Abstract
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.
Abstract
AIMS
The aims of this study are to share our experience of a large series of multifocal/multicentric glioblastomas (mGBM) and analyse the clinical, histological/molecular and neuroimaging ...characteristics as well as the outcomes of the patients in order to inform and contribute to future patient care.
METHOD
We conducted a retrospective single centre study of all multifocal/multicentric glioblastomas treated at our institution over a 10 year period. Data was collected from electronic patient records including patient demographics, clinical presentation, diagnostic imaging, treatment plans and histopathology/molecular findings. Time to recurrence/progression and overall survival was assessed.
RESULTS
1158 glioblastomas were treated surgically over this time period of which 121 multifocal/multicentric tumours were identified (10.4%). The median age at diagnosis was 63 years with a slight male predominance (54.5%). Half of all patients (61/121) presented with focal neurological deficits. 69% of patients underwent a craniotomy for diagnosis/debulking of the larger enhancing component of the tumour whilst 31% underwent only a biopsy. The median time to recurrence/progression was 154 days. Median length of survival was 269 days. Those who underwent craniotomy had significantly prolonged survival compared to biopsy alone 301 vs 198 days (p= 0.027) as did those who had a near total resection 401 vs 269 for subtotal resection (P=0.006) and those < 60 years (p=< 0.001). 88% of patients were IDH1 wildtype. Radiotherapy and chemotherapy confer a significant survival advantage when compared with no further treatment (p<0.001).
CONCLUSION
Near total resection of the larger enhancing component and post-operative chemo/radiotherapy can offer prolonged survival in patients with mGBM.
Abstract
AIMS
Improvements in the treatments for childhood and adolescent brain tumours, High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), have not advanced much and they ...continue to carry a very poor prognosis. These brain tumours are now defined by mutations affecting histone 3 proteins, indeed 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. We hypothesized that the histone 3 mutant tumours will have distinct mutation specific surfactome or cell surface proteins. We analysed the cell surface proteomics of H3.3 G34V and G34R mutated high-grade glioma in comparison to the H3 wild-type Glioma, to explore whether these proteins have the potential to be used as immunotherapeutic targets.
METHOD
We have at first isolated the cell membrane fractions from a range of patient cells carrying histone 3 mutations (G34R, G34V) relative to wild type histone 3. A comparative quantitative liquid chromatographic mass- spectrometry analyses of these cell surface membrane fractions were performed to identify specific targetable factors.
RESULTS
The results of these were analysed with the focus in identifying proteins that can be targeted for tumour specific immune modulation or immunotherapeutic intervention.
CONCLUSION
Results of these analyses will be presented.
Abstract
AIMS
Temozolomide-induced thrombocytopaenia is well-recognised; clinical-course varies widely. Aims: To identify risk factors for prolonged thrombocytopaenia; improve patient-care; inform ...trial design.
METHOD
Glioblastoma (GBM) patients requiring platelet transfusion were identified. (Local policy: transfuse when plt count ≤ 30 x 109/L). Inclusion criteria: First-line-standard-of-care temozolomide-chemo-radiotherapy (TMZ-CRT). Case-notes reviewed for demographics, blood-counts, radiotherapy and treatment parameters. Thrombocytopaenia grading: CTCAE V5. Date of onset measured from start of TMZ-CRT to date of platelets < 100 x 109/L, and to date of first instance of ≥ grade 3 thrombocytopaenia. Thrombocytopaenia duration: time to platelet count recovery to ≥ 100x109/L.
