Abstract
BACKGROUND AND AIMS
There is incomplete information on the impact of a third dose of the SARS-CoV-2 vaccine in advance chronic kidney disease (CKD). The aim of the present analysis was to ...evaluate the kinetics of humoral response in the CKD spectrum (KT, HD, PD and ND-CKD) 6 months after completing the initial vaccine schedule. Some patients of each group received a third dose before 6 months, providing a pragmatic insight into real-world responses to different vaccine schedules in patients with advanced CKD not on dialysis, on dialysis or in KT recipients.
METHOD
The SENCOVAC study describes the humoral response and safety of different SARS-CoV-2 vaccines in a real-world setting in 3687 CKD patients: 787 kidney transplant (KT), 319 peritoneal dialysis (PD), 2297 haemodialysis (HD) and 284 non-dialysis-CKD (ND-CKD) patients. Anti-Spike antibodies were assessed in an efficacy analysis at 28 days (n = 1755), 3 months (n = 1386), and 6 months (n = 1018, of whom 628 had received a third vaccine dose). Adverse events (AEs) were registered during follow-up, including SARS-CoV-2 infections in the safety analysis.
RESULTS
Among the patients included in the efficacy analysis, KT recipients presented lower anti-Spike antibody titers than other CKD cohorts at 28 days and 3 months (P < .001 for all). A total of 943 patients 249 (26%) KT, 108 (11%) PD, 511 (54%) HD and 75 (8%) ND-CKD had negative baseline anti-Spike antibodies. Again, at 28 days or 3 months, KT recipients developed lower anti-Spike antibody titers than PD (P < .001), HD (P < .001) and ND-CKD (P< .001) patients. At 6 months, patients that had received a third vaccine dose had higher anti-Spike antibody titers than those without the third dose 1837 (507–9726) UI/mL versus 80 (19–409) ml/UI; P < .001 and this was evident in all CKD cohorts. Anti-Spike titers after the third dose were higher in patients boosted with mRNA-1273 than with BNT162b2 1710 (322–9615) versus 472 (34–2094); P < .001). At 6 months, in patients that had received a third dose, a positive humoral response (anti-Spike antibodies > 36 UI/mL) was achieved in 584 (93%): 94 (80%) of 118 KT recipients, 20 (100%) of 20 patients on PD, 436 (96%) of 455 patients on HD and 34 (97%) of 35 patients with ND-CKD (Fig. 1). Among patients without humoral response 3 months after completing the initial vaccination schedule, 72 (69%) seroconverted after the third dose (62% KT, 76% HD, 100% ND-CKD, all PD patients had a positive humoral response at 3 months). Independent predictors of a positive humoral response at 6 months were not-KT (HR for KT 0.26, P = .011), third dose (HR 22.9, P < .001), initial mRNA-1273 (HT 1.78, P = .017) and humoral response at 3 months (HR 26.2, P < .001). Breakthrough SARS-CoV-2 infections occurred in 1.1% of patients, and mortality was 14.6%, none after the third dose.
CONCLUSION
In the CKD spectrum, anti-Spike antibody titers continued to decrease from 3 to 6 months after complete vaccination, and KT recipients presented higher rates of negative humoral response at 6 months. A third dose of mRNA vaccine increased anti-Spike antibody titers but was still insufficient to spur a humoral immune response in at least 38% of KT recipients and 24% of patients on HD that lacked anti-SARS-CoV-2 antibodies 3 months post-initial vaccination. New strategies are urgently needed to protect CKD patients that remain negative for anti-SARS-CoV-2 antibodies, given the high mortality of breakthrough SARS-CoV-2 infections.
FIGURE 1:
Presence of anti-Spike antibodies during follow-up in the different CKD cohorts. Data expressed as % of patients with presence of anti-Spike antibodies (i.e. titer > 36 IU/mL).
GRAPHICAL ABSTRACT
Graphical Abstract
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
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.
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
Glioblastoma multiforme (GBM) is a devastating disease with notoriously poor survival. Studies examining survival in patients given best supportive care (BSC) are few and far between. ...All patients harbouring brain tumours referred to the Neuro-oncology service at the Queen Elizabeth Hospital in Birmingham are recorded in the Somerset Cancer Registry. We set out to analyse survival times and identify patient and tumour-related factors significantly affecting prognosis.
Method
We identified 126 patients from 2015 to 2019 in our Somerset Cancer Registry with radiological diagnoses of glioblastoma for whom the Neuro-oncology MDT recommended BSC. We performed a retrospective analysis of clinical records and radiological images. 11 patients were excluded (8 due to insufficient imaging data, 2 who underwent subsequent surgery, 1 patient with brain metastases). Survival was measured in completed weeks since the index MDT decision. Associations between survival time and both patient- and tumour-related factors were assessed using Kaplan-Meier curves and log-rank tests. All analyses were performed using IBM SPSS 22 (IBM Corp. Armonk, NY), with p<0.05 deemed to be indicative of statistical significance throughout.
