bluuebunny/crossref_metadata_2025 huggingface dataset:
The essential oil blend Agolin Ruminant L reduces methane production in vitro and in vivo when included in the drinking water of cattle
Authors: Batley Ryan J , Romanzini Eliéder P , da Silva Kawane D , de Souza William L , Quigley Simon P , Harper Karen J , Trotter Mark G , Bernardes Priscila A , Naiker Mani , Costa Diogo F A
Published: October 2024

Two experiments were conducted to determine the potential for the essential oil blend Agolin Ruminant L (Agolin) to reduce enteric methane (CH4) emissions from beef cattle when delivered via drinking water. Experiment 1 evaluated aqueous solutions of Agolin (50 mg/L) and a nonprotein nitrogen and mineral solution (uPRO ORANGE [uPRO]; 1.7 mL/L) individually and in combination, where Agolin was added to concentrated uPRO at 3%, 4.5%, and 6% Agolin (w/w) prior to dilution with water at 1.7 mL/L, for a total of 5 treatments. These were incubated for 48 h with a medium-quality Rhodes grass (Chloris gayana) hay substrate, with gas production, CH4 concentration in gas, and digestibility measured in vitro. In experiment 2, Droughtmaster steers (n = 24) were fed a basal diet of Rhodes grass hay and were allocated to 1 of 3 water treatments (n = 8 per treatment) supplemented with either uPRO (2.27 mL uPRO/L water), or 1 of 2 inclusion rates of Agolin in combination with uPRO (2.27 mL uPRO and 6 µL Agolin/L water or 2.27 mL uPRO and 24 µL Agolin/L water) with enteric CH4 emissions, feed and water intake, and live-weight gain (LWG) measured over 56 d. In experiment 1, the inclusion of Agolin in uPRO at 6% (w/w) resulted in a reduction in CH4 production (15.8%; P = 0.003) and the proportion of CH4 in the gas produced (24.5%; P < 0.001). In experiment 2, steers consuming the lower quantity of Agolin via drinking water had a 16.4% (P = 0.0027) reduction in CH4 production over the experiment, declining from 140 g/d during week 1 to 117 g/d in week 8. This inclusion rate of Agolin in the drinking water also resulted in a 25 g (17.6%) CH4/d decrease in emissions by steers compared to control steers (P = 0.0205). However, no significant differences in CH4 yield (g CH4/kg dry matter intake), or CH4 intensity (g CH4/kg LWG) by steers were observed between treatments. These results demonstrated that Agolin reduces CH4 emissions when mixed in an aqueous solution under in vitro and in vivo conditions, providing a potential method to reduce enteric CH4 emissions from cattle in extensive production systems.
Mitochondria–giant lipid droplet proximity and autophagy suppression in nitrogen-depleted oleaginous yeast Lipomyces starkeyi cells
Authors: Duan Lan , Togou Akinobu , Ohta Keisuke , Okamoto Koji
Published: October 2024

Balancing energy production and storage is a fundamental process critical for cellular homeostasis in most eukaryotes that relies on the intimate interplay between mitochondria and lipid droplets (LDs). In the oleaginous yeast Lipomyces starkeyi under nitrogen starvation, LD forms a single giant spherical structure that is easily visible under a light microscope. Currently, how mitochondria behave in L. starkeyi cells undergoing giant LD formation remains unknown. Here we show that mitochondria transition from fragments to elongated tubules and sheet-like structures that are in close proximity to a giant LD in nitrogen-depleted L. starkeyi cells. Under the same conditions, mitochondrial degradation and autophagy are strongly suppressed, suggesting that these catabolic events are not required for giant LD formation. Conversely, carbon-depleted cells suppress mitochondrial elongation and LD expansion, whereas they promote mitochondrial degradation and autophagy. We propose a potential link of mitochondrial proximity and autophagic suppression to giant LD formation.
Modes of Securitization and Desecuritization of Transnational Kinship Ties: Overseas Chinese in Southeast Asia amidst Rising Chinese Power
Authors: Han Enze
Published: October 2024

