bluuebunny/crossref_metadata_2025_split huggingface dataset:
P01.01.A THE IMPACT OF BRAIN LESIONS ON HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH WHO CNS GRADE 3 OR 4 GLIOMA: A LESION-FUNCTION AND RESTING-STATE FMRI ANALYSIS
Authors: Kocher M , Heinzel A , Mottaghy F M , Filss C , Stoffels G , Lohmann P , Friedrich M , Shah N J , Caspers S , Weiss Lucas C , Ruge M I , Galldiks N , Fink G R , Langen K 
Published: September 2023

Abstract

BACKGROUND
In glioma patients, tumor development and multimodality therapy are associated with changes in health-related quality of life (HRQoL). It is largely unknown how different types and locations of tumor- and treatment-related brain lesions, as well as their relationship to white matter tracts and functional brain networks, affect HRQoL.

MATERIAL AND METHODS
In 121 patients with pretreated gliomas of WHO CNS grades 3 or 4, structural MRI, O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET, resting-state functional MRI (rs-fMRI) and self-reported HRQoL questionnaires (EORTC QLQ-C30/BN20) were obtained. Resection cavities, T1-enhancing lesions, T2/FLAIR hyperintensities, and lesions with pathologically increased FET uptake were delineated. Effects of tumor lateralization, involvement of white matter tracts or resting-state network nodes by different types of lesions and within-network rs-fMRI connectivity were analyzed in terms of their interaction with HRQoL scores.

RESULTS
Right hemisphere gliomas were associated with significantly less favorable outcomes in physical, role, emotional and social functioning, compared with left-sided tumors. Most functional HRQoL scores correlated significantly with right-sided white-matter tracts involvement by T2/FLAIR hyperintensities and with loss of within-network functional connectivity of right-sided nodes. Tumors of the left hemisphere caused significantly more communication deficits.

CONCLUSION
In pretreated high-grade gliomas, right hemisphere lesions are associated with reduced HRQoL scores in most functional domains except communication ability, compared to tumors of the left hemisphere. These relationships are mainly observed for T2/FLAIR lesions involving structural and functional networks in the right hemisphere. The data suggest that sparing the right hemisphere from treatment-related tissue damage may improve HRQoL in glioma patients.
P02.05.A DISSECTING THE DIFFUSE MIDLINE GLIOMA TUMOUR MICROENVIRONMENT COMMUNICATIONS USING MULTI-OMICS APPROACHES
Authors: Collot R , Ruiz Moreno C , Wezenaar A , Zomer A , Johnson H , Stunnenberg H , Rios A 
Published: September 2023

Abstract

BACKGROUND
Diffuse midline glioma (DMG) represents a highly aggressive pediatric brain tumour with no chance of survival. Treatment options are urgently needed, and efforts have been put towards the development of T cell immunotherapy. However, this should consider the unique tumour microenvironment (TME) of DMG, both in terms of anatomical location and developmental stage.

MATERIAL AND METHODS
To gain knowledge on this unique tumour niche, we implemented an immuno-competent, syngeneic mouse model based on in-utero electroporation (IUE) of the key driver-mutations to induce tumour formation at embryonic stage. By combining snRNAseq, Spatial Transcriptomics and state-of-the-art imaging, we characterized the spatial and molecular landscape of DMG.

RESULTS AND CONCLUSION
We observed a high intratumoral heterogeneity with spatially restricted cell populations. Importantly, their molecular profiles correlate with patient data, illustrating the clinical relevance of the IUE model. Analysis of cell-cell communications in the TME revealed a novel signalling between DMG and immunosuppressive myeloid cells, that could impact T-cell response. Using an advanced patient-derived DMG organoid co-culture model with macrophages and engineered T-cells, we are currently investigating the role of this pathway on T-cells mediated killing of DMG organoids. Thus, this project fills a critical need to delineate and overcome the immune-suppressive environment in DMG and potentiate T cell targeting.
P02.11.A INTEGRATED GENOMIC PROﬁLING OF LONG-TERM GLIOBLASTOMA SURVIVORS
Authors: Xu P , Chen Z 
Published: September 2023

Abstract

BACKGROUND
Glioblastoma (GBM) is a fatal brain tumor, and few patients survive beyond 5 years. Therefore, a study of genomic alterations in GBM long-term survivors (LTS) is essential for insights into tumor biology and biomarker identiﬁcation.

