 2023

BACKGROUND

The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients with brain tumors and complement radiographic assessment in defining overall outcomes. The scale has been incorporated in clinical trials, however, real-world use of the NANO scale to drive clinical decision-making and the predictive value of the NANO scale to determine overall survival remains unclear in glioblastoma.

MATERIAL AND METHODS

We report on an ongoing multi-center study of prospective NANO score collection to evaluate neurologic function in patients with glioblastoma, seen at Dana-Farber Cancer Institute (DFCI) and Sunnybrook Health Sciences Center (SHSC). Patient demographics, tumor histology, molecular status, treatment history, and progression dates are being captured. NANO score, Karnofsky performance status (KPS) and corticosteroid dose are collected at prespecified time points (prior to start of therapy, and during each subsequent MRI visit). Changes in the NANO score will be correlated to overall survival and subgroup analyses will be performed for specific domains of the NANO scale. Statistical analyses including descriptive data analysis and generalized linear models will be performed using R (version 3.4.3).

RESULTS

Since June 2020, 145 patients have been enrolled in this study across the two sites including 90 (62%) with ≥2 follow-up visits. 129 patients had baseline post-operative NANOs captured, with 45 (35%) patients having no deficits in any NANO domain at baseline. All patients with intact baseline NANO had a KPS of 80 or above. Adaptation to a virtual platform for NANO (vNANO) allowed for improved recruitment and follow-up of patients. Validation of vNANO is being performed in a subset of this population. Our interim analysis will be presented at the 2023 EANO meeting.

CONCLUSION

Evaluation of neurologic function by NANO is feasible in both an in-person and virtual framework in a prospective multi-center study in patients with glioblastoma. NANO is able to objectively track neurologic function throughout disease course in glioblastoma. Integration of vNANO may allow for reduced clinical visits and improve access to specialized care for patients in geographically remote locations.
P11.66.A COMBINATION OF TROFOSFAMIDE AND ETOPOSIDE IN RECURRENT GLIOBLASTOMA
Authors: Schmidt T , Agkatsev S , Feldheim J , Oster C , Blau T , Sure U , Keyvani K , Kleinschnitz C , Stuschke M , Herrmann K , Deuschl C , Scheffler B , Kebir S , Glas M , Lazaridis L
Published: September 2023

BACKGROUND

Standard of care treatment options at glioblastoma relapse are still not well defined. Few studies indicate that the combination of trofosfamide plus etoposide may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide plus etoposide treatment at disease recurrence of adult glioblastoma patients.

MATERIAL AND METHODS

We collected clinicopathological data from adult recurrent glioblastoma patients treated with the combination of trofosfamide and etoposide for more than four weeks (one course). A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors served as control.

RESULTS

A total of n=22 recurrent glioblastoma patients were eligible for this analysis. Median progression-free survival (3.1 versus 2.3 months, HR: 1.961, 95% CI: 0.9724-3.9560, p=0.0274) and median overall survival (9.0 versus 5.7 months, HR: 4.687, 95% CI: 2.034-10.800, p=0.0003) were significantly prolonged compared to the control cohort (n=17). In a multivariable Cox regression analysis, treatment with trofosfamide plus etoposide emerged as a significant prognostic marker regarding progression-free and overall survival. We observed high-grade adverse events in n=16/22 (73%) patients with hematotoxicity comprising the majority of adverse events (n=15/16, 94%). Lymphopenia was by far the most commonly observed hematotoxic adverse event (n=11/15, 73%).

CONCLUSION

This study provides first indication that the combination of trofosfamide plus etoposide is safe in adult glioblastoma patients and may be associated with prolonged survival in recurrent glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.
P11.75.B PSEUDOPROGRESSION IN A REAL-WORLD GLIOBLASTOMA COHORT: INCIDENCE, MANAGEMENT, PROGNOSTIC IMPACT, AND ASSOCIATED FACTORS
Authors: Blakstad H , Mendoza Mireles E E , Heggebø L C , Magelssen H , Sprauten M , Johannesen T B , Vik-Mo E , Leske H , Niehusmann P , Skogen K , Helseth E , Emblem K E , Brandal P
Published: September 2023

BACKGROUND

Radiotherapy remains a cornerstone in glioblastoma (GBM) management. A continued and unmet need in neuro-oncology is efficient non-invasive methods to differentiate post-radiation magnetic resonance imaging (MRI) changes from progressive disease (PD) in GBM patients. The clinical challenge is two-sided; avoid termination of effective therapy in case of pseudoprogression (PsP) and continuation of ineffective therapy in case of PD. We retrospectively assessed incidence, management, prognostic impact, and associated factors with PsP in a real-world GBM patient cohort.

MATERIAL AND METHODS

Adult (≥18 years) GBM patients diagnosed in the South-Eastern Health Region of Norway from 2015 to 2018, had received radiotherapy, and follow-up MRIs were included. Patient, tumor, and treatment characteristics were analyzed in relationship to re-evaluated MRI examinations at three and six months post-radiation using response assessment in neuro-oncology criteria.

