bluuebunny/crossref_metadata_2025_split huggingface dataset:
P06.09.B TRIAL IN PROGRESS: PHASE 1 DOSE-FINDING STUDY TO EVALUATE SAFETY AND TOLERABILITY OF CVGBM IN PATIENTS WITH NEWLY DIAGNOSED AND SURGICALLY RESECTED MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Tabatabai G , von Baumgarten L , van den Bent M , Burger M C , Freres P , Glas M , Hau P , Herrlinger U , Mildenberger I , Neyns B , Schäfer H , Seidel C , de Vos F , Galot R , Whenham N , Wick A , Falk M , de Freitas Chama L , Henze J , Kelemen P , Koch S D , Lutz J , Heidenreich R , Romer Roche P , Rost T , Schönborn-Kellenberger O , Gnad-Vogt U 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is characterized by a low mutational burden limiting the number of neoantigen targets for cancer vaccines. Vaccination against tumor-associated antigens over-presented via MHC class I and II in GBM is an alternative that has shown promise in previous trials. One cancer vaccine containing peptides presented by HLA-A*02-01 (class I) and some DR alleles (class II), showed evidence of peripheral vaccine-induced immune response against these peptides in patients with GBM. Our study will assess the safety and immunogenicity of the messenger ribonucleic acid (mRNA)-based multiepitope vaccine CV-GBM, an investigational therapeutic mRNA vaccine, encoding eight of these peptides that have demonstrated immunogenicity as peptide vaccines. CV-GBM consists of a mRNA with unmodified nucleotides formulated with lipid nanoparticles.

MATERIAL AND METHODS
CV-GBLM-001 is a first-in-human, open-label, international, dose-escalation phase 1 trial. HLA-A*02:01-positive patients with newly diagnosed MGMT-unmethylated GBM (CNS WHO Grade 4), including IDH-wildtype astrocytoma with a molecular signature of unmethylated MGMT-GBM who have had a gross total or partial resection and who completed post-surgery radiotherapy with or without chemotherapy, are eligible to receive CVGBM. The trial comprises a dose-escalation part (Part A) followed by a dose-expansion part (Part B). In Part A, the starting dose is 12 µg mRNA, which may be escalated to 25 µg, 50 µg and 100 µg, with 3 to 6 patients per dose level. Dose escalation will be guided by a Bayesian logistic regression model. Patients will receive 7 doses of CVGBM by intramuscular injection on Days 1, 8, 15, 29, 43, 57, and 71, followed by 6 optional doses at 6-week intervals, up to 1 year after the first dose or until disease progression or intolerable toxicity. An independent Data and Safety Monitoring Board will recommend the dose for expansion in Part B in which about 20 patients will be enrolled. Biomarkers and vaccine-induced innate and adaptive immunogenicity, including, but not limited to, systemically induced cytokines and chemokines and antigen-specific CD4+ and CD8+ T cells, will be monitored in the blood, and optionally in vaccine-draining lymph nodes and relapsed tumor. In addition to the primary safety objectives, secondary objectives of efficacy (progression-free survival, overall survival) and patient-reported quality of life outcomes will be assessed. Trial sponsor: CureVac SE, Germany.
P06.12.A NLGN4X-SPECIFIC TCR T CELLS TARGETING EXPERIMENTAL GLIOMAS
Authors: Krämer C , Kilian M , Chih Y , Kourtesakis A , Boschert T , Sanghvi K , de Roia A , Jung S , Jähne K , Shultz L , Harbottle R , Green E , Will R , Wick W , Platten M , Bunse L 
Published: September 2023

Abstract

BACKGROUND
A human leukocyte antigen (HLA)-A*02-restricted tumor associated antigen in the neuroligin 4 X-linked (NLGN4X) protein was found to be specifically overexpressed in human gliomas. Individualized multipeptide vaccination targeted NLGN4X and induced specific cytotoxic T cells responses in patients with newly diagnosed glioblastoma.

MATERIAL AND METHODS
Post vaccination NLGN4X-tetramer-sorted T cells were subjected to single cell T cell receptor (TCR) sequencing for TCR discovery. The identified TCR was delivered to human T cells (NLGN4X-TCR-T) and functional profiling was performed by flow cytometry and in vitro cytotoxicity assays. NOD scid gamma (NSG) major histocompatibility complex (MHC) I/II knockout (KO) (NSG MHC I/II KO) mice were challenged with NLGN4X-expressing experimental gliomas and treated with intracerebroventricular injection of NLGN4X-TCR-T to assess its therapeutic potential.

