bluuebunny/crossref_metadata_2025_split huggingface dataset:
IN VIVO APPLICATION OF LOCAL DRUG DELIVERY SYSTEMS AGAINST MEDULLOBLASTOMA GROUP 3 AND ATYPICAL/TERATOID/RHABOID TUMOURS
Authors: Moloney Dr Cara , McCrorie Dr Phoebe , ElSherbeny Mr Amr , Porter Mr Harry , Bastiancich Dr Chiara , Bayraktutan Ms Hulya , Oz Dr Umut Can , Nilsson Prof Karin Forsberg , Tyler Dr Betty , Alexander Prof Cameron , Smith Dr Stuart , Rahman Dr Ruman 
Published: October 2024

Abstract

AIMS
Local drug delivery systems (LDDSs) applied during neurosurgery offer a means of overcoming poor blood brain barrier (BBB) permeability and have been extensively investigated for the treatment of adult gliomas, but to the best of our knowledge, not for the treatment of paediatric cerebellar tumours. Here we report the applicability of an LDDS against medulloblastoma group 3 (MB3) and atypical teratoid/rhaboid tumours (AT/RT), both of which are associated with poor prognoses.

METHOD
We prepared and characterised an injectable and biodegradable poly(ethyleneglycol)-poly(caprolactone)- poly(ethyleneglycol) (PECE) hydrogel, which has been investigated with an array of therapeutic agents against numerous cancer types. Here, we loaded the PECE hydrogel with chemotherapeutics previously identiﬁed as being effective against primary MB3 and AT/RT in vitro, but which do not cross the BBB in vivo, namely CHIR99021, ribavirin and PG545. Biocompatibility and cytotoxicity of drug loaded hydrogels was assessed in vitro. LDDSs safety and eﬃcacy was evaluated using patient derived MB3 and AT/RT intracranial xenograft surgical resection models.

RESULTS
The hydrogel was both biocompatible and effected cytotoxicity following drug release. In vivo eﬃcacy experiments against MB3 indicated a comparable median survival in treatment arms receiving radiotherapy or CHIR99021 and PG545 loaded LDDS. However, combined radiotherapy and LDDS conferred a signiﬁcant survival enhancement, including long-term survivors. Against AT/RT, the median survival of arms receiving radiotherapy was comparable to that of the CHIR99021 and ribavirin loaded LDDS, with long-term survivors observed only in the latter arm.

CONCLUSION
The application of LDDSs against cerebellar brain tumours offers a promising novel therapeutic alternative. For MB3, the combination of radiotherapy and a LDDS signiﬁcantly enhances survival compared to radiotherapy alone. For AT/RT, the comparable survival of the LDDS and radiotherapy alone is encouraging and indicates the possibility of circumventing radiation-induced adverse effects for young children impacted by this disease.
NOVEL HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS WITH ANTICANCER ACTIVITY IN MEDULLOBLASTOMA
Authors: Roesler Prof Rafael , Fortes Ms Isadora Serraglio , Lopes Dr Marcela , Brunetto Dr André , de Farias Dr Caroline Brunetto , Jaeger Dr Mariane , Toson Mr Bruno , de Andrade Prof Saulo 
Published: October 2024

Abstract

AIMS
Medulloblastoma is the most common malignant brain tumor of childhood. Protein kinases are often overexpressed and constitute targets for the development of novel molecularly-targeted therapies in brain tumors. Here, we report the synthesis of new derivatives with kinase inhibitory activity and their anticancer activity in an early screening in medulloblastoma cells.

METHOD
The synthesis route was performed through six steps using a proper amino acid as starting material. The inhibitory activity of the ﬁnal derivatives on the protein kinase was measured by ﬂuorescence. Cultured DAOY medulloblastoma cells were used to examine anticancer activity.

RESULTS
The compounds display potent inhibitory activity on viability of DAOY medulloblastoma cells. The more promising derivative shows IC50 in the μM range in inhibiting the targeted protein kinase.

CONCLUSION
Further optimization of compounds in this series is currently being carried out. The encouraging preliminary results have revealed potential novel strategies for inhibiting kinase activity for the treatment of medulloblastoma.
UNVEILING THE MECHANISTIC INSIGHTS OF ARGININE DEPRIVATION COMBINED WITH RADIOTHERAPY FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Chatziathanasiadou Dr Maria , Symington Mr Jake , Huang Mr Huan , Thorne Dr Tom , O’Neill Mr Kevin , Syed Dr Nelofer 
Published: October 2024

Abstract

AIMS
Glioblastoma is a lethal form of primary brain tumour in adults. Despite surgery, radiation and chemotherapy, life expectancy is short rendering the need for novel therapeutic approaches. Metabolic therapies provide a multifaceted effect in the heterogeneous glioblastoma microenvironment as they target its reprogrammed metabolism while overcoming therapeutic obstacles such as the blood brain barrier. We have shown that arginine deprivation combined with radiation eliminates the tumours in vivo, however, the exact mechanism of action is yet unknown. Here, using spatial transcriptomics we explore the effects of arginine deprivation and radiation, alone and combined, on the glioblastoma microenvironment.