This paper explores under what context the transnational ethnic kinship ties between the overseas Chinese in Southeast Asia and China have not led to their securitization and in what context they have. As the rising great power with exponential economic growth for the past few decades, China has transformed itself from a dirt-poor backwater state to the second largest economy in the world and is also seemingly on the way to reclaim the historical dominant status in East and Southeast Asia. During this process, overseas Chinese in various home states in Southeast Asia have not experienced a uniform securitization of their kinship ties. This paper investigates some of the dynamic patterns about overseas Chinese in Southeast Asia’s relationship between the changing kin state and their home states in the recent past. Focusing on how states in Southeast Asia maintain different types of relations with China in the context of the latter’s rising, this paper contends that the ways in which overseas Chinese communities in the region manage their political space and negotiate their belonging are a function of a combination of international structural changes and domestic political factors. Empirically, this paper compares three states of Southeast Asia—Thailand, Myanmar, and Indonesia—in the different ways of their treatment of the ethnic Chinese, as well as the responding strategies utilized by the ethnic Chinese in navigating their political space and belonging.
The Vaginal Penetration Skills Scale (VPSS): a paradigm shift in genito-pelvic pain/penetration disorder screening, assessment, and stratification
Authors: Maldonado Mariana , Figueira Gabriel Loureiro , Nardi Antonio E , Sardinha Aline
Published: October 2024

Background

Receptive vaginal penetration skills have been implicated in the etiology, explanatory models, and treatment of genito-pelvic pain penetration disorder (GPPPD). However, there are no psychometric skills measures designed to screen, assess, and stratify GPPPD.

Aim

We aimed to develop and psychometrically evaluate a new scale—the Vaginal Penetration Skills Scale (VPSS)—to screen, assess, and stratify GPPPD.

Methods

This study included 148 Brazilian females with GPPPD symptoms (113 lifelong and 35 acquired) and 251 Brazilian females without sexual complaints. We conducted factor analyses considering all participants (n = 399). Then, we conducted latent class analysis within the GPPPD group to identify clusters of individuals with similar VPSS profiles. We assessed convergent validity through intercorrelation with the Brazilian versions of the Female Genital Self-Image Scale (FGSIS) and the 6-item Female Sexual Function Index (FSFI-6).

Outcomes

We developed complete and short-form versions of the VPSS (VPSS-29 and VPSS-SF11, respectively), each with 3 dimensions, to screen, assess, and stratify GPPPD.

Results

Factor analysis yielded a 3-factor VPSS model with the “Nonsexual Genital Self-Exploration,” “Nonsexual Vaginal Penetration Skills,” and “Sexual Vaginal Penetration Skills” dimensions for both VPSS versions. The reliability was excellent for the VPSS-29 (ω = 0.981, α = 0.981) and the VPSS-SF11 (ω = 0.959, α = 0.961). All 3 dimensions could detect significant differences between patients with GPPPD and healthy females. They also differentiated the patients with GPPPD, distinguishing gradient levels. For convergent validity, we found moderate to strong correlations (rho = 0.715–0.745) between the VPSS, FGSIS, and FSFI-6.

Clinical Implications

The VPSS can be applied easily in both clinical and research settings.

Strengths and Limitations

The VPSS provides a concise and thorough evaluation of receptive vaginal penetration skills in both sexual and nonsexual contexts among patients with GPPPD. The sample had limited diversity regarding gender and sexual orientation; therefore, it is important to validate the use of this scale in populations beyond the cisgender heterosexual female population to ensure its applicability in diverse settings.

Conclusion

These results support the reliability and psychometric validity of the VPSS as a self-report measure to screen, assess, and stratify GPPPD symptoms.
Deep Ancestral Introgressions between Ovine Species Shape Sheep Genomes via Argali-Mediated Gene Flow
Authors: Lv Feng-Hua , Wang Dong-Feng , Zhao Si-Yi , Lv Xiao-Yang , Sun Wei , Nielsen Rasmus , Li Meng-Hua
Published: October 2024

