During 2006–2021, Canada had 55 laboratory-confirmed outbreaks of foodborne botulism, involving 67 cases. The mean annual incidence was 0.01 case/100,000 population. Foodborne botulism in Indigenous ...communities accounted for 46% of all cases, which is down from 85% of all cases during 1990–2005. Among all cases, 52% were caused by botulinum neurotoxin type E, but types A (24%), B (16%), F (3%), and AB (1%) also occurred; 3% were caused by undetermined serotypes. Four outbreaks resulted from commercial products, including a 2006 international outbreak caused by carrot juice. Hospital data indicated that 78% of patients were transferred to special care units and 70% required mechanical ventilation; 7 deaths were reported. Botulinum neurotoxin type A was associated with much longer hospital stays and more time spent in special care than types B or E. Foodborne botulism often is misdiagnosed. Increased clinician awareness can improve diagnosis, which can aid epidemiologic investigations and patient treatment.
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.
Abstract
Aims
Glioblastoma Multiforme (GBM) is one of the most aggressive primary brain tumors with poor prognosis (median survival 18 months) and no cure. Management strategies often involve maximum ...safe resection followed by chemoradiotherapy. There has been a move from managing such patients electively rather than the traditional model of treating them as an emergency. While this may have advantages, this can delay the time from presentation to operation. This delay has recently been further compounded by the current COVID-19 pandemic.
There is no data available as to whether the surgical delays that are currently occurring have an impact on patient care, and may outweigh the benefits of elective management on health services.
We aimed to conduct a single centre observational study to assess how long patients should be waiting prior to surgery. We hypothesised that the longer the wait, the higher the pre-operative complication rate and worse the outcomes.
Method
698 patients in a GBM database over a 5-year period (29/10/14- 8/11/19) were studied. All patient data was accessed via electronic patient records
Surgical delay was defined as the interval between date of being put on the waiting list (the date seen in the neuro-oncology clinic) to date of surgery.
Primary outcome measure was preoperative complications, which was categorised into transient neurological decline, stroke, seizures, diabetes/erratic blood sugars, emergency admission, others (e.g., cardiovascular compromise, steroid complications, blood disorders)
Inclusion criteria included: First presentation supratentorial WHO Grade 4 GBM confirmed on histology (this included histological variants such as Gliosarcoma and Epithelioid Glioblastoma), and all patients who had been seen in the neuro-oncology clinic prior to surgery.
Exclusion criteria included all patients who were not thought to have a GBM or high-grade glioma on initial imaging, those admitted as an emergency without being seen in a neuro-oncology clinic, recurrent or secondary GBMs.
Results
460 patients met the inclusion criteria in this study. There was a pre-operative complication rate of 14.6% (67/460). 55% of complications were due to a transient neurological decline (37/67) with 16.4 % (11/67) of patients presenting with seizures. For those with surgical delays ≤7 days pre-operative complication rates were 2.2 % vs 15.9% in those with delays >7 days, p value 0.012, Odds ratio 8.53 (95% CI 1.48- 88.09). Results were statistically significant in those with delays greater than 10 and 14 days (p values 0.0026 and 0.0004 respectively)
ROC Curve analysis revealed an AUC of 0.66 with sensitivities of 99%, 90% and 76% at surgical delays of 7,10 and 14 days respectively.
The median length of hospital admission in both groups of patients was 5 days (p= 0.2065)
All statistical analysis was carried out using Prism 9 and SPSS
Conclusion
In spite of unchanged length of hospital stay, we note a significant increase in pre-operative complication rates as a result of surgical delays greater than 7,10 and 14 days, which introduces an interesting debate in the merit of delaying operations for further assessment in clinic. Our objectives would be to minimize complication rate, therefore a high sensitivity i.e. true positive rate would be most desirable. The 99% levels achieved at 7 days In the ROC analysis lends weight to introducing policy to fast-track admissions for primary GBM patients.