METHOD
Brains collected from CT2A immunocompetent mice 6 days after treatment with ADI-PEG20 (5 IU) for arginine depletion, radiation (8 Gy) or their combination were analysed by 10X Genomics Spatial Transcriptomics. Bioinformatic analysis was performed using the R package Seurat and the Ingenuity Pathway Analysis (Qiagen).

RESULTS
The induction of innate immune response was observed with all treatments, however, it was the prevailing element only in the combination treatment. Upregulated pathways in all treatments involved the activation of antigen presentation cells. The pro-inﬂammatory cascades included key molecules of an immune response such as Type I IFNs, IFN-γ, STAT1, ISG15 and IRFs. Protein translation pathways indicating resistance to treatment dominated the changes caused by the two monotherapies, while they were absent in the combination group. The upregulation of CXCL10 and CCL5 signiﬁed the transition to adaptive immune response. Cytosolic DNA sensing by the cGAS-STING was enriched in the radiation and combination groups providing a possible trigger for the innate immune response. Pyroptosis and extracellular matrix remodelling were uniquely presented in the combination group.

CONCLUSION
Our analysis indicates that arginine deprivation and radiation when combined enhance each other’s effect leading to a fortiﬁed immune response that is possibly initiated by cytosolic DNA sensing.
MITOCHONDRIAL MEMBRANE POTENTIAL IS A FUNCTIONALLY RELEVANT AXIS OF NON-GENETIC CELLULAR HETEROGENEITY IN GLIOBLASTOMA
Authors: Robinson Dr Ruth , Gaizley Ms Emily , Deltcheva Dr Elitza , Marguerat Dr Sam , Wray Dr Jason , Enver Prof Tariq 
Published: October 2024

Abstract

AIMS
Glioma stem cells (GSCs) are believed to underpin treatment resistance in glioblastoma by virtue of their self- renewal capabilities and presumed transcriptional plasticity. Understanding how cell state diversity is established and maintained is crucial to make therapeutic gains. We have previously shown mitochondrial membrane potential (MMP) to be a functionally relevant source of extrinsic noise in embryonic and haematopoietic stem cells. This study evaluates cellular MMP as an axis of variability in GSCs.

METHOD
MMP was measured by ﬂow cytometry in patient-derived GSC lines using cationic dyes that diffuse reversibly across the mitochondrial membrane in a voltage dependent manner. MMP-high and low populations (top and bottom 10-20%) were fractionated and subjected to RNA-sequencing and assays of proliferation and clonogenicity. Correlation between MMP and global transcription rate was investigated through a uridine analogue (5-EU) incorporation assay. The relationship between MMP and quiescence was assessed, with quiescence deﬁned as inducible histone2B-GFP label retention after 10 days. Timecourse data for MMP was obtained through sequential staining.

RESULTS
RNA sequencing identiﬁed differential gene expression and exon utilization according to MMP status. MMP- high cells upregulated cell cycle genes, while MMP-low cells exhibited a diverse signature suggestive of a more differentiated state. A greater proportion of MMP-high cells were in cycle, but MMP-low cells formed more colonies. MMP positively correlated with global transcription rate in both cycling and quiescent GSCs. Time- course experiments revealed dynamic periodicity in cellular MMP.

CONCLUSION
The MMP axis reveals transcriptional and functional heterogeneity in GSCs and importantly unmasks phenotypic variability within the treatment-refractory quiescent compartment. The positive correlation between MMP and transcription rate, along with splicing differences, suggests a mechanism underlying functional diversity. Given the oscillatory dynamics of MMP, we postulate that stable-low MMP may deﬁne a deeply quiescent, therapy-resistant state. Evaluating MMP as a tractable regulator of GSC fate is warranted.
EVALUATING THE RELATIONSHIP BETWEEN RADIOTHERAPY CLINICAL TARGET VOLUME AND GAIT ACTIVITY IN HIGH GRADE GLIOMA
Authors: Dadhania Dr Seema , Williams Dr Matthew 
Published: October 2024

Abstract

AIMS
Walking speed or peak cadence serves as a potential indicator of overall health, particularly in older individuals, with documented predictive value for various health-related outcomes. The emergence of wearable technology for gait analysis has facilitated early disease detection and monitoring in conditions like Parkinson’s disease. This study aimed to explore the association between gait metrics and radiotherapy Clinical Target Volume (CTV) in participants with High-Grade Glioma (HGG) enrolled in the BrainWear study, which captures longitudinal physical activity data through wearable devices.