RESULTS
We apply for the first time for therapeutic use of an HLA-A*02 restricted vaccine-induced TCR that binds to the NLGN4X antigen. We show the cytotoxic and polyfunctional phenotype of NLGN4X-TCR-T in various cellular models. Intracerebroventricular delivery of NLGN4X-TCR-T prolongs survival and leads to objective radiographic responses in experimental gliomas-bearing NSG MHC I/II KO mice.

CONCLUSION
NLGN4X-TCR-T demonstrates efficacy in a preclinical experimental glioblastoma model. On a global scale, we provide first evidence for the therapeutic retrieval of vaccine-induced human TCRs for the off-the-shelf treatment of glioblastoma patients.
P07.14.A OBSERVATIONS FROM THE FIRST 100 CASES OF INTRAOPERATIVE MRI - EXPERIENCES, TRENDS AND SHORT-TERM OUTCOMES IN PEDIATRIC VERSUS ADULT NEUROSURGICAL POPULATION
Authors: Barchéus H , Peischl C , Björkman-Burtscher I M , Pettersson C , Nilsson D , Farahmand D , Eriksson J , Skoglund T , Corell A 
Published: September 2023

Abstract

BACKGROUND
The intraoperative MRI (iMRI) at Sahlgrenska University Hospital installed in 2017 was the first introduced in Sweden. Herein, we present a single center study with our observations from the first 100 patients undergoing neurosurgery in the dedicated iMRI surgical theater.

METHODS
Patients undergoing surgery in the 3T iMRI hybrid surgical theatre at our neurosurgical department between December 2017 to May 2021 were included after informed consent. Demographic, clinical, surgical, histological, radiological and outcome parameters, as well as variables related to iMRI, were retrospectively collected and analyzed. Patients were subdivided into adult and pediatric cohorts.

RESULTS
A variety of neurosurgical procedures were performed; resection of tumors and epileptic foci, endoscopic skull base procedures including pituitary lesions, deep brain stimulation (DBS), laser interstitial thermal therapy (LITT) and biopsies. Mean age was 32 years (range 0-81 years), 41 patients were pediatric and 42% were female. An iMRI scan was carried out in 96% of cases and led to continuation of surgery in 50 percent of cases, mainly due to visualized remaining pathological tissue. Median time to iMRI from intubation was 280 minutes and median total duration of surgery was 445 minutes. The majority of patients experienced no postoperative complications (70%), 13 patients suffered permanent postoperative deficits, predominantly visual.

CONCLUSION
We demonstrate demographics, clinical, surgical and radiological variables from the first 100 patients planned for surgery in the iMRI surgical theatre after

INTRODUCTION
in 2017. We found that iMRI was performed in almost all cases. In the pediatric cohort, tumors and epileptic focus were main indications for surgery. In adults, indications were intrinsic brain tumors, transsphenoidal pituitary tumor and DBS. Utilization from a resource and patients perspective appears to be most beneficial in tumor surgeries (specially pediatric), epileptic surgery and DBS.
P08.06.B OPTUNE TREATMENT FOR PATIENTS WITH GLIOBLASTOMA: A MIXED METHOD STUDY OF PATIENTS´, NEXT OF KIN´S´, PHYSICIANS´ AND COMPANY STAFFS´ EXPERIENCES
Authors: Letter N , Kastbom L , Wahlberg E , Norrgård J , Degsell E , Karlsson M , Malmström A 
Published: September 2023

Abstract

BACKGROUND
Since the pivotal trial, showing a near 5-month survival advantage with the addition of Optune to standard treatment for glioblastoma (GBM), Optune has been introduced into clinical practice in many countries. In Sweden, the device is prescribed by physicians, while the service of equipment and control of its use occur in the patients’ home by staff from the private company providing the device, this potentially creating a conflict of interest. Also, the daily use of the device necessitates the help of a next of kin. These are unique arrangements for Swedish healthcare, leading to the need of a complex and possibly challenging collaboration, and also raising potential ethical dilemmas.This study investigates Optune treatment for patients with GBM, regarding experiences of those involved in the treatment, namely: patients, next of kin, physicians and staff from the private company providing the device.