Previous studies revealed extensive genetic introgression between Ovis species, which affects genetic adaptation and morphological traits. However, the exact evolutionary scenarios underlying the hybridization between sheep and allopatric wild relatives remain unknown. To address this problem, we here integrate the reference genomes of several ovine and caprine species: domestic sheep, argali, bighorn sheep, snow sheep, and domestic goats. Additionally, we use 856 whole genomes representing 169 domestic sheep populations and their six wild relatives: Asiatic mouflon, urial, argali, snow sheep, thinhorn sheep, and bighorn sheep. We implement a comprehensive set of analyses to test introgression among these species. We infer that the argali lineage originated ∼3.08 to 3.35 Mya and hybridized with the ancestor of Pachyceriforms (e.g. bighorn sheep and snow sheep) at ∼1.56 Mya. Previous studies showed apparent introgression from North American Pachyceriforms into the Bashibai sheep, a Chinese native sheep breed, despite of their wide geographic separation. We show here that, in fact, the apparent introgression from the Pachyceriforms into Bashibai can be explained by the old introgression from Pachyceriforms into argali and subsequent recent introgression from argali into Bashibai. Our results illustrate the challenges of estimating complex introgression histories and provide an example of how indirect and direct introgression can be distinguished.
Yunfuconcha new genus, a possible stem-archiheterodont bivalve from the Ordovician of Guangdong, South China
Authors: Zhang Ren-jie , Johnston Paul A , Niu Zhi-jun , Li Chu-an , Wang Zhi-hong , Hu Kun , Song Fang , He Yao-yan , He Jin-lan , Lin Xiao-ming , Yang Wen-qiang
Published: October 2024

Yunfuconcha bimenta, a new genus and species of bivalve from the Ordovician of western Guangdong, China, is described. Its unusual hinge consists of a palaeotaxodont-like dentition anteriorly and a heteroconch-like dentition posteriorly. The posterior hinge area exhibits a remarkable, broad, deeply inset, concave ligament area, which is reminiscent of the ventrally expanded ligament of some Recent and fossil lucinoids and the triangular resilifer in late Palaeozoic crassatellid heteroconchs. Lamellar posterior teeth and sockets complete the posterior dentition. The unusual combination of features, normally associated with either the Order Cardiolariatida (used here in place of Order ‘Afghanodesmatida’—the type genus Afghanodesma, is known only from wax impressions rendering it and its nominal higher taxa invalid) or various crassatelloids and lucinoids, make systematic placement of Yunfuconcha n. gen. uncertain below subclass rank. In view of presumed derived heteroconch-like characters of the posterior hinge, we place Yunfuconcha n. gen. in the Subclass Autobranchia, possibly as a stem archiheterodont or a stem heteroconch.
THE MOLECULAR HISTORY OF IDH-MUTANT ASTROCYTOMAS WITHOUT ADJUVANT TREATMENT
Authors: Ng Prof Ho Keung , Shi Dr Zhi-Feng , Li Dr Kay
Published: October 2024

AIMS

Hypermutation and malignant transformation are potential complications arising from temozolomide treatment of IDH-mutant gliomas. However, the natural history of IDH-mutant low-grade gliomas without temozolomide treatment is relatively un-studied. We set out to study the molecular history of paired IDH-mutant astrocytomas without adjuvant treatment in the interim.

METHOD

We retrieved retrospectively from our hospitals paired tumors from 19 patients with IDH-mutant, 1p19q noncodeleted Grade 2 astrocytomas where no interim adjuvant treatment with either temozolomide or radiotherapy was given between primary and ﬁrst recurrences. Two patients had multiple resected recurrences and radiotherapy but not temozolomide was given before the last specimens were resected. We studied the natural molecular history of these low-grade IDH-mutant astrocytomas without pressure of temozolomide with methylation proﬁling and copy number variation (CNV) analyses, target DNA sequencing, TERTp sequencing, FISH for ALT and selected biomarkers.

RESULTS

Recurrences were mostly higher grades (15/19 patients) and characterized by new CNVs not present in the primary tumors (17/19 cases). Few novel mutations were identiﬁed in recurrences. Tumors from 17/19 (89.5%) patients showed either CDKN2A homozygous deletion, MYC or PDGFRA ampliﬁcation at recurrences. There was no case of hypermutation. Phylogenetic trees constructed for tumors for the two patients with multiple recurrences showed a conserved evolution pattern.