METHOD
21 HGG participants provided accelerometer data before and after a course of radiotherapy. Using Spearman rank correlation analysis, we examined the relationship between CTV and gait features while considering the total radiotherapy dose and tumour location. Participant data was cut at the same time point of 14-days either side of the start or end of radiotherapy to ensure the data was aligned.

RESULTS
The analysis revealed a moderately negative correlation between CTV and peak cadence at the onset of radiotherapy. At the end of radiotherapy and in the two weeks following completion, both peak cadence in 1 minute and 30 minutes showed a stronger inverse correlation with CTV (Spearman’s ρ = -0.52 and ρ = -0.44 respectively, p-value &lt;0.05). This suggests that higher CTV may be associated with decreased peak cadence, particularly at the time of expected radiotherapy toxicity. Subgroup analysis focusing on patients with CTV covering the motor cortex further illustrated a more signiﬁcant inverse correlation between CTV size and peak cadence (Spearman’s ρ = -0.77, p-value &lt;0.05).

CONCLUSION
This study highlights the importance of understanding the interplay between tumour treatment volume, location and physical function. Further exploration of CTV volume in relation to anatomical areas such as the motor cortex could provide deeper insights into this relationship and provide opportunities for personalised monitoring in HGG.
DEVELOPMENT OF A HUMAN-SPECIﬁC 3D IN VITRO PAEDIATRIC CEREBELLAR TUMOUR MODEL USING DECELLULARISED BRAIN AUTOPSY TISSUE
Authors: McCrorie Dr Phoebe , Porter Mr Harry , Diksin Dr Mohammed , Moloney Dr Cara , Scurr Dr David , Grundy Prof Richard , Rahman Dr Ruman 
Published: October 2024

Abstract

AIMS
Group-3 medulloblastoma (MB) is a paediatric cerebellar tumour with a dismal prognosis. Our objective was to establish a 3D in vitro model termed ‘tumoursphere matrix’ to recapitulate physiologically-relevant communication between tumour cells and reactive brain elements, aiming to discern differential gene expression in cancer cells upon co-culture with astrocytes and human brain extracellular matrix (ECM).

METHOD
Non-disease human autopsy brain was decellularised to generate ECM and extensively characterised to show DNA reduction, ECM ligand retention and compatibility with different cell lines. D283, D341 and D425 cells were co-cultured with primary human cerebellar astrocytes within a PEGDA hydrogel containing decellularised ECM. Following 7 days of culture, co-cultured cells were separated using ﬂuorescence activated cell sorting to generate individual cell populations for transcriptomic analysis.

RESULTS
ECM characterisation showed a signiﬁcant reduction in cellular material whilst retaining ECM ligands. Reduction of DNA content to 174 ng/mg was corroborated by an absence of nuclei in immunohistochemical staining. Colorimetric assays indicated collagen and glycosaminoglycan retention in decellularised ECM, and immunoﬂuorescence conﬁrmed retention of ﬁbronectin, laminin and hyaluronic acid. Detection of all ECM ligands was cross-validated by Orbitrap-Secondary Ion Mass Spectrometry. Primary human cerebellar astrocytes, D283, D341 and D425 cells were cultured as spheroids within the ECM/PEGDA hydrogel for 7 days with no signiﬁcant decrease in cellular viability. Cytokine and Human Matrix Metalloproteinase (MMP) Antibody Arrays showed retained cytokine and MMP expression in all three cell lines in the presence of ECM material.

CONCLUSION
We have developed a bespoke 3D model which can co-culture cells for over 7 days, whilst recapitulating the in vivo tumour environment. RNA sequencing on all 3 cell lines in mono and co-culture is currently in progress to identify differentially expressed genes in medulloblastoma cells upon astrocytic and brain ECM crosstalk. We hypothesise that biochemical signalling underlying this communication network will reveal putative therapeutic vulnerabilities.
MATHEMATICAL MODELLING OF SURVIVAL IN LOW GRADE GLIOMAS AT MALIGNANT TRANSFORMATION WITH XGBOOST
Authors: Tan Ms Lily , Ruﬄe Dr James , Mohinta Ms Samia , Rees Dr Jeremy , Brandner Prof Sebastian , Nachev Prof Parashkev , Hyare Dr Harpeet 
Published: October 2024

Abstract

AIMS
To develop non-linear machine learning models using the XGBoost algorithm to predict a continuous (overall survival (OS) and a binary survival outcome (OS &gt; 5 years) using clinical, molecular and genetic, and radiomic data.