MATERIAL AND METHODS
The aim is to include 20 or more participants in each group (patients and next of kin, respectively). They are individually interviewed. The interviews are transcribed and analyzed using quantitative content analysis. Electronic questionnaires were sent during 2021-2022 to all physicians prescribing Optune at Departments of Oncology or Neurology in Sweden. The questionnaires included quantitative as well as open ended questions. Staff working for the company and visiting the patients and next of kin have also received electronic questionnaires focusing on experiences from their work.

RESULTS
Challenges were identified by the physicians, but they had varying opinions on the magnitude of the ethical problems. To date, 10 patients and 9 next of kin have been interviewed. Possible categories already identified are: “Information from the healthcare” and “Patient - company staff collaboration”. The questionnaires to the staff have been answered. The results of the interviews with patients and next of kin, as well as the results of the questionnaires to staff, will be presented.

CONCLUSION
The

INTRODUCTION
of Optune as a treatment of patients with GBM constitutes a new concept and a need for new solutions for tackling medical, practical and ethical issues.

SUPPORT
The Medical Research Council of Southeast Sweden (FORSS), and an ALF grant from Region Östergötland.
P09.08.B UNDERSTANDING THE HOLISTIC NEEDS OF PEOPLE LIVING WITH GLIOMA AND THEIR CAREGIVERS: A THEMATIC ANALYSIS OF THE SEMI-STRUCTURED INTERVIEWS FOR THE COBRA STUDY
Authors: Baddeley E , Sivell S , Retzer A , Nelson A , Bulbeck H , Seddon K , Grant R , Adams R , Watts C , Aiyegbusi O , Kearns P , Rivera S , Dirven L , Calvert M , Byrne A 
Published: September 2023

Abstract

BACKGROUND
The needs of people with brain tumours are unique, particularly in terms of neurocognitive impacts, and their subsequent effects on primary caregivers. Evidence suggests that those with brain tumours and their primary caregivers experience unmet needs in the clinical care setting.

MATERIAL AND METHODS
Semi-structured interviews with people with glioma and their caregivers, in the UK, with the aim to understand their priorities and lived experience of glioma, its treatment and treatment aims. Interviews formed part of a study to identify a core outcome set (COS) for glioma interventional trials (COBra study). The interview data were further analysed to identify concepts of importance to people with glioma and their caregivers within the clinical care setting.

RESULTS
Nineteen people with glioma and seven caregivers were interviewed (n=6 glioblastoma, n=4 astrocytoma, n=4 anaplastic astrocytoma/ oligodendroglioma, n=2 oligodendroglioma n=1 PXA tumour, n=1 ‘oligodendroglioma grade 3’ and n=1 ‘glioma grade 3’). Themes identified related to unmet needs and frustrations around communication, access to/need for support, caregiver impacts, neurocognitive symptoms and impacts to activities of daily living. Our findings also indicate the impact of treatment side effects, and how patients and caregivers negotiated tolerability in terms of trade-offs across the spectrum of glioma. Additionally, it was perceived that glioma grade did not correlate with symptom burden, and for those with longer survival, issues relating to late side effects were prominent - highlighting significant unmet needs across the spectrum of disease. Most described the lack of support and being left to deal with many of the unique burdens of the disease alone. Caregivers needs corresponded to the particular challenges experienced by their loved one, including late and longer-term effects of the disease, particularly neurocognitive impacts and the subsequent effects to patients’ activities of daily living as a result. Psychosocial impacts on caregivers were prevalent, reported by caregivers and also reported by patients interviewed with no caregiver present.

CONCLUSION
The qualitative data highlights the unmet needs of people with glioma and their caregivers, which are complex, unique and affect all those across the spectrum of glioma. As such, there is a need for a consistent and appropriate assessment of needs for patients and their caregivers in clinical practice, which need to incorporate the key concepts, such as communication, tolerability and support. These findings support further investigation into a holistic needs assessment for those with glioma.
P10.09.A TARGETING NITROSATIVE STRESS TO PREVENT NEUROBLASTOMA MALIGNANCY: INSIGHTS INTO THE MTOR SIGNALING PATHWAY
Authors: Ojha S K , Tripathi M K , Hamoudi W , Khaliulin I , Amal H 
Published: September 2023

Abstract

BACKGROUND
Neuroblastoma (NB) represents the most common pediatric tumor and its mechanisms remain elusive. Nitric oxide (NO) is one of the essential regulators of carcinogenesis of different tumors including NB. The mechanistic target of the rapamycin (mTOR) signaling pathway is another important regulator of tumorigenesis. In this study, we investigated the possibility to attenuate NB malignancy by inhibiting nitrosative stress and examined the interplay between NOS and mTOR signalling.

