bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous quantification of Gadoxetic acid and Cisplatin in hepatocellular carcinomas using laser ablation–inductively coupled plasma–mass spectrometry
Authors: Kronenberg Katharina , Werner Julia , Bohrer Peter , Steiger Katja , Buchholz Rebecca , von Bremen-Kühne Maximilian , Elinkmann Matthias , Paprottka Philipp M , Braren Rickmer F , Lohöfer Fabian K , Karst Uwe
Published: September 2023

The gadolinium-based contrast agent Gadoxetic acid and the platinum-based antitumor agent Cisplatin were quantitatively imaged in liver and liver cancer (hepatocellular carcinoma, HCC) tissue of rats by means of laser ablation–inductively coupled plasma–mass spectrometry. HCC bearing rats simultaneously received a tail vein injection of the hepatocyte-specific magnetic resonance imaging contrast agent Gadoxetic acid and a transarterial injection of Cisplatin 15 min before sacrifice and liver removal. Resecting HCC with adjacent liver tissue allows the comparison of Gd, Pt, and endogenous elements like Fe, Cu, and Zn in the various tissue types. Region of interest analysis reveals lower concentrations of Gd in HCC and higher Gd content in the adjacent liver, fitting the selective uptake of Gadoxetic acid into hepatocytes. Furthermore, two malignancy grades and their possible impact on the Gadoxetic acid and Cisplatin uptake are compared. For this, four high grade (G3) and two moderate grade (G2) HCCs were analysed, including a control sample each. Gd concentrations were lower in HCC irrespective of the grade of dedifferentiation (G2, G3) compared to adjacent liver. Despite local arterial Cisplatin injection, concentrations of Pt were similar or also reduced in HCC compared to liver tissue. In addition, endogenous Fe, Cu, and Zn were quantified. While Zn was homogenously distributed, higher Fe concentrations were determined in liver tissue compared to HCC. Hotspots of Cu suggest a deregulated copper homeostasis in certain liver lesions. The Gd and Fe distributions are compared in detail with cellular alterations examined by hematoxylin and eosin staining.
PRO-DRUG NANOPARTICLES AS SYNERGISTIC DRUG COMBINATION CARRIERS FOR IDH1-WT GLIOBLASTOMA
Authors: Cavanagh Robert , Baquain Saif , Oz Umut Can , Sikder Amrita , ElSherbeny Amr , Alexander Cameron , Scherman Oren , Rahman Ruman
Published: September 2023

AIMS

Synergistic combinations of doxorubicin and gemcitabine have been assessed for post-surgical treatment of IDH1 wild-type glioblastoma (GBM). As a complementary drug carrier, hyperbranched and micellar nanoparticles are being investigated to enable enhanced drug loading and sustained drug release.

METHOD

2D and 3D spheroid in vitro models have been generated from patient-derived glioblastoma cells resected from tumour core and invasive margin. Drug combinations were screened using synergy quantification from the Chou and Talalay method and synergy mechanisms investigated using measures of caspase 3/6-mediated apoptosis and γH2AX-mediated DNA damage. Polymeric nanoparticles (PEG-PCL) loaded with Cy5 were tested for internalisation and subsequent endocytosis pathway determination. Both single drug and drug combinations are currently being incorporated into PEG-PCL nanoparticles for in vitro assessment of biocompatibility, cellular uptake and cytotoxicity.

RESULTS

Data demonstrate synergism with doxorubicin and gemcitabine combinations is obtained in a molar ratio de- pendent manner. Consistent with this, enhanced apoptosis and DNA damage is observed in a synergistic manner. PEG-PCL nanoparticles demonstrate effcient cellular uptake and are internalised via dynamin-dependent caveolae and clathrin endocytotic pathways. Interestingly, nanoparticle internalisation is substantially in- creased (approx. 50%) in invasive GBM cells relative to proliferative core cells.

CONCLUSIONS

Doxorubicin and gemcitabine has been identified as a synergistic drug combination with the potential for sustained drug release when combined with PEG-PCL nanoparticle formulations. Together, the data has provided a platform of knowledge that will enable translation to pre-clinical in vivo models.
BULK RNA-SEQ DECONVOLUTION OF IMAGE-LOCALIZED HIGGRADE GLIOMA BIOPSIES REVEALS MEANINGFUL CELLULAR STATES
Authors: Curtin Lee , Bond Kamila , Velez Sebastian , Hawkins-Daarud Andrea , Urcuyo Javier C , De Leon Gustavo , Langworthy Jazlynn , Sereduk Christopher , Singleton Kyle W , Jackson Pamela R , Krishna Chandan , Zimmerman Richard S , Patra Devi P , Bendok Bernard R , Smith Kris A , Nakaji Peter , Donev Kliment , Baxter Leslie C , Mrugala Maciej M , Al-Dalahmah Osama , Hu Leland S , Tran Nhan L , Canoll Peter , Swanson Kristin R
Published: September 2023

AIMS

High-grade glioma continues to have dismal survival with current standard-of-care treatment, owing in part to its intra- and inter-patient heterogeneity. Typical diagnostic biopsies are taken from the dense tumor core to determine the presence of abnormal cells and the status of a few key genes (e.g. IDH1, MGMT). However, the tumor core is typically resected, leaving behind possibly genetically, transcriptomically and/or phenotypically distinct invasive margins that repopulate the disease. As these remaining populations are the ones ultimately being treated, it is important to know their compositional differences from the tumor core. We aim to identify the phenotypic niches defined by the relative composition of key cellular populations and understand their variation amongst patients.

