bluuebunny/crossref_metadata_2025 huggingface dataset:
Analytic Approaches to Clinical Validation of Results From Preclinical Models of Glioblastoma: A Systematic Review
Authors: Fitt Beth , Loy Grace , Christopher Edward , Brennan Paul , Poon Michael T C
Published: October 2022

AIMS

Analytic approaches to clinical validation of results from preclinical models are important in assessment of their relevance to human disease. This systematic review examined consistency in reporting of glioblastoma cohorts from The Cancer Genome Atlas (TCGA) or Chinese Glioma Genome Atlas (CGGA) and assessed whether studies included patient characteristics in their survival analyses.

METHOD

We searched Embase and Medline on 02Feb21 for studies using preclinical models of glioblastoma published after Jan2008 that used data from TCGA or CGGA to validate the association between ≥1 molecular marker and overall survival in adult patients with glioblastoma. Main data items included cohort characteristics, statistical significance of the survival analysis, and model covariates.

RESULTS

There were 58 eligible studies from 1,751 non-duplicate records investigating 126 individual molecular markers. In 14 studies published between 2017 and 2020 using TCGA RNA microarray data that should have the same cohort, the median number of patients was 464.5 (interquartile range 220.5–525). Of the 15 molecular markers that underwent more than one univariable or multivariable survival analyses, five had discrepancies between studies. Covariates used in the 17 studies that used multivariable survival analyses were age (76.5%), pre-operative functional status (35.3%), sex (29.4%) MGMT promoter methylation (29.4%), radiotherapy (23.5%), chemotherapy (17.6%), IDH mutation (17.6%) and extent of resection (5.9%).

CONCLUSION

Preclinical glioblastoma studies that used TCGA for validation did not provide sufficient information about their cohort selection and there were inconsistent results. Transparency in reporting and the use of analytic approaches that adjust for clinical variables can improve the reproducibility between studies.
Computer-aided Design of Novel CDK5 Inhibitors; Towards New Treatments of Glioblastoma
Authors: Khan Zahra , Stasik Izabela , Hayes Joseph
Published: October 2022

AIMS

Design and statistically optimize an in silico screening protocol; apply the screening protocol to a compound database; in vitro validation of selected inhibitors (isolated CDK5 enzyme binding assay).

METHOD

Two large compound databases, ZINC15 and Analyticon Discovery, were used to screen for potential CDK5 ATP-binding site inhibitors. They were first filtered using a generated pharmacophore model and then virtually screened using Glide SP docking with a solved CDK5-p25 structure (PDB: 3O0G). The selected candidates were validated using enzyme binding assays to determine their inhibitory activity on CDK5, as well as against a panel of kinases.

RESULTS

Over 17,000 compounds were screened during molecular docking studies and of these, ~11,600 compounds returned which are predicted to bind to CDK5. The top 10% of docked compounds were analysed and 30 candidates were selected for single concentration screening at 50 µM concentrations. The 9 most potent compounds were selected for IC50 determinations and revealed 6 compounds with IC50 <10 µM. The selected novel compounds were also screened against a panel of kinases (CDK2, CDK5, CDK9, GSK-3β) with varying selective profiles observed.

CONCLUSION

Low micromolar potent compounds have been identified through in silico screening and validated in using in vitro binding assays. One flavonoid compound in particular, cirsiliol (IC50 = 5.90 µM), displayed best selectivity towards CDK5, a challenge in kinase inhibitor design. The identified compounds will now pass to cellular studies to determine their effect on Glioblastoma cell lines.
The Outcomes Measured and Reported in Meningioma Clinical Effectiveness Trials Are Heterogeneous and Preclude Comparative Analysis of Results: A Systematic Review
Authors: Millward Christopher , Islim Abdurrahman , Keshwara Sumirat , Srikandarajah Nisaharan , Brodbelt Andrew , Marson Anthony , Williamson Paula , Jenkinson Michael
Published: October 2022

AIMS

Meningioma clinical trials have assessed interventions including surgery, radiotherapy, and pharmacotherapy, but heterogeneity of outcome measurement and reporting often precludes comparative analysis of trial results. This systematic review aimed to summarise the outcomes measured and reported in such trials.

METHOD

Systematic literature and trial registry searches were performed to identify published and ongoing intracranial meningioma clinical effectiveness trials. Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Deduplication, grouping, and classification of verbatim outcomes was performed to identify unique outcomes reported in the literature.

RESULTS

Thirty published articles and 18 ongoing studies were included, describing 47 unique studies: phase II n=33, phase III n=14. Common interventions included: surgery n=13, radiotherapy n=8, and pharmacotherapy n=20. 660 verbatim outcomes were reported, of which 85 were defined. Following deduplication, 416 unique verbatim outcomes remained and were grouped into 119 unique ‘non-verbatim’ outcomes. Those reported most frequently included: blood loss n=15, need for blood transfusion n=12, radiographic response to treatment n=19, eye toxicity after radiotherapy, gastrointestinal toxicity from pharmacotherapy n=40, haematological toxicity from pharmacotherapy n=31, metabolic and nutrition toxicity from pharmacotherapy n=42, progression-free survival n=46, and overall survival n=37.