RESULTS

PsP incidences at three and six months post-radiation were 20% and 8%, respectively. In adjusted analyses, methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter and absence of neurological deterioration were associated with PsP at both three (p<0.001 and p=0.04, respectively) and six months (p=0.003 and p=0.04, respectively) post-radiation. Patients with PsP at MRI three months post-radiation had a median OS of 24.8 months compared to 11.4 months for patients with PD and 18.7 months in patients with stable disease (SD); the difference was significant only when comparing patients with PsP and PD (p<0.001). There was no survival benefit of treatment change for patients retrospectively evaluated as PD three months post-radiation (p=0.8). Median OS for patients in the PsP group was 31.8 months and thus longer than in the PD group (13.1 months) and the SD group (24.1 months). The difference was only significant when comparing patients with PsP and PD (p<0.001).

CONCLUSION

PsP incidence in this retrospective material was similar to previous reports. In addition to the previously described correlation of methylated MGMT promoter with PsP, we also found that the absence of neurological deterioration significantly correlated to PsP. Continuation of temozolomide courses did not compromise survival for patients with PD at three months post-radiation; therefore, we recommend continuing adjuvant temozolomide courses in case of inconclusive MRI findings.

Funding: European Union's Horizon 2020 Programme European Research Council Grant 758657-ImPRESS.
P11.76.A SPECTRUM OF TP53 SOMATIC MUTATIONS IN A PROSPECTIVE STUDY OF PATIENTS WITH GLIOMA
Authors: Cabezas-Camarero S , Pérez-Alfayate R , García-Barberán V , Gandía M , García-Feijóo P , López-Cade I , Sotelo M J , Cerón M , Casado-Fariñas I , Pérez-Segura P
Published: September 2023

BACKGROUND

TP53 mutations occur frequently in gliomas, being most common in IDH-wild-type (WT) glioblastomas (GB) and in IDH-mutant (MUT) oligodendrogliomas (OD). Our aim was to describe the mutation spectrum of TP53 somatic mutations in patients (pts) with glioma.

MATERIAL AND METHODS

This was a prospective multicenter study of patients with glioma diagnosed at four different institutions in Spain. Next-generation sequencing (NGS) of formalin-fixed paraffin-embedded (FFPE) or fresh tumor samples were used for sequencing the TP53 gene in an Illumina Miseq instrument (Illumina, Inc.). Only TP53 pathogenic mutations were considered as valid and are reported here.

RESULTS

Between February 2017 and March 2020, 61 glioma patients (pts) were enrolled among which 17 different pathogenic mutations in TP53 were detected. Mutant allele frequency (MAF) was > 4% in all cases. TP53 pathogenic mutations occurred at the following loci: L145P, R158H, R175H, H193R, G199V, R202C, R213X, H214R, Y234C, R248Q, I255S, E271Vfs*36, R273C, P278T, G278T, G279E, R280K. Additional clinical characteristics and survival results will be presented at the meeting.

CONCLUSION

TP53 occur frequently in glioma but widely distributed across the whole exome. The contribution of each specific pathogenic TP53 mutation in gliomas should be further studied.
P12.08.A CELL-EXTRINSIC D-2-HYDROXYGLUTARATE PROMOTES HYPERMETHYLATION AT LINEAGE-SPECIFIC REGULATORY REGIONS TO PREVENT MICROGLIAL ACTIVATION IN IDH-MUTANT GLIOMAS
Authors: Laurenge A , Pugliese P , Richard Q , Picca A , Jouannet S , Labreche K , Bielle F , Iavarone A , Ceccarelli M , Mallat M , Sanson M , Castro-Vega L
Published: September 2023

BACKGROUND

Tumor-associated macrophages and microglia (TAMs) are highly abundant myeloid cells in diffuse gliomas. Their composition and transcriptional programs differ according to the IDH mutation status of glioma cells. The underlying mechanisms remain until now little known.

MATERIAL AND METHODS

We compared bulk DNA methylome (Methylation EPIC array) and transcriptome of TAMs (CD11b+ purified by magnetic-activated cell sorting) from 25 IDH-mutant and 11 IDH-wildtype gliomas. The contamination of the CD11b+ fraction by tumor cells was determined by the detection of IDH and/or TERT mutations using droplet digital PCR. Only samples with a purity of at least 95% were used for analyses. To determine experimentally direct effects of D-2-hydroxyglutarate (D-2-HG), which is the oncometabolite produced and realeased into the microenvironment by IDH-mutated glioma cells, we used primary cultures of human microglial cells obtained from glioma surgery or epilepsy surgery. We exposed microglia or not to (D-2-HG) during 14 days, and analyzed their DNA methylome and transcriptome.

RESULTS

TAMs from IDH-mutant gliomas compared with TAMs from IDH-wildtype gliomas exhibit decreased expression of pro-inflammatory pathways (mainly IFN-γ, IFN-α, and TNF-α signaling) and genes related to G2-M checkpoint, glycolysis and Epithelial-Mesenchymal Transition (EMT). We uncovered that TAMs from IDH-mutant gliomas exhibit significant hypermethylation at promoters and enhancers linked to decreased expression of genes involved in inflammatory responses. Notably, these hypermethylated regions were enriched for binding motifs of transcription factors controlling an environment-dependent transcriptional network in microglial cells (such as PU.1, AP-1, C/EBP and RUNX). These findings were confirmed by comparing methylome data of TAMs from IDH-mutant gliomas and methylome of microglia from normal brains available in the literature. A 14 days exposition to D-2-HG of human microglial cells in vitro partially recapitulates the observed methylation changes. Transcriptome analyses of these cells show that this oncometabolite dampens the IFN-α/γ pathways and attenuates the response to LPS while inducing a metabolic shift toward oxidative phosphorylation.