MATERIAL AND METHODS
In our study, we reviewed medical records from Sun Yat-sen University Cancer Center for GBM patients received initial surgery between the years 2000 and 2018. Thirty patients with GBM had an overall survival of more than 5 years. In addition to established prognostic factors such as radiochemotherapy and total surgical excision, we sought to identify genomic alterations associated with LTS by collecting surgically resected tumor tissues and normal blood controls from 13 GBM LTS (overall survival &gt; 60 months) and 19 short-term survivors (STS, overall survival &lt; 24 months). We performed whole exome sequencing and transcriptome sequencing on these samples.

RESULTS
Our findings revealed no significant differences in the composition of driver genes between the two groups. However, mutation signature analysis indicated that the proportion of mutation signature 19 was higher in the LTS than in the STS (P=0.059). Analysis of copy number variants showed that the longer survivors group had higher copy number variants at the chromosomal level (P=0.049). At the chromosome arm level, the proportion of 19p amplification and 19q amplification in the longer survivors group was significantly higher than in the short survival group (P=0.001/0.002). And in the TCGA GBM dataset, GBM patients with 19p amplification also had a better prognosis (log-rank P=0.04).

CONCLUSION
In conclusion, our study identified the proportion of mutation signature 19 and amplification of 19p as potential genomic alterations that could be used as prognostic biomarkers for GBM. This study could pave the way for new therapeutic approaches to this challenging disease.
P02.15.A PRONEURAL, CLASSICAL AND MESENCHYMAL PROTEIN SIGNATURES LACK PROGNOSTIC VALUE IN WHO 2021 ADULT TYPE DIFFUSE LOWER-GRADE GLIOMAS
Authors: Dénes A , Olsson Bontell T , Barchéus H , Ferreyra Vega S , Carén H , Lindskog C , Jakola A S , Smits A 
Published: September 2023

Abstract

BACKGROUND
Mesenchymal transformation in glioblastomas is associated with therapy resistance and increased aggressiveness. In WHO 2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition between phenotypic states, has not been studied. Most reports correlating proneural, classical or mesenchymal signatures with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype as well as the transition of phenotype predicted survival in a clinical cohort of WHO 2021 defined dLGGs.

MATERIAL AND METHODS
We used a TMA-based approach and five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2) to examine 183 primary and 49 recurrent tumors from patients with previously diagnosed dLGG. Of the 49 recurrent tumors, nine tumors relapsed a second time, and one a third time.

RESULTS
In total, 71.0% of all tumors could be subtyped into proneural, classical or mesenchymal. Proneural was the predominant subtype among IDH-mut tumors (78.5%), while in IDH-wt tumors mesenchymal was more common (63.6%). A significant difference in survival was found between subtypes (proneural, classical and mesenchymal) in the total cohort (p&lt;0.001), but not when molecularly stratified (IDH-mut: p=0.220, IDH-wt: p=0.623). Upon relapse, proneural signature was retained in 66.7% of the proneural IDH-mut dLGGs (n=21), whereas IDH-wt tumors (n=10) mainly retained or gained mesenchymal phenotype. There was no significant difference in survival between IDH-mut gliomas remaining proneural and those switching to mesenchymal signature (p=0.347).

CONCLUSION
Subtyping into proneural, classical and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but statistical significance between phenotypes and survival was lost after molecular stratification according to the WHO 2021 criteria. IDH-mut tumors mainly remained proneural at recurrence, while IDH-wt tumors mostly retained or gained mesenchymal phenotype. This phenotypic shift, which in glioblastoma is associated with increased aggressiveness, did not affect survival. Sample sizes were, however, too small to draw any firm conclusions on whether this negative finding is due to lack of statistical power or reflects a true biological difference from glioblastomas.
P03.08.A HIGH-DIMENSIONAL CHARACTERISATION OF THE CELLULAR AND MOLECULAR CHANGES IN THE HUMAN BRAIN AFTER RADIOTHERAPY
Authors: Millner T O , Panday P , Pomella N , Badodi S , Marino S 
Published: September 2023

Abstract

BACKGROUND
In the UK ~40,000 intrinsic and metastatic brain tumours are diagnosed each year. Although targeted radiotherapy (RT) is integral to increasing survival of cancer patients, it has significant side-effects, the cellular and molecular mechanisms of which are not fully understood. During RT treatment epigenetic changes occur in the neoplastic tissue, but few studies have assessed these in non-neoplastic brain tissue and results are highly variable.

