Abstract
Aims
Morbidity and mortality following resection of malignant primary brain tumours is high. The benefits of reoperation for recurrent tumours are uncertain and it is not known how ...frequently patients in England undergo further tumour resections. The aim of this study was to describe 30-day and one-year readmission rates, the clinical reasons for readmission and the rate of resections for recurrent tumours.
Method
Patient data was extracted from Hospital Episode Statistics (the hospital administrative data for NHS hospitals in England) for all supratentorial, malignant, primary brain tumour resections performed from April 2013 to March 2017. All subsequent non-elective readmissions to any NHS hospital and all readmissions for further tumour resection within 30 days and one year were analysed for the primary clinical diagnosis and primary procedure performed.
Results
A total of 6,982 patients were identified and the 30-day and one-year readmission rates were 18.6% (n=1,298) and 57.4% (n=4,007), respectively. The rates of reoperation for tumour resection were 0.5% (n=33) and 6.2% (n=432), respectively. The commonest reasons for 30-day readmission were post-operative complications (17.9% of admissions), general medical complications (17.3%) and surgical site infection (9.6%). The most frequently performed neurosurgical procedures were for treatment of surgical site infection (37.6% of procedures). The commonest reasons for readmission within one year were general medical complications (17.4%), seizures (14%), systemic infections (11.4%) and post-operative complications (11%). Almost half of all neurosurgical procedures performed within one year were reoperation for tumour resection (45.6%), while treatment of surgical site infection (17.9%) and CSF shunt insertions and revisions (9.1%) were also common.
Conclusion
This study provides a descriptive analysis of the rates of readmission, diagnosis on readmission, and the need for further neurosurgical procedures. The rate of non-elective readmissions within one year is high and these data may be useful for service planning and for counselling patients about their treatment. Additionally, these data contribute to the development of quality indicators, for benchmarking and comparing quality of care provision between neurosurgical units. Further research, with linkage to histology data and performance status, would support an analysis of the role of resection of recurrent, malignant, primary brain tumours.
Abstract
Aims
Molecular profiling is increasingly used in the diagnosis of CNS and non-CNS neoplasms. More than a quarter of all soft tissue tumours are characterized by specific recurrent ...chromosomal translocations which can be used as molecular signatures. With increasing frequency, EWSR1 rearrangements are found on both mesenchymal tumours and primary glial/neuronal tumours.
Here we present a case of intracranial myxoid mesenchymal tumour (IMMT), a rare tumour which is becoming more recognised in recent years, affecting mainly children and young adults, and rarely older adults. It can be found in intraaxial and extraaxial location, with frequent dural connection. The tumour is defined by the genetic hallmark of EWSR1-CREB family gene fusion. Including our case, 16 intracranial tumours with this gene fusion have been reported to date.
Our goal is to contribute further to the characterisation of the morphological spectrum, fusion partners and biological behaviour of rare EWSR1-CREB (non-ETS)-rearranged tumours of the CNS.
Method
Case: The patient is a 27 year old woman with a frontal lobe lesion, radiologically described as a tumour with dural attachment. She underwent surgical debulking, and tumour tissue was histologically examined with conventional immunohistochemistry. Additional genetic testing included targeted mutation screening, FISH, EPIC (Illumina BeadChip) methylation array and next generation sequencing. Histology showed a mitotically active neoplasm with relatively uniform cells, round nuclei and oligodendroglioma-like clear cell change, but no myxoid change. Glomeruloid microvascular proliferation and large areas of tumour necrosis were present. Immunohistochemistry was focally positive for GFAP, and negative or normal for synaptophysin, IDH1 R132H mutation, ATRX and p53. The ki-67 index reached ~20%. Sequencing of IDH1 and IDH2 did not reveal rare IDH mutations, and FISH did not show 1p19q codeletion. Testing for BRAF V600 mutation was negative.