CONCLUSION

In summary, our studies demonstrated in contrast to the phenomenon of temozolomide-induced hypermutation, IDH-mutant, 1p19q non-codeleted Grade 2 astrocytomas which were not treated by temozolomide instead acquired new CNVs at tumor recurrences. These ﬁndings improve our understanding of the molecular life history of IDH-mutant astrocytomas.
DEVELOPING CEREBROSPINAL ﬂUID METABOLOMIC BIOMARKERS FOR MINIMAL RESIDUAL DISEASE AND RELAPSE IN EPENDYMOMA AND MEDULLOBLASTOMA
Authors: Whitby Dr Alison , Shastri Mrs Bhoomi , Halsey Prof Christina , Grundy Prof Richard , Kim Dr Dong-Hyun , Dandapani Dr Madhumita
Published: October 2024

AIMS

Relapse rates of 30% and 50% in medulloblastoma and ependymoma lead to poor outcomes for paediatric brain tumours. Occurring usually within two years, relapses imply minimal residual disease (MRD) is present below the imaging detection threshold. Patient outcomes might be improved by diagnosing MRD using a sensitive, minimally invasive cerebrospinal ﬂuid (CSF) liquid biopsy, as CSF is proximal to tumour. Metabolites arising from aberrant cancer metabolism may be biomarkers in CSF.

METHOD

With only 25µl CSF, extracted with 75µl methanol, liquid chromatography coupled with tandem high-resolution mass spectrometry (LC-MS/MS) could differentiate these paediatric brain tumours (n=47; day 14 post-surgery) from controls (n=49).

RESULTS

Fourteen metabolites were increased in abundance in tumours and four decreased compared to controls. These included amino acids and derivatives (n=8), metabolites in one carbon metabolism (n=1), carnitine cycle (n=2), aerobic glycolysis (n=2), purine catabolism (n=2), ascorbate degradation (n=1) and creatinine synthesis (n=2). From those, betaine/creatinine ratio gave an area under the curve (AUC) of 0.96 (excellent) in receiver operating curve analysis. Using a cut-off ratio of 0.1775 for discriminating brain tumours from controls, had sensitivity and speciﬁcity of 92% and 89%. Speciﬁcally identifying tumours, a ratio of betaine/threonate with cut-off 2.1514 discriminated ependymomas from controls (sensitivity/speciﬁcity 92%/91%). A ratio of malic acid/hypoxanthine with cut-off 0.04429 discriminated medulloblastomas from controls (sensitivity/speciﬁcity 100%/98%). Medulloblastomas (n=14) were largely similar to ependymomas (n=33); nevertheless, three metabolites met the criteria of corrected p<0.05. A ratio of glutarate semialdehyde/malic acid with cut-off 0.04243 discriminated ependymomas from medulloblastomas (sensitivity/speciﬁcity 79%/82%) in a good model (AUC 0.85).

CONCLUSION

This is the ﬁrst report of CSF metabolites in ependymoma. Ratios between metabolites levels could be useful as biomarkers to detect brain tumours and distinguish brain tumour type speciﬁcally and sensitively. Further work to develop a liquid biopsy test for the detection of MRD is ongoing.
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

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

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

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

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

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 <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 <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

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

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 > 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 > 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 > 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 > 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

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 >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

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

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.
OCCUPATIONAL THERAPY PRE-ASSESSMENT OF LOW GRADE GLIOMA PATIENT WITH COMPLEX NEEDS ALMOST HALVES POST-OPERATIVE LENGTH OF STAY
Authors: Laycock Ms Claire , Sokhal Ms Sunita , Mathew Mr Ryan
Published: October 2024

AIMS

Due to tumour eloquence, patients with low grade gliomas (LGGs) often have complex Occupational Therapy (OT) needs post-operatively. This need can impact length of stay and OT resource. Limited studies have focused on pre-assessment for this patient group. To address these challenges, we aimed to identify the impact of a newly-introduced Occupational Therapy (OT) pre-surgical assessment service for low grade glioma patients.