METHOD

We have established an image-localized research biopsy study, that samples from both the invasive margin and tumor core. From this protocol, we currently have 202 samples from 58 patients with available bulk RNA-Seq, collected between Mayo Clinic and Barrow Neurological Institute. Using a single-cell reference dataset from our collaborators at Columbia University, we used CIBERSORTx, a deconvolution method, to predict relative abundances of 7 normal, 6 glioma, and 5 immune cell states for each sample.

RESULTS

We find that these cell state abundances connect to patient survival and show regional differences. For example, proneural glioma states were higher in invasive regions, whereas proliferative and mesenchymal states were higher in the tumor core.

CONCLUSIONS

Our analysis demonstrates a need to characterize the residual tissue following glioma resection to better understand the recurrent disease.
DUAL PET IMAGING OF NEOPLASTIC AND INflAMMATORY BIOMARKERS IN HIGH GRADE GLIOMA
Authors: Alfaifi Bandar , Jackson Alan , Hinz Rainer , Lewis Daniel , Coope David
Published: September 2023

AIMS

To characterize spatial distributions of 18kDa translocator protein (TSPO) and amino acid uptake as measured through dynamic [11C] (R)-PK11195 and [11C]-methionine PET in high-grade glioma.

METHOD

Twelve patients with newly diagnosed high-grade glioma underwent dual PET studies. [11C] (R)-PK11195 binding potential (BPND) maps were generated using simplified reference tissue model with grey-matter cerebellar time- activity-curve as tissue input-function. [11C]-methionine uptake was calculated as tumour-to-background ratio (TBR). Volumes of interest (VOIs) were defined on T1W post-contrast MRI as contrast-enhancing (CE) tumour and a ‘peritumoural’ region 5mm from the CE edge. Voxel-wise comparison of the tracers used Pearson’s correlation coeffcient. VOIs were furthermore subdivided into higher/lower TSPO (BPND > 0.17) and higher/lower methionine (TBR > 1.7).

RESULTS

Within the CE, voxel-wise comparison showed a strong correlation (r > 0.7) in eight subjects, moderate correlation (r > 0.5) in three subjects and weak correlation (r < 0.5) in one subject. Volume (mm3) with high BPND/high TBR accounted for 62±29% whereas high BPND/low TBR accounted for 13±16%. Within the peritumoral area, there was a small reduction in the proportion of subjects in the strong correlation group (6/12) but the pro- portion of voxels with higher TSPO binding and lower methionine uptake was substantially greater (35±16%).

CONCLUSIONS

Within high-grade glioma, there is a strong overall correlation between TSPO expression and amino acid uptake. However, in the peritumoural region there are areas of elevated TSPO expression without increased methionine uptake which could represent an inflammatory component or a discrete neoplastic cell population that may not be adequately defined with standard imaging biomarkers.
BRAIN TUMOUR GENETIC NETWORK SIGNATURES SUPERIORLY FORECAST SURVIVAL
Authors: Ruffle James , Mohinta Samia , Pombo Guilherme , Gray Robert , Kopanitsa Valeriya , Lee Faith , Brandner Sebastian , Hyare Harpreet , Nachev Parashkev
Published: September 2023

AIMS

Gliomas typically exhibit a spectrum of genetic mutations, reflecting multiple, potentially complex interactions across distinct molecular pathways. Predicting disease evolution and prescribing individually optimal treatment plausibly requires statistical models complex enough to capture the intricate genetic structure underpinning oncogenesis.

METHOD

Here we formalize this task as the discovery of distinct patterns of connectivity within network representations of the interactions between genetic loci. Evaluating multi-institutional clinical, genetic, and outcome data from 4023 consecutive patients over a 14-year period, we employ Bayesian stochastic block modelling to reveal a hierarchical network structure of tumour genetic interactions spanning glioblastoma, oligodendroglioma, and astrocytoma.

RESULTS

We show that this structure not only identifies diagnosis but predicts patient survival with greater fidelity than the latest WHO tumour classification or linear models of genetic features. For example, a diagnosis of IDH- wildtype glioblastoma yielded median survivals varying from 289 days in patients with the signature of marked EGFR amplification, MGMT methylation, and histone mutations, to 425 days in those with the signature of TERT mutations, histone, and EGFR wild-types, and variable MGMT methylation.

CONCLUSIONS

Our findings illuminate the complex dependence between features across the genetic landscape of brain tumours and show network analysis reveals distinct signatures of survival with better prognostic fidelity than current gold standard diagnostic categories, paving the way for personalised prognostication.
NHS BRAIN CANCER HEALTHCARE AND RESEARCH: DOES IT MATTER WHERE YOU ARE TREATED?
Authors: Huskens Nicky , Goetz Camille , Bushby Katie
Published: September 2023

AIMS

The Tessa Jowell Centre of Excellence designation initiative recognizes and awards neuro-oncology centres for excellence in patient treatment, care and research.

METHOD

Twenty-eight NHS centres were assessed through an extensive application form, virtual site visits and patient feedback. Applications were reviewed against a set of standards established through an iterative process in- volving expert specialists in brain cancer treatment and care.

RESULTS

Many pockets of excellence and innovations were found across the entire patient pathway. Centres demonstrated consistencies in service provision, common challenges threatening service development and sustainability, as well as areas of significant variations. Patients are most likely to experience variations in genetic testing of their tumour samples, access to clinical studies and the extensiveness of nurse and allied health professional- led care and support they receive. To date, 17 centres have been awarded Excellence status and all applicant centres have obtained support through the Tessa Jowell Academy to develop services and innovate.