MATERIAL AND METHODS
To explore the effects of RT on patient-specific methylation, we retrospectively identified 19 samples, mainly metastatic tumours, that had undergone stereotactic-RT followed by resection, and contained peri-lesional brain tissue, as well as 14 controls. Peri-lesional brain was micro-dissected, followed by DNA methylation profiling and RNA-sequencing.

RESULTS
Clustering of DNA methylation data showed distinct patterns between the two groups, whilst RNA-seq revealed 1,887 differentially expressed genes. Pathway analysis with GSEA identified differentially represented pathways, including: innate immune system, trans-synaptic signalling, olfactory signalling, regulation of supramolecular fibre organisation, and pattern specification. Computational deconvolution of cellular composition showed increased activated dendritic cells and B-cells, and reduced smooth muscle cells and several sub-sets of astrocytes in the RT samples.

CONCLUSION
We are currently further investigating these findings using spatial transcriptomics and proteomics to produce the first high-dimensional characterisation of the irradiated human brain. This will also provide the first direct evidence of epigenetic dysregulation after targeted-RT, and assess novel epigenetically-regulated genes, which will be validated with single cell tissue-based imaging techniques. A range of epigenetic-based drugs are undergoing clinical trials and we aim to identify targets for radiomitigation in brain tumour patients.
P03.12.A PHASE III RANDOMIZED TRIAL COMPARING PREOPERATIVE HYPOFRACTIONATED RADIOSURGERY (HSRS) TO POSTOPERATIVE HYPOFRACTIONATED RADIOSURGERY (HSRS) FOR PATIENTS WITH LARGE BRAIN METASTASES SUITABLE FOR SURGICAL RESECTION SUPPORT TRIAL
Authors: Navarria P , Pessina F , Clerici E , Bellu L , Politi S , Marini B , Riva M , Bono B , Reggiori G , Raspagliesi L , Scorsetti M 
Published: September 2023

Abstract

BACKGROUND
Standard of care for patients with large brain metastases (BMs) suitable for surgery is surgical resection followed by radiosurgery in single or multifractions (SRS/HSRS) on tumor bed. Although a satisfactory local control is obtained, an increasing rates of leptomeningeal disease (LMD) related to surgery, and symptomatic radionecrosis related to SRS/HSRS have been observed. In the last years the employ of preoperative SRS/HSRS has been investigated in retrospective studies. Advantages seem to be: better target delineation to intact lesion, reduction of normal brain irradiated considering useless of margins, potential prevention of any cells spilled during resection, greater oxygenation ratio of intact region, sterilization effect, and resection of majority of irradiated tissues. Preoperative HSRS versus postoperative ones will be investigated in multicentric randomized phase III trial. Primary endpoint is rate of leptmeningeal disease secondary endpoints, local control, symptomatic radiation necrosis, surgical morbidity, quality of life (QoL) and neurocognitive functions assessment between the two modalities; brain distant progression (BDP), and overall survival (OS) will be evaluated too.

MATERIAL AND METHODS
Inclusion criteria are: patients aged 18-80 years, diagnosed malignant primary tumor, KPS≥70, oligometastatic disease, limited brain metastases (up to 4), large BM suitable for surgery. Exclusion criteria are: prior WBRT, SCLC, or germinal cell tumour or Lymphoproliferative disease, prior neurosurgery, and incompatibility to perform MRI. Stratification factors will be: histology of primary tumor (Breast, NSCLC, Melanoma, Other) and BMs location (sovra-or infra-tentorial). In Arm A (experimental) patients undergo preoperative HSRS, 27 Gy in 3 fractions, followed by surgery. In Arm B (control): patients undergo surgical resection followed by postoperative HSRS at the same doses. Outcome evaluation will be assess using MRI, total body CT scan and/or CTPET, neuropsychological and Quality of life assessment before and after treatments. For distinguish RN occurrence and disease progression delayed-contrastMRI, and perfusion MRI will be employed. Considering that estimated 1 year LMD is 10% for postoperative HSRS, and ≤ 2% for preoperative enrolment of 146 patients is expected (73 per Arm).

