tbuckley/cabot-search huggingface dataset:
USING CCA-MRI TO PREDICT RESPONSE TO STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES
Authors: Dr James de Boisanger, Ms Julia Henderson, Mr Yifan Guo, Dr Matthew Blackledge, Dr Emma Harris, Dr Philip Benjamin, Dr Andrew Mackinnon, Dr Philip Rich, Mr Martin Brewer, Dr Francesca Solda, Dr Antonia Creak, Dr Liam Welsh, Dr Nicola Rosenfelder
Journal: Neuro-Oncology (2024)

Abstract AIMS Brain metastases (BMs) from different primary cancers may have different radiosensitivity, for example melanoma and renal cell cancers are considered more radioresistant. Radiosensitivity is determined by the intrinsic radiobiological properties of tumours, which include vascularisation and oxygenation. Contrast Clearance Analysis (CCA)-MRI measures delayed contrast behaviour to offer a window into tumour vascularity. The CCA colour map shows areas of contrast accumulation (red), suggesting vascular damage, and rapid contrast clearance (blue), suggesting intact and increased vasculature. We aim to interrogate CCA-MRIs pre-stereotactic radiosurgery (SRS) for differences in contrast handling between BMs from different primaries. METHOD 10 patients, with 70 BMs, were included in the study. All had CCA-MRIs pre-SRS as part of their planning-MRIs. Radiotherapy-planning-CT scans were fused with the planning-post-contrast-T1-MRI, with consultant clinical oncologist-approved contoured targets, and the CCA-images. Threshold analysis was performed to obtain proportions of red and blue within the enhancing areas of each tumour. RESULTS There was a signiﬁcant difference in the proportion of blue between BMs from different primaries (p=0.0294). In pairwise-comparisons, only the difference between lung and renal was signiﬁcant (mean difference 37.65%, p=0.0390). The difference between the proportion of red was also signiﬁcant overall (p=0.0084) (Figure 2). In pairwise comparisons, renal was signiﬁcantly different from lung, breast and melanoma (mean difference 12.65%, p=0.0161; mean difference 12.97%, p=0.0154; and mean difference 11.29%, p=0.0169, respectively). CONCLUSION This study offers a novel insight into the vascularity of BMs from different primaries. Further research to explore if these ﬁndings can explain differential SRS outcomes is underway.
SUPERSOFT SPONGE-LIKE CRYOGEL AS AN IMPLANT TO TREAT GLIOBLASTOMA
Authors: Mr Yu Wang, Dr Vadim Le Joncour, Prof Pirjo Laakkonen, Dr Ben Newland
Journal: Neuro-Oncology (2024)

Abstract AIMS Create cylindrical cryogels with well-deﬁned size. Investigate clemastine drug loading capicaty and drug release patterns. Investigate in vitro and in vivo safety and antitumor eﬃcacy. METHOD A 3D printed template was designed and printed to make cylindrical shape cryogels. The morphology of cryogels was characterized by bright ﬁeld photos, SEM, FTIR and confocal microscopy photos. The mechanical property was evaluated by uniaxial compression tests. The orthotropic glioblastoma tumor model was established by engrafting BT12 human glioblastoma stem cells intracerebrally into immunocompromised nude mice. The tumor was surgically removed after two weeks and the cryogel was implanted into the resection cavity. Animals were euthanized after two weeks, and their brains were collected for the immunohistochemistry. RESULTS Cylindrical cryogels were prepared to exactly ﬁt the biopsy resection cavity in the mouse glioblastoma tumor resected model. The macropore structure in the cryogel was observed under confocal microscopy. Young’s modulus of the cryogel was only 1.6 kPa. The loading capacity of clemastine in one cryogel was more than 100 μg. Clemastine could be sustained released for around a week. In vitro cell viability studies showed that empty cryogels were not toxic to the tumor cells and drug loaded cryogels killed the tumor cells in a time and concentration dependent manner. In vivo studies further conﬁrmed that cryogels could be safely implanted into the brain. Although the implantation of clemastine loaded cryogels did not prevent the growth of the primary tumor, it reduced the amount of invasion tumor cells compared with the mice only resected the tumor. CONCLUSION Cryogels were easily created by the 3D printed templates. The soft material avoided mechanical mismatch with the brain tissue. The cryogel did not show any toxicity in in vitro and in vivo studies, which indicated it would be a promising material to be implanted into the brain.
TARGETED THERAPY IN DIFFUSE INTRINSIC PONTINE GLIOMA: A COMPREHENSIVE REVIEW OF MONOCLONAL ANTIBODIES
Authors: Ms Christie Dib, Mr Johnny Zaatar, Ms Karmen Sarouﬁne, Ms Linda Elias, Mr Michel Alagha, Ms Odette El Ghawi, Ms Jana Khalil, Mr Yves Nakhle, Ms Elissa Haidar, Mr John-Victor El Khoury, Dr Jihad Hawi
Journal: Neuro-Oncology (2024)