CONCLUSIONS

Based on the findings, patients being treated for brain cancer in any UK centre will be able to obtain an effective standard of care, delivered by a motivated team. There are however areas of striking variation, with disparities in the design, quality and extent of the treatment and care pathway. Service development and addressing gaps in treatment and care will require a tailored approach at both a hospital and national level. In 2023/24, a new application round will open for all UK centres to re-apply to be assessed.
TRANSFORMING BRAIN CANCER TREATMENT, CARE AND RESEARCH: A CASE STUDY OF A SPECIALISED NATIONAL DIGITAL LEARNING AND NETWORKING PLATFORM FOR NHS HEALTH PROFESSIONALS
Authors: Huskens Nicky , Burton Olivia , Goetz Camille , Bushby Katie
Published: September 2023

AIMS

The aim of this case study is to highlight the outcomes of a specialized digital learning platform, the Tessa Jowell Academy, to share excellence and jointly tackle challenges in brain cancer treatment, research and care. The free platform is co-designed with the professional community to address unmet needs and offers members features such as virtual courses, a clinical trial finder and a peer-to-peer learning service.

METHOD

Performance data has been collected over the last 12 months from: online member surveys and platform data (workshop registrations, member registrations, member logins, resource downloads, video views, certificate downloads, feature requests, clinical trial updates and national network sign-ups).

RESULTS

The platform has over 800 member registrations from 29 NHS hospitals from a range of disciplines. There have been: 42 peers matched through the platform, 19 clinical trials added, 4 national networks set-up and 35 workshops delivered to 1200 attendees live and on-demand. Common themes from member feedback include increased learning and networking opportunities, increased specialist support, improved confidence in MDT participation and increased knowledge of other sub-specialties.

CONCLUSIONS

It is well evidenced that specialized knowledge sharing between centres can contribute to better outcomes, improved patient satisfaction and access to research for rare diseases. This case study highlights the national demand and potential benefits of a specialized, national digital learning platform for NHS professionals working in brain cancer. As the platform grows, the impact will continue to be measured on a national level.
PLASMA PROTEOMICS AND MACHINE LEARNING FOR NOVEL BIOMARKER DISCOVERY IN ADULT MALIGNANT GLIOMA
Authors: Pedersen Henriette , Elbæk Kirstine Juul , Vandborg Michael Wodstrup , Lim Yi Chieh , Azam Aleena , Pedersen Sarah Skovlunde Hornshøj , Skjøth-Rasmussen Jane , Schoof Erwin , Hamerlik Petra
Published: September 2023

AIMS

Plasma is a valuable source for identifying non-invasive biomarkers, and when combined with an examination of the highly dynamic proteome, it has the potential to lead to the identification of novel biomarkers in glioma. The aim of this study was to uncover plasma-based protein biomarkers for adult malignant glioma.

METHOD

Mass spectrometry-based proteomics with tandem mass tag (TMT) labelling of plasma from healthy individuals and adult malignant gliomas was performed. A differential abundance analysis was carried out to identify proteins that were deregulated in primary gliomas compared to healthy individuals. Machine learning was employed to identify a diagnostic biomarker panel.

RESULTS

When comparing plasma from healthy individuals to that of primary gliomas, several high and low abundant proteins were found to be deregulated. To improve the accuracy and ability of biomarkers to detect malignant gliomas, machine learning was employed and led to a development of a classifier, which performed with high accuracy, specificity, and sensitivity.

CONCLUSIONS

The discovery of a plasma-based protein classifier, once validated, may facilitate an earlier diagnosis of glioma patients, and thereby reduce time-to-treatment.
PCV VS. LOMUSTINE FOR PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Fofanah Isata , Pigott Thomas , Mansell Julie , Flatley Michael , Hatfield Paul , Bhaumik Suchandana , Short Susan , Murray Louise
Published: September 2023

AIMS

Almost all patients with glioblastoma relapse after initial treatment. At relapse, chemotherapy using multi-agent PCV (Procarbazine, Lomustine and Vincristine) or single agent Lomustine is often employed. Lomustine is an oral agent, and therefore spares patients from additional hospital visits for intravenous vincristine and removes the need for dietary restrictions while taking procarbazine, and so would be an attractive option, especially if there was no difference in survival compared to PCV. There are currently no data regarding whether PCV or Lomustine is superior. This project examines survival in patients treated with PCV or Lomustine for recurrent glioblastoma.

METHOD

A retrospective study was performed including patients treated at Leeds Cancer Centre between January 2015 and December 2019. Patients had a histological diagnosis of glioblastoma and received (chemo)radiotherapy at initial presentation. PCV or Lomustine was used at recurrence. Factors predictive of overall survival (OS) were investigated.

RESULTS

116 patients were included (66 received PCV, 50 received Lomustine). Performance status (PS) was 0, 1 and 2/3 in 22, 59 and 35, respectively. Median OS from first PCV or lomustine was 5.7 months (95% confidence interval: 5.1-6.3). The median number of cycles was 2 for both PCV and Lomustine with 115/116 (99%) discontinuing treatment due to disease progression. On univariate analysis, PS and type of chemotherapy were statistically significant. On multivariate analysis, only PS remained significant.

CONCLUSIONS

After adjusting for PS, there was no statistically significant difference in OS for patients treated with PCV or Lomustine. This finding has treatment implications and requires validation in a larger cohort.
RADIOGENOMICS FOR IMMUNOTHERAPY IN GLIOBLASTOMA
Authors: Ghimire Prajwal , Karami Golestan , Modat Marc , Booth Thomas
Published: September 2023

AIMS

Immunotherapy is an effective precision medicine treatment for several cancers. Obtaining imaging signatures of the underlying genome (radiogenomics) in glioblastoma patients, has the potential to identify immune biomarkers pre-operatively and allow personalized neo-adjuvant treatment. The increased use of whole genome sequencing data, and the developments in bioinformatics and machine learning provide the opportunity for such developments. Therefore, we performed a systematic review of radiogenomic biomarkers for immunotherapy in glioblastoma to identify current and potential targets for immunotherapy.