CONCLUSION

Our findings establish a link between an extrinsic cell-effect of D-2-HG and the hypermethylation of DNA of microglial cells at regulatory regions in IDH-mutant gliomas. Our observations support the concept that oncometabolites may disrupt directly the function of immune cells of the tumor microenvironment.
P12.10.A VASCULOGENIC MIMICRY OCCURS IN PRIMARY AND RECURRENT GLIOBLASTOMA AND IS NOT ASSOCIATED WITH PSMA EXPRESSION
Authors: Tooney P , Maddison K , Faulkner S , Bowden N , Graves M , Fay M
Published: September 2023

BACKGROUND

Glioblastomas are highly vascular tumours that overexpress vascular endothelial growth factor (VEGF), however the anti-VEGF antibody bevacizumab has not demonstrated significant overall survival benefit for patients. Vasculogenic mimicry (VM), the ability of tumour cells to form functional microvasculature lacking an endothelial lining, may compensate for insufficient or inhibited angiogenesis. VM has been reported in primary glioblastoma tissue, but not investigated at progression in recurrent tumours. Prostate specific membrane antigen (PSMA) is expressed in abnormal vessels within primary glioblastoma tumours. We aimed to determine whether VM occurs in primary and recurrent glioblastoma tumours and whether VM vessels also express PSMA.

MATERIAL AND METHODS

Thirty-five matched pairs of primary and recurrent formalin-fixed paraffin-embedded glioblastoma tissue were immunohistochemically labelled for the endothelial cell marker CD34 and PSMA, and counterstained with periodic acid-Schiff (PAS). Vascular structures were categorised as endothelial vessels (CD34+/PAS+) or VM (CD34-/PAS+). Vessels were counted in ten regions within each tumour and a vessel density/mm2 for each vessel category was determined.

RESULTS

Data are expressed as median values. Endothelial vessels accounted for most blood vessels observed. There was a significant decrease in endothelial vessel density in recurrent (41.34 vessels/mm2) compared to primary (86.98 vessels/mm2) glioblastomas (p <0.001). VM was observed in 15/35 primary tumours (42.86%) and 10/35 recurrent tumours (28.57%). VM accounted for only a small proportion of the overall vasculature and VM density was not different between the primary and recurrent groups (p = 0.266). Kaplan-Meier analyses with log rank tests indicated that VM-tumours had longer median OS time than VM+ tumours, regardless of whether VM status was determined based on the primary or recurrent tumour. However, there was no significant difference in survival distribution between VM+ and VM-tumours (primary χ2(1) = 0.381, p = 0.537; recurrent χ2(1) = 3.552, p = 0.059). PSMA is expressed in endothelia lined vessels based on serial section labelling for PSMA and CD34. PSMA expression significantly decreased in recurrent (median H-score = 0.22) compared to primary (median H-score = 0.44) tumours (one-tailed p = 0.031; n = 32) mirroring the CD34+ vessel density.

CONCLUSION

VM contributes to a relatively small proportion of the overall vasculature in glioblastoma tumours and was not associated with OS nor the expression of PMSA. Since VM- tumours had longer OS than VM+ tumours, assessment of VM in recurrent tumours in a larger cohort may determine if there is a clinical significance for VM in recurrent glioblastoma.
P13.12.A SUBTYPES AND SURVIVAL ANALYSIS ANALYSIS OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA WITH RADIOMICS FEATURES
Authors: BARILLOT N , HERNANDEZ I , KIRASIC E , HOUILLIER C , MOKHTARI K , HOANG-XUAN K , ALENTORN A
Published: September 2023

BACKGROUND

Primary Central Nervous System Lymphoma (PCNSL) is a rare and heterogeneous disease with dismal prognosis. Recently, four molecular clusters with clinical relevance have been identified with different potential therapeutic targets in each group. Nevertheless, multi-omics data collection and analysis are expensive and not adapted for clinical practice. Therefore, the identification of surrogate markers to identify PCNSL subtypes from routine data is required, like using hematoxylin and eosin slides from brain biopsies.

MATERIAL AND METHODS

We used a cohort of 108 patients and we selected the 5000 nuclei for each patient among roughly 1,5M nuclei. Once hematoxylin and eosin slides have been digitized, tessellated, normalized and the nuclei have been segmented and filtered with the computation of a solidity score, the PyRadiomics package provides us with more than 800 features for each nuclei. Firstly, we were interested in survival analysis. In a second time, we also used these features for training classification models. We used a partial least squared Cox model, which is a classic Cox model applied to latent components constructed by using linear combinations of the original variables.

RESULTS

Results for our first cohort are promising (C-index of 0.87, std 0.01), with a significant increase compared to the clinical features model (C-index of 0.68, std 0.03). We are now challenging these results with three other cohorts of brain and systemic lymphoma.

CONCLUSION

This study paves the way for a stratification of the clinical evolution based on the machine learning analysis of digital pathology in PCNSL that could be easily translated to a broad range of diseases or other brain tumors.
P14.03.A DO GLIOMA PATIENTS PRODUCE AUTO-ANTIBODIES FOR GLIOMA-SPECIFIC PHOSPHO-PROTEIN MODIFICATIONS
Authors: Zeneyedpour L , Stingl C , Kros J M , Sillevis Smitt P A E , Luider T M
Published: September 2023

BACKGROUND

Many studies have shown that dysregulation of protein phosphorylation plays an important role in the development of cancer. Aberrantly phosphorylated peptides can be derived from dysregulated cell signaling pathways in various cancers and may serve as tumor-specific antigens and might be promising targets for cancer immunotherapy. Several techniques are available to purify immunoglobulins (IgG) from plasma or other body fluids using affinity to immobilized binders In contrast, Melon Gel resin retains non-IgG proteins and hence allows enrichment of IgG directly from the sample without affinity binding. We have developed a technique for the detection of auto-antibodies in HGG.

