bluuebunny/crossref_metadata_2025_split huggingface dataset:
P04.10.A ASSESSMENT OF VDR STATUS BY IMMUNOHISTOCHEMISTRY IN CHILDHOOD MALIGNANCIES - VDR EXPRESSION PATTERN OF CNS TUMORS
Authors: Juhász O 
Published: September 2023

Abstract

BACKGROUND
Childhood cancers, including CNS tumors, the second most prevalent entities after hematological malignancies cannot generally be prevented or identified through screening, the disease is often diagnosed at advanced stages, and this obviously affects patient outcomes negatively. There is an urgent need for identifying prognostic and therapeutic biomarkers. Our previous work has shown a correlation between lower vitamin D levels in children with cancer and adverse prognosis. VDR expression in childhood solid tumors has been linked to tumor characteristics and patient survival only in few studies, moreover literature found that VDR plays a role in the development of the central nervous system.

METHODS
For this study, 177 children with solid tumors were selected whose biopsies and tumor tissue formalin-fixed, paraffin-embedded tissue blocks were available for immunohistochemical (IHC) analysis at Semmelweis University, Budapest (Hungary). To investigate the association between the presence of VDR in the tumor tissue and outcome, tumor samples and the survival dataset of 110 children were available.

RESULTS
We found that minor VDR expression was associated with a significantly less favorable prognosis (p = 0.0061) in the examined childhood solid tumors. The rate of VDR expression differed significantly between tumor types (p &lt;0.0001). In case of CNS tumors pathological observations on VDR expression characteristics partly not correlated with previous literature. In some ependymoma samples an utterly novel VDR pattern was observed.

CONCLUSION
In conclusion, VDR expression measured by IHC staining is inversely associated with aggressive characteristics in different childhood cancers. The downregulation of VDR expression in more aggressive childhood cancers suggests that functional vitamin D activity may slow or block cancer progression. The presence of VDR may have prognostic and therapeutic implications for CNS malignancies. Knowledge of the VDR status in childhood solid tumors provides clinicians with a valuable biomarker and based on this, additional therapy (vitamin D, and analogs) to use alongside conventional first-line oncotherapy.
P05.01.B PROGNOSTIC MARKERS OF DNA METHYLATION AND NGS SEQUENCING IN PROGRESSIVE GLIOBLASTOMA FROM THE EORTC-26101 TRIAL
Authors: Kessler T , Schrimpf D , Doerner L , Hai L , Kaulen L , Ito J , van den Bent M , Taphoorn M , Brandes A A , Idbaih A , Domont J , Clement P M , Campone M , Bendszus M , von Deimling A , Sahm F , Platten M , Wick W , Wick A 
Published: September 2023

Abstract

BACKGROUND
The EORTC-26101 study was a randomized phase 2 and 3 clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. Other than for progression-free survival (PFS), there was no benefit from addition of bevacizumab for overall survival (OS). However, molecular data allows for the rare opportunity to assess prognostic biomarkers from primary surgery for their impact in progressive glioblastoma.

MATERIAL AND METHODS
We analyzed DNA methylation array data and panel sequencing from 170 genes of 380 tumor samples of the EORTC-26101 study. These patients were comparable to the overall study cohort in regards of baseline characteristics, study treatment and survival.

RESULTS
295/380 (78%) of patients’ samples were classified into one of the main glioblastoma groups receptor tyrosine kinase (RTK)1, RTK2 and mesenchymal. There were 10 patients (2.6%) with isocitrate dehydrogenase (IDH) mutant tumors in the biomarker cohort. Patients with RTK1 and RTK2 classified tumors had lower median OS compared to mesenchymal (7.6 vs. 9.2 vs. 10.5 months). O6-methylguanine DNA-methyltransferase (MGMT) promotor methylation was prognostic for PFS and OS. Neurofibromin (NF)1 mutations were predictive of response to bevacizumab treatment.

CONCLUSION
Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.
P05.03.B METHYLOME PROFILING OF GLIOBLASTOMAS WITH FGFR3/TACC3 FUSION
Authors: Picca A , Gareau T , Mohand Oumoussa B , Carpentier C , Dridi-Aloulou A , Di Stefano A , Mokhtari K , Bielle F , Sanson M 
Published: September 2023

Abstract

BACKGROUND
Glioblastomas (GBMs) with the FGFR3-TACC3 (F3T3) gene fusion have histological, molecular, metabolic, and clinicoradiological characteristics. They have a better prognosis compared to other GBMs. Recent findings suggest that methylome profiling could further stratify these patients identifying a subgroup (defined as “outlier” F3T3+ GBMs, or GBM-F3T3-O) with a methylation profile resembling gangliogliomas (GGs), low-grade histological appearance, and a better outcome.