METHOD

A systematic review was performed following PRISMA guidelines on the databases of PubMed, Medline and Embase. QUADAS 2 questionnaire was utilized for quality assessment. Qualitative analysis was performed. Insuffcient data prevented meta-analysis. PROSPERO: CRD42022340968

RESULTS

Five articles were included, and all articles were retrospective studies. Biomarkers identified from MRI im- ages included apparent diffusion coeffcient (ADC) values, relative cerebral blood flow (rCBV) values and radiomic features that correlated with genomic markers from tumour cells and immune cells (tumour associated macrophages (TAMs), T cells and antigen presenting cells. Risk of Bias and applicability concerns were raised by QUADAS quality assessment.

CONCLUSIONS

Radiogenomic immune biomarkers are likely to provide early treatment options to patients with glioblastoma and will help improve quality of life of patients. There is a paucity of prospective studies identifying these diagnostic biomarkers, and interpretation is limited due to high risk of bias and poor generalisability . Targeted immunotherapy based on these biomarkers has the potential to allow individualised neo-adjuvant precision treatment options in clinical trials, plausibly leading to enhanced overall survival of these patients.
CLIC1 ION CHANNELS AS BIOELECTRIC TARGETS FOR TTFIELDS IN PAEDIATRIC HIGH-GRADE GLIOMA
Authors: Griffn Michaela , Smith Paul , Khan Raheela , Smith Stuart
Published: September 2023

AIMS

Develop and validate a comprehensive understanding of CLIC1 and its prognostic significance, coupled with a functional analysis in pHGG cells.

To develop electrical and pharmacological methods of manipulating CLIC1 for combination with TTFields

METHOD

Chloride Intracellular Channel (CLIC) channel expression patterns were identified via RNA sequencing of in- house patient tissues. siRNA depletion of CLIC1 and CLIC4 was assessed using functional assays, alone and in combination with TTFields and or CLIC inhibitor. Whole transcriptome gene expression analysis (Human Clairom™ Array) of pGBM cells treated with TTFields was carried out. Whole cell and cell attached patch clamp protocols were used to assess ion channel activity in pHGG.

RESULTS

CLIC1 deficiency was associated with increased overall survival(p=<0.003). siRNA depletion propagates a re- duction in the proliferation, migration and invasion of pHGG cells, associated with cell cycle arrest. CLIC1 deficiency exacerbated the effect of TTFields, reducing clonogenic and proliferative capabilities. Combination of metformin and TTFields increased the sensitivity of cells to TTFields. Whole transcriptome gene expression analysis found that cells treated with TTFields exhibited a down-regulation in CLIC1 compared to untreated cells, with tolerance to long-term TTFields treatment being associated with recovery of CLIC1 expression.

CONCLUSIONS

These data provide rationale that genetic, electrical, and pharmacological manipulation of CLIC1 can reduce the capacity of childhood brain tumours to proliferate and invade. TTFields treatment results in a dysregulation of CLIC channel expression and function, and combination with CLIC inhibitions demonstrates a synergistic effect. CLIC channels may be a suitable target for combination therapy to enhance the treatment effcacy of TTFields.
GRAPHENE NANOMATERIAL REPROGRAMMING OF IMMUNE CELLS TO UNLOCK THE EffCACY OF IMMUNOTHERAPY IN GLIOBLASTOMA
Authors: Kisby Thomas , Stylianou Maria , Kostarelos Kostas
Published: September 2023

AIMS

Immunotherapy has substantiated its promise and achieved striking clinical effcacy in at least a subset of patients in several cancer types. However, in patients with glioblastoma multiforme (GBM), immunotherapies have lacked effcacy as a consequence of the highly immunosuppressive “cold” tumour microenvironment. Small, thin graphene oxide (GO) nanosheets possess notable pharmacokinetic properties in GBM including deep translocation throughout the whole tumour volume and selective internalization by tumour associated macrophages and microglia (TAMMs) following local administration. The current study aimed to investigate whether this selective nanomaterial-TAMM interaction could be exploited to reprogram the immune- microenvironment of GBM.

METHOD

GO nanosheets were non-covalently complexed with a TLR7/8 agonist to form a stable immunomodulatory nanosystem (imodGO) which was tested in primary macrophages in vitro, and an orthotopic syngeneic GBM model in vivo.

RESULTS

ImodGO enhanced the polarization of macrophages toward a pro-inflammatory M1-like phenotype in vitro without disrupting their phagocytic or cytokine producing capacity. A single intratumoral administration of the same nanocomplex in an intracranial GL261 model was also effective in increasing M1-like TAMMs (CD86+, MHCII+, TNFα+) while decreasing immunosuppressive M2-like TAMMs (Ym1+, Arg1+) which resulted in a wider reprogramming of the brain tumour immune-microenvironment. Repeat imodGO administration was able to significantly inhibit tumour progression highlighting the therapeutic potential of this nanomaterial enabled immunomodulatory strategy.

CONCLUSIONS

Based on these results, imodGO has emerged as a novel strategy to ameliorate the immunosuppressive char- acter of GBM. Further work is warranted to assess whether imodGO could enhance the effcacy of systemic immunotherapies used in combination.
REVIEW OF THE INTRODUCTION OF WHOLE GENOME SEQUENCING AS NHS STANDARD OF CARE FOR BRAIN TUMOUR PATIENTS AT QUEEN ELIZABETH HOSPITAL BIRMINGHAM, UK
Authors: Wykes Victoria , Hyatt Meena , Goel Aimee , Parikh Shefali , Berki Fred , Cole Naomi , Freeth Sarah , Garratt William , Goddard claire , Pohl Ute , Nagaraju Santosh , Chowdhury Yasir , O’Hallaran Phillip , Petrik Vladimir , Ughratdar Ismail , Zisakis Athanasios , Benghiat Helen , Meade Sara , Sanghera Paul , Glover Kate , Hughes Lowri , Vafadar Natasha , Wallis Yvonne , Raghavan Manoj , Watts Colin
Published: September 2023

AIMS

Describe delays in the NHS pathway from initial consent for whole genome sequencing (WGS) to delivery of the final WGS report (WGS-R) to the treating oncologist.