MATERIAL AND METHODS

To perform an Ab-peptide binding assay, we used a phospho-peptide library (a mixture of phospho-peptides obtained after phospho-enrichment of enzymatically digested fresh-frozen GBM tissue) and three plasma samples from HGG patients and a healthy donor as source of IgG. After mixing of the plasma samples with the phospho-peptide library the IgG purification was performed using the Melon Gel resin. We separated possible unbound peptides using a 30 kDa-molecular-weight (MW) filter device. The high MW fraction, containing IgGs and IgG-peptide complexes were acidified and precipitated to release Ab-bound peptides. Subsequently, the IgG-bound peptides were measured and identified in a mass spectrometer.

RESULTS

Performing the developed Ab-peptide binding assay using the HGG and healthy plasma samples combined with the GBM phospho-peptide library, we detected EGFR phospho-peptide GSHQIS[+80]LDNPDYQQDFFPK (S1166) in three of four IgG-bound fractions of samples incubated with HGG plasma and not in the corresponding unbound fractions. This result indicates the presence of auto-antibodies against EGFR phospho-peptide S1166 in the plasma of the three HGG patients. A contrasting result was obtained in the donor sample, where the EGFR peptide was detected almost exclusively in the unbound fraction. With the use of Avastin as negative control instead of plasma, the EGFR peptide S1166 was solely found in the unbound fraction.

CONCLUSION

An antibody-peptide-antigen complex enrichment with Melon Gel was successfully applied to find auto-antibodies that recognize disease-related phospho-peptides. This method has the potential to detect the putative presence of auto-antibodies without knowledge of the antigen. We demonstrated in a proof of concept the presence of auto-antibodies against an EGFR phospho-peptide in plasma of HGG patients. This antibody-peptide binding assay could potentially be further applied to other types of cancer to find targets for therapeutic interventions.
P14.11.B A MULTICENTER STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND WITH SYSTEMIC MICROBUBBLE OSCILLATORS FOR BLOOD-BRAIN BARRIER DISRUPTION FOR LIQUID BIOPSY IN GLIOBLASTOMA (LIBERATE)
Authors: Ahluwalia M S , DeGroot J , Lee J , Mogilner A , Schwartz T , Burns T , Shah B , McDermott M , Bettegowda C , Ozair A , Khosla A A , Sahgal A , Mishra M , Achrol A , Lipsman N , Woodworth G
Published: September 2023

BACKGROUND

Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) levels in blood due to the blood-brain barrier (BBB). This results in challenges to the identification of blood-based biomarkers and the development of novel biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with intravenously administered microbubble oscillators non-invasively causes BBB disruption (BBBD). This clinical trial aimed to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM.

METHODS

LIBERATE is a prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating the safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged 18-80 years with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being included. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered intravenous oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using a 220 kHz LIFU device is performed with real-time acoustic feedback for effective cavitation. Before and after the procedure, phlebotomies and MRI brain are performed to evaluate outcomes. The primary study endpoint is defined, per subject, as the ratio between their cfDNA level in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to a ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in cfDNA sample from 1-hour post-LIFU sample and biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N=50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hours, and 3 hours to determine the time of greatest yield, (3) correlation of MRI parameters related to grading of BBBD and biomarkers positive in cfDNA from post-LIFU blood samples.

RESULTS

Patient enrollment commenced in 2022, and 8 patients have been recruited by 04/11/2023.

CONCLUSION

Findings from this trial will be critical to liquid biopsy in GBM (Clinical trial information: NCT05383872).
P14.13.B DECODING GLIOBLASTOMA: SIM4ULATING TUMOUR MICROENVIRONMENT TO DETECT NOVEL BIOMARKERS USING ORGAN-ON-CHIP MODELS
Authors: Bayona C , Randelovic T , Wrona M , Salafranca J , Ochoa I
Published: September 2023

BACKGROUND

Glioblastoma (GBM) is the most common malignant primary brain tumour in adults, with a survival rate of 14 months even after current treatment. There are two major limitations in understanding how the tumour works and what markers could facilitate its diagnosis. On the one hand, the great heterogeneity is responsible for the ineffectiveness of treatments. This underlines the importance of developing more complex models that can simulate different elements of the tumour microenvironment of GBM, including hypoxic gradients that lead to the generation of the characteristic necrotic core. On the other hand, the diagnostic techniques currently used have their inherent limitations and entail serious risks for the patients. Therefore, the development of diagnostic markers that allow real-time monitoring of tumour status without posing a very high risk, could improve diagnosis and treatment of patients with GBM.

METHODS

Our approach consisted on a gas impermeable and pillarless microfluidic device composed of a central chamber, where U-251 MG cells were highly dense seeded in a collagen matrix, and two side channels that provided oxygen and nutrients to the cells. The device was used to generate the necrotic region characteristic of glioblastoma, then, the medium that flowed through the lateral channels in contact with the cells was collected on different days of necrotic core formation and analysed by solid-phase microextraction system coupled with gas chromatography-mass spectrometry. This technique was used to detect the presence of differential volatile organic compounds (VOCs) secreted by tumour cells in different microenvironments.