Abstract AIMS Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor, marked by its poor prognosis and frequent recurrence despite conventional therapy. Our review examines the molecular landscape of DIPG, highlighting key factors driving tumor progression. We evaluate the therapeutic potential of various monoclonal antibodies (mAbs) targeting these factors, providing insights into their mechanisms and ongoing clinical trials. Our aim is to guide future investigations and immunotherapeutic strategies for DIPG. METHOD A narrative review was conducted using the PubMed database to identify relevant review articles, clinical trials, and observational studies published within the past 10 years, focusing on the use of mAbs in DIPG. The search terms “monoclonal antibodies”, “diffuse intrinsic pontine glioma”, and “targeted therapy” were employed. Additionally, a search was conducted on clinicaltrials.gov to gather information on ongoing and completed clinical trials. RESULTS Current human clinical trials on the checkpoint inhibitors anti-PD-1 (Nivolumab, Pembrolizumab, Balstilimab, Cemiplimab), anti-PD-L1 (Durvalumab), and anti-CTLA-4 (Ipilimumab, Zalifrelimab) have not demonstrated signiﬁcant improvement in overall patient survival. One major limitation has been the small sample size and limited expression of such markers in DIPG. Conversely, combination therapies involving anti-VEGF (Bevacizumab) and anti-EGFR (Nimotuzumab and Cetuximab) have shown promising results in small sample studies, but these results are not conclusive. Trials on anti-CD276 (Omburtamab) and CD40 agonist (APX005M) have shown no speciﬁc clinical or tumor outcomes in DIPG. Newer emerging agents like anti-TIM3 and anti-IL13Ra2 have shown very favorable results in in-vivo and in-vitro studies. CONCLUSION Current evidence is insuﬃcient to support the use of mAbs in DIPG. More large-size studies investigating the combinations of checkpoint inhibitors with different therapeutic agents are needed. Additionally, the promising results seen with anti-VEGF and anti-EGFR mAbs in their respective combination therapies warrant exploration in large-scale studies to draw more accurate conclusions. Furthermore, human trials should be conducted on anti-TIM3 and anti-IL13Ra2.
MGMT METHYLATION AND ITS PROGNOSTIC SIGNIﬁCANCE IN INOPERABLE IDH WILDTYPE GLIOBLASTOMA: A SIX-YEAR REVIEW AT A TERTIARY NEURO-ONCOLOGY CENTER
Authors: Dr Prajwal Ghimire, Prof Keyoumars Ashkan, Mr Jose Lavrador, Mr Francesco Vergani, Mr Ranjeev Bhangoo
Journal: Neuro-Oncology (2024)

Abstract AIMS IDH wild-type glioblastoma has the worst prognosis among glioma patients. The methylation of the O6- Methylguanine-DNA Methyltransferase (MGMT) gene is a valid biomarker for predicting response to therapy with alkylating agents and, independently, prognosis. Patients undergoing biopsy only without subsequent treatment have poor prognosis. We aimed to study the survival impact of MGMT methylation in this subset of patients. METHOD We collected six-year retrospective (2017-2023) data at a tertiary neuro-oncology center for patients undergoing biopsy as the only surgical procedure for an unresectable IDH wildtype glioblastoma. Data was collected from patient records including neuro-oncology MDT documentation. Patients were grouped into four categories according to different types of treatment received after biopsy (biopsy only, Biopsy + chemotherapy(CT), biopsy + radiotherapy(RT), biopsy + complete/incomplete STUPP, biopsy + STUPP + 2nd Line). Analysis was performed in python and R statistical software. Survival analysis was performed with Kaplan-Meier Analysis in python. RESULTS 166 glioblastoma IDH wildtype patients were included in the study with mean age of 62.5 years (M: F = 1.5: 1). 50% (n=83) patients had unmethylated MGMT status (0-5%), 29.5% (n=49) patients had methylated MGMT status (&amp;gt;15%) and 19.2% (n=32) patients had borderline methylated MGMT status (5-15%). 21%(n=35) patients did not receive any treatment post biopsy,, 6.6% (n=11) received CT only, 15% (n=25) RT only, 27% (n= 45) complete/incomplete STUPP therapy, whereas 13.2% (n=22) received STUPP therapy along with second line treatment. In biopsy only group, there was no notable difference in survival outcomes among the different methylation statuses. For biopsy and any-other-form-of-treatment groups showed a distinct trend of better survival compared to the borderline or unmethylated groups. Overall, methylated patients had better survival as compared to unmethylated or borderline groups. CONCLUSION Methylated MGMT status is a predictor for better overall survival in unresectable IDH wildtype glioblastoma patients undergoing biopsy and treatment.
DYSREGULATION OF M6A RNA METHYLATION, R-LOOPS AND THE DNA DAMAGE RESPONSE IN PAEDIATRIC HIGH-GRADE GLIOMAS
Authors: Ms Lauryn Walker, Dr Masar Radhi, Dr Helen Knight, Dr Stuart Smith
Journal: Neuro-Oncology (2024)