CONCLUSION

Outcome measurement and reporting across meningioma clinical trials is heterogeneous and may preclude comparative analysis of trial results. The unique outcomes identified from this systematic literature review will be prioritised through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set (COS) for use in future meningioma clinical trials.
Impact of the Neuro-Radiologist and Neuro-Surgeon in Contouring With the Neuro-Oncologist on Local Relapse Rates for Brain Metastases Treated With Stereotactic Radiosurgery
Authors: Robinson Maxwell , Sayal Karen , Tunstall Clare , Padmanaban Sriram , Watson Rhona , Pretorious Pieter , Joseph Robin , Jeyaretna Sanjeeva , Hobbs Claire
Published: October 2022

AIMS

The audit evaluates the value of MDT, including neuro-radiologist and neuro-surgeon, review of contouring carried out by a clinical oncologist in stereotactic radiosurgery (SRS).

METHOD

Lesions were contoured first by clinical oncologist then reviewed/edited by MDT. Iinitial contour was compared with final using Jaccard conformity and geographical miss indices. Dosimetric impact of contouring change was assessed using plan metrics to both original and final contour. The impact of contouring review on local relapse, overall survival and radio necrosis rate was evaluated with at least 24 months follow up.

RESULTS

113 patients and 142 lesions treated over 22 months were identified. Mean JCI was 0.92 (0.32-1.00) and 38% needed significant editing (JCI<0.95). Mean GMI was 0.03 (0.0-0.65) and 17% showed significant miss (GMI>0.05). Resection cavities showed more changes, with lower JCI and higher GMI (p<0.05). Dosimetric analysis indicated a strong association of conformity with PTV dose metrics. Greater association was seen in resection cavity, i.e. geographical nature of a typical contouring error gives rise to greater potential change in dose. Clinical outcomes compared well with published series. Median survival was 20 months and local relapse free rate of 0.89 (0.8-0.94) at 40 months. Radio-necrosis free rate 0.9 (0.83-0.95) at 40 months with median 17 months to developing radionecrosis for those that did.

CONCLUSION

MDT contour review adds significant value to SRS resulting in reduced local recurrence rates. No improvement in clinical oncologist contouring over time was shown indicating a collaborative approach is needed regardless of experience of clinical oncologist - particularly for resection cavities.
Retrospective Review of Carcinomatous Meningitis Management at a Tertiary Centre: Reflections on Current and Future Management
Authors: Williams Simon , Topping Oliver , Sanghera Paul , Hassan-Smith Ghaniah
Published: October 2022

AIMS

Carcinomatous meningitis (CM) arises following metastatic deposition of neoplastic cells in the meninges triggering a complex series of pathological changes, typically representing a terminal complication of underlying malignancy. No uniform management strategy exists for CM patients, despite research highlighting numerous treatment modalities. We present a single centre retrospective study of CM patients managed over a ten year period, along with analysis of current and future treatment modalities for CM.

METHOD

Patient datasets were identified using diagnostic codes. Inclusion criteria were patients with malignant cells identified in CSF, or those with radiological features consistent with CM with a background of cancer and supporting clinical features. Data regarding patient symptomatology, management, and outcome were then gathered from electronic patient records.

RESULTS

Ten cases of carcinomatous meningitis were identified. The most common primary tumour site was breast (30%). The most common presenting symptoms were headache (70%), weakness (60%), vomiting (50%), and confusion (50%). Radiological evidence of CM in the form of leptomeningeal enhancement was noted in 60% of cases. Management of CM cases was variable – six patients underwent no further anti-cancer treatment, two patients underwent chemotherapy, and two patients were planned for radiotherapy. Median length of survival from time of CM diagnosis was 30 days (IQR 15 – 63).

CONCLUSION

CM patients have a poor prognosis, and significant variability exists in management. New therapeutic options are emerging, particularly in the field of targeted biologic therapies, and engagement with specialist oncology teams is recommended. Early palliative care support is essential in the management of CM patients.
Stereotactic Radiosurgery for Brainstem Metastases
Authors: Hickman Mitchell , Benghiat Helen , Meade Sara , Hayes Geoff , Hartley Andrew , Sanghera Paul
Published: October 2022

AIMS

Limited data exists on outcomes following SRS for brainstem metastases (BSM). The purpose of this audit was to explore the use of SRS using Cyberknife for BSM at a single centre; reporting rates of toxicity and survival outcomes.

METHOD

Patients undergoing SRS for BSM from 2013 to 2021 were identified from a prospective database. Clinical characteristics were collected including; gender, age, histology and KPS. The use of previous WBRT, the volume and the dose delivered to the BSM were also recorded. All target volumes were peer reviewed by a neuro-radiologist.

RESULTS

41 patients with a BSM were identified. The median age was 62 years (range 35-78). Histology was lung 15 (36.6%), breast 13 (31.7%) and other 13(31.7%). The median brainstem target volume was 0.36cc (range 0.01 – 5.63cc). 32 patients had single fraction (dose range 14.5 to 18Gy) and 9 patients had 3 fractions (dose range 17-24Gy). 7 patients had previous WBRT. Median overall survival was 242 days (range 19-1213). A radiological response or stable disease was seen in 26 out of 30 patients with post SRS imaging available for review. 2 patients developed a 6th nerve palsy. 12 patients required a prolonged course of dexamethasone. No statistically significant relationship was observed between patient age, brainstem lesion size or fractionation and the need for prolonged use of dexamethasone but there was a trend with lung cancer patients requiring prolonged dexamethasone (p=0.06).

CONCLUSION

Brainstem SRS is viable option with an acceptable late toxicity profile. Updated information on survival and local control will be presented.
Motor Seizures Confer Overall Survival Benefit in WHO Grade 2 Glioma
Authors: Fairclough Sam , Mathew Ryan , Goodden John , Chumas Paul , Maguire Melissa
Published: October 2022

AIMS

The prevalence of epilepsy in WHO grade 2 glioma is high, with seizures often being the presenting symptom. We explore the epidemiology of seizures in this patient population in a regional neurosurgical centre.