METHOD

Patients (n=16, prospective, consecutive, Jan-Jul 2023) planned for LGG surgery at Leeds Teaching Hospitals NHS Trust were offered an OT pre-assessment. Mixed methods analysis. Assessments and data collected included existing needs and deﬁcits, length of stay, and OT sessions (number/contacts, time spent). Comparison was made to patients (n=16, retrospective, consecutive, Jun-Dec 2022) planned for LGG surgery who had not received this service. Complexity was deﬁned using standardised, clinically-accepted factors (social, cognitive and/or physical deﬁcits).

RESULTS

Patients with complex needs (4 in each group) beneﬁtted signiﬁcantly from OT pre-assessment with reductions in: length of stay (11.9 v 6.5 days, 45.4% decrease), median time spent (134 v 95 mins, 29.1% decrease), median number of contacts (5.4 v 3.4, 37.0% decrease). Patient, surgeon, CNS and other AHP feedback was overwhelm-ingly positive.

CONCLUSION

Patients with complex needs undergoing surgery for low grade gliomas signiﬁcantly beneﬁt from pre- assessment; reducing length of stay and liberating occupational therapy resource. This also reduces costs and increases productivity/eﬃciency. Further work in more LGG patients, other brain tumour patients, and the identiﬁcation of key pre-assessment variables and interventions will guide the development of the service.
SINGLE INSTITUTION RETROSPECTIVE ANALYSIS OF COMPLICATIONS ASSOCIATED WITH SURGICAL DEBULKING OF BRAIN METASTASIS
Authors: Liew Dr Yong Yie , Hazra Mr Abhijit , Kannan Mr Siddarth
Published: October 2024

AIMS

Surgical resection of brain metastasis is associated with complications, which worsen patient’s quality of life, results in oncological treatment delays and death. Surgical complication data aids decision making, leads to objective risk beneﬁt analysis and informed consent. The aim of this study is to quantify rates, types and risk factors for complications related to surgical debulking of brain metastasis.

METHOD

Retrospective analysis on adult patients with brain metastasis, who underwent surgical debulking between 2017 and 2023 at Royal Preston Hospital. Data collected included demographics, diagnosis, 30-days post-operative complications, 30-days mortality, 30-days post-operative palliation, primary tumour, Karnofsky-Performance Score (KPS), ﬁrst vs. repeat resection, use of drain and type of suture materials etc. Univariate analysis was carried out using Graphpad software.

RESULTS

Two-hundred and twenty-seven patients qualiﬁed. The most common primaries were lung (n=93, 41%), breast (n=43, 18.9%), and skin (n=31, 13.7%). The most common complications were Hospital-acquired pneumonia (HAP) (n=27, 11.9%), surgical site infection (SSI) (n=19, 8.4%), wound dehiscence (n=14, 6.2%), thromboembolic events (n=12, 5.3%) and CSF leak (n=8, 3.5%). Thirty days mortality and post-operative palliation (due to surgical complications) were both 3.5% each (n=8). Two-hundred and six (93.2%) had KPS ³70 whilst 15 (6.8%) had KPS < 70 [range 30-60 pre-operatively (median 60)). KPS < 70 was statistically signiﬁcant for post-operative palliation (p=0.01), HAP (0=0.02) and urine infection (p=0.002), but not for 30-day mortality. Twenty-ﬁve (11.1%) patients undergoing repeat resections, experienced higher wound infections (p=0.002).

CONCLUSION

Surgical debulking is associated with signiﬁcant post-operative complications, with 7% either dying or not receiving any further treatment, 18.1% percent developing serious wound complications (SSI, CSF leak, Wound dehiscence) and 19.4% experiencing signiﬁcant medical complications (HAP/UTI/Thromboembolism). Pre- operative KPS < 70 and repeat resections are associated with statistically increased risk of complications.
RE-VISITING BIOPSIES FOR SUSPECTED CNS LYMPHOMAS: TO BIOPSY OR NOT TO BIOPSY?
Authors: Mathew Mr Mesi , Rajaraman Mr Chittoor , Achawal Mr Shailendra , Razak Mr Adam , O’Reilly Mr Gerry
Published: October 2024

AIMS

It is a common practice to get a histological diagnosis before treatment of suspected CNS (central nervous system) lymphoma. Should CNS lesions be routinely biopsied in patients with background systemic lymphoma?