RESULTS

The microfluidic device enabled the generation of an in vitro glioblastoma tumour microenvironment characterised by a necrotic zone in the centre of the tumour mass after seven days of cell culture. This allowed the study of VOCs in different microenvironment conditions, and showed that devices with a necrotic core exhibited a much more complex VOC footprint. Among the compounds detected were some types of aldehydes, phenols and nitrogen compounds. Clinical validation of the GBM VOC profile is ongoing.

CONCLUSION

Our impermeable and pillarless device has allowed us to simulate elements of the tumour microenvironment that are difficult to reproduce with other models, such as central necrotic zones surrounded by cells with nutrient availability. In addition, it offers a promising advance in the characterisation of the metabolic fingerprint of glioblastoma that bring us closer to real-time monitoring of the disease with less invasive methods than those currently used.
P15.05.B THE IMPACT OF IOMRI ON GLIOBLASTOMA RESECTION AND CLINICAL OUTCOMES IN A STATE-OF-THE-ART NEURO-ONCOLOGICAL SETUP
Authors: Schwendner M , Zhang W , Ille S , Wiestler B , Meyer B , Krieg S M
Published: September 2023

BACKGROUND

Intraoperative magnetic resonance imaging (ioMRI) is applied to improve the extent of resection in patients suffering from primary brain tumors, especially glioblastoma (GBM). While some older randomized trials reported data on safety and feasibility, ioMRI’s actual impact in a modern neurosurgical setting has not been sufficiently investigated. We therefore aimed to evaluate the effect of ioMRI on tumor resection and progression-free survival (PFS) in GBM patients in a modern high-volume center.

MATERIAL AND METHODS

Patients undergoing ioMRI for resection of supratentorial GBM were prospectively included between March 2018 and June 2020. In all cases, ioMRI was performed after complete macroscopic tumor resection. The extent of resection (EOR) was determined by volumetric analysis. Gross total resection (GTR) was defined as EOR ≥95%. Furthermore, progression-free survival (PFS) was analyzed through univariate and multivariate Cox proportional regression analysis.

RESULTS

Overall, 172 patients were enrolled in this study. The mean EOR increased from 93·9% on ioMRI to 98·3% (p<0·0001) on postoperative MRI, with residual tumor volume decreasing from 1·3 ± 4·2 cm3 to 0·6 ± 2·5 cm3(p=0·0037). The GTR rate increased from 78·5% to 93·0% (p=0·0002). Logistic regression revealed recurrent GBM (odds ratio [OR] =3·047, 95% confidence interval [CI] 1·165-7·974, p=0·023) and tumor volume less than 15 cm3 (OR=3·031, 95% CI 1·062-8·651, p=0·038) as independent risk factors leading to STR. Tumor resection performed additionally after ioMRI lead to equally long PFS compared to patients with complete tumor removal achieved before ioMRI (HR=0·898, 95%CI 0·543-1·483, p=0·67).

CONCLUSION

ioMRI serves as a valuable tool in a modern neurosurgical setting, severely decreasing residual tumor volume. ioMRI considerably helps to achieve comparable PFS even in cases, where an unexpected tumor residual is found on ioMRI after initial resection.
P15.15.B DIFFUSE ADULT-TYPE GLIOMA INFILTRATION DEFINED ON FET-PET
Authors: Harat M , Miechowicz I , Rakowska J , Zarębska I , Małkowski B
Published: September 2023

BACKGROUND

O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET is a valuable tool in glioma imaging used to the definition of biopsy site, monitoring of treatment response and differentiation of treatment-related changes from glioma progression The physiological uptake within reactive astrogliosis may limits FET-PET ability to precisely define glioma extent. For the implementation of FET-PET into clinical trials, a methodological PET standardization is urgently needed to enable more precise and reproducible FET PET quantification. The primary aim of our study was to define a glioma infiltration using threshold based method between astrogliosis and tumoral tissue in FET-PET.

RESULTS

Astrogliosis presented similar uptake to grade 2 glioma samples. Standard threshold method (1,6x uptake in contralateral brain) in PET aquisiton 40-60 minutes post injection is effective but the accuracy decrease outside contrast enhancement within FLAIR to 56% sensitivity and 41% specificity. Adding second aquisition increased sensitivity within FLAIR to 71%. Finally, using tumor-to-plexus ratio, it is possible to differentiate astrogliosis and grade 2, and achieve sensitivity of 73% and specificty of 84% within FLAIR or 90% sensitivity with 61% specificity. ROC curves are significantly different related to method used with best results specific to new strategy.

CONCLUSION

Determining glioma extent using standard threshold method in PET or FLAIR is limited. Improving is possible with dual aquisition and/or different tumor to background ratio. This may largely improve delineation of glioma for surgery or radiotherapy.
P15.17.B DYNAMIC FDG PET AS A PREDICTOR OF SURVIVAL IN PATIENTS WITH GLIOMAS
Authors: Moosa S , Ramanathan P , Qureshi Z , Kundu B , Quigg M
Published: September 2023

BACKGROUND

The neuroimaging characteristics of treatment-related necrosis (TRN) induced by chemotherapy and radiotherapy mimic those of tumor progression (TPR). This can make it challenging for clinicians to deliver prognoses for patients with gliomas and subsequently optimize their treatment regimens. In this study, we evaluate the utility of dynamic FDG (dFDG) PET, which provides information about dynamic metabolic changes, for predicting survival in patients who have undergone treatment for gliomas.