METHOD

Electronic health records of patients with histologically-proven WHO grade 2 glioma (n=227) were reviewed with data collected including patient demographics, epilepsy prevalence and seizure semiology. Relationships between epilepsy and overall survival were calculated using a Cox proportional hazards model in the statistical software “R,” controlling for all other variables – including histological diagnosis.

RESULTS

Overall, 196/227 (86.3%) patients were diagnosed with epilepsy - either at presentation (179/196, 91.3%), or during the course of their disease (17/196, 8.7%) . Mean follow-up was 7.0 years. Diffuse astrocytoma histology was associated with reduced overall 10-year survival (HR 4.68, p<0.001) compared with oligodendroglioma. The majority of patients experienced focal onset seizures (n=118) as their predominant seizure type, with generalised (n=64) and unknown onset seizures (n=14) less likely. Almost two-thirds (64.8%) of those with epilepsy had experienced at least one generalised tonic-clonic seizure. During seizures, loss of awareness (n=132) and presence of motor activity (n=147) were frequently encountered. Predominantly experiencing seizures without any motor activity also appeared to confer poorer survival outcomes (HR 2.39, p<0.05), even when controlled for histology.

CONCLUSION

Most WHO Grade 2 glioma patients experience focal seizures, though generalised tonic-clonic seizures are common. Motor seizure activity is a frequent feature in WHO Grade 2 glioma and may confer a survival benefit, when compared to patients that have primarily non-motor seizure activity.
Brain Tumour Diagnosis and Relationships Among Patients: A Social Science Perspective on Changing Tumour Classification
Authors: Llewellyn Henry , Dulley Louise , Higgs Paul , Louis David , Sampson Elizabeth , Stone Paddy , Thorne Louis
Published: October 2022

AIMS

Peer-to-peer relationships between people with a brain tumour are critical to how they cope with illness. These are often premised on shared diagnoses. However, as molecular genetic/epigenetic markers revise tumour classification, the terms of such relationships could also change. We explore these relationships and the potential repercussions for patients whose diagnoses are revised according to new tumour classification.

METHOD

We draw on two UK-based ethnographic studies of brain tumour care. The first examined how patients navigated complex healthcare systems (2014-2016); the second explored changing classification and personalised medicine (2020-2021). Both involved repeated qualitative interviews with patients, families, clinicians and classification experts, and observations of routine care. Here, we focus on interviews and observations with patients (N=29).

RESULTS

Patients described how peer-to-peer relationships helped them understand their condition, envision their futures, find solidarity, navigate medical decisions, and access non-standard treatments. Many described the importance of finding people who shared their diagnosis. One patient, whose diagnosis was revised to a less aggressive tumour years after being first diagnosed, described how a radical change in prognosis challenged her relationships with peers, and contributed to significant survivor guilt as she outlived them.

CONCLUSION

Our findings confirm the importance of peer-to-peer relationships for patients. They suggest how changing tumour classification could have significant unforeseen social and psychological impacts for patients, including survivor guilt, by changing the nature of such relationships. We speculate that this will become more common in an era of personalised medicine and when breakthroughs in cancer understanding are more rapidly integrated in routine care.
How Can Clinical Teams Support Patients With a Brain Tumour Diagnosis With Sex Relationships and Intimacy?
Authors: Kostick Ellie , La Jessica , Hurwitz Victoria , Hedges Sarah , Robinson Charlotte , Suarez Aeron , Ashkan Keyoumars , Bhangoo Ranjeev , Gullan Richard , Vergani Francesco , Brazil Lucy , Al-Salihi Omar , Swampillai Angela , Chia Kazumi , Cikurel Katia , Joe Dorothy , Finnerty Gerald , Lavrador Jose Pedro
Published: October 2022

AIMS

There is a gap in supporting patients with sexual relationships and intimacy. The aim of this study is to establish if patients with a brain tumour feel they are able to ask questions and concerns about sex, relationships and intimacy following diagnosis; is there an unmet need and how can this be addressed.

METHOD

An anonymous survey was sent to patients known to a neuro-oncology team. Questions were in relation to their experiences of sex relationships and intimacy. Patients were asked if they had concerns about changes in their relationships since their diagnosis. They were also asked for their comments on the subject so we can better understand how as a service we can improve to ensure holistic care.

RESULTS

There are 40 responses. The majority of respondents had concerns about their relationship since diagnosis and that their relationships have changed. 57% were concerned about a physical relationship with a partner/ future partners. 50% agreed their physical relationship had changed. 45% of people agreeing their emotional relationships have changed. 38 out of the 40 people questioned, had not asked their clinical team for advice about sex and relationships. 46% suggested clinicians initiating these conversations.

CONCLUSION

Sex relationships and intimacy are significant for most adult populations, encompassing connection with their loved ones, self esteem and psychological and emotional well-being. With brain tumour diagnosis this part of people’s lives can hugely impacted. Historically clinicians have found this a difficult subject to discuss. Further work is required to understand the barriers initiating this subject
Introducing “Cloudbuster” as 3D Analysis and Quantification Tool of Cellular Glioma Morphologies in 3D Microscopy
Authors: Rohwedder Arndt , Knipp Sabine , Esteves Filomena , Hale Michael , Treanor Darren , Bruning-Richardson Anke
Published: October 2022

AIMS

A faithful representation of real tumour conditions in vivo such as a 3D glioma spheroid in a 3D experimental setting has become highly desirable for brain tumour research as it aids the study of tumour behaviour such as cell invasion and initiation of metastasis. However, data resulting from such studies need to be accurately analysed to correctly assess, for example, inhibitor effects on spheroid morphology and cell migration. To aid 3D data analysis we aimed to develop a reliable system for quantification of observed morphological changes such as number, morphology and size of invasive cells and spheroid extensions.