METHOD

A 10-year retrospective review of biopsy-proven CNS lymphoma was conducted. Data was analyzed using SPSS for Windows, version 25 (SPSS, Inc., Chicago, Illinois, USA), and a p-value < 0.05 was considered signiﬁcant for the appropriate test statistic.

RESULTS

Patients with background systemic lymphoma whose brain MRI appearances were in favour of lymphoma after MDT discussion all had histologically-proven lymphoma after brain biopsy. Pre-biopsy MDT diagnosis was congruent with post-biopsy histology in 87.6% of cranial lesions (p-value 0.003) and 40% of spinal lymphomas (p-value 0.002). Secondary CNS lymphoma was seen in 21.2%. Stereotactic brain biopsy was the most common biopsy technique for cranial lesions (79.8%). Histology was Diffuse B Cell Lymphoma in 93% of cases. The mean Ki67 percentage for cranial lymphomas was higher than that of spine (p-value 0.028) The complication rate for cranial biopsy was 8.9%. Transient motor deﬁcits (4.4%) and post-operative haematoma (2.2%) were the most common. The 24-hour post-brain biopsy mortality rate was 1.1%, while overall 30-day post-op mortality rate was 4.4%. The mean percentage of Ki67 was higher among patients who had complications (p-value 0.001).

CONCLUSION

In a setting of properly constituted neurooncology MDT, a sub-set of patients with suspected brain lymphoma and background systemic lymphoma might not require brain biopsy.

KEY WORDS

Lymphoma, Brain, Spine, Biopsy, Complication
EVALUATING GLIOMA PATIENT PERCEPTIONS TOWARDS REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION FOR REHABILITATION
Authors: Ali Mr Ahmad , Aliaga-Arias Mr Jahard , Zakaria Mr Rasheed , Jenkinson Prof Michael , Pescador Ms Ana Mirallave , Vergani Mr Francesco , Lavrador Mr Jose
Published: October 2024

AIMS

Repetitive Transcranial Magnetic Stimulation (rTMS) is established for depression, chronic pain, and motor rehabilitation after stroke. It is an emerging tool for other purposes including cognitive rehabilitation. Recent evidence supports its use for motor rehabilitation after brain surgery. We sought to evaluate patient perceptions towards rTMS.

METHOD

Two studies were undertaken. Group 1 – patients who received seven days of rTMS for motor rehabilitation for post-operative weakness (MRC 0-1 in any limb) following resection of a glioma or other resective pathology were prospectively surveyed on the last day of their rTMS treatment, as well as their next of kin (NOK). Group 2 – patients who had previously been treated for a glioma but did not receive rTMS were retrospectively surveyed through two brain tumour charities, as well as their NOK.

RESULTS

Group1: 21 responses. 11 patients, 10 NOK. Commonest pathology was glioblastoma(n=3). Group2: 24 responses. 16 patients, 8 NOK. Commonest pathology was grade 2 glioma(n=7). Most Group1 respondents reported a positive experience with rTMS(n=15). Group1 patients experienced substantial subjective improvements in motor functioning(n=6), some improvements(n=3), or no change(n=2). None reported worsening. Experiencing adverse symptoms (e.g. headache) was associated with reduced likelihood of motor improvements(p=0.01). Most improvements were in gross rather than ﬁner motor domains. Patients in Group2 were accepting of longer and more frequent rTMS sessions than Group1(p=0.03 and p=0.01 respectively). The commonest concerns raised pertained to seizures, side effects, and geographic availability. The commonest hope raised pertained to cognitive or motor improvements.

CONCLUSION

rTMS is well-tolerated and patients and their NOK support its use. Respondents would ﬁnd longer and more sessions acceptable. Understandably, there is less tolerance for rTMS in the early post-operative period. However, enthusiasm for rTMS is substantial in the later stable post-operative phases. Our ﬁndings support the further development of rTMS as a tool for improving patient rehabilitation.