MATERIAL AND METHODS
We performed DNA methylation profiling (Infinium MethylationEPIC Array v1.0) of 32 adult diffuse gliomas with FGFR3 gene fusions (30 FGFR3-TACC3, one FGFR3-ACLY, and one FGFR3-MYO18A), plus two paired samples of a diffuse glioma with two distinct contingents (one with positive FGFR3 staining and FGFR3-TACC3 gene fusion, the other with intense EGFR staining and EGFR gene amplification). All cases corresponded to “glioblastoma, IDH-wildtype” according to the WHO CNS5. Methylation data were submitted to the DFKZ brain tumor classifier (molecularneuropathology.org), versions 11b4 and 12.5 and to dimensionality reduction with t-distributed stochastic neighbor embedding (tSNE). Copy-number variation (CNV) estimation based on conumee package was obtained from DFKZ website.

RESULTS
With the brain tumor classifier v11b4, most cases (26/34, 76%) were classified as methylation class (MC) GBM (17/26 with a significant score ≥0.9). Out of them, 23/26 (88%) were significantly (score ≥0.5) classified in the “GBM, mesenchymal” (16/26, 62%) or in the “GBM, RTK II” methylation families (7/26, 27%). With the classifier v12.5, again most tumors were classified as “GBM, mesenchymal” (18/34, 53%) or “GBM, RTK II” (9/34, 26%), of which twelve (12/34, 35%) with a score ≥0.9. Two were classifed as GG (score 0.69 and 0.39), both having “GBM, mesenchymal” as a second hit (score 0.19 and 0.33, respectively). Five had GG as a second hit, although with low scores (range &lt;0.01-0.25). After tSNE dimensionality reduction of our and literature cases, most tumors clustered together with other GBM, mesenchymal and GBM, RTK II cases. Only two cases fell within a distinct cluster corresponding to GBM-F3T3-O tumors from the literature. These included two histologically defined GBMs with a survival of 26 and 100 months. Recurrent inferred CNV included chromosome (chr) 7 gain (96%) and chr10 loss (85%), followed by chr20 gain (46%), chr22q loss (46%), and chr19 gain (33%). The presence of chr19 gain (alone or associated with chr20 gain) was associated with increased survival (p=0.01).

CONCLUSION
Glioblastomas with FGFR3 fusions (mostly F3T3) have an epigenomic profile close to other mesenchymal and RTK II GBMs. Methylation analysis identifies methylation (GBM-F3T3-O) and CNV (chr19 gain) profiles associated with better survival.
P06.04.B NEW APPROACHES FOR EXPANDING GLIOBLASTOMA INFILTRATING LYMPHOCYTES
Authors: Khasraw M , Hotchkiss K , Blandford E , Mohan A , Railton C , Brown M , Noldner P , Zhou Y , Parrott R , Fecci P , Antonia S , Patel A , Shaz B 
Published: September 2023

Abstract

BACKGROUND
Adoptive cell therapy using tumor infiltrating lymphocytes (TILs) has shown promise in melanoma and Non-Small Cell Lung Cancer. TILs culture and expansion from GBM remains challenging due to paucity of infiltrated T-cells that are also exhausted. This hinders creation of potent TILs. We have developed a new efficient method to manufacture potent TILs from GBM samples.

METHODS
We have developed efficient TILs manufacturing methods using both solid and aspirated liquid samples collected during vacuum assisted excision containing tumor fragments that may stem predominantly from the tumor margins and provide a source for TILs. We followed the traditional two steps: initial expansion (preREP) where T-cells are expanded with tumor cells to selectively expand tumor antigen-reactive TILs, followed by a large-scale expansion (REP) after further activation. For both steps we optimized media and reagents.

RESULTS
TILs cultures from solid tumors were established from enzymatically digested tissue and by fragment plating. Successful TILs yield from liquid samples required enzymatic digestion, debris removal and RBC lysis prior to culture initiation. PreREP TILs yields ranged from a few million to 2 billion viable cells for solid and liquid samples. REP of TILs from liquid samples expanded similarly from solid samples. REP of TILs reached up to 556-fold expansion (mean: 346, range: 95-556) providing promising numbers of activated TILs. The potency of the TILs was demonstrated with tumor specific Interferon-gamma production when cultured with matched tumor digest or neurospheres.