METHOD

We established a novel workflow that reconstructs a 3D entity from, for example, microtome sectioned glioma spheroids or confocal image z-stacks into pointclouds and subsequent comparison of basic readout parameters. The workflow requires little computational effort. Sliced image stacks are successfully scaled down towards a 1x1x1 ratio at threshold with subsequent edge detection and transformed into a pointcloud and analysed within minutes on a standard workstation /computer, e.g. shared graphics (4x 1.80 GHz CPU, 15 GB RAM).

RESULTS

We were able to validate the usefulness of this workflow using 3D data generated by various means including z-stacks from confocal microscopy and immunohistochemistry sectioning and demonstrate the possibility to accurately characterize inhibitor effects in depth.

CONCLUSION

We developed and validated ‘Cloudbuster’ as a 3D quantification tool to accurately assess structural changes detected in brain tumour cells after drug treatment, resulting in a versatile and adaptable 3D morphology analysis tool.
Brain Tumour Lessons From Alzheimer’s Disease: Beta-Amyloid and SorLA Expression in Glioblastoma
Authors: Jones Lydia , Jones Vicky , Shaw Lisa , Stasik Izabela , Smith Christopher
Published: October 2022

AIMS

Exploring how two proteins strongly associated with Alzheimer’s disease are expressed in glioma. Amyloid beta (Aβ) is a peptide cleaved from amyloid precursor protein (APP) that is shuttled around the cell by sorting-related receptor with A-type repeats (SorLA). Low expression of SorLA has been linked to increased risk of Alzheimer’s disease as APP processing shifts towards production of the plaque-forming Aβ42 rather than the more benign Aβ40.

METHOD

Expression of Aβ40, Aβ42 and SorLA was determined in immortalised cell lines (grade 4 glioblastoma U87MG, grade 2 astrocytoma 1321N1, foetal astrocytes SVGp12), glioblastoma patient-derived cells (PD301, PD304) and normal human astrocytes through western blotting or immunocytochemistry.

RESULTS

SorLA was present in all cells. Relative optical density was more than 60-fold higher for U87MG glioblastoma cells and approximately 10-fold higher for 1321N1 astrocytoma cells than SVGp12 cells. Similarly, SorLA had a significantly higher expression (p<0.01) in patient derived cells than normal human astrocytes. High expression of SorLA was accompanied by lower Aβ42 in patient derived cells compared to normal human astrocytes. Expression of Aβ40 was similar across patient derived cells and normal human astrocytes.

CONCLUSION

These data suggest that SorLA is retained in glioblastoma and remains functional to drive APP processing away from Aβ42 production. Future work will determine how high SorLA expression contributes to the increased motility and invasiveness seen in glioblastoma cells by transfecting siRNA to knock down SorLA.
The Two-Week-Wait Referral Pathway: Not Fit for Purpose
Authors: Moosa Almira , Rees Jeremy
Published: October 2022

AIMS

The two-week-wait (2WW) referral pathway was set up by the Department of Health to improve early diagnosis and overall survival of cancer. Brain tumours, however, present with non-specific neurological symptoms. As such, this study set out to evaluate the efficacy of the 2WW pathway in detecting brain cancer in patients referred by primary care.

METHOD

Data from 217 patients referred via the 2WW pathway from January to September 2021 were extracted retrospectively, using the electronic health record system within the University College London NHS Foundation Trust. Details of the diagnoses, imaging results, and follow-up treatments were analysed.

RESULTS

Of the 217 patients referred with a suspected brain tumour, 0 patients received a new diagnosis of brain cancer. However, 4 cases of benign tumours were newly diagnosed through the 2WW pathway, with an additional 17 cases of benign tumours being referred for further management, having been detected on previous external imaging. 9 cases of known malignant brain tumours were referred for on-going management, having been treated previously elsewhere.

CONCLUSION

The 2WW pathway does not detect new cases of brain cancer. It is rather being used as a means of rapid referral of patients in primary care with benign tumours or previously identified brain cancer. This study therefore suggests that the initial aspiration of detecting brain cancer earlier via this pathway has not been fulfilled, but it is a useful tool for GPs to refer patients with brain tumours into Neuro-oncology services.
Redefining a Rare CNS Tumour Through Targeted Genetic Sequencing
Authors: Abuhusain Hazem , Bagga Veejay
Published: October 2022

AIMS

Isolated cerebellar vermis lesions in adults is a rare location and entity with few literature case reports detailing gangliogliomas and gangliocytomas. Using targeted genetic sequencing, traditional histological diagnosis can be refined further, with a clear impact on prognosis as well as possible genetic counselling implications.

METHOD

A single case of cerebellar vermis lesion, identified incidentally through imaging of a neck nodule, with subtle features of ataxia and mild impairment of initiation of speech. Sub-total resection of lesion underwent standard histopathological work-up, followed by targeted genetic sequencing to obtain an integrated diagnosis.

RESULTS

Histological assessment identified atypical ganglion cells labelled with Synaptophysin on immunohistochemistry. Features closely resembled dysplastic cerebellar gangliocytoma (Lhermitte-Duclos Disease). Further targeted sequencing showed no evidence of IDH1, IDH2, TERT promoter, or histone mutation, however, BRAF mutation was present, supporting an alternate diagnosis of ganglioglioma.