MATERIAL AND METHODS

Clinical and radiographic information were obtained for 21 adult patients with known or suspected recurrent gliomas and had radiographic worsening reported on MRI within 6 months of completion of radiation and chemotherapy. All patients underwent dFDG PET imaging, and the prognostic significance of rate constants from the suspected tumor region were analyzed using Cox regressions.

RESULTS

Based on dFDG PET imaging, higher values of the k3 rate constant predicted a hazard ratio of 6.7 of death within 12 months of diagnosis. Hazard ratios of the k1 and k2 parameters were not significant in prediction of 12-month survival.

CONCLUSION

The k3 kinetic parameter of dFDG PET imaging, a marker for glucose uptake and metabolism, is predictive of 12-month survival in glioma patients who have questionable tumor progression. Clinicians can use this information to estimate the likelihood of TPR versus TRN in patients with gliomas and subsequently tailor their treatment plans based upon expected survival.
P16.05.B SAFETY AND EFFICACY OF INTRA-CSF BIOLOGIC AGENTS IN TREATMENT OF NEOPLASTIC MENINGITIS
Authors: Trifoi M , Appiah A , Sichinga K , Aregawi D , Glantz M
Published: September 2023

BACKGROUND

Neoplastic meningitis (NM) is an increasingly frequent, profoundly morbid, and almost invariably fatal complication of solid and hematologic malignancies. Despite multimodal therapy, median survival in randomized trials is approximately 4 months. Biologic agents are widely utilized in management of extra-CSF disease, but often have limited ability to penetrate the CSF. Intra-CSF administration of biologic agents has not been widely investigated. We describe the safety and efficacy of tumor-specific, intra-CSF biologic therapy in a large group of patients with neoplastic meningitis.

MATERIAL AND METHODS

We queried the database of a large, international neoplastic meningitis registry (NeMeRe) to identify patients with neoplastic meningitis who received at least one dose of neoplastic meningitis-directed therapy with a biologic agent. Detailed patient demographic, treatment, toxicity and outcome data was extracted and analyzed for the first 140 consecutive patients treated at our institution.

RESULTS

These 140 patients received an intrathecal biologic agent as part of a histology- and molecular profile-directed intraventricular chemotherapy treatment approach. Agents included rituximab (58 patients with lymphoma, 224 cycles), trastuzumab (42 patients with malignant primary brain tumors, 211 cycles; 15 patients with breast cancer, 149 cycles; 1 patient with esophageal cancer, 9 cycles), panitumumab (4 patients with lung cancer, 9 cycles), nivolumab (1 patient with melanoma, 5 cycles; 2 patients with breast cancer, 2 cycles; 2 patients with GBM 12 cycles; 2 patients with lung cancer, 4 cycles; 2 patients with gastric adenocarcinoma, 17 cycles; 2 patients with renal clear cell carcinoma, 17 cycles; 1 patient with AML, 2 cycles; 1 patient with multiple myeloma, 8 cycles) and alpha-interferon (10 patients with melanoma, 31 cycles; 2 patients with renal clear cell carcinoma, 18 cycles). Grade I/II toxicity occurred in 5.8% of rituximab, 3.2% of trastuzumab, 0% of panitumumab, 16.3% of nivolumab, and 3.2% of alpha-interferon containing cycles. There was no grade III toxicity. Median survivals in patients with lymphomatous meningitis (304 days), solid tumor NM from primary brain tumors (243 days), HER2 -positive breast cancer (not reached, >315 days), lung cancer (192 days), and melanoma (307 days) were encouraging. No difference in survival was seen between patients with and without treatment-related toxicity in any histologic group.

CONCLUSION

This large registry-based cohort study suggests that rituximab, trastuzumab, panitumumab, nivolumab, and alpha interferon may be safely administered into the CSF as part of a multi-agent intra-CSF treatment regimen. Survival, while very tentative, is encouraging. A prospective, multi-center evaluation of these agents in patients with neoplastic meningitis is warranted.
P16.07.B PROSPECTIVE DOUBLE ARM PHASE 2 RANDOMIZED TRIAL FOR PATIENTS WITH MULTIPLE BRAIN METASTASIS AND/OR LEPTOMENINGEAL CARCINOMATOSIS: COMPARISON OF WHOLE BRAIN RADIATION THERAPY (WBRT) ALONE AND WBRT PLUS SILIBININ
Authors: Clerici E , Navarria P , Bellu L , Marini B , Lobefalo F , Scorsetti M
Published: September 2023

BACKGROUND

Occurrence of brain metastases (BMs) is increasing given availability of Magnetic Resonance Imaging (MRI) able to detect also small brain lesions, and most effective systemic therapy able to better control extra-cranial disease. Estimated 20% of patients with cancer will develop BMs. In case of limited brain metastases, radiosurgery or hypofractionated radiosurgery is treatment of choice. A subgroup of patients characterized by extensive brain disease and/or leptomeningeal carcinomatosis can require whole brain radiotherapy (WBRT). Since the 1950s, WBRT has been the most treatment used for patients with multiple BMs, given its effectiveness in palliation, widespread availability, and ease to deliver. However, the median overall survival (OS) recorded is restricted to 3 months, on the average. A better understanding of molecular and cellular mechanisms underlying brain metastasis might be expected to lead of improvements in overall survival. Recent studies demonstrated that active signal transducer and activator of transcription 3 (STAT3) in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis, even at advanced stages of colonization. Silibinin is a natural polyphenolic flavonoid isolated from seed extracts of herb milk thistle. It has been shown to impair STAT3 activation, and in preclinical studies, show an anticancer effects in vitro and in vivo. Based on this background, we designed a double arm phase 2 randomized trial evaluating the benefit of Silibinin associated to WBRT respect to WBRT alone. Primary endpoint is OS, secondary endpoints are toxicity in term of corticosteroid therapy use, brain failure (BF) and progression free survival (PFS).