CONCLUSIONS
We successfully expanded TILs that are rich in cytotoxic T-cells, demonstrated their tumor reactivity and further expanded the preREP TILs to reach therapeutic doses. We have characterized the TILs by scRNA and TCRseq and analyze paired TCR reads using scRNA sequencing. Overrepresented TCR alpha and beta chains will be linked by a P2A site and will be cloned into a lentiviral vector to establish a TCR library which will be transduced into novel Jurkat Triple Parameter Reporter Cell Lines under the control of different T cell activation programs. TCR Jurkat Libraries will be cocultured with original tumor material and sorted to identify tumor reactive TCRs; enabling us to define the percentage of TCRs that are enriched by TIL isolation that are specifically reactive to tumor vs bystander expanded TCR cells. Ultimately, we aim to bring this therapy to patients in a clinical trial.
P06.15.B IMMUNOTHERAPEUTIC TARGETING OF FIBROBLAST ACTIVATION PROTEIN (FAP) IN TREATMENT REFRACTORY GLIOBLASTOMA USING NOVEL CAR-T CELL THERAPY
Authors: Tatari N , Mohamed Seid Hedad H , Zingg A , Bartoszek E M , Tschan V , Schenker T , Ritz M , Miletic P , Venugopal C , Etter M , Singh S K , Läubli H , Hutter G 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is the most common malignant primary adult brain tumor, characterized by extensive cellular and genetic heterogeneity. The Standard of Care (SOC) therapy and clinical trials have not been successful in improving patients’ survival which underscores an urgent need for developing new effective therapies for this treatment refractory disease.

MATERIAL AND METHODS
In silico and in vitro analysis have revealed high level of Fibroblast Activation Protein (FAP) expression in GBM tissue in multiple cell populations including endothelial cells, fibroblasts, stromal cells and tumor cells, but not on normal brain tissue, making FAP a safe and suitable therapeutic target as it allows for destruction of tumor cells as well as effective elimination of their supporting microenvironment. As Chimeric antigen receptor (CAR) expressing T cells have shown promising results against multiple cancers in the past few years, we aimed to target FAP in GBM by FAP specific CAR-T cells generated using a novel GMP-ready FAP-CAR construct produced based on a virus-free CAR gene transfer using advanced sleeping beauty transposon technology and preclinically test their anti-tumor efficacy against GBM at in vitro and in vivo level.

RESULTS
Our data revealed that co-culturing CAR-T cells with FAP+ GBM cells (U87) results in increased surface expression of T-cell activation markers. Moreover, FAP CAR-T mediated cytotoxicity against FAP+ GBM cells was also observed in the co-culture of GBM and CAR-T cells. For further validation, the effect of FAP CAR-T cells will be tested on patient-derived GBM organoids. The in vivo efficacy of FAP CAR-T cells is currently under investigation and we anticipate that the treatment of GBM tumor-bearing mice with FAP CAR-Ts results in extended survival and reductions of tumor burden.

CONCLUSION
These rigorously obtained data show high level of efficacy for FAP-specific CAR-T cells against GBM suggesting that clinical development of this therapeutic modality can provide a novel therapeutic strategy for GBM patients that can be used in combination with SOC or other immunotherapeutics. Therefore, upon successful completion of the preclinical study, we plan to conduct a phase I dose-escalation trial of autologous FAP-CAR T cells for patients with recurrent Glioblastoma.
P07.02.B A FATTY-ACID BASED PROBE FOR NEAR INFRARED FLUORESCENCE GUIDED SURGERY OF GLIOBLASTOMA
Authors: Ali M , Khodakivskyi P , Goun E , Lamfers M L M , Lowik C W G M , Dirven C M F , Balvers R K , Mezzanotte L 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is the most aggressive primary tumor of the brain with a median survival of 15 months. Maximal safe resection is the initial standard-of-care, but resection is limited by the diffuse invasiveness of the tumor. Fluorescence imaging has been shown to aid intra-operative tumor identification, but the current options fail to do so consistently. Recent literature has shown fatty acid (FA) metabolism and uptake to be altered in glioblastoma. For this reason, we introduce a novel, near-infrared fluorescent dye, fatty-acid indocyanine green (FA-ICG), that aims to target the enhanced fatty acid uptake of glioblastoma. We evaluate this dye in in vitro and in vivo models.

