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
Gamma Knife Stereotactic Radiosurgery (GK-SRS) is an effective treatment option for limited brain metastases (BM); however, there is a paucity of data about its use in the elderly. Our ...aim is to explore the clinical outcomes of elderly cancer patients treated for BM with GK-SRS at our institution.
METHOD
We identified cancer patients aged ≥80 years at the time of receiving GK-SRS to BM between July 2017 and August 2021 from our electronic institutional database. Descriptive statistics and Kaplan–Meier analysis were performed using SPSS v.22.
RESULTS
A total of 24 patients were identified, with a median age of 83 years (range 80.1-89.9). The most common primary tumours were melanoma (58.4%) and lung (20.8%). In 14 patients (58%), multiple BM were treated simultaneously with a median of 2 lesions (range 2-15). The median target volume was 1.34cc (range 0.03-15.06). Prescribed doses ranged from 18Gy – 25Gy, prescribed to the 41-97% isodose line. After a median follow-up of
6.9 months (range 1.9-49.4 months), the local control rate (LCR) was 91.3% and the median post-GK-SRS overall survival was 9.8 months (95%CI 5.4-14.3). This compares to our previously published data from our wider GK-SRS-treated BM patient cohort, which showed a median survival of 15.6 months and LCR of 94.6%.
CONCLUSION
GK-SRS is an effective treatment modality for selected cancer patients with BM, including those over 80 years of age. Multi-institutional prospective studies are warranted to further explore the safety and functional outcomes of GK-SRS in elderly cancer patients.
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.
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
Intracranial metastases are common in patients with breast cancer. Stereotactic radiotherapy (SRT) can improve overall survival (OS) in selected patients; however there is uncertainty ...over the presence of prognostic indicators in this cohort. Here, we aim to determine whether the number of brain metastases, receptor status and presence of extracranial disease affected OS.
METHOD
Retrospective analysis was performed for all patients receiving SRT for brain metastases from breast cancer between 2014-2020 at Barts Cancer Centre. Overall survival (OS) was calculated using the Kaplan-Meier method. Differences between groups were assessed using the Log-rank (Mantel-cox) test.
RESULTS
109 patients with a histopathologically confirmed diagnosis of breast cancer were included. The median age at treatment was 52 years (IQR:46-60). Of 103 patients with documented receptor status, 22 patients were ER+/HER2+, 32 ER+/HER2-, 20 ER-/HER2+ and 29 triple-negative. 68/105 patients had extra-cranial metastatic disease at treatment with SRT. A median of 2 lesions were treated per patient (range:1-15). Median OS for all patients was 67.4 weeks. Median OS was 91.4 weeks for ER+/HER2+ patients, 64.9 weeks for ER+/HER- patients, 71.4 weeks for ER-/HER2+ and 37 weeks for ER-/HER2- (p=0.001). Median OS was 55.1 weeks for patients with extra-cranial metastatic disease and 91.4 weeks in those without (p=0.017). Median OS was 72.1 weeks in patients with 1-2 brain metastases and 53.7 in those with extensive (3+) brain metastases, however this was not statistically significant (p=0.892).
CONCLUSION
A trend towards worse OS in patients with triple-negative receptor status and extra-cranial metastatic disease at treatment with SRT warrants further investigation.
Abstract
AIMS
To use two-sample Mendelian Randomisation to prioritise novel genes for drug targeting in glioma risk using expression, protein and splicing quantitative trait loci (eQTLs, pQTLs and ...sQTLs, respectively).
METHOD
We used genetic variants from GWAS to compare the effects of eQTLs, pQTLs and sQTLs on genetic liability to glioma risk (n=12,496). eQTL data was retrieved from the MetaBrain study of five different brain tissues (n=108 to 2,970). pQTL data was retrieved from the BrainQTL study of dorsolateral prefrontal cortex tissue (n = 330), and sQTL data was retrieved from Genotype-Tissue Expression (GTEx) Project (v8) of 13 brain tissues (n=114 to 209). SNPs which were trans-QTLs (>1 Mb) due to risk of horizontal pleiotropy, and greater than GWAS significance (P > 5 × 10-8) were excluded. Instruments were constructed using independent SNPs (r2 < 0.001). Results underwent relevant sensitivity analysis; colocalisation and Steiger filtering.
RESULTS
We found 123 MR associations for 28 genes with genetically predicted altered expression, protein or splicing levels affected risk of glioma. These included genes recurrently associated with glioma risk such as TERT, RTEL1, CDKN2A/B and EGFR, and novel putative genes; BTN3A2, GALNT6, GMPPB and FAIM. Following sensitivity analyses, we found that 58 MR associations for 25 genes had robust evidence.
CONCLUSION
We identified four novel associations not previously found in GWAS; BTN3A2 (6p22.2), FAIM (3q22.3), GALNT6 (12q13.13) and GMPPB (3p21.31) are implicated in glioma risk and are also not located on a known glioma risk locus. Further analysis is required to identify the suitability of these genes for drug targeting in glioma.