Results
Although the histology initially suggested a diagnosis of oligodendroglioma, the integrated diagnosis was compatible with glioblastoma, IDH wildtype. Methylation array analysis by EPIC array did not result in classification of currently known entities, neither confirming glioblastoma, nor providing a new diagnosis, when analysed on both brain tumour and sarcoma classifier. This suggested a novel tumour entity not yet represented in the classifier algorithm. Additional testing including next generation sequencing revealed EWSR1 gene rearrangement with fusion partner ATF1 (EWSR1-ATF1 fusion). Based on this, the diagnosis was revised to the emerging new entity of ‘intracranial myxoid mesenchymal tumor’ (IMMT) characterised by EWSR1 fusion with members of the cAMP response element binding protein (CREB) family (ATF1, CREB1 and CREM). Subsequent immunohistochemistry demonstrated positive staining for CD99 and EMA but not desmin. The patient underwent various oncological treatments and is recurrence-free 3 years after initial diagnosis.
Conclusion
Histologically, IMMT demonstrates a spectrum of features that overlaps with other tumours, but often displays circumscribed growth, uniform cellularity, cytoplasmic clearing and variable myxoid change. The clinical behaviour of these tumours is not fully understood, however provisionally considered intermediate grade.
EWSR1-CREB family fusion is not specific but shared with a diverse group of extracranial tumours including soft tissue, salivary gland, odontogenic and myoepithelial tumours. Therefore, clinico-radiologico-pathological correlation is essential to achieve the final diagnosis, and ensure the absence of a primary tumour elsewhere.
Familiarisation with IMMT, its characteristic genetic profile and its as yet underreported natural course is crucial, as it can clinically mimic other intracranial tumours such as malignant meningioma or glioma but appears to behave less aggressively than high grade glioma.
It is also important to further our understanding of its optimal treatment through review of larger case series and global comparison of patient management.
Abstract
Aims
Extent of resection is associated with better survival in patients with glioblastoma. Numerous surgical adjuncts can be used to achieve maximal safe resection - including ...fluorescence-guidance with 5-aminolevulinic acid (5-ALA), neuronavigation, intraoperative ultrasound (IoUS), intra-operative MRI (iMRI), tractography, electrophysiological monitoring and awake surgery. We evaluated the availability, use and operative aim and success associated with these adjuncts.
Method
This is a prospective cohort study of 27 of 31 neurosurgical centres in the UK and Ireland from 6 January to 19 March 2020. Consecutive cases were identified through neuro-oncology multidisciplinary meetings. Eligible cases included adults with a supratentorial histopathologically confirmed glioblastoma with pre/post-operative reported T1-weighted MRI with contrast deemed suitable for resection. Outcomes included the availability and usage of surgical adjuncts, and the percentage of operations that achieved their aim of complete resection, defined as complete resection of enhancing tumour (CRET) on post-operative T1-MRI. We present the initial descriptive statistics from this national study.
Results
232 patients with glioblastoma were included. In 142 patients (61.2%) the surgical aim was CRET. 5-ALA and neuronavigation were available in all centres (Figure 1). The most commonly used neurosurgical adjunct was neuronavigation (88.2%) (Figure 2). The proportion of patients receiving 5-ALA in CRET and debulking-only groups was 65.0% and 48.9%, respectively. 35 different combinations of adjuncts were found in total, with 13 unique combinations only used in one instance (Figures 1 & 2). CRET was achieved in 69/142 (45.8%) patients in which was the aim. 9/90 (10%) patients in the debulking-only group achieved CRET, of which 7/9 (77.8%) had received 5-ALA. Of the three most frequently used combination of adjuncts for patients deemed feasible for CRET, the most successful in terms of achieving CRET was the combined use of neuronavigation, 5-ALA and IoUS, with post-operative CRET at 47.4% (Figure 3).
Conclusion
ELISAR-GB has collated prospective data to demonstrate the current use of intraoperative adjuncts in the UK and Ireland. There is marked heterogeneity with regards to combinations of adjuncts used. A CRET of 47% is lower than would be expected compared to previously published literature, possibly due to a more stringent definition of complete resection in this study. Based on these early descriptive results, there is no clear combination of adjuncts that shows superiority and use of 5-ALA does not always result in CRET when it is the surgical aim. Of interest, 5-ALA is being used for operations that do not aim for complete resection, a change in indication. The FUTURE GB trial will provide more conclusive evidence on the efficacy of surgical adjuncts to maximise extent of resection.
