Abstract
AIMS
Several studies have evaluated health-related quality of life (HRQoL) through patient-reported outcomes (PROs) in high-grade glioma (HGG) patients. No systematic review has summarised ...this increasingly important research area.
METHOD
Seven electronic databases were systematically searched. Primary research articles evaluating HRQoL in HGG patients through PRO assessment were included. Global, physical, mental, and social health were summarised descriptively. Risk of bias (RoB) of included studies was assessed using The Joanna Briggs Institute Critical Appraisal tool or Newcastle Ottawa Scale. Quality of study reporting was assessed using a modified ISOQOL checklist.
RESULTS
Twenty-six studies were included (4,451 patients): cross-sectional (n=14), longitudinal (n=12). RoB and quality of reporting were satisfactory. Ten PRO measurement instruments were identified, of which EORTC-QLQ-C30 (n=15) was utilised most frequently. Fatigue significantly impacted both physical and global health. HRQoL improved after surgery but recurrence, fatigue, and difficulties with activities of daily living were associated with worsening HRQoL. HGG patients had higher anxiety and depression scores than the general population, negatively impacting overall HRQoL. Social health was superior for patients with good supportive networks, but a majority do not return to full-time employment post-diagnosis. Long-term survivors reported improvements in their physical, social and emotional functioning over time.
CONCLUSION
With HGG life expectancy less than 12 months post-diagnosis, HRQoL is of paramount importance to patients. PRO assessment of HRQoL can be used to evaluate self-reported functioning and well-being in both routine practice and clinical trial settings and provide opportunities for timely intervention.
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 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.
Abstract
AIMS
Medulloblastoma (MB) comprises four main groups (SHH, WNT, group 3 and group 4), with distinct molecular, clinical and demographic features. These differences suggest opportunities for ...tailored and improved treatment. Despite its promise, translation into targeted therapy has been slow, limited by the lack of laboratory models that recapitulate patient tumours. Sporadic and inherited forms of SHH-MB are frequently due to mutations in the tumour suppressor gene PTCH1. Here, we aim to exploit human induced pluripotent stem cells (hiPSC) and CRISPR/Cas9 gene editing, to target PTCH1 in a clinically relevant context, thereby establishing an innovative model of MB.
METHOD
CRISPR/Cas9 mutation of PTCH1 in hiPSCs was followed by their differentiation into cerebellar organoids. Mutant organoids were studied for early consequences on cerebellar development and tumorigenesis.
RESULTS
PTCH1-mutation resulted in enhanced SHH-pathway activity in cerebellar organoids. Homozygous PTCH1-mutation prevented the formation of cerebellar progenitor cells, closely mimicking the effects of high SHH- signalling on neuronal progenitors in early embryonal development. Heterozygous PTCH1-mutant hiPSCs could be differentiated into cerebellar organoids, displayed increased growth rate and expressed oncogenes specific to SHH-MB, resembling preneoplasia and MB stem cells.
CONCLUSION
These results show that cerebellar organoids are a promising new model to study early oncogenic events in MB. Our model presents opportunities for the discovery of new targets which could benefit patients with a genetic predisposition to MB in particular. Refined knowledge of early drivers will be invaluable to guide drug selection and improve prospects for clinical translation.
Abstract
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.
Abstract
AIMS
To review the data of patients in NHS Tayside who survived >24 months from a diagnosis of GBM, identifying trends in: (i) fixed demographic features; (ii) genetic mutations; (iii) ...treatment pathways.
METHOD
A retrospective case note review of patients with a new diagnosis of GBM 2015-2020, identifying those with >2 year survival. Data analysed: demographics (gender, age), mutations (IDH1, MGMT), and treatment (surgical, chemotherapy/radiotherapy).
RESULTS
84 patients identified. 18 survived >24 months (2 year survival rate of 21.4%). Median survival = 31 months (range 24-110 months); 18 patients: M:F ratio = 1.6:1; Median age at diagnosis 54.5 (range 34-72 years); 13 methylated MGMT, 2 unmethylated (3 unknown); 2 mutated IDH1, 10 wildtype (6 unknown); 16 maximum surgical resection; 17 chemoradiation and adjuvant chemotherapy; 17 received radiation dose of 60Gy in 30#, 1 received 40Gy in 15#; 11 had disease progression requiring further treatment; 5 had no progression, 2 progressed but did not have further treatment.
CONCLUSION
In Stupp data a 2 year survival of 26.5% was reached. In our real world cohort, a 2 year survival of 21.4% is satisfactory. MGMT methylation was common, but not exclusively the case. Only 2 were IDH1 mutated, possibly reflecting the frequency of occurrence in the GBM population, but demonstrating that it is not a prerequisite for improved survival. Younger age, and maximal surgical resection followed by chemoradiation and adjuvant chemotherapy are associated with improved prognosis. Recognising our dataset is small, we recommend further studies using a larger cohort to improve understanding of better outcomes in this patient group.
Abstract
AIMS
There have been no significant improvements in the treatments for childhood and adolescent High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), which have a very ...poor prognosis. These cancers harbour mutations affecting histone 3 (H3) proteins, 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. Several studies have highlighted the epigenetic changes associated with these mutations, however their precise role in tumourigenesis is still unknown. We hypothesize that H3 mutations promote an aberrant interaction landscape and analysis of these interactome will highlight important pathophysiological consequences in these tumours.
METHOD
Two different affinity chromatographic proteomic analyses were performed using different recombinant H3 wild type (WT) and H3 mutant histone proteins (K27M, G34R and G34V) to purify their binding partners, from cell extracts of control and pHGG/DIPG patients cell lines. The purified samples were then subjected to Liquid Chromatography-Mass Spectrometry (LC-MS) to identify their co-bound partners.
RESULTS
The results have isolated unique and common differential interaction partners of the H3 mutants and with cellular proteins in comparison to H3 WT protein, in the pHGG tumour cells.
CONCLUSION
The role these altered protein interactions are being investigating in tumour initiation, progression and/or maintenance of H3 mutated pHGG/DIPG, with the aim to manipulate their function as alternate therapeutic intervention. Results of these analyses/experiments will be presented.
Abstract
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.
Abstract
AIMS
The aim of this study was to quantify the accuracy of surgical biopsy for brain lesions using different image-guidance techniques, in our tertiary neurosurgical centre.
METHOD
...Retrospective data was collected from electronic and paper patient notes. Data collected included: age, sex, comorbidities, pre-operative functional images, surgeon grade, biopsy method, number of targets, number of samples, result from frozen section and fixed sample histopathology, complications, and length of stay. Methods of biopsy included: ultrasound-guided, frame-based biopsy and frameless Brainlab guided biopsy (free-hand, Varioguide and registration tool -guided).
RESULTS
A percentage of 11.5% of cases (total = 52) were US-guided biopsy. Navigated frameless biopsies comprised 76.9% of all cases. In these cases, 42.3% of cases were guided by the registration tool, 23% used a fixed “Varioguide” instrument alignment tool and 11.5% were completed using the free-hand method. Overall accuracy of biopsy for all cases was 82.69%. Accuracy rates of different frameless methods were: 81.8% for Brainlab registration- guided biopsy, 66.7% for Brainlab Varioguide biopsy and 100% for Brainlab free-hand frameless biopsies. The percentage of complications was 5.8%.
CONCLUSION
In our centre, the accuracy of image-guided surgical biopsy for brain lesions was as high as 82.69% with a low complication rate of 5.8%. The Brain lab free-hand technique had the highest diagnostic yield and safety amongst all frameless stereotactic techniques.
Abstract
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.