CONCLUSION

Precision medicine is facilitated with advanced diagnostic techniques. This redefines categorisation of some CNS tumours, particularly rare entities. Techniques are especially valuable to individual patient management as they can have a direct impact on aspects of clinical work-up, prognosis, follow-up, and in some cases, genetic counselling.
First Line Treatment of Adult Glioblastoma Patients in England 2103-2018 from the GlioCova Project
Authors: Le Calvez Kerlann , Mauricaite Radvile , Williams Matt
Published: October 2022

AIMS

The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Here we present detailed analysis of first-line treatments of adult glioblastoma (GBM) patients.

METHOD

We identified all adults patients diagnosed with a GBM. We focused on the first line of treatment and we defined ‘maximal’ first-line treatment as surgical resection followed by chemo-radiotherapy with 59-60 Gy and with at least one cycle of adjuvant chemotherapy Temozolomide.

RESULTS

15,294 patients were diagnosed with a glioblastoma (60% male) with a median age of 66. 79% of patients received some treatment, with younger patients more likely to be treated (>90%, 18 - 59; < 30%, > 80). 54% underwent debulking surgery; 23%, biopsy. 14% received ‘maximal’ treatment and 21%, none. Patients who had no treatment had a median survival of 2 months whereas patients who received ‘maximal’ treatment had a median survival of 16 months.

CONCLUSION

Most adult patients with a GBM in England have a histological diagnosis, and some oncological treatment. However, only 14% receive ‘maximal’ treatment. Of the 3222 patients who received none, some of these may have had purely private treatment; however, our dataset includes any private sector work undertaken in NHS hospitals. Survival remains poor, but outcomes in those receiving maximal treatment match those from clinical trials. However, most patients do not receive maximal treatment, and so the easiest route to improving outcomes may be optimise delivery of treatment in the 65% of patients who receive sub-maximal treatment. More information on https://blogs.imperial.ac.uk/gliocova
Deep Learning for Tumour Segmentation with Missing Data
Authors: Ruﬄe James , Mohinta Samia , Gray Robert , Hyare Harpreet , Nachev Parashkev
Published: October 2022

AIMS

Brain tumour segmentation remains a challenging task, complicated by the marked heterogeneity of imaging appearances and their distribution across multiple modalities: FLAIR, T1-weighted, T2-weighted, and contrast-enhanced T1-weighted sequences (T1CE). But the use of all four imaging sequences is not always possible. The causes for this are legion, with common examples including corruption by image artefacts and acquisition constraints, such as those imposed in pre-operative stealth studies. We therefore aimed to quantify how well tumour segmentation models perform with incomplete imaging data.

METHOD

We developed a collection of 30 state-of-the-art deep learning tumour segmentation models, nnU-Net-derived, and deployed them across all possible combinations of imaging modalities, trained, and tested with five-fold cross-validation on the 2021 BraTS-RSNA glioma population of 1251 patients, with additional out-of-sample comparison to neuroradiologist hand-labelled lesions from our own centre.

RESULTS

Regardless of imaging available, models largely performed well. The best models with varying degrees of missingness were as follows: single sequence available - FLAIR (Dice 0.938); two sequences available - FLAIR + T1CE (Dice 0.943) and three sequences available – FLAIR + T1CE + T2 (Dice 0.945). In comparison, a model with complete data (FLAIR + T1 + T1CE + T2) achieved a similar Dice coefficient of 0.945.

CONCLUSION

Tumour segmentation models with missing sequences – common in clinical practice - still delineate lesions well, often with comparable performance to when all data is available. This provides opportunity for quantitative imaging in patients and clinical situations wherein full MRI acquisitions are not possible.
Lynch/Turcot Syndrome and Sporadic Mismatch Repair Deficient High-Grade Gliomas – A Case Series
Authors: Briggs Mayen , Bruty Jonathan , O’Donovan Dominic , Liu Hongxiang , Tischkowitz Marc , Tarpey Patrick , Hewer Ekkehard , Giger Olivier
Published: October 2022

AIMS

The DNA mismatch repair (MMR) system is critical for genomic stability correcting errors generated during DNA replication with germline pathogenic variants (PVs) causing Lynch syndrome. Although acquired MMR deficiency is associated with temozolomide resistance, the incidence in treatment naïve tumours is unknown and not routinely screened for. Here we present three MMR deficient gliomas and describe their comprehensive molecular profile.

METHOD

Thirteen gliomas; 9/34 that had undergone sequencing of 50 cancer-associated genes and found to have frameshift/multiple point PVs, indicative of defective MMR, and four MSI-high tumours, identified following microsatellite analysis for 1p/19q co-deletion as part of routine care, were selected for analysis. MMR expression was then assessed by immunohistochemistry. Seven tumours showed loss of one or more MMR proteins and were molecularly characterised using PCR-based Promega MSI analysis and NGS-based Illumina TruSight500 panel.

RESULTS

Pathogenic variants in MMR genes and hypermutated phenotypes (TMB > 10mutations/Mb) were identified in three cases. One individual harboured an additional POLE PV resulting in an ultra-hypermutated phenotype (>100mutations/Mb). Two MMR PVs were germline, leading to a new diagnosis of Lynch syndrome. Only one of three tumours was found to be MSI-high using the Promega MSI analysis whilst all three were identified as MSI-high using TruSight500 MSI calling algorithms.