Abstract
AIMS
A hyaluronic acid-based hydrogel with mechanical properties comparable to human brain tissue is being investigated as an implantable drug-delivery vehicle for post-surgical treatment of ...IDH1 wild-type glioblastoma (GBM). Hydrogels are to be loaded with polymeric pro-drug nanoparticles to enable controlled drug release and increased drug penetration through brain parenchyma for enhanced treatment of residual disease within and beyond the invasive margin.
METHOD
A panel of patient-derived glioblastoma cell lines resected from tumour core and invasive margin, have been used to generate tumour spheroids. Chemotherapeutic drug screening has been performed to select lead compounds for formulation and gel loading. Synergies of drug combinations have been studied for potential combination loading. Upcoming work will investigate nanoparticle internalisation, spheroid penetration and prodrug nanoparticle potency. Nanoparticle loaded hydrogels are then to be studied for validation of effective in vitro application.
RESULTS
Current results demonstrate that patient-derived cell lines can generate robust, reproducible tumour spheroids with diameters approx. 350-400 µm. Patient-to-patient differences in drug potencies were observed, with differences also noted between counterpart core and marginal cells from the same patients, illustrating the importance of using patient-derived cells and distinct regional cells to study heterogenous disease such as GBM. Drug combination experiments indicated synergy of topoisomerase I inhibitor (Irinotecan) with PARP inhibitor (Ola-parib). Interestingly, combination of PARP inhibition with topoisomerase II inhibitors (Doxorubicin, Etoposide) was found not synergistic.
CONCLUSION
Together, data gathered on single drug and drug-drug combinations will inform upcoming formulation and in vitro application of hydrogels planned, with eventual translation to pre-clinical in vivo models.
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.
Neurosurgery Database for Brain Tumour Patients De Luna, Paolo Jose; McKintosh, Edward; Scandura, Glenda ...
Neuro-oncology (Charlottesville, Va.),
10/2022, Letnik:
24, Številka:
Supplement_4
Journal Article
Recenzirano
Odprti dostop
Abstract
AIMS
We develop an electronic database system for brain tumour patients. This aims to provide accessible and comprehensive data in a unified database for all neuro-oncology patients at Barts ...Health NHS Trust.
METHOD
The database was created using Microsoft Access with data categorised using forms and tables. Initially, patients were added retrospectively using the neuropathology list and the neuro-oncology multi-disciplinary team patient lists. Once creation and validation was complete, patients were added prospectively. Queries on neuro-oncology patients can be launched to produce datasets which can be copied to Microsoft Excel spreadsheets for sorting, calculation, and graph creation.
RESULTS
At the time of writing, records of 1171 neuro-oncology patients who were accepted for MDT discussion at Barts Health NHS Trust are included in the database. It is used to routinely run data queries more efficiently and complete in a shorter time. Queries include post-operative complications, overall survival, histological diagnosis, and average surgery waiting time. These queries have already been used to publish audit-based research papers and will be used increasingly as part of routine clinical governance.
CONCLUSION
The database yields data about treatment of our brain tumour patients with increased completeness and significant reduction in time to return queries, compared to using standard data management. The database has been used to produce data, including tumour types, seizure incidence, and post-operative complications. We have been successful in producing published research, although low absolute complication numbers in the current dataset have not yet allowed comparison of complications rates at individual clinician and team level.
Abstract
AIMS
To audit the use of 5-ALA at WCFT to determine adherence to NICE guidance NG99 and the Trust guideline.
METHOD
Data was retrospectively evaluated from 77 patients prescribed 5-ALA at ...WCFT Jan 2020 – Jan 2022.
RESULTS
Of the 77 patients, 61 (79%) patients had 5-ALA induced fluorescence documented intraoperatively which aided resection and 7 patients (9%) had no confirmed fluorescence. In patients with no fluorescence noted, the administration time to operation time was variable. The remaining 9 patients (12%) had no documentation on the presence or absence of fluorescence. Prior to surgery, 67 patients had an MDT outcome of likely high grade glioma. 66 patients had this confirmed with histology post-surgical resection. The remaining patients had various MDT diagnosis documented including oligoastrocytoma, oligodendroglioma and lesion. 87% of patients had the correct dose of 20mg/kg prescribed. 14 patients (18%) did not have liver function tests (LFT) checked during admission as per Trust policy. Of those checked, 29 patients (37%) had new derangement of LFT.
CONCLUSION
The use of 5-ALA has aided surgical resection, enabling greater resection in the majority of patients prescribed for at WCFT. It has been used in accordance with NICE for HGG resections in 87% of cases. Some improvement could be made in ensuring the correct dose is prescribed and the appropriate monitoring (LFT) is carried out post procedure. Theatre documentation could be improved so future audit can more easily identify extent of resection and extent of fluorescence.