Further directions could include assessing the impact reduced surgical services and redeployment might have had on complications rates and length of hospital stay on patients admitted over the COVID 19 pandemic.
Abstract
Aims
Cerebellar mutism syndrome occurs in 25% of children following resection of posterior fossa tumours. Characterised by mutism, emotional lability and cerebellar motor signs, the syndrome ...is usually reversible over weeks to months. Its pathophysiology remains unclear, but evidence from diffusion MRI studies has implicated damage to the superior cerebellar peduncles in the development of this condition. The objective of this study was to describe the application of automated tractography of the cerebellar peduncles to provide a high-resolution spatiotemporal profile of diffusion MRI changes in cerebellar mutism syndrome.
Method
A retrospective case-control study was performed at Lucille Packard Children’s Hospital, Stanford University. Thirty children with midline medulloblastoma (mean age ± standard deviation 8.8 ± 3.8 years) underwent volumetric T1-weighted and diffusion MRI at four timepoints over one year. Forty-nine healthy children (9.0 ± 4.2 years), scanned at a single timepoint, were included as age- and sex-matched controls. Cerebellar mutism syndrome status was determined by contemporaneous casenote review. Automated Fibre Quantification was used to segment each subject’s cerebellar peduncles (Figure 1), and fractional anisotropy was computed at 30 nodes along each tract. A non-parametric permutation-based method was used to generate a critical cluster size and p-value for by-node ANOVA group comparisons. Z-scores for patients’ fractional anisotropy at each node were calculated based on values from controls’ corresponding nodes; these were analysed using mixed ANOVA with post-hoc false discovery rate-corrected pairwise t-tests.
Results
13 patients developed cerebellar mutism syndrome. Automated fibre segmentation successfully identified the cerebellar peduncles in the majority of participants, but was more robust at follow-up timepoints (78.7% vs. 44.7% pre-operatively). Fractional anisotropy was significantly lower in the distal regions of the left superior cerebellar peduncle pre-operatively (p=0.0137) in patients compared to controls, although patients could not be distinguished pre-operatively with respect to cerebellar mutism syndrome status (Figure 2). Post-operative reductions in fractional anisotropy in children with cerebellar mutism syndrome were highly specific to the distal left superior cerebellar peduncle, and were most pronounced at follow-up timepoints (p=0.006; Figure 3). There were no significant differences in other cerebellar peduncles, either in along-tract fractional anisotropy or Z-scores, with respect to cerebellar mutism syndrome status.
Conclusion
A novel application of an automated tool to extract diffusion MRI data along the length of the cerebellar peduncles is described in a longitudinal retrospective cohort of paediatric medulloblastoma. Changes in fractional anisotropy in the cerebellar peduncles following tumour resection are described in a heretofore unprecedented level of spatiotemporal detail. In particular, children with post-operative cerebellar mutism syndrome show changes in the distal regions of the left superior cerebellar peduncle, and these changes persist up to a year post-operatively. These findings will have direct clinical implications for neurosurgeons performing resection of midline paediatric posterior fossa tumours.
Abstract
Aims
The co-existence of non-epileptic attacks (NEAD) in patients with brain tumour related epilepsy (BTRE) is poorly described. Non epileptic attacks (NEAD) co-occur in up to 30% of ...patients with epilepsy PWE. Adverse life events are associated with development of NEAD; their co-occurrence in those with BTRE is potentially un-surprising.
We sought to characterise the evolution of symptoms in this cohort.
Method
Clinical trajectories of patients with BTRE and co-existing NEAD were characterised. The diagnosis of NEAD was based on the epilepsy specialist’s observation of attacks and /or capture of attacks on video. Some patients had additional video EEG correlate.
Patients had been referred because of persisting symptoms in spite of escalating antiepileptic therapy.
Results
Of eight patients, six were initially misdiagnosed with escalating seizures. One patient developed NEAD de novo following tumour biopsy, the remaining patients developed NEAD following onset of BTRE. Onset of NEAD was not temporally linked with the diagnosis of a brain tumour. In five patients, NEAD onset occurred when seizures were controlled (< 1 seizure/ month). All patients reported fear of developing uncontrolled seizures as being associated with their symptoms and identified their NEAD as more disabling than their epilepsy.