CONCLUSION

We describe the comprehensive molecular profile of seven treatment naïve gliomas, three being MMR deficient. We show TruSight500 to be more sensitive and reliable for detecting MSI compared to Promega. Given the implications, this additional analysis should be considered as part of the molecular report on all gliomas.
Extent of MGMT Promoter Methylation Modifies the Effect of Temozolomide on Overall Survival in Patients with Glioblastoma: A Regional Cohort Study
Authors: Poon Michael T C , Keni Shivank , Vimalan Vineeth , Ip Chak , Smith Colin , Erridge Sara , Weir Christopher , Brennan Paul
Published: October 2022

AIMS

MGMT methylation in glioblastoma predicts response to temozolomide but dichotomizing methylation status may mask the true prognostic value of quantitative MGMT methylation. This study evaluated whether extent of MGMT methylation interacts with the effect of temozolomide on overall survival.

METHOD

We included consecutive glioblastoma patients aged ≥16 years diagnosed (April 2012–May 2020) at a neuro-oncology center. All patients had quantitative MGMT methylation measured using pyrosequencing. Those with MGMT methylated tumors were stratified into high and low methylation groups based on a cut-off using Youden index on 2-year survival. Our accelerated failure time survival models included extent of MGMT methylation, age, postoperative Karnofsky performance score, extent of resection, temozolomide regimen, and radiotherapy.

RESULTS

There were 414 patients. Optimal cut-off point using Youden index was 25.9% MGMT methylation. The number of patients in the unmethylated, low and high methylation groups was 223 (53.9%), 81 (19.6%), and 110 (26.6%), respectively. In the adjusted model, high (hazard ratio [HR] 0.60, 95% confidence intervals [CI] 0.46– 0.79, P=0.005) and low (HR 0.67, 95% CI 0.50–0.89, P<0.001) methylation groups had better survival compared to unmethylated group. There was no evidence for interaction between MGMT methylation and completed temozolomide regimen (interaction term for low methylation P=0.097; high methylation P=0.071). This suggests no strong effect of MGMT status on survival in patients completing temozolomide regimen. In patients not completing the temozolomide regimen, higher MGMT methylation predicted better survival (interaction terms P<0.001).

CONCLUSION

Quantitative MGMT methylation may provide additional prognostic value. This is important when assessing clinical and research therapies.
Exploring the Role of Specialist Physiotherapy in Awake Craniotomy Surgery for the Neuro-Oncology Patient
Authors: Jones Amy , Price Sally , Lavrador Jose Pedro , Gullan Richard , Vergani Francesco , Bhangoo Ranjeev , Rajwani Kapil , Ashkan Keyoumars , Mirallave-pescador@nhs.net Ana
Published: October 2022

AIMS

To describe the methods used to assess and monitor motor function during awake craniotomy surgery for tumour resection.

METHOD

A service review was carried out over 10 months. Patients with highly motor eloquent lesions – invasion of primary motor cortex or fronto-parietal connections involved in motor cognition – were included. Clinical notes were reviewed and summarised using descriptive analysis. Dexterity and grip strength were measured using 9-hole peg test and handheld dynameter pre/intra and post-operatively. Patient occupation/interests were reported to guide bespoke assessments to trial intra-operatively.

RESULTS

From April 2021 to January 2022, 13 patients (mean age 39.7 years, 4 female:10 male, 9 low grade:5 high grade gliomas) were included. Mean score 9-hole peg test 22.2sec pre-operatively, 30.6sec post-operatively; handheld dynameter 26.7kg pre-operatively, 18.4kg post-operatively. At discharge 5 of 7 impaired patients demonstrated motor improvement. For motor coordination, motor tasks used frequently included repetitive finger tapping, open/closed hand. Bespoke tasks included texting/writing, playing instruments, and computer games. Movement was closely monitored and verbal feedback given to the neurosurgeons throughout. With video analysis movement comparisons were made.

CONCLUSION

The role of physiotherapy in awake surgery is evolving to provide movement analysis for complex motor tasks such as upper limb sequencing and dexterity. A combination of standard and bespoke assessments have been trialled and their feasibility within surgery tested. A post-operative deterioration of motor function (power and cognition) is expected after surgery for highly eloquent motor gliomas. However, intraoperative motor assessment for motor cognition allows function preservation and potentiates its recovery.
Cardiovascular Events After Primary Malignant and Non-Malignant Brain Tumour Diagnosis: A Population Matched Cohort Study in Wales (United Kingdom)
Authors: Poon Michael T C , Jin Kai , Brennan Paul , Figueroa Jonine , Sudlow Cathie
Published: October 2022

AIMS

It is uncertain whether the elevated cardiovascular diseases (CVD) risks in patients with brain tumours is due to differences in the distribution of risk factors. We compared CVD risks among patients with a primary brain tumour to a matched general population cohort.

METHOD

Using data from the Secured Anonymised Information Linkage (SAIL) Databank in Wales, we identified adults aged ≥18 years with a diagnosis of brain tumour identified in the cancer registry between 2000-2014, and a matched cohort (case-to-control ratio 1:5) by age, sex and primary care provider from the general population. Outcomes included fatal and non-fatal major vascular events and venous thromboembolism (VTE). We used multivariable Cox models adjusted for clinical risk factors to compare risks.