Abstract
Aims
Glioblastoma multiforme (GBM) is an aggressive brain malignancy. Performance status is an important prognostic factor but is subjectively evaluated, resulting in inaccuracy. Objective ...markers of frailty/physical condition, such as measures of skeletal muscle mass can be evaluated on cross-sectional imaging and is associated with cancer survival. In GBM, temporalis muscle has been identified as a skeletal muscle mass surrogate and a prognostic factor. However, current manual muscle quantification is time consuming, limiting clinical adoption. We previously developed a deep learning system for automated temporalis muscle quantification, with high accuracy (Dice coefficient 0.912), and showed muscle cross-sectional area is independently significantly associated with survival in GBM (HR 0.380). However, it required manual selection of the temporalis muscle-containing MRI slice. Thus, in this work we aimed to develop a fully automatic deep-learning system, using the eyeball as an anatomic landmark for automatic slice selection, to quantify temporalis and validate on independent datasets.
Method
3D brain MRI scans were obtained from four datasets: our in-house glioblastoma patient dataset, TCGA-GBM, IVY-GAP and REMBRANDT. Manual eyeball and temporalis segmentations were performed on 2D MRI images by two experienced readers. Two neural networks (2D U-Nets) were trained, one to automatically segment the eyeball and the other to segment the temporalis muscle on 2D MRI images using Dice loss function. The cross sectional area of eyeball segmentations were quantified and thresholded, to select the superior orbital MRI slice from each scan. This slice underwent temporalis segmentation, whose cross sectional area was then quantified. Accuracy of automatically predicted eyeball and temporalis segmentations were compared to manual ground truth segmentations on metrics of Dice coefficient, precision, recall and Hausdorff distance. Accuracy of MRI slice selection (by the eyeball segmentation model) for temporalis segmentation was determined by comparing automatically selected slices to slices selected manually by a trained neuro-oncologist.
Results
398 images from 185 patients and 366 images from 145 patients were used for the eyeball and temporalis segmentation models, respectively. 61 independent TCGA-GBM scans formed a validation cohort to assess the performance of the full pipeline. The model achieved high accuracy in eyeball segmentation, with test set Dice coefficient of 0.9029 ± 0.0894, precision of 0.8842 ± 0.0992, recall of 0.9297 ± 0.6020 and Hausdorff distance of 2.8847 ± 0.6020. High segmentation accuracy was also achieved by the temporalis segmentation model, with Dice coefficient of 0.8968 ± 0.0375, precision of 0.8877 ± 0.0679, recall of 0.9118 ± 0.0505 and Hausdorff distance of 1.8232 ± 0.3263 in the test set. 96.1% of automatically selected slices for temporalis segmentation were within 2 slices of the manually selected slice.
Conclusion
Temporalis muscle cross-sectional area can be rapidly and accurately assessed from 3D MRI brain scans using a deep learning-based system in a fully automated pipeline. Combined with our and others’ previous results that demonstrate the prognostic significance of temporalis cross-sectional area and muscle width, our findings suggest a role for deep learning in muscle mass and sarcopenia screening in GBM, with the potential to add significant value to routine imaging. Possible clinical applications include risk profiling, treatment stratification and informing interventions for muscle preservation. Further work will be to validate the prognostic value of temporalis muscle cross sectional area measurements generated by our fully automatic deep learning system in the multiple in-house and external datasets.
Abstract
Aims
Paediatric cancer is a leading cause of non-communicable disease deaths for children worldwide, with more than 90% of deaths occurring in low-and-middle-income countries (LMICs). The ...COVID-19 pandemic may have exacerbated disparities in paediatric cancer outcomes between LMICs and HICs. The World Health Organization (WHO) Global Initiative for Childhood Cancer has identified gliomas as a common cancer that can act as a benchmark for assessing global paediatric cancer care. This study aims to ascertain the short and medium-term outcome across 17 countries during the COVID-19 pandemic by determining 30- and 90-day all-cause mortality rates for paediatric glioma patients who underwent treatment.
Method
A multicentre, international, mixed- (retrospective and prospective), collaborative cohort study in 17 countries. Patients were recruited between March 12th 2020 and July 12th 2020.