MATERIAL AND METHODS
FA-ICG consists of palmitic acid, a long-chain, saturated fatty acid, that has been covalently linked to indocyanine green (ICG), as described previously. We validated FA-ICG in vitro in one animal cell line and four (two primary and two recurrent) patient-derived neurosphere glioblastoma cell lines. We performed in vitro temporal uptake dynamics and oleic acid based inhibition assays for FA-ICG and ICG on all cell lines. Time uptake was investigated by starving and then incubating cells with either dye for an increasing length of time. Similarly, inhibition was tested by incubating cells with increasing concentrations of oleic acid (in addition to either FA-ICG or ICG). Subsequently, the dye was tested in an NRMI mouse model without tumor for pharmacokinetic properties. Mice were injected with the dye and blood was collected at multiple time points post-injection. Quantification of fluorescence signals in serum was performed using a fluorescent standard curve.

RESULTS
FA-ICG was taken up by all glioblastoma cells lines. Across all cell cultures, uptake of FA-ICG showed a stepwise increase of up to 5-30 times higher uptake (compared to uptake at baseline) when cells were starved longer, while ICG uptake showed the same trend in only three out of five cell lines (and only up to 5 times higher uptake than at baseline). Oleic acid was found to inhibit FA-ICG uptake by 40% at low concentrations and up to 80-90% at higher concentrations across all cell lines, while ICG was unaffected. In vivo pharmacokinetics showed FA-ICG to have a mean half-life of 65 minutes in blood.

CONCLUSION
Our findings indicate that the uptake of FA-ICG is affected by starvation and oleic acid competition across all cell lines while ICG uptake is only partially affected by starvation. In vivo pharmacokinetic shows the half-life of FA-ICG to be significantly longer than that of ICG in literature. Taken together, these findings might point to an enhanced targeting and retention mechanism of FA-ICG in glioblastoma. Therefore, these results support the further translation of FA-ICG for fluorescence guided surgery in GBM.
P08.01.A FAMILY SUPPORT NEEDS IN GLIOBLASTOMA - FROM RELATIVES’ PERSPECTIVES
Authors: Ståhl P , Henoch I , Smits A , Rydenhag B , Ozanne A 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma is the most common and aggressive brain tumour in adults. In spite of standard treatment by surgery followed by radiation and chemotherapy, the average life expectancy is only 10-15 months. As such, glioblastoma affects the family situation and relatives around the patient need support. There is a lack of knowledge about their experiences of support during the illness. The aim of this study was to investigate support needs during the illness trajectory in glioblastoma from the relatives’ perspectives.

MATERIAL AND METHODS
In this study, 12 relatives (7 partners, 3 children, 1 sister, 1 friend) to patients with a histologically-confirmed diagnosis of IDH-wt glioblastoma since at least 2 months and age ≥ 18 years at the time of diagnosis, were interviewed individually based on a semi-structured interview guide. Interviews took place on one occasion by physical or digital meeting or via telephone, based on the participant's preferences. The interviews were audio recorded and transcribed verbatim. Data collection occurred from March 2022 until December 2022. The analysis using inductive qualitative content analysis is in progress.

RESULTS
Preliminary results show that relatives were mostly satisfied with the support from the health care. However, they lived in a very stressful situation and parts of the support could be better organized. It was important for them with clear and correct information regardless of the outcome. The waiting time before and after MRI, living in limbo with anxiety of what would be found, was particularly stressful and they desired processing with faster answers. Availability to the health care was an important factor and because of the difficult situation they preferred digital meetings instead of physical meetings. Further, they found it difficult to manage the contacts with different health care instances and thought it would be helpful with support to navigate them to correct instance.

CONCLUSION
The preliminary results indicate that support to the families should be more structured och focused on clearness, high availability and openness for the family’s needs, and guidance in the health care system.
P08.07.B TRANSITION CLINIC IN NEURO-ONCOLOGY WHICH MODEL IS BETTER? THE PATIENT'S OPINION
Authors: Azuelos A , Haisraely O , Atar N , Jan E , Taliansky A 
Published: September 2023

Abstract

BACKGROUND
The period between adolescence and adulthood is important and complicated for all people. Is much more complicated for young adults (YA) that were diagnosed and treated for central nervous system (CNS) tumors in childhood and adolescence. They have to continue a lifelong multidisciplinary surveillance that is time and energy consuming. Patients that does not have any or significant neurological deficit desire to start a ”normal” to age life that includes independence from the parents and reduction of hours spent in the hospital. They try to undergo surveillance in community health services but that way is complicated and the surveillance is made irregularly or not at all. If they undergo surveillance in hospitals where it is regularly made, the patients lose school or work days and suffer from high anxiety level because of the “to be a patient again ” feeling . Attempts to create the optimal surveillance model for those patients were made, but the best model is still unknown.