METHOD
Patients with LGGs treated at a single institution (2005-2020) with histology and MRIs at the time of malignant transformation (MT) were retrospectively included in this study. MRIs underwent in-house tumour segmentation pipeline with radiomic feature extraction of whole-tumour, enhancing, non-enhancing and oedema components, and masked disconnectome map components. Patients were split into training and testing sets for the development of the survival models, which were assessed with mean absolute error (MAE) and root mean square error (RMSE) for the prediction of OS; and receiver operating characteristics analysis for the prediction of OS &gt; 5 years.

RESULTS
Of 553 patients, 415 patients were included in the training set and 138 patients in the testing set. The XGB Regressor model was able to predict overall survival (OS) from the time of malignant transformation (tMRI) with an MAE of 953 days (RMSE: 1163 days). The XGB Classiﬁer model was able to predict the probability of OS &gt; 5 years from tMRI with an accuracy of 64% (sensitivity: 58%, speciﬁcity: 70%). Age, IDH1 mutation, 1p/19q co- deletion, regularity of tumour shape, and disconnectome-related perilesional components were most predictive of survival outcome.

CONCLUSION
This study has investigated the predictive capabilities of clinical, molecular and genetic, and radiomic data to develop survival analysis models, using XGBoost, to predict OS and OS &gt; 5 years in patients with LGG at tMRI. We corroborate previous ﬁndings that age, 1p/19q co-deletion and IDH1 mutation are positive prognosticators for survival. However, further investigation into the radiomics of the disconnectome, especially of the perilesional oedema compartment, presents an intriguing and novel avenue for survival analysis of patients with LGG.
ANALYSING THE RATE OF RECURRENCE AND LEPTOMENINGEAL DISEASE IN POSTERIOR FOSSA BRAIN METASTASES FOLLOWING POSTOPERATIVE RADIOTHERAPY- SINGLE CENTRE EXPERIENCE
Authors: Hegazy Dr Farida , Wong Dr Helen , Forshaw Mrs Michelle , May Dr Chloe , Shenoy Dr Aditya , Mehta Dr Shaveta 
Published: October 2024

Abstract

AIMS
The management of posterior fossa brain metastases is complex and necessitates a multidisciplinary approach involving neurosurgeons and oncologists. Post-operative radiotherapy (PORT) to surgical cavity has demonstrated positive oncologic outcomes as well as preserving cognitive function when compared to conventional whole brain radiation therapy. However, larger post-operative volumes in posterior fossa and greater target volume uncertainty due to presence of pseudomeningocele may result in an increased risk of local recurrence (LR) and leptomeningeal disease (LMD). The aim of this retrospective single centre study was to determine the rates of LR and LMD in patients with posterior fossa metastases who underwent PORT to surgical cavity.

METHOD
Retrospective analysis of data of patient who underwent PORT in between 2017-2022, for posterior fossa brain metastases at our centre. Clinical, imaging and radiotherapy data was collected from electronic medical records. Statistical analysis was performed using SPSS Statistics version 28.0.1.

RESULTS
We identiﬁed 42 patients meeting the study criteria. The median age of the patients was 60.5 years. 71.4% of patients were females, while 28.6% were males. 52.4% of patients had pseudomeningocoele on their radiotherapy planning scans. The median time gap between the date of surgery and initiation of radiotherapy was 34.5 days. 20 out of 42 (47.6%) patients had local recurrence of a posterior fossa brain metastasis and 7 out of 42 (16.7%) patients developed LMD. Out of 7 patients with LMD, 4 patients had pseudomeningocoele present at the time of PORT. The timing of radiotherapy after surgery (≤4 weeks or &gt;4 weeks) showed no statistically signiﬁcant impact on LR (p-value: 0.413, log-rank test).

CONCLUSION
The risk of LR remains high despite PORT. This study highlights the challenges in management of posterior fossa metastases. High LR and LMD rates underscore the need for improved treatment strategies.
VALIDATION OF 2HG-TARGETTED MR SPECTROSCOPY FOR IDENTIFYING IDH-MUTANT GLIOMAS
Authors: Langsen Mr Michael , Waldman Prof Adam , Thompson Dr Gerard , Vallatos Dr Antoine , Thrippleton Dr Michael 
Published: October 2024

Abstract

AIMS
Diffuse gliomas, the most common adult primary brain tumour, are classiﬁed by their histological and molecular characteristics and genetic proﬁle. Isocitrate dehydrogenase (IDH) mutant gliomas correlate with longer mean survival and progression-free survival time. In tumour cells, IDH mutations lead to metabolic changes and the production of oncometabolite 2-hydroxyglutarate (2HG). MR spectroscopy (MRS) can assess metabolic changes in disease states in-vivo and non-invasively. In this study, we demonstrate a validation pathway for two advanced MRS methods to be used as IDH-mutation biomarkers in clinic.