Results
129 patients were recruited with the majority being histologically diagnosed as low-grade gliomas (n = 86/118, 72.9%). Seven children had a change to their planned chemotherapy treatment because of the COVID-19 pandemic. Similarly, seven children and eleven children had a change to their planned radiotherapy treatment and surgical treatment respectively because of the COVID-19 pandemic. Five patients died within the 30-day follow-up period, with all five patients being in LMICs. A sixth child, also in a LMIC, died within the 90-day follow-up period. This significant difference in mortality between LMICs and HICs was present when controlling for confounding for factors such as grade, ASA status, sex, weight, and age.
Conclusion
There has been relatively minimal change to the treatment of paediatric gliomas worldwide compared to their initial planned care. There was a significant difference in mortality for childhood gliomas between LMICS and high-income countries during the COVID-19 pandemic. There needs to be a concerted effort to improve equity in health outcomes globally.
Abstract
Aims
Gliomas are the most frequent brain tumours, representing 75% of all primary malignant brain tumours in adults. IDH1 (and IDH2) driver mutations occur in >80% of low grade gliomas and ...secondary GBMs, in <10% of primary GBMs and other cancers. How IDH1/2 mutations contribute to tumorigenesis is mostly unknown. IDH1/2 convert isocitrate to α-ketoglutarate, but when mutated possess a novel enzymatic function that reduces α-ketoglutarate to D2-hydroxyglutarate (2HG). Indeed 2HG accumulates in IDH1/2-mutant tumours, and this discovery suggested that 2HG may have a role in IDH1/2-mutant tumours onset and progression, possibly by causing dysregulations of various enzymes in the cells. Studies are undergoing to clarify the causative role of 2HG in IDH1/2-mutant tumours, but it is still not clear whether 2HG is the driver/oncometabolite. Our aim is to understand the role of 2HG in developing and adult mouse tissues and whether its accumulation might cause features of gliomagenesis.
Method
A constitutive D2hgdh Knock-out mouse (D2hgdh KO) was generated and the relative molecular and cellular analysis were performed.
Results
Brains dissected from D2hgdh KO mice appeared to be histologically normal. No differences were found in the proliferation and labelling retaining capacity of neural stem and progenitors cells (NSC/NPC) of the D2hgdh KO mice compared to controls. A comprehensive metabolites analysis showed that D2hgdh KO mouse accumulated 2HG in various organs and tissues, included total brains and in the NSC/NPC microdissected from the subventricular zone, the site of origin of many human gliomas. The DNA amount of 5mC and 5hmC extracted from brains of D2hgdh KO mice was similar to controls. A normal number of haematopoietic progenitors was also found.
Conclusion
Although D2hgdh KO mice accumulated 2HG in all tissues analysed, they did not develop any abnormalities and remained completely asymptomatic. This suggests that a mere increment of 2HG in developing and adult tissues may be not sufficient to cause tumorigenesis (and gliomagenesis), leading some doubts on the oncogenic roles of the 2HG in IDH1/2-mutant tumours.
Abstract
Aims
Signs and symptoms that develop in people with brain tumours are often attributed to their tumour. The prevalence and management of functional neurological symptoms in brain tumour ...patients have received little attention. This is surprising because functional neurological symptoms complicate management greatly and misdiagnosis can lead to inappropriate treatment and iatrogenic side-effects. Therefore, we investigated the presentation, diagnosis and management of functional neurological disorders (FND) in patients who had a brain or meningeal tumour.
Method
A retrospective case review was performed from 2017 - 2021 to identify adult brain tumour patients who developed a functional neurological disorder that caused significant disability necessitating expedited investigations. All patients attended a regional neuro-oncology centre. We recorded type of brain tumour and diagnostic investigations. The onset of functional symptoms was divided into three time windows: before tumour diagnosis, after diagnosis and before treatment or after tumour treatment. A neuropsychological review looked for evidence of previous adverse life events. Therapeutic interventions for functional neurological disorder and their outcomes were documented. The case review was combined with a systematic review of the literature to identify the published presentations of functional neurological disorder in the adult brain tumour population. MEDLINE, EMBASE and PsycINFO databases were searched for studies published between January 1980 and February 2021.