RESULTS
Between 2017-2021, 69 patients required platelet transfusion; 68/69 identified on routine monitoring. 49 patients were analysed (6:no CRT; 5:trial study drug; 7:≥ 2nd line treatment; 2:inadequate data). Median age: 59 (range 25-73); 61% female. First incidence of thrombocytopaenia during concurrent TMZ-CRT: 27/49 patients; during adjuvant TMZ in 22/49 (13/22 following 6-week-TMZ-CRT, 9/22 following 3-week-TMZ-CRT). In concurrent patients, median time to thrombocytopaenia: 33 days (range 23-38); median duration: 44 days (range 20-105; 5 not recovered); number of transfusions: 1-2:9 pts; 3-4:6pts; 5-7:3pts; 8-10:7pts; >10:2pts. Of 22 adjuvant patients transfused, 8/22 developed ≥G3 thrombocytopaenia post-cycle-2; 19/22 resolved after 1 or 2 transfusions. Thrombocyopaenia was associated with ≥G3 neutropaenia in 11% of patients requiring <5 transfusions vs 75% requiring ≥ 5. Comparison of < 5 vs ≥ 5 transfusion-patients did not identify differences in any demographic or treatment parameters.
CONCLUSION
Risk factors for prolonged TMZ-induced thrombocytopenia vs swiftly-resolving thrombocytopaenia remain elusive. This needs to be reflected in consent processes and in design of clinical trials.
Abstract
AIMS
Glioblastomas (GBMs) are characterised by highly hypoxic regions and the ability to invade into healthy brain tissue promoting tumour dissemination and recurrence; the development of ...novel anti-migratory inhibitors to target cell invasion and recurrence must consider varying treatment responses in this tumour background. As proof of principle we investigated the anti-migratory activity of two, previously characterised, small molecule inhibitors under normoxic and hypoxic conditions. We hypothesised that anti-migratory drug activity is dependent on hypoxia levels.
METHOD
Glioma cell line U251 was exposed to BIO-indirubin and Y-27632 alone or in combination and activity was assessed in 2D scratch assays under normoxic (21% O2) and hypoxic (0.1% O2) conditions. Live cell imaging was performed and analysis was carried out using ImageJ.
RESULTS
Treatment with BIO, Y-27632 or in combination had a statistically significant effect on the inhibition of migration in normoxia and hypoxia (p=0.01); BIO inhibited migration and Y-27632 promoted migration under normoxia, whereas BIO maintained the anti-migratory effect under hypoxia, the effect of Y-27632 was switched towards anti-migratory activity and combination treatment potentiated. The effect of Y-27632 was concomitant with a phenotypic shift in cells under hypoxia from highly elongated to possessing shorter extensions.
CONCLUSION
An anti-migratory effect of Y-27632 on cell migration was induced under hypoxic conditions suggesting that the adoption of amoeboid migration by the cells allowed targeting migratory pathways under the control of RhoA and ROCK. This confirms that candidate drug activity must be assessed under both conditions to be considered as drugs complementary to chemotherapy as potential novel treatment option.
Abstract
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.
Abstract
AIMS
Paediatric high-grade gliomas (pHGG) are the leading cause of cancer-related death in children. Histone H3.3 mutations are an important hallmark of pHGG, but for which their underlying ...oncogenic mechanisms are incompletely understood. This research aims to identify potential molecular effectors in these tumours that may be therapeutically effective.
METHOD
To assess potential molecular effectors, we employed proteomic profiling using LC-MS/MS and determined plasma membrane proteins of the surfactome that are differentially expressed on the surface of H3.3 mutant (G34R, G34V), compared to H3.3-wildtype human glioma cells in culture.
RESULTS
Profiling of plasma membrane-enriched fractions identified 34 membrane proteins exclusively detected from H3 G34V mutant cells compared to H3 wild-type cells, and 10 membrane proteins exclusively detected from H3 G34R mutant cells, with 39 membrane proteins shared between both H3 G34R/V genotypes. One of these shared membrane proteins, GLUT1 (glucose transporter) has very recently been reported to be over-expressed and linked to tumour phenotypes in mouse glioma cells manipulated to carry the most common DIPG-associated H3.3-K27M mutation Miya et al. Neuro-Oncology Advances 2021. Here, we explore the functional significance of GLUT1 differential expression in H3.3 mutant (G34R, G34V) human glioma cells.
Abstract
AIMS
The aim of this study was to test if a correlation exists between the median voxel DTI-Q and overall survival in patients with GBM.
