Abstract
AIMS
To assess the benefit of combining maximal resection, Gliadel wafer insertion, CCRT and 4 or more cycles of adjuvant TMZ.
METHOD
We retrospectively reviewed a cohort of 110 patients who ...had undergone neurosurgery followed by chemo-radiotherapy (CRT) 60 Gray in 30 fractions and had at least one cycle of adjuvant TMZ from 2007 to 2016. Minimum follow up period 5 years.
RESULTS
Patients who had maximal safe debulking plus Gliadel wafer insertion, median OS was 19.5 months (95% confidence interval 14-30) those without wafers median OS was 16 months (95% confidence interval 14 – 21), P=0.06; significant on cox regression modelling. (P-value 0.008). Those continuing to receive at least 4 cycles of adjuvant TMZ median OS improved by 10 months compared to those unable to complete 4 cycles (10 vs 20 months). On cox analysis the number of adjuvant cycles of TMZ significantly affects OS, P-value 0.0003. Of these significant predictors of OS when combined (n=12) median OS was 18 months. Compared to 16 months for those who did not receive Glidel wafers and could not complete 4 cycles of TMZ following CRT. OS log-rank test P-value 0.4
CONCLUSION
We were not able to demonstrate a statistically significant improved OS for those undergoing wafer insertion and completing at least 4 cycles of TMZ. Data may be inconclusive due to the small numbers, we conclude standard of care should still remain maximal safe debulking followed by CCRT and TMZ.
Abstract
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.
Abstract
AIMS
Butterfly glioblastomas (bGBM) are a rare subset of WHO grade IV tumours, that carry a poor prognosis with a median survival ranging between 3 to 6 months. Our study aims to add to the ...literature on how these tumours should be best managed when presenting to a neurosurgical unit.
METHOD
We performed a retrospective analysis from January 2009 to June 2021 of the electronic patient records of single large neurosurgical centre in London. We assessed patient demographics, initial clinical presentation, tumour characteristics (location, mutation, volumetric size), clinical management and overall survival (Kaplan-Meier estimator).
RESULTS
42 cases of bGBM were identified. These patients were managed with radiotherapy alone (n=3), with biopsy +/- adjuvant therapy (n=36) or attempted surgical resection (n=3). A further 38 cases of suspected bGBM were identified based on presentation and radiological imaging, however these patients were managed conservatively and did not undergo tissue diagnosis. No significant difference in survival was seen between conservative management compared to biopsy alone, with radiotherapy only or chemotherapy only (P=0.499) However, survival was significantly increased when patients received adjuvant chemoradiotherapy following biopsy or resection (P=0.04).
CONCLUSION
Butterfly glioblastoma has a devastating prognosis. Our study would suggest that unless a patient completes full adjuvant therapy with both chemotherapy and radiotherapy following biopsy or resection, they should be managed conservatively. This avoids unnecessary procedural interventions and can be deemed cost saving to the NHS. A larger prospective cohort study is recommended.
Abstract
AIMS
Glioma stem cells (GSC) show high levels of DNA replication stress and exhibit abnormal S phase in comparison to differentiated, non GSC tumour cells. We investigated the DNA ...replication phenotypes of GSC and mechanism of GSC specific cytotoxicity following DNA replication stress response inhibition with combined ATR/PARP inhibition (CAiPi).
METHOD
Paired GSC enriched (‘GSC’) and GSC deplete differentiated (‘bulk’) populations were cultured from resected GBM specimens and maintained in neurobasal media with growth factors or serum containing media respectively. Cell viability, neurosphere and clonogenic assays were used to assess cytotoxicity whilst DNA replication was interrogated utilising immunofluorescent repair foci, flow cytometry and DNA fibre assay. CAiPi consisted of VE821 (ATRi) with Olaparib (PARPi).
RESULTS
GSC show reduced DNA replication rates and alterations in cell cycle profile and demonstrate extreme sensitivity to CAiPi. CAiPi resulted in significantly elevated levels of 53BP1 nuclear bodies in GSC indicating genomic under- replication, however did not preferentially reduce fork speed compared to non-GSC. Analysis of replication fork structures revealed an increase in new origin firing in GSC dependent upon PARP trapping. GSC cytotoxicity was reduced by roscovitine induced inhibition of origin firing, suggesting an important role of dysregulated origin firing in CAiPi response. CAiPi is also potently radiosensitising by clonogenic assay.
CONCLUSION
Taken together these data suggest that GSC are vulnerable to dysregulation of origin firing which results in under-replication of their genome and reliance upon G1 cell cycle resolution of DNA damage. We propose that CAiPi is an attractive therapeutic strategy for translation to the clinic.
Abstract
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.
Abstract
AIMS
The 2021 WHO classification includes molecular characterizations to a much greater degree. Molecular markers play an important role in deciding treatment choice and predicting ...prognosis. Molecular markers are often performed in separate laboratories. This has led to concerns about the amount of time taken to get further molecular markers and the delay in diagnosis. Therefore our aim was to determine the waiting time for molecular markers to be returned from the lab following surgery.
METHOD
We retrospectively collected data for patients who had molecular analysis conducted in 2020 for gliomas at The Walton Centre, Liverpool. Descriptive statistics were conducted using SPSS V27.0.
RESULTS
182 patients were included. 130 patients waited <4 weeks, 46 patients >4 weeks, and 6 patients >8 weeks for molecular marker results. The median waiting time was 21 days (range: 11-219, IQR: 17.00-31.00). For patients who waited >4 weeks and >8 weeks, there were 7 WHO Grade I, 7 Grade II, 2 Grade III, and 26 Grade IV tumours. The median time taken between surgery and treatment to begin was 15 working days (range: 7-86, IQR: 12.00- 25.00). M-array took the longest time to return with a median of 63.5 days (range: 48-93, IQR: 60.00-80.00). Following which was NGS results which took a median of 32 days (range: 21-219, IQR: 27.00-40.00)
CONCLUSION
Most patients received their results in less than 4 weeks, however nearly a third had a waiting time of greater than 4 weeks. Reasons for delays need to be explored further to allow for quicker intervention from the MDT.
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
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
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
Malignant glioma cell line models are integral to pre-clinical testing of novel potential therapies. Accurate prediction of likely efficacy in the clinic requires that these models are ...reliable and consistent. We assessed this by examining the reporting of experimental conditions and sensitivity to temozolomide in glioma cells lines.
METHOD
We searched Medline and Embase (Jan 1994-Jan 2021) for studies evaluating the effect of temozolomide monotherapy on cell viability of at least one malignant glioma cell line. Key data items included type of cell lines, temozolomide exposure duration in hours (hr), and cell viability measure (IC50).
RESULTS
We included 212 studies from 2789 non-duplicate records that reported 248 distinct cell lines. The commonest cell line was U87 (60.4%). Only 10.4% studies used a patient-derived cell line. The proportion of studies not reporting each experimental condition ranged from 8.0–27.4%, including base medium (8.0%), serum supplementation (9.9%) and number of replicates (27.4%). In studies reporting IC50, the median value for U87 at 24 h, 48 h and 72 h was 123.9 μM (IQR 75.3–277.7 μM), 223.1 μM (IQR 92.0–590.1 μM) and 230.0 μM (IQR 34.1–650.0 μM), respectively. The median IC50 at 72 h for patient-derived cell lines was 220 μM (IQR 81.1–800.0 μM).
CONCLUSION
Temozolomide sensitivity reported in comparable studies was not consistent between or within malignant glioma cell lines. Drug discovery science performed on these models cannot reliably inform clinical translation. A consensus model of reporting can maximise reproducibility and consistency among in vitro studies.