Results
Six patients (5 female, 1 male) were identified from the case review with a median age of 41 (range 29 - 56) years old. Four patients had non-epileptic attack disorder, which was diagnosed with videotelemetry of habitual attacks. One patient had a functional hemiparesis with normal central motor conduction time. One patient had a functional speech disorder with normal EEG. Half of these patients had functional neurological symptoms prior to surgery/oncological treatment. Five patients (83%) were referred for further neuropsychiatric or psychological evaluation. A history of significant psychological trauma prior to the brain tumour diagnosis was elicited in four (66%) patients.
Conclusion
Patients with either a brain or meningeal tumour may develop functional neurological symptoms. Our findings suggest the possibility that diagnosis of a brain tumour may precipitate a debilitating functional neurological disorder. The neurobiological basis for functional neurological disorders is being actively investigated. There are suggestions in the literature that some brain diseases increase the risk of developing a functional neurological disorder. Further work is needed to determine whether this is true for patients with brain tumours. Increased awareness of functional neurological disorders will improve management. Withdrawal of unnecessary treatment, such as anticonvulsant drugs, reduces the risk of iatrogenic side effects. Initiation of multi-disciplinary care pathways, e.g. physiotherapy, speech and language therapy and psychological treatments, promotes recovery. Collectively, these interventions improve our patients’ quality of life.
Abstract
Aims
Every year, the Queen Elizabeth Hospital Birmingham (QEHB) neuro-oncology team review over 2000 individuals with brain tumour. Patient and public involvement (PPI) has been fragmented ...to date. Initially we invited two patient advocates and a core group of allied health professionals to meet virtually to discuss development of a local PPI group, its aims, specific goals, and timescales to maintain momentum. In March 2021 we launched “BERTI: Brain tumour Education and Research paTient and public Involvement group, West Midlands”. Our inaugural meeting will be virtual in April 2021 and will be followed by three meetings per year.
Method
We developed information leaflets to promote the BERTI initiative. A membership form has been developed to record baseline information (non-clinical) e.g. contact details, which tumour type the individual is interested in, which aspect of BERTI they are interested in (Education, Research or Clinical service development). Patient advocates have reviewed all patient and public facing forms. All forms have been checked by Information Governance at QEHB to ensure General Data Protection Regulation compliant. Contact details and non-clinical data will be stored in a password protected database on a NHS computer network. Information to ensure members can unsubscribe from this group is easy to find and will be done immediately. A BERTI email account has been set up with a core group of professionals having access who are all fully trained in data protection and have GDPR certification. We will produce an annual BERTI newsletter.
Results
BERTI is a group for people affected by brain tumours in any way. We include patients, friends and family, health professionals and researchers who are committed to improving the care of people with a brain tumour. It is run between the QEHB and University of Birmingham (UoB).
BERTI provides a forum to meet other people affected by brain tumours and
- Share experiences;
- Understand the condition better;
- Work with clinical staff and researchers to improve clinical care and facilitate research for people living with brain tumours.
We will meet three times per year, virtually at the moment but face to face once Covid restrictions ease. We will have a formal talks explaining certain aspects of brain tumour or research initiatives. Throughout, there will be dedicated time set aside for group discussions to promote a genuine two-way dialogue between health-care/research professionals and individuals affected by brain tumour.
Conclusion
The PPI group will be allowed to evolve rather than start out too prescriptive. It will capitalise on its strengths and skills of its composite members. There are no set models rather principles that will provide the foundations for a group which is supported to fulfil their specific purpose.
The views of the PPI group will be presented at the quarterly Neuro-Oncology Multi-disciplinary team business meetings to provide a forum to discuss issues. We aim to foster a PPI friendly environment, deliver real engagement and involvement across the group.
Abstract
Aims
Previous work has shown that increased numbers of macrophages are associated with more rapid schwannoma tumour growth and we are interested in signals that control entry of macrophages ...and other immune cells into these tumours. Activation of the Raf-kinase domain and the Raf/MEK/ERK pathway within Schwann cells has been observed to induce an inflammatory response in peripheral nerves in the absence of injury. Activation of an inducible Raf-kinase transgene in Schwann cells allows modelling of acute demyelination of peripheral nerves without nerve injury. This Raf-oestrogen receptor fusion protein (Raf-TR) is activated by the oestrogen analogue Tamoxifen and so allows targeted, controlled activation of the Raf/MEK/ERK pathway within the Schwann cells.