RESULTS

There were 2,869 and 3,931 people diagnosed with malignant and non-malignant brain tumours, respectively, in Wales. They were matched to 33,785 controls. Within the first year of tumour diagnosis, malignant tumour was associated with VTE (hazard ratio [HR] 21.58, 95% confidence interval 16.12-28.88) and stroke (HR 3.32, 2.44-4.53). People with malignant tumour surviving one year had higher risks of VTE (HR 2.20, 1.52-3.18) and stroke (HR 1.45, 1.00-2.10) compared to their matched controls. Individuals with non-malignant tumours had higher risks of VTE (HR 3.72, 2.73-5.06), stroke (HR 4.06, 3.35-4.93) and aortic and peripheral arterial disease (HR 2.09, 1.26-3.48) within the first year of diagnosis compared with their controls.

CONCLUSION

The elevated risks of CVD suggest risk reduction a potential strategy to improve life quality and survival in people with malignant and non-malignant brain tumour.
Photodynamics of Subependymal Giant Cell Astrocytoma (SEGA) with 5-Aminolevulinic Acid (5-ALA/Gliolan©)
Authors: Ghani Imran , Patel Sabina , Bodi Istvan , Vergani Francesco , Ashkan Keyoumars , Bhangoo Ranjeev , Lavrador Jose Pedro
Published: October 2022

AIMS

5-ALA (Gliolan©) is a valuable surgical tool used predominantly in high grade tumours, which utilises tissue fluorescence to improve the visualisation of the brain-tumour interface. This ensures safe maximal resection, while preserving healthy brain. While Gliolan© use in low grade tumours has previously been reported with variable results, reports of its use and success in the context of SEGA are extremely rare. This report highlights the use of Gliolan© in a patient presenting with a Subependymal Giant Cell Astrocytoma (in a background of tuberous sclerosis), facilitating maximal safe resection and preserving eloquent tissue.

METHOD

Tumour resection was performed with pre-operative DTI-fiber tracking and mapping. A transsulcal minimal invasive parafascicular approach (tsMIPS) was carried out with assistance of NICO BrainPath© tubular retractor system (60x13.5), neuronaviagtion, Gliolan©, intra-operative neuro monitoring (IONM), and ultrasound guidance

RESULTS

The tumour was found to have both bright and pale fluorescence in the cystic and solid components respectively. Resection was limited to the soft cystic component only, as the solid tumour component showed anatomical attachment to the subgenual area and the fornix. No fluorescence was perceived at the end of resection. The patient made a good recovery with no post-operative deficits. Histopathology confirmed subependymal giant cell astrocytoma (SEGA, WHO grade I). No adjuvant treatment was required

CONCLUSION

This reports suggests 5-ALA may be beneficial in the safe resection of SEGAs. Further studies and technological advances in the area of photodynamics, imaging, and intra-operative mapping may be helpful to fully evaluate the efficacy of 5-ALA in SEGAs and other low-grade tumours.
Effects of Glycogen Synthase Kinase-3β (GSK3β) Inhibition in Glioblastoma Using Novel Compounds
Authors: Rzepecka Klaudia , Lawrence Clare , Moualla Dima , Hayes Joseph , Alder Jane
Published: October 2022

AIMS

GSK3β is a constitutively conserved serine/threonine kinase involved in a number of biological processes including cell cycle progression, apoptosis, cellular metabolism, proliferation and differentiation. High expression levels in the brain make this kinase a potential target for treatment of neurological disorders. The aim was to investigate the anti-proliferative and cytotoxic effects of four novel highly selective, type-II GSK3β inhibitors identified by in silico analysis of naturally occurring compounds.

METHOD

We demonstrate the effects on the cell viability of immortalised cell lines (grade 4 glioblastoma U87MG, foetal astrocytes SVGp12) and short-term glioblastoma patient derived cultures (PD301 and PD304). The compounds were incubated with cells for 24, 48 and 72h and then assayed for cell viability using MTS. The concentration of inhibitors was determined from previous IC50 experiments on purified GSK3β enzyme. The changes in activity status of GSK3β pre- and post-treatment were also determined using immunohistochemistry or Western Blotting.

RESULTS

Two of the compounds caused significant decrease in cell viability at 24h and 3uM as shown by decrease in viability of 20.5% relative to control. This decrease was larger in the glioma cell lines relative to the glial non-cancerous control (13%). Western blot analysis revealed that activating phosphorylation sites were detectable. More work is needed to determine if this is the mechanism by which reduction in cell viability occurs.

CONCLUSION

Two of the selected novel compounds have demonstrated ability to decrease glioblastoma cell viability. Future studies will include analysis of the compounds in relation to the BBB-glioma in vitro model.
A Retrospective Review of the Clinical Outcomes of Lung Cancer Patients Referred into the Regional Neuro-Oncology Pathway in 2020 in Merseyside, United Kingdom
Authors: Heseltine Jonathan , Corte Ana , Kennedy Oliver , Sharples Harry , Brodbelt Andrew , Mehta Shaveta
Published: October 2022

AIMS

The aim of this project was to review the outcomes of patients referred via our regional neuro-oncology pathway who received neurosurgery, SRS, whole brain radiotherapy (WBRT), chemotherapy (SACT) or best supportive care (BSC).

METHOD

All lung cancer patients discussed at our Neuro-Oncology MDT in 2020 were identified. Patient characteristics and outcomes were obtained from the regional lung and neuro-oncology MDT notes and electronic case notes from Clatterbridge Cancer Centre. Overall survival (OS) was calculated from the date of diagnostic scan to death. The date of data cut-off was 15/10/2021.