Review number of patients with mutations that inform, diagnosis, prognosis or treatment.

METHOD

Prospective audit of time to key stages along WGS pathway and review of final WGS-R.

RESULTS

WGS pathway and process:

Data snapshot at 24/02/2023 showed 96 patients consented for WGS: 12/96 awaiting surgery; 41/96 awaiting GTAB discussion; 1/96 WGS sample used for histopathological diagnosis, 1/96 ineligible.

41/96 WGS results discussed at a GTAB meeting; 39/44 with complete WGS-R sent to the treating oncologist, including discussion at the local neuro-oncology multi-disciplinary team meeting.

Median time from consent to final WGS-R was 225 days (range 145-567).

WGS results:

4 patients with glioblastoma (GBM) have RB1 variant, associated with improved progression-free and overall survival (Dono et al 2021).

10 patients had clinically actionable mutations with recommended trials or compassionate-use drugs. 1/10 patient with GBM and High Tumour Mutational Burden who completed standard of care (SOC) treatment has commenced anti-PD1 immunotherapy (Nivolumab; Goodman et al 2017). 5/10 patients are currently on SOC treatment, 3/10 had deteriorated and 1/10 were deceased at time of WGS-R.

Excellent concordance of WGS data with SOC genetic/immunohistochemistry testing.

No germline mutations identified.

CONCLUSIONS

Nearly a third of patients had genetic variants that may have the potential to inform future clinical management. Further investment in the WGS pathway is required to deliver timely results to allow application of precision medicine for brain cancer patients.
ADENOSINE TO INOSINE RNA EDITING ASSOCIATED TUMOUR MICROENVIRONMENT AS A THERAPEUTIC TARGET IN GLIOBLASTOMA
Authors: Chen Sean Chun-Chang
Published: September 2023

AIMS

Glioblastoma (GBM) remains incurable because of the high level of intratumor heterogeneity and the poor understanding of its complex genetics. We recently identified adenosine to inosine (A-to-I) RNA editing as a sex- specific prognostic factor in GBM. However, the underlying mechanism remains unclear. We sought to identify RNA editing-associated molecular effectors and assess their prognosis potential.

METHOD

We analyzed RNA-Seq data of 196 primary IDH wild-type GBMs from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) cohorts. Genome-wide A-to-I RNA editing events were characterized and GBM tumours were split into two subtypes based on RNA editing signatures (high- and low-editing). Differential expression and tumour microenvironment analyses between the two subtypes were performed to identify molecular effectors. Survival impact of these effectors was determined using Cox proportional hazards model.

RESULTS

Genes more highly expressed in the high-editing subtype were enriched in immune-related pathways, while those more highly expressed in the low-editing subtype were enriched in cell proliferation and stemness path- ways. Consistent with differential expression analysis, high-editing GBMs exhibited higher infiltration levels of macrophages, monocytes and dendritic cells. Intriguingly, increased cell proliferation and elevated infiltration of dendritic cells were associated with poorer survival in men only, whereas enhanced CSF1 (colony stimulating factor 1) response and elevated infiltration of monocytes and Th1 cells conferred poorer survival outcomes in women only.

CONCLUSIONS

Our study suggests sex-specific impact of A-to-I RNA editing in the pathogenesis of glioblastoma, highlighting the importance of developing sex-specific treatments and opening a new avenue for the design of novel therapeutic targets.
MICROLENS - A DESIGN-CENTRED APPROACH TO AI IN HEALTHCARE
Authors: Pakzad-Shahabi Lillie , Mauricaite Radvile , PPI ICL_ICHT Neuro-oncology , Williams Matthew
Published: September 2023

AIMS

MicroLens aims to co-develop tools and functions that enable patients & caregivers to view and understand their own images.

METHOD

We used an explicit design-led approach, foregrounding user needs. Over 7 months we used a series of 4 meetings, written reports and online questionnaires capturing the views of 20 staff, patient and caregiver participants (55% patients & caregivers; primary & metastatic brain tumours) to explore feasibility and requirements for an AI-enhanced online medical image viewing tool.

RESULTS

There were two distinct patterns of preferred usage: smartphone-based “snapshot” approach vs. online plat- form with detailed review of all images. Participants wanted to use it as a “scan photo album” and said help in understanding the scans would be useful, but the desired level of technical performance was relatively low: patients and caregivers would mostly be happy with labelling of common simple structures and sides, rather than detailed annotation. Further benefits and concerns raised were ability to

• share with family members who could not attend hospital appointments.

• review their scans outside of an appointment.

• better understand images.