Patients were eventually managed with polytherapy -two found adjunctive clobazam helpful and four were offered antidepressant/ anxiolytic medication. Behavourial strategies including mindfulness were also discussed. At time of last follow up, seven patients had on-going NEAD symptoms in spite of good seizure control.
Conclusion
NEAD can co-occur with BTRE and should be considered in those with rapidly escalating symptoms in spite of antiepileptic therapy and radiologically stable lesions. Both making the diagnosis of NEAD and providing ongoing support is challenging. These patients require a multidisciplinary approach with support from allied specialties including neuropsychiatry and neuropsychology.
Abstract
Aims
Primary central nervous system lymphoma (PCNSL) is a rare form of non–Hodgkin lymphoma with exclusive manifestations in the central nervous system, leptomeninges and eyes. It forms ...around 5% of all primary brain tumours. It is an aggressive tumour which has a poor prognosis if left untreated. It is imperative that diagnosis is made timely so treatment can be started promptly. Therefore, we performed an audit looking into the speed of diagnostic process of PCNSL in our tertiary Neuro–oncology Unit.
Method
Single-centre retrospective review of PCNSL cases referred to a tertiary Neuro–Oncology Unit over a six month period from June to November 2020.
Results
A total of 1309 cases were discussed in the Neuro–oncology MDT meeting over the study period. Fourteen cases (6 male, 8 female; median age range 66 59–83 years) were identified as highly likely PCNSL. Neuroimaging suggested PCNSL as the likely diagnosis in twelve patients. Twelve patients were started on steroids after CT or MRI brain scans. Nine patients had a surgical target and proceeded to have diagnostic brain biopsy. Two patients had different working diagnoses and three patients were deemed unsuitable for brain surgery. One patient required repeat brain biopsy. A tissue diagnosis was made in twelve patients. One patient deteriorated rapidly and one patient had a brain lesion that was deemed too high risk for surgery. The median time between neuroimaging and biopsy was 25 days. The median time taken from first investigation to the pathological confirmation of PCNSL was 36 days (range 6–86 days).
Conclusion
The chief reason for delay in diagnosis of PCNSL was that patients were started on steroids before diagnostic investigations were completed. Steroids caused the brain lesions to become smaller or disappear. Accordingly, time was needed to allow withdrawal of steroids before diagnostic investigations could be repeated. Diagnostic delays may have been exacerbated by logistical issues associated with COVID–19. We propose that there needs to be greater awareness of how early introduction of steroids can markedly delay the diagnosis of PCNSL.
Abstract
Aims
Despite improved understanding of effector T-cell trafficking into the central nervous system, initial trials with anti-PD1/PD-L1 immune checkpoint inhibitors (ICIs) have failed to meet ...their primary endpoints. PTEN loss of function is frequent in GBM and has been correlated with not only poor overall prognosis, but also impaired antitumour responses, including reduced T cell infiltration into tumour and reduced efficacy of ICIs.
Ipatasertib is a novel, potent, selective, small-molecule inhibitor of Akt. We have shown that Ipatasertib efficiently depletes FOXP3+ regulatory T cells from the tumour microenvironment (TME) resulting in increased infiltration of effector T cells in solid tumours (Lopez 2020, AACR).
We hypothesize that the use of AKT inhibition in PTEN glioblastomas may deplete the TME of suppressive immune cells, and render malignant brain tumours more responsive to ICIs. We present updated data for the combination of Ipat+ATZ in patients with glioblastoma.
Method
Patients with relapsed WHO grade IV GBM with stable neurological symptoms ≥5 days prior to enrolment, requiring <3mg Dexamethasone were recruited into two cohorts of this early phase, open-label, single-centre trial studying the combination of Ipatasertib (Ipat) and Atezolizumab (ATZ): a dose finding cohort (A2; n=9) and an expansion cohort (B3; n=7, recruitment ongoing).