Abstract AIMS Paediatric high-grade gliomas (pHGG) are virtually incurable malignant brain tumours. The regulation of R- loops is necessary for ensuring genomic stability. The formation of R-loops at DNA damage sites promotes DNA repair via m6A methylation of the RNA strand. We aimed to investigate whether m6A methylation, R-loop homeostasis and the DNA damage response is dysregulated in pHGG and whether inhibitors, such as ATM inhibitors, could be potential therapeutics for pHGG. METHOD To assess the global levels of m6A, R-loops, yH2AX, total ATM and phosphorylated ATM in paediatric HGG cell lines compared to control human astrocytes, immunocytochemistry was initially performed. Immunocyto- chemistry was also performed to assess localisation between m6A and R-loops, R-loops and yH2AX, R-loops and total/phosphorylated ATM, m6A and total/phosphorylated ATM, and total/phosphorylated ATM and yH2AX in pHGG cell lines and human astrocytes. We are also exploring two ATM inhibitors, AZD1390 and AZD0156, and are currently investigating their effects on m6A methylation, R-loops and the DNA damage response in pHGG. As a molecular mechanism involving the tumour suppressor ARID1A was recently discovered that is crucial for maintaining genomic stability, we are also exploring the role of this protein in pHGG. We are also investigating the potential involvement of m6A readers in the pathogenesis of pHGG. RESULTS Immunocytochemistry revealed that dysregulation of global m6A, R-loop, yH2AX and ATM occurs in pHGG cell lines as higher levels of expression was generally observed compared to human astrocytes. Moreover, m6A, R-loops, yH2AX and ATM appear to colocalise as high Pearson’s correlation coeﬃcient values were obtained. Experiments exploring ATM inhibitors, ARID1A and m6A readers in pHGG are currently in progress, however the results will be presented. CONCLUSION It appears that dysregulation of m6A methylation, R-loop homeostasis and the DNA damage response occurs in pHGG and that molecular mechanisms involving m6A methylation and R-loops could be impaired.
EVALUATION OF AN ALLIED HEALTH PROFESSIONAL PREHABILITATION SERVICE IN NEURO-ONCOLOGY
Authors: Ms Rosie Humphreys, Ms Madeleine Farrow, Ms Charlotte Moran
Journal: Neuro-Oncology (2024)

Abstract AIMS The evidence base for the beneﬁts of prehabilitation in the cancer population is increasing. So far, the focus has been on colorectal, breast and lung cancer sites with no current research into the effects in patients with primary or secondary brain tumours. It is hypothesised that patients with brain cancer would beneﬁt from prehabilitation as current evidence demonstrates the positive effects of exercise, cognitive and language rehabilitation in this patient group. The aim of this project is to demonstrate the feasibility and impact of a two-year prehabilitation pilot service. The service comprises physiotherapy, occupational therapy and speech and language therapy for patients with brain cancer in the pre-operative phase. METHOD A pilot study was carried out at a tertiary UK neurosurgery centre. Patients over the age of 17 with a diagnosis of primary or secondary brain tumour awaiting surgery were eligible for the prehabilitation service. The impact was measured through Length of Stay, Quality of Life (EQ-5D-5L), emergency department attendances and admission rates 90 days post-surgery. RESULTS 128 patients were seen in prehabilitation from 01/11/2022 to 31/01/2024. Length of hospital stay post-surgery was lower for the prehabilitation group (0.9 days with 95% conﬁdence interval) compared to control group. A mean improvement in the EQ-5D-5L Index from pre-operative assessment to post-surgery follow up was demonstrated CONCLUSION This study reveals data demonstrating the beneﬁts of prehabilitaiton for patients with brain tumours. Prehabilitation for this patient group appears to improve clinical outcomes alongside patients’ quality of life. Future directions for the service will focus on expanding the provision to patients with spinal and benign tumours, where this is also a possibility of therapeutic need in the pre and post-operative phase.
EPIGENETIC MODULATION OF STEMNESS AND DIFFERENTIATION BY VALPROIC ACID IN MEDULLOBLASTOMA
Authors: Prof Rafael Roesler, Ms Natalia Hogetop Freire, Dr Caroline Brunetto de Farias, Dr André Brunetto, Dr Mariane Jaeger, Dr Algemir Brunetto, Dr Alice Laschuk Herlinger, Dr Lauro Gregianin
Journal: Neuro-Oncology (2024)