• Use tools to assist in the interpretation reducing staff workload

• image-share causing more work for staff

CONCLUSIONS

Patients, caregivers and staff all expressed a clear view that an AI-enhanced online tool to allow patients to view and understand their images would be useful. However, there were significantly different use cases between different patients, and the level of functionality that patients & caregivers expressed a need for was substantially simpler than that originally envisaged. We are currently implementing a prototype.
EXTRACELLULAR VESICLES TRANSFER RESISTANCE TO VINCRISTINE IN SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Wade Philippa , Hume Alistair , Kerr Ian , Coyle Beth
Published: September 2023

AIMS

• To determine the expression patterns of specific ATP-binding cassette (ABC) transporters in medulloblastoma

• To assess whether ABC transporters play a role in acquired drug resistance in SHH medulloblastoma using drug-tolerant cell line models

• To assess whether extracellular vesicles transfer drug-tolerance in SHH medulloblastoma and determine the mechanism by which they do this

METHOD

Drug-tolerant cell lines were generated by continuous culture in drug-containing culture medium. ABC trans- porter gene and protein expression was assessed via qPCR and western blot. EVs were isolated from EV-depleted medium using size-exclusion chromatography. Nanoparticle tracking analysis was used to quantify and deter- mine size. Cytotoxicity analysis was used to determine EV-mediated transfer of resistance in the presence or absence of an ABC transporter inhibitor. RNA sequencing of EVs from matched vehicle and drug tolerant cell lines was carried out.

RESULTS

Analysis of drug-tolerant cell lines revealed significant increases in specific drug transporter gene expression across medulloblastoma subgroups. ABCB1 protein expression was significantly higher in drug-tolerant sonic- hedgehog (SHH) lines and inhibition of ABCB1 in a drug-tolerant SHH line abolished acquired resistance to vincristine. Cytotoxicity assays on sensitive cells, after pre-treatment with drug-tolerant EVs, showed a significant increase in vincristine resistance, implicating EVs in the transfer of resistance.

CONCLUSIONS

Data to date supports the hypothesis that multidrug transporter carrying extracellular vesicles may transfer their multidrug resistant phenotype to surrounding cells in medulloblastoma. We are currently testing this using inhibitors and knockout lines, in addition to RNA sequencing, with the hopes of providing new therapeutic targets to patients with medulloblastoma.
TESSA JOWELL BRAIN MATRIX PLATFORM STUDY: PRELIMINARY ANALYSIS OF THE PRIMARY FEASIBILITY & PROCESS-CENTRED OBJECTIVE
Authors: Watts Colin , Patel Amit , Savage Joshua , Ansorge Olaf , Wykes Victoria , Wallis Yvonne , Sharpe Rowena , Mant Rhys , Brooks Hannah , Short Susan , Ashkan Keyoumars , Brennan Paul , Chalmers Anthony , Smith Stuart , Jenkinson Michael , McBain Catherine , Waldman Adam , Thompson Gerard , Billingham Lucinda
Published: September 2023

AIMS

The Tessa Jowell BRAIN MATRIX (ISRCTN14218060) is an ongoing platform study, collecting disease, treatment, and outcome data prospectively in glioma patients, across nine UK hospitals. We report a preliminary analysis of the primary feasibility and process-centred objectives.

METHOD

Primary Objective: Test the feasibility of establishing an integrated histological-molecular diagnosis using Whole Genome Sequencing (WGS) and Epigenomic Classification (EC) (‘Heidelberg Classifier’) data in NHS practice within 28 days.

Primary Outcome: Time (from surgery) to integrated histological–molecular diagnosis (TTMD) using WGS and EC.

Secondary Outcome: Time to completion of each node (stage) of the tissue and imaging pathway.

RESULTS

Data snapshot on 23-Feb-2023 confirmed 250 patients recruited. Nine nodes along the tissue & imaging pathway were defined. Twenty-one patients had completed the pathway and time to each node was calculated. Median time to complete the pathway was 404 days (range 124-653). There was a trend of improvement in TTMD in recently recruited patients.

CONCLUSIONS

The patient pathway from surgery to clinical feedback through a Genomic Tumour Advisory Board (GTAB) utilises NHS-accredited pathways and protocols. Delays inherent in the pathway emphasise the urgent need for infrastructure and operational delivery improvements of the NHS Genomic Medicine Service for brain cancer patients as the current timeframe is not clinically relevant for informing patient care. These data also highlight geographical inequality in accessing genomic medicine within England, across the seven Genomic Laboratory Hubs, and the devolved nations. Detailed analysis of the delays at each node will identify opportunities and solutions to inform discussions with the NHS and Genomics England.
DIAGNOSTIC ACCURACY AND PROCESS EVALUATION WITH HEALTH ECONOMICS ANALYSIS OF AN ULTRA-FAST DIGITAL CONFOCAL MICROSCOPY SCANNER FOR REAL-TIME INTRA-OPERATIVE BRAIN TUMOUR DIAGNOSIS
Authors: Bolton William , Ramakrishnan Piravin , Reveendran Dharsshini , Crispi Vassili , Adebola Oluwaseyi , Sinha Rohit , Digby Richard , Chakrabarty Aruna , Mathew Ryan
Published: September 2023

AIMS

Real-time intra-operative brain tumour tissue analysis in theatre can shorten turnaround times and facilitate repeated sampling; the latter can improve diagnostic accuracy and guide resection to maximise extent. We were the first team in the world to demonstrate the feasibility of an ultra-fast confocal microscopy scanner (Histolog®, SamanTree Medical SA) for real-time intra-operative brain tumour tissue diagnosis. The aim of this study is to demonstrate the diagnostic accuracy of Histolog® within a larger cohort of patients with brain tumours.

METHOD

An observational study with varying brain tumour types was conducted in a Tessa Jowell Brain Tumour Centre of Excellence. Adult patients undergoing brain biopsies or tumour debulking surgery were included. Multiple, freshly excised tissue samples were stained, and images captured within 60 seconds on Histolog® in the OR in parallel to current diagnostic pathways which included frozen section and smear cytology. Quantitative blinded concordance analysis between Histolog® images and gold standard histopathology was performed by a Consultant Neuropathologist.