Here, in order to understand drivers of tumour formation, we assess the effect of MAPK activation in Merlin-null Schwann cells upon immune cell infiltration within the PNS.
Method
RafTR-P0CRE-NF2fl/fl mice of 4-6 weeks age were injected daily (IP) with 2mg of 4-hydroxy-tamoxifen or vehicle (corn oil) control for 5 consecutive days. RafTR was activated on either a Merlin (NF2) wild-type (NF2 fl/fl, P0-CRE-) or NF2 null (NF2 fl/fl, P0-CRE+) background and effects on immune cell infiltration studied in each condition.
Immunofluorescence was performed in the dorsal root ganglia (DRGs) and sciatic nerves of mice to identify various immune cell infiltrates at various timepoints. These will include neutrophils, mast cells, T-Cells and macrophages using the cell markers Csf3r, C-kit, CD3 and IBA1 respectively.
Results
At 21 days post treatment, a significantly increased infiltration of macrophages within the sciatic nerve and dorsal root ganglia was observed in mice treated with Tamoxifen when compared to vehicle controls. Loss of NF2 led to a massive increase in the number of macrophages recruited to peripheral nerves in tamoxifen-treated mice compared to Cre- mice and Cre+ treated with vehicle alone. Further assessment of other immune cell infiltration including neutrophils, mast cells and T cells are ongoing.
Conclusion
Raf/MEK/ERK signalling, in the absence of tumour suppressor Merlin, significantly increases the infiltration of inflammatory cells such as macrophages into peripheral nerves even in the absence of injury. As this effect is enhanced in NF2 null mice, this suggests that Merlin plays an important role in inhibiting the inflammatory response in peripheral nerves. It also suggests that Merlin could be involved in maintaining the blood nerve barrier (BNB), as in its absence the greater influx of immune cells into the nerves and DRGs suggests a more complete loss of BNB function than just activation of the Raf/MEK/ERK cascade alone.
Abstract
Aims
Since 2016, the University Hospital Southampton NHS Foundation Trust (UHSFT) has been commissioned by NHS England to deliver SRST to brain metastases. At UHSFT, all referrals are ...discussed at the Wessex Neurosciences multidisciplinary team meeting. Referrals that satisfy the criteria set by NHS England (estimated prognosis greater than 6 months, absence or controlled extracranial disease or potentially controllable extracranial disease with a Karnofsky Performance Status >70%) will be offered SRST. This retrospective study was performed to assess overall survival rates of patients with brain metastases treated with SRST with further tumour subtype analysis. We also benchmarked our results with other SRST centres.
Method
Retrospective data collection was performed for all the patients who have been treated with SRST. Patients who received SRST to a single metastasis, multiple metastases and/or to the resection cavity between 01/01/2017 to 30/09/2019 were included in this study. All treatment was delivered using a LINAC based SRST platform. Prescription doses ranged from 13.5 Gy to 21 Gy in a single fraction, 21 to 24 Gy in 3 fractions and 25 Gy in 5 fractions. Patients are treated using a stereotactic thermoplastic immobilisation shell and dynamic conformal arc therapy with ExacTrac TM and Cone Beam CT imaging. Dates of death were obtained from the NHS Digital Spine and survival analysis using median overall survival was performed using the Kaplan Meier Method.
Results
277 patients were treated between 01/01/17 and 30/9/2019. The median overall survival from the Kaplan Meier Method was shown to be 14.7 months and the 6-month overall survival was 71% for all patients.
Sub-group analysis of individual tumour sites showed: lung (n=110) median OS 12.1 months, melanoma (n=58) median OS 26.4 months, breast (n=46) median OS not reached (67% still alive) but 18 months survival was 70%, renal (n=22) median OS 15.4 months and colorectal (n=19) median OS 6 months. “Other” tumour sites (n=22) included patients with ovarian, neuroendocrine, sarcoma, testis, oesophagus, unknown primary and gallbladder which were grouped together due to small patient numbers. 41% of patients treated were alive at the time of analysis.
Conclusion
Patients with brain metastases treated with SRST at UHFST have similar outcomes compared to other SRST centres. These patients have a median overall survival of 14.7 months. However, 29% of patients analysed did not survive more than 6 months. Further collection and analysis of the data might improve patient selection and their outcomes.
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