The Ice-CAP A2 cohort assessed safety, pharmacodynamic, and preliminary clinical activity of Ipat (200mg or 400mg OD) + ATZ (1200mg Q3W) in pts with potentially resectable relapsed WHO Grade IV GBM. Pts had a 14-21-day run-in phase of Ipat then surgical tumour resection. Combination Ipat+ATZ commenced post surgery. Patients who declined surgery or who were deemed high risk for surgery proceeded directly to combination.
Patients in the expansion cohort B3 commenced directly on Ipat+ATZ at the RP2D of 400mg Ipat with ATZ.
Results
16 evaluable recurrent GBM pts were enrolled across two cohorts. Median age 56 yrs (25-71 yrs). Median ECOG PS 1. Median lines of prior therapy 1 (range 1-4). 10 pts had PTEN loss by IHC (H<30) and/or PTEN mutations on next generation sequencing.
No DLTs, treatment-related (TR) serious adverse events (AEs), or immune-related AEs were observed. Most common TR AEs were G1 diarrhoea (44%), mucositis (17%), rash (28%).
Clinical benefit rate (CR, PR and SD> 6 cycles) at clinical cutoff date (23/02/21) in patients with PTEN aberration was 30% (3/10). A 58-year-old man with PTEN loss had MRI at Cycle 5 showing worsening enhancement suggestive of disease progression. Resection of the lesion showed intense lymphocyte infiltration and pathological CR. He is currently on Cycle 22 with no evidence of disease. Two other patients with PTEN loss with radiological stable disease per RANO criteria remain well on study for >6 cycles.
Conclusion
Combination Ipat+ATZ appears safe and tolerable in GBM pts, with 400mg Ipatasertib OD + 1200mg ATZ Q3W declared as RP2D. Early efficacy signals were detected with PTEN loss being a promising predictive biomarker for response to combination. An expansion cohort enriched with pts with PTEN loss is ongoing.
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
Brain Tumour Related Epilepsy (BTRE) has a significant impact on Quality of Life with implications for driving, employment and social and domestic activities. Management of BTRE is ...complex due to the higher incidence of pharmacoresistance and the potential for interaction between anti-cancer therapy and anti-epileptic drugs (AEDs). Neurologists, oncologists, palliative care physicians and clinical nurse specialists treating these patients would benefit from up-to-date clinical guidelines. We aim to review the current evidence to adapt current NICE guidelines for Epilepsy and to outline specific recommendations for the optimal treatment of BTRE, encompassing both primary and metastatic brain tumours.
Method
A comprehensive search of the literature from the past 20 years on BTRE was carried out in three databases: Embase, Medline and EMCARE. A broad search strategy was used and the evidence was evaluated and graded based on the Oxford Centre for Evidence-Based Medicine Levels of Evidence.
Results
All patients with BTRE should be treated with AEDs. There is no proven benefit for the use of prophylactic AEDs, although there are no randomised trials testing newer agents. Seizure frequency varies between 10-40% (Class 2a evidence) in patients with Brain Metastases (BM) and from 30% (high-grade gliomas) to 90% (low-grade gliomas) (Class 2a evidence) in patients with Primary Brain Tumours (PBT). In patients with BM, risk factors include number of BM and melanoma histology (Class 2b evidence). In patients with PBT, risk factors include frontal and temporal location, oligodendroglial histology, IDH mutation and cortical infiltration (Class 2b evidence). There is a low incidence of seizures (13%) after stereotactic radiosurgery for BM (Class 2b evidence). Non-enzyme inducing AEDs are recommended as first line treatment for BTRE, but up to 50% of patients with BTRE due to PBT remain resistant (Class 2b evidence).
Conclusion
The review has highlighted the relative dearth of high quality evidence for the management of BTRE, and provides a framework for further studies aiming to improve seizure control, quality of life, and indications for AEDs.
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