RESULTS
Enrollment started at April 2023 and among first patients included the treatment has proven to be safe.

CONCLUSION
Preoperative HSRS in large BMs suitable for surgical resection need prospective evaluation aiming to improve outcome, and reduced treatments side effects.
P04.02.A CEREBELLAR GLIOMA WITH BRAF ACTIVATION: A MOLECULARY DISTINCT GLIOMA SUBGROUP WITH MAPK ACTIVATION
Authors: Hinz F , Schweizer L , Reinhardt A , Reuss D E , Sill M , Witt O , Pfister S M , Jones D T W , von Deimling A , Sahm F 
Published: September 2023

Abstract

BACKGROUND
Rendering the correct tumor diagnosis is key to optimise cancer therapies and to orient patients and relatives regarding prognosis and general understanding of the disease. With the rising impact of molecular diagnostics more molecular profiles of tumors are being generated and assembled in central institutes. With this critical data assembly in world-wide repositories such as www.molecularneuropathology.org, new tumor groups with differing prognosis and driver alterations can be discerned.

MATERIAL AND METHODS
By analysing the epigenetic profiles from over 125.000 CNS tumor samples a distinct group of cases was identified (n=24). The samples in this group did not match an established reference methylation class in the Heidelberg brain tumor classifier (version 12.5). In a first analysis with the clinical data external suppliers have provided, these tumors are located in the cerebellum and typically in children (mean age = 9 years).

RESULTS
The variable histology ranged from low grade glial/glioneuronal appearances such as pilocytic astrocytoma (n= 12), ganglioglioma (n= 4), gangliocytoma (n= 1) to ependymoma (n= 2) and anaplastic ependymoma (n=1). For some cases just a descriptive histopathological diagnosis could be rendered (n= 6). A prominent feature in radiology and histology were micro- and macrocalifications (n =5). From 24 cases, 17 tumors (89% of all analysed tumors) harboured a BRAF V600E mutation. One case revealed a PRKAR2B:BRAF fusion. 6 cases could not be analysed because no remaining tumor material was available. While clinical follow-up data collection is still maturing, relapses were reported in 2 patients, and stable disease was reported in 12 cases. For 10 cases no follow up data is available, yet.

CONCLUSION
We found an epigenetically distinct group of childhood brain tumors located in the posterior fossa with an enrichment of BRAF V600E mutations. Clinical follow-up is yet to be evaluated, but recurrence was observed in a proportion of patients with available follow-up.
P04.06.A A PHASE II MONOCENTRIC STUDY OF LIMITED USE OF HIGH DOSE OF CHEMOTHERAPY AND PROTON THERAPY IN PEDIATRIC HIGH RISK MEDULLOBLASTOMA AND OTHER EMBRYONAL CANCERS
Authors: Guidi M , Fonte C , Tellini M , Castelli B , Gori C G , Giunti L , Di Nicola M , Buccoliero A M , Caporalini C , Giordano F , Rombi B , Desideri I , Pugi A , Tortora K , Greto D , Genitori L , Leo M , Sardi I 
Published: September 2023

Abstract

BACKGROUND
Despite the multimodal approach, medulloblastoma remains a leading cause of cancer-related death in children. We proposed the preliminary data of an interventional, open-label, phase II study to evaluate the safety and efficacy of standard and high-dose chemotherapy associated with craniospinal proton therapy in patients with metastatic medulloblastoma and other embryonal cancers.

MATERIAL AND METHODS
A total of 19 patients have been enrolled from the beginning of the study from February 2018 to May 2022 . The median age was 7,5 years (range; 13 males and 6 female). The protocol predicted the first phase of induction with 4 cycles of chemotherapy. After induction patients with favorable histology without evidence of disease were enrolled to proton therapy (with concomitant vinorelbine biweekly). The maintenance phase with Lomustine repeated every 9 weeks and vinorelbine every 3 weeks for overall 12-18 months (PR). Conversely LC/A MB, pineoblastoma or other high risk embryonic tumors were subjected to consolidation phase with high dose of chemotherapy with tiothepa followed by autologous HSC transplant and successive maintenance phase of 6 months.