RESULTS

A total of 50 cases are included in this analysis. This will include the quantitative analysis of n=50 cases and the concordance rating between Histolog® and gold standard traditional (frozen section and smear cytology) intra- operative histopathological diagnosis. The pilot data (n=12) that led to this larger study indicated a concordance rate of 83%.

CONCLUSIONS

Histolog® demonstrates non-inferior diagnostic accuracy when compared to current gold standard but significantly reduces the intra-operative time to achieve diagnosis. Future studies will investigate the effect of real- time margin zone analysis and explore machine learning for automatic computer aided diagnosis.
NON-CELL AUTONOMOUS INDUCTION OF A CANCER STEM CELL MOLECULAR PHENOTYPE IN AN IN VITRO MODEL OF SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: van Essen Max , Cowley Sally , Becker Esther , Schuster-Böckler Benjamin , Jacob John
Published: September 2023

AIMS

• Design a novel in vitro model of sonic hedgehog (SHH) medulloblastoma (SHH-MB) by co-culture of two distinct human SHH-MB cell lines with wild-type cerebellar organoids derived from human induced pluripotent stem cells.

• Investigate how the phenotype of SHH-MB cells grown in co-culture differs from conventional monolayer or tumour spheroid cultures.

METHOD

DAOY and ONS76 cell lines were cultured as monolayers, tumour spheroids or co-cultured with wild type cerebellar organoids for twenty-five days. Cells were then processed for single cell RNA-seq yielding thousands of sequenced transcriptomes, which were analysed using the R package, Seurat and other software.

RESULTS

Tumour cells in co-culture could be distinguished from non-malignant cells by their distinct transcriptional profiles. Subpopulations of both cancer cell lines in co-culture upregulated neuronal differentiation genes. In co-culture only, a distinct subset of DAOY cells expressed multiple cancer stem cell markers including SOX2, OTX2, GLI2 and NES. The upregulation of SOX2 by these cells correlated with the co-expression of ERBB4, which encodes a tyrosine kinase receptor.

CONCLUSIONS

SHH-MB cells exhibited striking differences in their phenotype when grown under physiological conditions in co-culture. First, subpopulations of both types of cancer cells expressed a neuronal differentiation programme. Second, a cancer stem cell phenotype is revealed in TP53 mutant tumour cells that is centred on SOX2. Signalling by ERBB4 is a candidate in the upregulation of SOX2 in these cells and has previously been implicated in the pathogenesis of Group 4 medulloblastoma. Future experiments will test whether SOX2 and ERBB4 are co-expressed in patient tumour cells.
GENOMIC LANDSCAPE AND ACTIONABLE MUTATIONS OF BRAIN METASTASES IN NON-SMALL CELL LUNG CANCER: A SYSTEMATIC REVIEW
Authors: Andrews Lily , Thornton Zak , Saleh Ruqiya , Dawson Sarah , Daly Richard , Higgins Julian , Davies Philippa , Kurian Kathreena
Published: September 2023

AIMS

Lung cancer causes the most deaths worldwide due to cancer. Non-small cell lung cancer (NSCLC) represents the largest subgroup (80-90%), with most patients presenting at an advanced stage of disease. Brain metastases (BM) develop in about 27% of these cases, leading to a poor survival outcome. Previous literature has suggested that BM derived from NSCLC have a different genomic profile compared to the primary NSCLC. We aim to review the literature to discover the genomic landscape of BM derived from NSCLC.

METHOD

Embase, MEDLINE, Web of Science, and BIOSIS were searched, and any records found were assessed for eligibility. For the included papers, patient information, smoking status, genomic data, matched primary NSCLC, and PD-L1 expression was extracted.

RESULTS

72 papers were included in the review, with data on 2,340 patients. The most mutated genes were EGFR (n=560), TP53 (n=331), KRAS (n=328), CDKN2A (n=97), STK11 (n=72). Frequently mutated missense mutations included L858R (n=80) in EGFR and G12C (n=17) in KRAS. Ever versus never smokers were found to have differing mis- sense mutations in TP53 and EGFR, with the expectation of L858R and T790M. BM were suggested to have a different genomic landscape compared to the primary NSCLC. PD-L1 expression was found to be low in BM derived from NSCLC.

CONCLUSIONS

To our knowledge, this is the first systematic review which assessed the genomic landscape of BM derived from NSCLC. This review highlights the most mutated genes, missense mutations, and their clinical actionability. Differing genomic profiles were suggested in primary compared to BM and smoking status.
TUMOUR TREATING FIELDS WITH DDR INHIBITORS EFFECTIVELY LEADS TO CHEMO-/RADIO-SENSITISATION OF GLIOMAS
Authors: Jones Callum , Vanderlinden Aurelie , Myers Katie , McGarrity-Cottrell Connor , Rominiyi Ola , Collis Spencer
Published: September 2023

AIMS

High grade gliomas are the most common CNS malignancies and cause ~200,000 deaths/year globally. Glioblastoma (WHO grade IV) confer the worst prognoses with their treatment being hindered by glioma stem cell-like (GSC) tumour sub-regions and high intratumoural spatio-heterogeneity. Tumour Treating Fields (TTFields) exert clinically approved alternating electric fields of intermediate frequency which induces anti-mitotic effects within concomitant deleterious effects on cellular responses to DNA damage (DDR). Therefore, treatment resistance could be overcome with TTFields with clinically developed DDR inhibitors (DDRi) to cause chemo-/radio- sensitisation.

METHOD

Surgically resected samples derived from the tumour core and invasive edge were processed to create GSC cell lines, offering highly clinically relevant models. These were grown in either 2D or in 3D-printed AlvetexTM scaffolds, treated with DDRi, subjected to chemo-/radio-therapy and then placed under TTFields (200 kHz, 48- 72 hrs). Survival was measured by clonogenic assays after 3 weeks. Immunofluorescence and western blot analysis were used to analyse the combination treatment effects on the DDR.