METHOD
Simulated, phantom, and healthy volunteer experiments were performed to optimise and validate three MRS sequences tuned for measuring 2HG. A PRESS sequence was used with TR/TE of 2500/97 ms aiming at the 2HG peaks around 2.25 ppm. An edited PRESS sequence, named MEGA-PRESS, tailored to 2HG 4.02 ppm peak was used with TR/TE of 3000/68 ms, 128 averages, and with editing pulses at 1.9 and 7.5 ppm. A long TE semi-LASER MRS sequence, with improved voxel localisation, was also used (TR/TE: 2500/110 ms).

RESULTS
Simulations were performed to ﬁnd optimised sequence parameters and to develop basis sets for analysing the phantom and healthy volunteer acquisitions. Tumour-mimicking phantoms with variable concentrations of 2HG and cystathionine were created and validated with 800 MHz NMR spectroscopy. Phantoms were then used to assess the sensitivity and speciﬁcity of the MRS for 2HG and cystathionine. MEGA-PRESS proved Synthetic in-vivo 2HG spectra, combined from healthy volunteers and simulated or phantom-2HG spectra, were used to assess the spectral quality needed to reliably measure 2HG.

CONCLUSION
MEGA-PRESS proved to be the most robust MRS method and demonstrated accurate and precise measurement of phantom and synthetic 2HG with acceptable SNR. Clinical validation of the technique will need to be performed on LGG patient population, and the overall accuracy will be compared with patient IDH mutation status.
MENINGIOMA SIZE IS POSITIVELY CORRELATED WITH TUMOR WHO GRADE
Authors: Kocyigit Dr Said , Orhun Dr Omer , Yasar Dr Ahmet Harun , Danyeli Dr Ayca Ersen , Dincer Prof Alp , Pamir Prof Necmettin , Ozduman Prof Koray 
Published: October 2024

Abstract

AIMS
It is well established that the surgical outcome is poorer in larger meningiomas. Vascular/ neural encasement and bone/dural/vascular invasion complicate surgical resection. Nevertheless, it is also likely that meningiomas will become biologically more aggressive with increasing size and tumor cell burden. To prove this hypothesis we studied radiological features of 316 meningiomas and correlated these features with tumor WHO-grade.

METHOD
316 meningioma patients who were operated on and who received pathological diagnoses at one single institution were analyzed. Pathological grading was revised by one single neuropathologist according to WHO 2021 criteria. 123 high-grade (WHO grade 2 and 3) patients were initially selected and later substituted with a further 193 age and anatomical-location-matched individuals. Preoperative MRI studies were analyzed for size, hyperostosis, intratumoral calciﬁcation, mass effect, peritumoral edema, shape (globular/en-plaque), lobulation, cystic component, intratumoral heterogeneity, dural tail, and necrosis/hemorrhage. Univariate analysis as well as logistic regression were performed.

RESULTS
High-grade meningiomas were signiﬁcantly more common to have lobulation (p: 7.111 x 10-8), necrosis/hemorrhage (p: 1.176 x 10-6), peritumoral edema (p: 3.421 x 10-6), intratumoral heterogeneity (p: 1.201 x 10-5), mass effect (p: 0.0002408), and cystic component (p: 0.003519) compared to WHO grade 1 meningiomas. Logistic regression indicated that tumor volume was an independent and signiﬁcant parameter. High-grade tumors were signiﬁcantly larger (40.83 cm3 vs 22.18 cm3, p: 3.518 x 10-6). Skull base meningiomas were of signiﬁcantly lower grade (p: 0.001318). Mean volume was signiﬁcantly higher in high-grade meningiomas. Mean tumor volume varied signiﬁcantly among histopathological subtypes but was highest in anaplastic and atypical subtypes. Tumor volume was strongly correlated with mitosis (p: 2.353 x 10-6), hypercellularity (p: 1.22 x 10-4), spontaneous necrosis (p: 3.273 x 10-4), brain invasion (p: 0.02491), macronucleus (p: 0.05327), small cell (p: 0.09425), and ki-67 levels (p: 2x10-16).

CONCLUSION
Tumor size is strongly correlated with WHO grade in meningiomas.