MATERIAL AND METHODS

Forty-four patients will be enrolled in two years. Patients with histological or cytological confirmation of solid tumor malignancy, clinical indication for WBRT and Karnofsky performance status (KPS) ≥60 will be enrolled. In arm A experimental, WBRT is concomitant to Silibinin, in arm B control, WBRT alone will be administered. In both arms, total dose of radiotherapy is 30 Gy in 10 fractions. Quality of life and use of corticosteroids will be evaluated first, last day of RT, and during follow-up. Outcome will be evaluated by MRI or CT at 2 months after RT, and every 3 months thereafter.

RESULTS

From March 2023, 6 patients were enrolled, 2 patients in Arm A and 4 in arm B. Primary histology was breast cancer in 3 patients and non small cell lung cancer in 3. In arm A, 1 patients dismissed RT for worsening of general conditions related to rapid lung progression.

CONCLUSION

WBRT with or without Silibinin was well tolerated, no acute toxicities or increase of corticosteroids were observed.
P17.12.B FEASIBILITY OF PROLYL OLIGOPEPTIDASE (PREP) AS TUMOR BIOMARKER IN GLIOBLASTOMA PATIENTS: A PILOT STUDY
Authors: Casili G , Caffo M , Scuderi S , Basilotta R , Lanza M , Filippone A , Paterniti I , Campolo M , Cuzzocrea S , Esposito E
Published: September 2023

BACKGROUND

Prolyl oligopeptidase (PREP) is a serine protease that hydrolyzes biologically active oligopeptides on their carboxyl side. PREP has been connected with multiple physiological and pathological conditions. Moreover, increased PREP activities have been found in tumors, although its involvement in the modulation of cancer mechanism is still unclear. Thus, the identification of PREP and clarification of its clinical significance are important for improving the diagnosis and treatment of brain tumors. The purpose of this study was to analyze the expression of PREP and its diagnostic and prognostic value in patients with Glioblastoma (GBM). Materials and

METHODS

In this study, GBM patients and controls were enrolled and clinical data and PREP expression, from serum and biopsies, were collected. The relationships between PREP, Protein phosphatase 2A (PP2A), STAT3 and Transforming growth factor-β (TGF- β) were also analyzed from clinical data.

RESULTS

Our study found that PREP was significantly upregulated in the serum samples and in biopsy from GBM patients compared with controls. This upregulation was negatively correlated with survival, but significantly correlated with age and Mindbomb Homolog-1 Index (MIB1). Also, PREP expression was inversely correlated with tumor suppressor PP2A in biopsy from GBM patients, while PREP protein levels resulted to be positively correlated with STAT3 and TGF-β protein expression.

CONCLUSION

s: The detection of PREP in serum and biopsies have the potential to serve as diagnostic and prognostic biomarker in GBM patient. The findings may provide diagnostic and therapeutic target for GBM.
P17.16.B INVESTIGATION OF REGORAFENIB TUMOR SENSITIVITY AND UNDERLYING TREATMENT INDUCED MOLECULAR MECHANISMS IN GLIOBLASTOMA RECURRENT TUMORS
Authors: Morelli M , Lessi F , Giacomarra M , Marranci A , Menicagli M , Santonocito O S , Aretini P , Pasqualetti F , Di Stefano A L , Franceschi S , Mazzanti C M
Published: September 2023

BACKGROUND

Glioblastoma (GB) is the most aggressive brain malignant tumor with a highly unfavorable prognosis. Maximal surgery resection, temozolomide chemotherapy (TMZ), and radiotherapy (RT), currently remain the best treatment option. Recently the phase II REGOMA clinical trial, has shown that regorafenib (REGO), a multikinase inhibitor that targets angiogenic, stromal and oncogenic tyrosine kinase receptors, significantly improves survival in GB patients.The aim of this study was to investigate Regorafenib tumor sensitivity and underlying molecular mechanisms in GB recurrent tumors leveraging on an ex vivo drug response functional precision medicine approach, that we have developed recently consisting of an in vitro vital patient-derived GB 3D organoid model and NAD(P)H Fluorescence Lifetime Imaging (FLIM).

MATERIAL AND METHODS

In-vitro 3D GB organoids were derived from 17 patients’ resected recurrent GB tumors. For 5 of these we had the matched primary tumor, and for other 3 we collected also the tumor peripheral portion. Totally, we obtained 25 samples. After 3 days from culture, organoids were treated with TMZ and REGO and drug response, using NAD(P)H FLIM, was assessed in the following 72 hours to stratify tumors in Sensitive (S) and Non Sensitive (NS). Whole-exome was performed on 14 tissue samples, comprising 5 primary/recurrence tumor pairs and whole-transcriptome on 11 recurrent samples before and after treatment.