MATERIAL AND METHODS
NOD.CB17-Prkdc-scid/NCrHsd mouse were used for xenograft subcutaneous tumor model to evaluate the ability of HU-53 treatment regimens. Tumor weight and volume were measured during the study. The experiments were also carried out on the human-derived SH-SY5Y cells. Nitrite content was measured biochemically by griess assay. Immunoblotting and immunofluorescence assessed nitrosative stress and its effect on mTOR signaling. Genetic knockdown of nNOS was done in SH-SY5Y with siRNA to check effect of NO on neuroblastoma growth.

RESULTS
Treatment with HU-53 resulted in a significant decrease in tumor weight (p &lt; 0.0005) and volume (p &lt; 0.0002) as compared to mice treated with vehicle. Furthermore, we observed that the HU-53 treatment resulted in decreased levels of nitric oxide and nitrosative stress as confirmed by checking the level of nitrite content and 3-Nitrotyrosine which are important mediators of neuroblastoma growth. Genetic nNOS knock-down also prevented cell proliferation, reduced nitrosative stress (p &lt; 0.0002), and the level of synaptophysin, the marker of NB carcinogenesis. Interestingly, NO inhibition elevated the levels of the core negative regulator of mTOR signaling, TSC2 and decreased the phosphorylation of the components of the mTOR signaling pathway, AKT, mTOR, and RPS6, indicating the reduced activity of this pathway. Thus, these results show inhibition of NO production help in reduced activation of mTOR pathway and prevent tumor growth.

CONCLUSION
Our results indicate that nitric oxide inhibition prevents neuroblastoma tumor growth and suggest that the NO-mTOR axis could serve as a novel potential target for NB treatment.
P10.12.B MOLECULAR MECHANISMS INVOLVED IN THE DEVELOPMENT OF BRAIN METASTASIS FROM THE MATCHED PAIRED LUNG ADENOCARCINOMA AND BREAST CANCER
Authors: Najjary S , Kros J M , de Koning W , Mustafa D A M 
Published: September 2023

Abstract

BACKGROUND
Up to 50% of patients with common cancers will develop brain metastases and incidences of this devastating complication are still rising. In our recent work, we found that the immune response in the brain is significantly stronger when the metastasis develops from lung adenocarcinoma (LUAD) compared to breast cancer (BC). Importantly, we discovered the higher expression of the drug target, VISTA, only in the brain metastasis of the LUAD. The aim of the current study was to investigate the molecular mechanisms driving the formation of brain metastasis from the two different lineages of cancer. In addition, we aimed to examine the expression level of the drugable molecules between primary tumors and their brain metastasis.

MATERIAL AND METHODS
Primary tumor and their matched brain metastasis samples of 11 LUAD and 11 breast cancer (total = 44 samples) were included in this study. RNA was extracted from the FFPE samples and the targeted gene expression profiles were measured using the PanCancer IO360™ Panel that includes 770 cancer-related genes (NanoString technology). Data were analysed using the nSolver software.

RESULTS
A first comparison was made between the primary tumors with their brain metastases for LUAD and BC separately. The second comparison was made between the common genes of both lineages. Pathway analysis indicated that there is higher metabolic stress in breast cancer-brain metastasis compared to that in the lung. In addition, we identified 12 common up-regulated genes in brain metastasis, despite the origin of the primary tumor. Importantly, by comparing the primary tumors of BC and LUAD with their brain metastasis, we found that VISTA is predominantly highly expressed in the primary tumors of LUAD and their matched brain metastasis.

CONCLUSION
Although the general mechanisms of metastasis have been described, our study demonstrates that different cancer lineages utilize various genes/pathways to metastasize to the brain. Moreover, primary LUAD and their brain metastasis express high levels of VISTA highlighting the possibilities for targeted therapy.
P10.13.A AN ATRAUMATIC ACCESS TO HUMAN GLIOBLASTOMA IN A XENOGRAFT ANIMAL MODEL BY CEREBRAL OPEN FLOW MICROPERFUSION FOR THE ASSESSMENT OF BIOMARKER IN THE TUMOR MICROENVIRONMENT
Authors: Altendorfer-Kroath T , Asslaber M , Hummer J , Zügner E , Schimek D , Prugger E , Stanzer S , Prietl B , Pieber T R , Bernhart E , Magnes C , Birngruber T 
Published: September 2023