Abstract AIMS Changes in epigenetic processes, including histone acetylation, are proposed as key events affecting tumor cell function and the initiation and progression of pediatric brain cancers. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we report VPA-induced alterations in features related to stemness and differentiation in medulloblastoma (MB) cells. METHOD Human MB cells were treated with different concentrations of VPA and cell viability was measured with a trypan exclusion assay. Cell cycle was evaluated with ﬂow cytometry. Expansion of MB cancer stem cells (CSCs) was evaluated by a neurosphere formation assay. Reverse transcriptase polymerase chain reaction (RT-qPCR) was used to analyze mRNA expression and Western Blot to analyze protein levels. H3K9 histone acetylation (H3K9ac) was measured with immunoﬂuorescence, and chromatin Immunoprecipitation (ChIP) was used to evaluate the occupancy of gene promoter regions by H3K9ac. RESULTS VPA reduced MB cell viability and expansion of MB CSCs, induced morphological changes consistent with neuronal differentiation, and increased expression of differentiation markers tubulin beta 3 class III (TUBB3) and enolase 2 (ENO2). Expression of stemness markers SOX2 and Nestin was differentially affected by VPA in cells representative of SHH or Group 3/4 MB molecular subgroups. VPA increased H3K9ac and its occupancy of promoter regions of TP53 and CDKN1A genes. CONCLUSION Our results indicate that VPA may exert antitumor effects in MB by inﬂuencing histone acetylation, which may result in modulation of stemness and stimulation of neuronal differentiation.
IN VIVO APPLICATION OF LOCAL DRUG DELIVERY SYSTEMS AGAINST MEDULLOBLASTOMA GROUP 3 AND ATYPICAL/TERATOID/RHABOID TUMOURS
Authors: Dr Cara Moloney, Dr Phoebe McCrorie, Mr Amr ElSherbeny, Mr Harry Porter, Dr Chiara Bastiancich, Ms Hulya Bayraktutan, Dr Umut Can Oz, Prof Karin Forsberg Nilsson, Dr Betty Tyler, Prof Cameron Alexander, Dr Stuart Smith, Dr Ruman Rahman
Journal: Neuro-Oncology (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.
GENES ENCODING CELL SURFACE RECEPTORS AS NOVEL PROGNOSIS BIOMARKERS IN BRAIN TUMORS
Authors: Prof Rafael Roesler, Dr Samir Bark, Dr Rafael Badalotti, Dr Viviane Buffon, Mr Matheus Dalmolin, Prof Marcelo Fernandes, Prof Osvaldo Malafaia, Dr Gustavo Isolan
Journal: Neuro-Oncology (2024)

Abstract AIMS A number of cell surface receptors that bind growth factors, neurotransmitters, and hormones are known to inﬂuence cancer initiation and progression. For example, CD114 (also called GCSFR or CSFR), which is encoded by the CSF3R gene, is a receptor for the granulocyte colony stimulating factor (GCSF) and a marker of cancer stem cells expressed in various cancer types. Also, the γ-aminobutyric acid (GABA) type A (GABAA) receptor for the inhibitory neurotransmitter GABA is proposed to play a role in brain cancer. Here, we report how the mRNA expression levels of CSF3R, the gene that encodes CD114, and genes encoding subunits of the GABAA receptor, are related to prognosis of brain tumor patients assessed by overall survival (OS). METHOD Data were obtained from brain tumor datasets, mainly the French and The Cancer Genome Atlas (TCGA) datasets for gliomas and the Cavalli dataset for medulloblastoma. Gene expression was analyzed using the R2 Genomics Analysis and Visualization Platform. OS was calculated using the Kaplan-Meier estimate. RESULTS Levels of CSF3R⁄CD114 transcripts are higher in different types of gliomas, namely astrocytoma, pilocytic astrocytoma, and glioblastoma (GBM), in comparison to non-tumoral neural tissue. Higher expression of CSF3R in gliomas is associated with poorer outcome indicated by a shorter OS. Genes for GABAA receptor subunits associated with OS in gliomas include GABRA2, GABRA3, GABRG1, GABRG2, and GABRB3. Higher GABRA5 expression was associated with shorter patient OS in Group 3 and Group 4 medulloblastoma. CONCLUSION These ﬁndings indicate that gene expression levels of CSF3R and GABAA receptor subunits are potential biomarkers of poorer prognosis in patients with brain tumors.
EVALUATING THE RELATIONSHIP BETWEEN RADIOTHERAPY CLINICAL TARGET VOLUME AND GAIT ACTIVITY IN HIGH GRADE GLIOMA
Authors: Dr Seema Dadhania, Dr Matthew Williams
Journal: Neuro-Oncology (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 &amp;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 &amp;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.