RESULTS

Stratification of tumor cases in S and NS groups was performed both for TMZ and REGO treatment. We found 32% (n=8) and 76% (n= 19) of TMZ and REGO S tumors, respectively. Interestingly there was never a TMZ S case that was NS to REGO. Heterogeneity was found in the TMZ and REGO responsiveness for the tumor core/peripheral pair portions and in the primary/recurrence tumors pairs. It is noteworthy that all primary tumors were responsive to REGO.The drug-responsive stratification performed using our approach was also well reflected at the molecular level, as shown from transcriptome and exome

RESULTS

, where differently expressed genes and mutated genes were found in S versus NS tumors.

CONCLUSION

GB recurrent tumors resulted more responsive to REGO when compared to TMZ treatment, as expected. Thanks to our functional precision medicine approach, we were able to study the molecular alterations occurring due to the treatment, discovering biomarkers of sensitivity or resistance.
P17.18.B RADIOTHERAPY IN GLIOBLASTOMA MULTIFORME COULD BE PLANNED WITH MARGINS LESS THAN 2 CM WITH LESS THAN 1 CM FROM THE SURGICAL BED
Authors: Oñoro Guzman. l H
Published: September 2023

BACKGROUND

The administration of radiotherapy (Rt) plus adjuvant temozolamide (TMZ) with IMR and VMAT techniques has become an increasingly valuable tool in the local control of glioblastoma multiforme with a survival current Rt techniques allow specific conformation with the use of better radiological images that allow us greater precision. For many years large Rt field sizes have been associated with significant adverse effects.Although we continue to give very wide margins that lead us to irradiate non-compromised organs at risk, which translates into a higher rate of radionecrosis and acute and chronic neurological toxicity.Therefore, we consider it valid to ask ourselves if we could reduce the standard margins applied in the planning of Rt.

MATERIAL AND METHODS

Analysis of 98 GBM patients treatedat the barros luco hospital between 2021 and 2023 with surgery followed by adjuvant therapy, radiotherapy plus concomitant chemotherapy at the Institute. Nacional de Cáncer de Santiago de Chile we reviewed the time of recurrence and the location in relation to the surgical margins vs. radiotherapy margins or other nearby areas.

RESULTS

After the analysis, we can see that 65% of the recurrences presented a dominant failure pattern, within the field and less than 1cm from the margin between the surgical bed and the radiotherapy margin, evaluated with perfusion brain resonance imaging and spectroscopy

CONCLUSION

n the local control of GBM, the application of adjuvant therapy is essential in a period of not less than 2 months after surgery, in this institutional analysis we can observe a considerable number of patients under 40 years of age with this pathology, for which reason to consider reducing the diameter of Rt margins can be considered an option, in order to limit deleterious effects in healthy organs in the times that there are advanced Rt techniques, the increasingly frequent application of brain radiosurgery (SRS) thatIt can be used as a rescue method in case of recurrences at the edge of the margin, using radiological images (MRI with perfusion and spectroscopy/C-methionine PET/CT. Figure we can see the CTV and PTV to be treated with modulated intensity technique, evidencing the large field size that receives radiation between 54 to 60 Gy.Radiation oncology must continue to develop and improve the delivery, targeting, and dose of radiation therapy in the GBM to improve its survival and treatment-associated toxicity.
P18.05.A THE GROWTH PATTERN OF MENINGIOMA CELLS IN CELL CULTURE UNDER DIFFERENT CONDITIONS
Authors: Linsler S , Moroldo A , Oertel J , Urbschat S
Published: September 2023

BACKGROUND

Cell cultures is an established method in tumor research. Thereby, the growth rate is important for the results. Depending on the experimental and clinical setting, the used tissue is exposed to different conditions. Interestingely, the different cell and tissue conditions are not well reported yet. Although, it is likely that the different conditions influence the growth pattern of cell cultures in primary cell lines. Here, the authors present their experimental analysis of cell culture of primary meningioma cells after different initial tissue conditions.

MATERIAL AND METHODS

From June to December 2022 ten primary human meningiomas were collected after surgery at the Neurosurgical Department of the Saarland University. Primary cell cultures (Passage 0 = P0) were set up on the day of surgery and one day postoperatively. These tissues were kept overnight in nutrient solution in the refrigerator. They were splitted in two P1 cultures (Passage 1). The termination of the cell culture occured when the flasks were fully grown. One P1 culture was used for Fluorescence in situ hybridization. The other one was frozen on liquid nitrogen. The latter is thawed after six months and cultivated again. Additionally, swab preparations were made for Fluorescence in situ hybridization. The frozen tissue of these meningiomas was also used for further cell cultures.

RESULTS

Eight of ten cases (80%) of the meningioma cell cultures (from the day of surgery and one day postoperatively) have grown. In one case only the cell culture from the day of surgery has grown and in another one there were only single cells, no growth out of this tissue. The cell cultures prepared from frozen tissues have not shown any culture growth. There were not any significant differences between the growth of the cell culture from the day of surgery and of the cell culture from one day after surgery. The results of the Fluorescence in situ hybridization have shown a loss of 1p in one meningioma, a loss of 22q in three meningiomas, a loss of 1p and 22q in three meningiomas and a normal chromosome set in three tumours. Further, there were not any differences between the evaluation of swab preparations and drop preparations. Until now, six out of six thawed cell cultures of the first three meningiomas can be cultured again after six months in liquid nitrogen.

CONCLUSION

It has been shown that the growth pattern of meningioma cell cultures is independent of the set up at the same day or one day after surgery if there are enough living cells in the tissue. On the other hand, meningioma cell culturing of frozen tissues is not possible in the same setting.