Abstract

BACKGROUND
Orthotopic xenograft studies strongly promote the development of targeted/personalized cancer therapies to improve the still poor life expectancy of glioblastoma patients. In recent years, the tumor microenvironment has increasingly become subject of investigations, as it could have an impact on the progression of the cancer. However, examination of the tumor microenvironment with currently available methods inevitably causes trauma that might compromise the reliability of the obtained data. We aimed to implement an atraumatic access to human glioblastoma with cerebral Open Flow Microperfusion (cOFM) by implantation of xenograft cells in rodent’s brain of different species (mouse and rat) with intact blood brain barrier (BBB) and subsequent development of a xenograft glioblastoma at the interface between the cOFM probe and the surrounding brain tissue. Thereafter, we used the cOFM probe to collect interstitial fluid (ISF) from the tumor microenvironment for metabolome and biomarker assessment.

MATERIAL AND METHODS
Human glioma cells were implanted at a well-defined position into immune-deficient rodent’s brain via cOFM or syringe. Characteristics of the mature tumors from both groups were assessed. ISF from tumor microenvironment was collected without further traumatization by using cOFM, and the collected tumor ISF samples were analyzed using a UHPLC-HRMS metabolomics platform. A targeted (Biocrates MxP®) and an untargeted (Metaboanalyst) approach were used to analyze the metabolomics data.

RESULTS
For the first time xenograft cells were successfully introduced into rodent brain with intact BBB using cOFM, and the tumor tissue that developed around the cOFM probe was unaffected by the presence of the probe. Thereby, an atraumatic access to the tumor was created. The mature cOFM-induced tumors resembled the syringe-induced ones and showed typical features of human glioblastoma. The cOFM sampling procedure did not alter tumor morphology.

CONCLUSION
This novel atraumatic access to human glioblastoma in a rodent brain was used to collect ISF from functional tumor microenvironment in vivo without trauma generation. The thereby generated reliable data are likely to promote drug research, biomarker identification, and enable investigation of the BBB of a functional tumor.
P10.15.A THE ROLE OF NONCODING RNAS IN THE PROGRESSION OF IDH-MUTANT ASTROCYTOMAS TO GRADE 4
Authors: Hartewig A , Jaatinen S , Annala M , Helén P , Haapasalo J , Zhang W , Haapasalo H , Nykter M , Rautajoki K J 
Published: September 2023

Abstract

BACKGROUND
Low grade IDHmutant astrocytomas are heterogeneous brain tumors that have a prognosis of 7-10 years. However, this prognosis is significantly worsened if the tumors progress to grade 4 astrocytomas. Noncoding RNAs, especially long noncoding RNAs and microRNAs, have been studied increasingly in the past years in various cancers including gliomas, and a general dysregulation was observed. The dysregulated RNAs were shown to regulate crucial disease processes, such as cell proliferation, apoptosis, and therapy resistance. Thus, several noncoding RNAs were identified as promising biomarkers and potential therapy targets, some of which are already being tested in clinical trials. Despite advances in the field, little is known about the role of noncoding RNAs in the progression of IDHmutant astrocytomas.

MATERIAL AND METHODS
We collected matched samples and clinical information from six IDHmutant astrocytoma patients before and after progression to grade 4 and subjected them to RNA- and small RNA-sequencing. We defined which microRNAs and long noncoding RNAs were significantly up- or downregulated upon progression. We also predicted the target genes of differentially expressed microRNAs utilizing machine learning algorithms and experimentally validated databases. The predicted targets were filtered for negative correlation in gene expression, and their biological relevance was assessed with gene set analysis and literature research.

RESULTS
We found 33 differentially expressed microRNAs upon progression, out of which 19 were up- and 14 were downregulated. A total of 443 negatively correlating targets were identified for the microRNAs (0-115 per microRNA). The target genes were associated with DNA repair, proliferation, and G-Protein coupled receptor signaling. Furthermore, we observed 19 up- and 14 downregulated lncRNAs within the differentially expressed genes. Six of them have been reported to be cancer-related, including known tumor-suppressors and lncRNAs known to promote cell proliferation, invasion and migration.

CONCLUSION
The study identified a number of noncoding RNAs associated with the progression of IDHmutant astrocytoma to grade 4. Further studies are needed to evaluate their potential to act as biomarkers or therapy targets.