RESULTS
At December 2022, the median follow up was 23 months. 18 patients had high risk medulloblastoma and one had a primary leptomeningeal primitive neuroectodermal tumor. After the induction phase 14 patients showed CR, 3 PR, 1PD, 1SD. At subsequent re-evaluations two of the three patients with PR, showed disease control, one CR and the other SD and the patient with PD showed CR. At the end of proton therapy 18 patients had CR. During the reporting period three patient died for progression of the underlying disease. At 15 months from the start of treatment the PFS and OS were 68.8% (95% CI: 34.1% - 87.6%) and 94.7% (95% CI: 68.1% - 99.2%) respectively. The principal expected side effects of chemotherapy were hematology toxicity (fever and neutropenia prevalent after etoposide and carboplatin plus vinorelbine). Among the unexpected side effect was CMV retinopathy with complete blindness and leukoencephalopathy after high dose of thiotepa and proton irradiation.

CONCLUSION
As the study did not reveal any safety issues, proton therapy combined with intensive chemotherapy, and myeloablative chemotherapy only in selected cases and always before irradiation, proved feasible and successful in treating high-risk medulloblastomas and other embryonal tumors.
P04.07.B CHARACTERIZATION OF ARHGAP36/MYC-INDUCED GROUP 3 MEDULLOBLASTOMA
Authors: Gianesello M , Ballabio C , Badaloni A , Bonanomi D , Tiberi L 
Published: September 2023

Abstract

BACKGROUND
Medulloblastoma (MB) is one of the most common pediatric brain cancers of the central nervous system. It is stratified into 4 molecular subtypes (WNT, SHH, group 3, and group 4), which differ from one to the other for various features, such as cellular morphology, age of onset, set of mutations, and percentage of survival. A common point between the four MB subgroups is the absence of treatments for this disease. The current gold standard treatment has deleterious side effects for the patients, which spans from growth defects to low hormone levels and problems with learning. Analyzing transcriptomic data of group 3 MB patients we found ARHGAP36 as a possible gene involved in tumor formation or propagation. Rho GTPase-Activating Protein 36 (ARHGAP36) is a gene that plays a role in regulating PKA activity. Specifically, the ARHGAP36 protein can inhibit PKA function through two distinct mechanisms. Firstly, it acts as a pseudosubstrate for the catalytic subunit of the PKA protein. Secondly, it can drive protein degradation via a lysosome-mediated process.

MATERIAL AND METHODS
We took advantage of the Piggybac/transposon technology to induce a strong and stable overexpression of our genes of interest to generate two different models, one in-vivo and one in-vitro with induced pluripotent stem cells-derived human cerebellar organoids. We also exploited the cre/LoxP system in transgenic mice to overexpress ARHGAP36 under the control of specific promoters. The analysis was conducted using standard techniques such as RT-qPCR and Western Blot, together with immunofluorescence of the cerebellar section and live imaging of the modified cerebellar organoids. The gene expression profile of the tumors obtained in mice was analyzed by RNA sequencing and compared to known group 3 MB mouse models.

RESULTS
We analyzed RNA-sequencing data from medulloblastoma patients and found that high expression of ARHGAP36 correlated with poor prognosis in patients. Through PKA inhibition, ARHAP36 induces ectopic activation of SHH signaling and cell proliferation leading to abnormal development of the cerebellum in mouse embryos. Notably, despite its inductive activity on the SHH pathway, ARHGAP36 expression is higher in group 3 and group 4 MB, rather than in the SHH subgroup. In this study, we demonstrate that intracranial transfection of P0 mouse pups with plasmids overexpressing MYC and ARHGAP36 can generate group 3 medulloblastoma in-vivo. We studied and then confirmed the involvement of the binding with PKA as a tumorigenic mechanism in the MYC/ARHGAP36 co-overexpression using several mutated forms of the gene. We studied the obtained tumors for the presence of group 3 MB immunophenotypical markers, as well as their gene expression profile by RNA-seq.

CONCLUSION
These findings can become of key interest as possible druggable targets to efficiently treat group 3 medulloblastoma patients in the future.