METHOD
The median voxel anisotropic (DTI-Q) values, ...calculated for the whole brain, the contrast-enhancing hemisphere and the contralateral hemisphere, were calculated using FSL (FMRIB Software Library, Oxford) for 33 patients with a primary diagnosis of GBM. Overall survival was calculated by subtracting the date of initial resection surgery from the date of death, for each included patient. Using R statistical software, the Pearson’s correlation coefficient was computed to establish the significance of the relationship between overall survival and whole brain median DTI-Q values, contrast-enhancing hemisphere median DTI-Q values and non-contrast-enhancing hemisphere median DTI-Q values.
RESULTS
There is a significant correlation between the median voxel DTI-Q of the whole brain and overall survival (t = -2.5362, df = 31, p-value = 0.01646), median voxel DTI-Q of the contrast-enhancing hemisphere and overall survival (t = -2.1235, df = 31, p-value = 0.0418) and the median voxel DTI-Q of the contralateral (non-contrast-enhancing) hemisphere and overall survival (t = -2.5212, df = 31, p-value = 0.01705).
CONCLUSION
The median anisotropic component of the diffusion tensor, calculated for the whole brain, contrast-enhancing and non-contrast-enhancing hemisphere, is significantly related to overall survival. This demonstrates the potential utility of DTI metrics as prognostic biomarkers that can readily be calculated in routine practice.
Abstract
AIMS
CaPaBLE tests the feasibility and acceptability of assessing quality of life (QoL) using the patient-, or caregiver-generated index (PGI/CaGI) methodology in patients with HGG and their ...caregivers.
METHOD
CaPaBLE, (https://www.isrctn.com/ISRCTN45555598), followed patients and/or their caregivers up to 6 months. Standard measures for patients were EORTC QLQ-C30/BN20, for caregivers the CarGOQOL questionnaire. The QoL topics raised through PGI/CaGI have been coded to the most relevant domain from their respective standard measure for an initial assessment of concordance.
RESULTS
36 patients, 24 caregivers recruited to study; completing an average of 3 study assessment timepoints. PGI and CaGI generated 240 and 160 topics respectively. Patient concerns most frequently coded to EORTC domain of Role Functioning; Caregiver concerns mostly coded to CarGOQOL domain of Burden. Other topics frequently raised by patients such as the driving and sex life, and future planning by caregivers are not specifically raised in standard questionnaires.
CONCLUSION
Nearly all topics raised by patients and caregivers were mapped to the domains of their respective standard QoL measure. However, almost half of all topics raised by patients and caregivers mapped to a minority of the domains included in standard measures; whilst a notable number of topics are not specifically included in standard measures at all. This raises questions regarding the efficiency and relevance of such questionnaires to patient and caregivers’ daily lives.
Abstract
AIMS
to make molecules that deliver more Boron than BPA for boron neutron capture therapy BNCT
METHOD
Boronated compounds were designed based on known LAT-1 substrates, synthesized using ...boronation techniques and purified using preparative HPLC. The compounds were formulated to achieve high concentrations when compared to BPA-fructose (BPA-F). Boronated compounds were tested for boron uptake and retention in multiple cell lines expressing either LAT1 and/or PEPT1. Compounds were further tested in multiple human xenograft models representing the cancer indication currently treatable by BNCT as well as in one syngeneic colon tumor model that may have high PEPT1 expression. Intracellular and intra tumor boron concentration were measured by ICP OES. We also synthesized 2 dipeptides and tested them in BNCT experiments with our collaborators at Kyoto University in Japan. They were tested in a CT26 mouse syngeneic model using neutrons from KURR1.
RESULTS
We synthesized multiple boronated compounds with better solubility than BPA (100 mg/ml v 30mg/ml in fructose). They were readily taken up in multiple cell lines and one of these compounds had longer retention than others. In competition experiments we were able to show that this compound was a superior substrate for LAT1. We also showed better BNCT results with our molecules compared to BPA.
CONCLUSION
BPA works for BNCT but it has limitations such as poor solubility. We made several new boronated compounds with better solubility than BPA and showed that we could deliver 2-3 x more boron in vitro and in vivo and better BNCT outcomes at KURR1.
