Abstract
AIMS
(1) To determine if specific and unique chloride intracellular channel (CLIC) expression patterns exist in paediatric glioblastoma. (2) To assess if these expression patterns can be ...exploited as a treatment strategy. (3) To assess the combination of ion channel manipulation with Tumour Treating Fields (TTFields).
METHOD
CLIC channel expression patterns were identified via multivariate analysis of in-house and publicly available data sets and RNA sequencing of in-house patient tumour samples. siRNA depletion or inhibition via IAA94 of CLIC1 and CLIC4 was assessed using cell cycle, clonogenic, migration and proliferation assays, alone and in combination with TTFields. Whole transcriptome gene expression analysis (Human Clairom™ Array) of pGBM cells treated with TTFields was carried out.
RESULTS
Clinical correlation determined that CLIC4 and CLIC1 deficiency was associated with increased overall survival, with siRNA depletion propagating a reduction in the proliferation, migration and invasion of pHGG cell lines associated with cell cycle arrest. Furthermore, CLIC1 and CLIC4 deficiency exacerbated the killing capacity of TTFields, reducing clonogenic and proliferative capabilities. Whole transcriptome gene expression analysis of paediatric GBM cell lines treated with TTFields and found that cells treated with TTfields exhibited a down-regulation in CLIC1 and CLIC4 compared to untreated cells.
CONCLUSION
These data provide rationale that genetic, electrical, and pharmacological manipulation of ion channels can reduce the capacity of childhood brain tumours to proliferate and invade. CLIC channels may be a suitable target for combination therapy to enhance the treatment efficacy of TTfields and help bring this non-invasive therapy to paediatric patients.
Abstract
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.
Abstract
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.
Abstract
AIMS
This study aimed to describe our institutional use of a commercially available mixed reality viewer within a multi-disciplinary planning workflow for awake craniotomy surgery and to ...report an assessment of its usability.
METHOD
Three Tesla MRI scans, including 32-direction diffusion tensor sequences, were reconstructed with BrainLab Elements auto-segmentation software. Magic Leap mixed reality viewer headsets were registered to a shared virtual viewing space to display image reconstructions. System Usability Scale was used to assess the usability of the mixed reality system.
RESULTS
The awake craniotomy planning workflow utilises the mixed reality viewer to facilitate a stepwise discussion through four progressive anatomical layers; skin, cerebral cortex, subcortical white matter tracts and tumour with surrounding vasculature. At each stage relevant members of the multi-disciplinary team reviewed key operative considerations, including patient positioning, cortical and subcortical speech mapping protocols and surgical approaches to the tumour. The mixed reality system was used in 10 consecutive awake craniotomy procedures over a 5-month period. Ten participants (2 Anaesthetists, 5 Neurosurgical trainees, 2 Speech therapists, 1 Neuropsychologist) completed System Usability Scale assessments, reporting a mean score of 71.5. Feedback highlighted the benefit of being able to rehearse important steps in the procedure, including patient positioning and anaesthetic access and visualising the testing protocol for cortical and subcortical speech mapping.
CONCLUSION
This study supports the use of mixed reality for multi-disciplinary planning for awake craniotomy surgery, with an acceptable degree of interface usability. We highlight the need to consider the requirements of non-technical, non-neurosurgical team members when involving mixed reality activities.
Abstract
AIMS
To monitor changes in IVIM parameters in response to JAS239 treatment in preclinical glioblastoma models.
METHOD
C57BL/6 mice were injected intracranially with 5x105 GL261 glioblastoma ...cells and tumours were observed on T2 weighted MRI. Mice were imaged on day 0 (T0, baseline), day 3 (T3), 6 (T6) of treatment and post-treatment day 10 (T10). IVIM DWI was performed using a single-shot spin-echo echo planar sequence and processed using Matlab to acquire IVIM parameters of f, D, and D*.
RESULTS
Percentage changes in values with respect to baseline from saline treated control mice were compared to JAS239 treated animals with respect to baseline. Treated mice showed a slight increase in ADC and pseudo-diffusion on day 3 and day 6, with an increase in the perfusion fraction on day 6. However, no statistically significant difference between the two groups with respect to all 3 parameters (P>0.05). Analysis of the change in parameters post treatment (T10) also showed no statistically (P>0.05) significant difference between the mice treated with JAS239 and the control group treated with saline.
CONCLUSION
In this study of the IVIM based parameters, we observed no significant differences in these parameters which indicates that JAS329 may be ineffective in the treatment of GL261 tumours. There was no significant change in the diffusion and perfusion related parameters in the tumour region. IVIM parameters may be useful in studying the tumour microenvironment, however, these may not be sensitive in detecting tumour resistance to ChoK inhibitor therapies.
Abstract
AIMS
The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Despite poor outcomes, there is little work ...on end of life care in primary brain tumour patients. The majority of patients with cancer prefer to die at home, but most do not.
METHOD
We identified all patients with a malignant primary brain tumour diagnosed in England between 2013-2018 and who died up until 1st of August 2020.
RESULTS
20,684 patients were selected. The median age at diagnosis was 68 years (IQR=19), 42% were female. 55% died within 6 months of diagnosis. 36% of people died at home (compared to 24% of the entire population in England), 25% died in hospital, 15% died in a hospice, 9% died in a nursing home. 15% had an unrecorded or other place of death.