RESULTS

Full datasets were available for 100 patients discussed at the Neuro-Oncology MDT. 65 were adenocarcinomas, 4 had ALK or EGFR mutations and 49 were synchronously presenting with brain metastases and lung cancer. At data cut-off 84 deaths had occurred. The median OS in days was calculated for surgery (207), SRS (360), surgery and cavity boost (298), SACT (249), WBRT (102) and BSC (60). A grouped comparison of SRS and surgery versus other interventions or best supportive care found a statistically significant advantage favouring SRS or surgery (Median OS 360 days, p=0.001). When comparing the synchronous versus asynchronous setting, the combined median OS of the neurosurgical, SRS or SACT cohorts was 276 versus 170 days but there was no difference in WBRT or BSC.

CONCLUSION

This real-world data details the number of lung cancer patients referred to and receiving neurosurgery or SRS via the Merseyside neuro-oncology MDT. This data supports pre-existing evidence that those who receive SRS or neurosurgery have a superior OS.
The Changing Landscape of Diffuse Low Grade Glioma (DLGG) Management in the West of Scotland: A Single Centres 10-Year Experience
Authors: Tilling Elliot , Lammy Simon , Bridgman Elsie , Johnson Hannah , Stan Alexandru , Taylor Aaron , Grivas Athanasios
Published: October 2022

AIMS

Management strategies for patients diagnosed with diffuse low grade glioma (DLGG) remain controversial. Current evidence favours resection over biopsy. This has resulted in more aggressive intervention. We examined management trends in the West of Scotland over a 10 year period.

METHOD

Patients diagnosed with DLGG between 2010 and 2019 were included and grouped according to time of diagnosis: 1) 2010-2012, 2) 2013-2016 and 3) 2017-2019. Clinical characteristics, management and overall survival (OS) were investigated and comparatively analysed. Survival between resection and biopsy groups was also analysed.

RESULTS

84 patients were included (n=25 in Group 1, n=35 in Group 2 and n=24 in Group 3). Biopsy was less commonly performed in Group 2 (17%) and Group 3 (21%) compared to Group 1 (56%) p=0.014. The frequency of post-operative seizures: G1: n=3 (12%), G2: n=1 (2.9%), G3: n=2 (8.3%) (p=0.385) and focal neurological deficit: G1: n=4 (16%), G2: n=8 (22.9%), G3: n=6 (25) (p=0.718) and mean length of stay (LoS) in days: G1: 7.7, G2: 8.8, G3: 7.4 (p = 0.548) were similar across the groups. Survival analysis revealed no significant difference between groups: G1 52%, G2 69%, G3 75% (p=0.172). Patients managed by resection (n=58) versus biopsy (n = 26) observed improved survival (resection OS 70% compared to biopsy OS 39% (p= 0.005)).

CONCLUSION

Resection results in improved survival over biopsy. This has resulted in an institutional change over time. But no significant difference was observed in OS between different time periods.
Treatment of Glioblastoma Multiforme at Progression or Recurrence: A Service Evaluation
Authors: Quarrell Thomas Matthew , Millar Zack , Doherty Gary , Jena Rajesh , Harris Fiona
Published: October 2022

AIMS

After initial treatment, glioblastoma multiforme (GBM) invariably reoccurs or progresses. When this happens, there is no established standard of care and treatment choice is made on a case-by-case basis. In our service, there is a multidisciplinary approach to progression, with oncologists and surgeons cooperating closely. This means that our cohort is ideal for studying treatment at progression.

METHOD

We performed a retrospective cohort service evaluation on patients diagnosed with isocitrate dehydrogenase wildtype GBM over a 4-year, 5-month period. We focused on patients who had received Stupp regimen treatment. Analysis was though a cox-proportional hazard model with multiple imputation analysis for missing data when appropriate.

RESULTS

The variable most strongly correlated with the treatment chosen at progression was patient performance status (Kruskal Wallis chi-squared = 22.804, p=0.00014). Some variables, such as age at progression or initial surgical management, were unexpectedly not correlated with the chosen treatment. Of the possible treatments at progression, only surgical management approached borderline significance for increasing survival relative to best supportive care (p=0.06). Performance status had at most a moderate, non-significant impact upon survival post-progression. The MGMT methylation status of the tumour emerged as a powerful predictor of survival post-progression (p=0.01).

CONCLUSION

A range of variables are correlated with which treatment is chosen at progression, but they do not always relate to the post-progression survival. Of all treatments, we can only demonstrate surgical management as having an impact upon survival, suggesting a more moderate effect of medical therapies relative to best supportive care.
Coping Better Together
Authors: Rodway Alison
Published: October 2022

AIMS

Coping Better Together is a patient education course that is offered by The Walton Centre for brain tumour patients following surgery. The diagnosis and treatment of brain tumours impacts patients and families long past the time of diagnosis, surgery and adjuvant treatment. The Coping Better Together Course recognises the impact on health and wellbeing and aims to equip patients and families with information, strategies and resources that improve quality of life.

METHOD

The course comprises of education sessions from a wide range of health care professionals, consultants, clinical nurse specialists and allied health care professionals. It provides opportunity for networking allowing patients and families to meet with others facing similar difficulties. Prior to the impact of the Covid pandemic this course was run off site and solely in person. The impact of Covid has brought the course within The Walton Centre allowing for both face to face attendance and virtual access, thus making it more accessible.

RESULTS

Feedback from the day is highly favourable and valued by those who attend. Patients and families report that they receive valuable information and go away better equipped in dealing with both symptoms and living with the effects of their diagnosis.

CONCLUSION

This in house CNS led patient education course has an impact on quality of life and improves patient experience. The course provides a framework that can be easily utilised, followed and adapted by other healthy care professionals in providing education and support to brain tumour patients and their families.