RESULTS

TTFields with DDRi led to significant chemo/radio-sensitisation in both 2D and 3D intratumoral core/edge GSC models. Western blot and immunofluorescence analyses revealed that DNA damage was heightened by the combination treatments with lesion resolution being impaired.

CONCLUSIONS

DDRi with concurrent TTFields effectively leads to significant chemo-/radio-sensitisation in clinically relevant 3D GSCs which model spatio-heterogeneity which is thought to impede treatment effcacy. Given that all the DDRi used are BBB penetrable and are either clinically approved or in clinical trials, TTFields could additionally compliment these treatment regimens in gliomas to boost their effcacy.
PSYCHOLOGY EDUCATION WORKSHOPS ARE AN INNOVATIVE METHOD OF OFFERING PSYCHOLOGICAL INPUT TO A WIDER POPULATION
Authors: Hurwitz Victoria , Groves Mark , Butler Carly , Kostick Ellie , La Jessica , Hedges Sarah , Delacroix Louise , Suarez Aeron , Robinson Charlotte , Chia Kazumi , Brazil Lucy , Al-Salihi Omar , Swampillai Angela
Published: September 2023

AIMS

People diagnosed with brain tumours are well recognised as needing psychological support. Service provision is limited and can be diffcult to gain engagement. Providing psychology education workshops aims to be inclusive, bring patients and loved ones together and offer an opportunity for peer support.

METHOD

Patients who had finished or were coming to the end of their current treatment were invited to attend a psychology education workshop. Their loved ones were also invited to attend via the patient’s invitation letter. A clinic code was set up to enable us to monitor who was invited, who attended and importantly who did not. This also aimed to integrate the workshop into standard of care on completion of treatment. Feedback was obtained from attendees at the end of the workshop verbally as well as offering the opportunity to give anonymous written feedback.

RESULTS

On average a third of people invited attended each group. Half of these attended with one or more loved ones. 100% of attendees found the workshop helpful. Feedback included “Useful to realise that my emotions are similar to his” – Carer and “Having the shared experience of being here with (loved one) has started to open things up for us as a family” – Family member.

CONCLUSIONS

Patients and carers valued the workshop. This format offered a more accessible introduction to psychology. The workshop was enough to provide some patients and carers with strategies to look after their psychological well-being and served as a method of identifying those with greater need.
RADIOGENOMIC DATASETS IN GLIOBLASTOMA: AN ESSENTIAL HURDLE
Authors: Ghimire Prajwal , Karami Golestan , Modat Marc , Booth Thomas
Published: September 2023

AIMS

To evaluate current available datasets for radiogenomic analysis in glioblastoma

METHOD

A scoping review was performed in the literature from 2000-2023. List of datasets (open access, controlled, paid) available in the literature were tabulated. Qualitative analysis was performed.

RESULTS

Multiple datasets and data portals were available. Clinical data was available on all portals. MRI and Radiomics datasets were available on The Cancer Imaging Archive(TCIA). Genomics datasets were available in Genomics England (DNA sequencing reads and variants), The Cancer Genome atlas(TCGA) data portal, Chinese cancer genome atlas (CCGA) data portal and The Georgetown Database of Cancer (G-DOC) (sequencing reads, Tran- scriptome profiling, simple nucleotide variation, copy number variation, DNA methylation). Raw datasets were controlled with permission-only access whereas rest were available for access and download on registration. Datasets were available in UK Biobank with a fee.

CONCLUSIONS

Non-uniformity in datasets is a huge hurdle in pre-processing of the datasets and analysis. Collaborative data portals with user friendly interface are likely to provide uniformity and resolve biases as a part of the hurdle in analysis of these datasets.
OUTCOMES OF STEREOTACTIC RADIOSURGERY/RADIOTHERAPY (SRST) IN MALIGNANT MELANOMA WITH CRANIAL METASTASES - THE WESSEX EXPERIENCE
Authors: Ah-Chuen Jonathan , Johnson Emma , Conibear Isobel , Carr Ruth , Simpson Eleni , Sinclair Georges , Clarke Enrico , Ching Jeng
Published: September 2023

AIMS

To assess overall survival in malignant melanoma with cranial metastases following stereotactic radio- surgery/radiotherapy (SRST).

METHOD

Patients with metastatic melanoma who received SRST for their cranial metastases at the Wessex Neuro- Oncology Unit were evaluated between January 2017 and January 2023. Subtype analysis based on BRAF mutation was also performed. Their overall survival (OS) was plotted using Kaplan-Meier graph.

RESULTS

121 patients were identified. The mean age at referral was 62 years (range 30-90). 50 patients had a BRAF mutation while 71 were BRAF wild type. This is a heterogenous cohort of patients, ranging from cranial-only disease to widespread disease, receiving one to two lines of systemic treatment. The median OS in patients with malignant melanoma with cranial metastases following SRST is 15 months (similar in both BRAF mutant and BRAF wildtype subgroups). The 3-year survival rate is 22.8% (BRAF mutant – 27.3%, BRAF wildtype - 20.3%). There is a small group of patients (28%) that died within six months of SRST.

CONCLUSIONS

Limitations were the small number of patients, short follow up period and heterogeneity in terms of systemic therapy. Our experience reveals in malignant melanoma, the median OS is 15 months after SRST to their cranial metastases. We found that BRAF mutation is non-discriminatory when predicting response to SRST and not the sole factor in predicting OS. A small cohort did not benefit from SRST as they survived for 6 months or less. Further analysis of this subgroup is needed to improve patient selection and treatment personalisation.