47% (n=9,682) patients had radiotherapy, of which 8.7% (n=1,806) had radiotherapy in the 3 months before death; 29% (n=5,947) patients received chemotherapy (6%(n=1,292) during the last 3 months). 87%(n=18,013) patients had surgery (36%(n=7,370) during the last three months). For all treatments the chance of patients dying at home decreases if the patient has treatment in the last three months of life.
CONCLUSION
To our knowledge, this is the first work exploring the relationship between anti-cancer treatment near the end of life and the location of death. Further work will focus on building a comprehensive model to predict rates of death in hospital, and examine variation on a national level.
Abstract
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.
Abstract
AIMS
Lomustine (CCNU) based regimens are frequently used for recurrent glioblastoma multiforme (GBM). The usual CCNU regimen is 100-130mg/m2, day 1 x 6-weekly cycle for up to 6 cycles. ...Efficacy is limited, with median progression-free survival (PFS) approximating 1.0-3.0 months with higher haematological toxicities, particularly thrombocytopenia around 13-25%. The Clatterbridge Cancer Centre, UK, has adopted the regimen of 40mg once a day over 4 days x 4-weekly for up to 6 cycles. This study aims to identify the efficacy and toxicity profile of this regimen in recurrent GBM.
METHOD
A retrospective analysis on 113 recurrent GBM patients, treated with single-agent CCNU as a second-line, between June 2016 and January 2020. Kaplan-Meier survival estimates identified PFS, PFS at 6 months (PFS6) and Overall Survival (OS) using SPSS v.27. Overall Responses were based on imaging or clinical assessment in patients with at least 2 CCNU cycles. SACT assessments and blood test records, using CTCAE v5.0 grading, identified clinical adverse events.
RESULTS
We observed an 18.8% overall response rate with 2.4% partial response and 16.5% stable disease. There was a CCNU-specific 8-month median OS, 4-month median PFS, and 20.4%% PFS6. This regimen was well-tolerated. The most common toxicity was grade 1 fatigue (38.9%). The Grade 3 or 4 haematological toxicity was low with 12% thrombocytopenia and 2.7% neutropenia rates in patients.
CONCLUSION
This study suggests a reasonable alternative to the usual regimen, offering improved tolerance, lower toxicity rates, and equivalent efficacy. We propose prospective studies comparing differing CCNU regimens to mitigate retrospective studies’ limitations.
Abstract
AIMS
Brain tumours are heterogenous entities comprising multiple broad tissue sub-types when imaged with MRI. Delineating the enhancing tumour component is vital for neuro-oncological ...therapeutic planning, to-date only demonstrable with contrast-enhanced imaging. But not all patients can undergo this necessary contrast-enhanced acquisition, whether due to allergy, renal impairment, or scanning acquisition parameters. We therefore evaluated how well fully convolutional deep learning models identify a patient’s enhancing tumour when contrast-enhanced imaging was not available.
METHOD
We constructed a suite of deep-learning models to segment brain tumours when contrast-enhanced imaging was missing. Specifically, we developed all possible combinations of other structural sequences being provided, including T1-weighted, T2-weighted and FLAIR. Models were trained and tested with five-fold cross-validation on the 2021 BraTS-RSNA glioma population of 1251 patients, with additional out-of-sample validation with neuroradiologist hand-labelled lesions from our own centre.
RESULTS
Models missing post-contrast imaging still achieved a Dice coefficient for the whole tumour of 0.942. Model performances for identifying enhancing-tumour – despite no contrast-enhanced imaging being provided to the model – ranged from Dice coefficients of 0.759 (single sequence model) to 0.790 (three sequence T1 + T2 + FLAIR model). Moreover, models lacking contrast-enhanced imaging still robustly quantified the volume of enhancing tumour (R2 range 0.953-0.976).
CONCLUSION
Models missing contrast-enhanced imaging still identify both whole lesions and enhancing tumour components, and accurately quantifying the enhancing volumetric burden. These models provide opportunity for lesion detection in patients or clinical situations in which contrast-enhanced imaging cannot be acquired, and challenge the current nosology of defining ‘enhancing tumour’.
Abstract
AIMS
Glioblastoma (GBM) is the most common primary brain tumour in adults and has a very poor clinical outcome. An audit of the clinical outcomes of patients with glioblastoma at our centre ...was conducted and compare with the results reported nationally in the National Cancer Registration Service and Hospital Episode Statistics 2007– 2011.1 ) as well as international standards.
METHOD
Patients with GBM in North Wales Cancer Treatment Centre from October 2014 to September 2018 were identified using Canisc databases. We censored 2 patients because of no further follow up due to transferred to other centres. Treatment and outcome data was retrospectively collected using electronic record systems and the case notes.
RESULTS
The total 117 patients with GBM were identified. The craniotomy and Debulking surgery was done in 67, Biopsy only in 29 and no surgery in 21 patients. Median OS of all patients was 9.2 months. The median OS in the patient group of under 70 years treated with Concurrent chemo-radiotherapy (60 Gy) followed by adjuvant chemotherapy was 16.9 months. Median OS of patients aged 70 years and above who had “radiotherapy” or “no radiotherapy” were 6.5 months versus 1.9 months respectively.
CONCLUSION
Our results are comparable to the national outcomes. We would be reporting further on the differential survivals of different age groups and with results of genetic biomarker stratifications.