MATERIAL AND METHODS
We questioned CNS tumor patients 20-40 years old that were transferred from a pediatric to an adult neuro-oncology service in Sheba MC.

RESULTS
The response from 38 patients was obtained: 11 patients with pilocytic astrocytomas, 11 other gliomas, 3 gangliogliomas, 2 germ cell tumors, 3 medulloblastomas, 3 NF1 patients with optic pathway gliomas, 4 with pineal region tumors, 1 with immature teratoma. 33% of patients are married and live with the spouse, 55% live with their parents, 4 % live by themselves. Of the respondents 18 % are students and 47% are permanently employed. Most of the patients prefer to undergo surveillances in community health services and visit hospitals as rare as possible. All patients expressed an understanding of the importance of a lifelong surveillance as recommend by the treating neuro-oncologist. The patients strongly expressed the need to have a dedicated case coordinator that can help organize the test’s flexible timetable and an effective communication between the teams

CONCLUSION
According to our patient’s opinion, the preferable model of surveillance for high functioning YA CNS tumor patients is the cooperation of the hospital’s neuro-oncology unit and the community health service. The first is responsible for planning the surveillance and taking the appropriate medical actions according to the

RESULTS
. The second is responsible for the realization of the program. The assignment of a case coordinator that connects between all of the teams is crucial.
P08.10.B COIMBRA: THE IMPACT OF RADIOTHERAPY ON QUALITY OF LIFE AND DISEASE PROGRESSION IN PATIENTS WITH BRAIN METASTASES AND THEIR CAREGIVERS
Authors: Cialdella F , van Grinsven E E , van der Boog A T J , Nagtegaal S H J , Smid E J , Claes A , Kleynen C E , Seravalli E , Philippens M E P , van Zandvoort M J E , Verhoeff J J C 
Published: September 2023

Abstract

INTRODUCTION
Brain metastases (BMs) are diagnosed in 10-30% of all cancer patients, and this incidence is expected to rise due to advancements in primary tumor management. Besides improving survival, the impact of treatment on quality of life (QoL) and course of disease is highly relevant for patients and their caregivers. The Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) study aims to gather data on natural disease progression, treatment response, tumor recurrence, complications, QoL (for both patient and caregiver), cognitive performance and survival of patients with BMs. Additionally, the study evaluates feasibility, performance and added value of new MRI techniques in patients with BMs, while providing an infrastructure for efficient and pragmatic randomized evaluation of new interventions. DESIGN/

METHODS
The prospective COIMBRA study is designed to monitor a cohort of patients with BMs and their caregivers who are referred to a tertiary academic radiation oncology department (ClinicalTrials.gov Identifier: NCT05267158). The study is designed according to the Trials within Cohorts (TwiCs) framework, an adaptive design that allows for the evaluation of multiple interventions over time. Patients receive state of the art treatment, which includes stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). Clinical data, QoL and cognitive functioning are collected at baseline and at regular intervals post-treatment. Additionally, new MRI techniques can be evaluated for their feasibility and performance in patients with BMs. PRELIMINARY

RESULTS
Since April 2019, 419 patients have been included of whom 51.2% were men and the majority of the patients had lung cancer (53.6%). SRS was administered in 92.4% and 68.1% received systemic therapy. Median overall survival was 18.3 months. Questionnaires available at both baseline and 6 months after radiotherapy showed that 65.3% experienced stability or improvement in QoL measured via the EORTC QLQ-C30 questionnaire. Fewer patients reported anxiety or depression after SRS compared to before treatment (28.4% vs 47.8%). Caregivers’ baseline responses indicated that 59% had to adjust their daily lives due to the patients’ diagnosis.

CONCLUSION
Our study successfully collected in-depth clinical and QoL data from patients with BMs and their caregivers. The results suggest a modest improvement in anxiety and QoL after SRS. These findings highlight the need for ongoing evaluation of interventions in this patient population in order to ultimately guide personalized treatment strategies.