Results
Data were available for N=115 patients (69 males, 46 females), with a mean age of 79 ± 8 years. All patients died within 32 weeks of diagnosis, with a median survival time of 8 weeks. Only 8 patients survived for more than 20 weeks. Survival was significantly shorter in those with a greater number of main cerebral structures affected (p=0.044), with a median of 6 vs. 10 weeks for 3 or more vs. 1 structures affected (hazard ratio: 1.61, 95% CI: 0.99-2.62). Bilateral tumours involving the corpus callosum were also associated with shorter survival (p=0.039). None of the other factors considered were found to be significantly associated with survival, including age (p=0.193), gender (p=0.371), performance status (p=0.300) and tumour size (p=0.331).
Conclusion
With the exception of the number of main cerebral structures affected (frontal, parietal, temporal and occipital lobes, corpus callosum, insula, basal ganglia and brain stem), patient- and tumour-factors traditionally used by the MDT to prognosticate do not correlate with survival time in patients receiving BSC for radiological diagnoses of GBM. With 50% of the cohort dying within 8 weeks it is clear that we must reconsider the timing of referrals to palliative and hospice care. Finally, the fact that some patients survived for more than half a year with no surgical or oncological treatment suggests that the process of selecting patients for BSC vs aggressive treatments needs refinement.
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
There is limited evidence on cerebrovascular risks in glioblastoma and meningioma patients. We aimed to compare cerebrovascular risks of these patients with the general population.
...Method
We used population-based routine healthcare and administrative data linkage in this matched cohort study. Cases were adult glioblastoma and meningioma patients diagnosed in Wales 2000-2014 identified in the cancer registry. Controls from cancer-free general population were matched to cases (5:1 ratio) on age (±5 years), sex and GP practice. Factors included in multivariable models were age, sex, index of multiple deprivation, hypertension, diabetes, high cholesterol, history of cardiovascular disease, and medications for cardiovascular diseases. Outcomes were fatal and non-fatal haemorrhagic and ischaemic stroke. We used flexible parametric models adjusting for confounders to calculate the hazard ratios (HR).
Results
Final analytic population was 16,921 participants, of which 1,340 had glioblastoma and 1,498 had meningioma. The median follow-up time was 0.5 year for glioblastoma patients, 4.9 years for meningioma patients, and 6.6 years for controls. The number of haemorrhage and ischaemic stroke was 154 and 374 in the glioblastoma matched cohort, respectively, and 180 and 569 in the meningioma matched cohort, respectively. The adjusted HRs for haemorrhagic and ischaemic stroke were 3.74 (95%CI 1.87-6.57) and 5.62 (95%CI 2.56-10.42) in glioblastoma patients, respectively, and were 2.42 (95%CI 1.58-3.52) and 1.86 (95%CI 1.54-2.23) in meningioma patients compared with their controls.
Conclusion
Glioblastoma and meningioma patients had higher cerebrovascular risks; these risks were even higher for glioblastoma patients. Further assessment of these potentially modifiable risks may improve survivorship.
Abstract
Aims
Our lab is interested in signals that trigger schwannoma tumour formation and we have previously shown that peripheral nerve injury triggers tumour formation in nerves with Schwann ...cell-specific loss of the Merlin (NF2) tumour suppressor. The Ras/Raf/MAPK/ERK pathway activity in myelinating Schwann cells is involved in nerve regeneration, causing demyelination and recruitment of inflammatory cells in areas of nerve damage, as well as dedifferentiation of myelinating Schwann cells into a repair-competent state. We have used a mouse model expressing a tamoxifen-inducible Raf-Kinase estrogen receptor fusion protein (Raf-TR) in myelinating Schwann cells of the PNS in either a control wild-type Merlin or Merlin-null background. This allows us to determine the effects of an injury-like signal in Schwann cells and its role in generating schwannoma tumour development. We present here a detailed analysis of the proliferation of Schwann cells within the nerve and morphological changes in PNS structure following Raf-TR activation.
Method
The P0-promotor driving the Raf-TR transgene is active in myelinating Schwann cells but inactive in the non-myelinating population, allowing specific targeting of the myelinating Schwann cell population. In addition to the Raf-TR gene, the mice exhibit a separate P0-promotor controlled Cre floxed NF2 gene which undergoes Cre-mediated recombinase at embryonic day 13.5 causing NF2 knockout in all developing Schwann cells. Mice aged between 4-6 weeks received intraperitoneal injections of either 2mg Tamoxifen or oil vehicle for 5 consecutive days and were then studied at either 10 or 21 days post-first injection. The peripheral nervous system of the mice was studied with fluorescent immuno-histochemistry staining, semithin sections and transmission electron microscopy (TEM) on sciatic nerves and dorsal root ganglia (DRG).
Results
Activation of the Ras/Raf/MAPK/ERK pathway in NF2 null Schwann cells led to higher rates of proliferation within sciatic nerves at 10d post-tamoxifen injections. At both 10d and 21d Raf-TR+ NF2-null mice sciatic nerve fascicles were visibly larger with significantly more cell bodies present than controls, however at 21d the rate of proliferation had reduced. In the DRG, proliferation was higher in Raf-TR+ NF2-null mice compared to controls, with proliferation remaining high at 21 days. Quantitative imaging of peripheral nerve semi-thins analysed to date showed no significant difference in the number of myelin rings present in the fascicles between different genotypes. Additionally, dual immuno-histochemistry staining with Myelin Basic Protein and EdU, markers for myelin and proliferation respectively, appeared to show proliferation in the non-myelinating Schwann cell population. Results from staining with other cell markers will also be presented, as well as a detailed analysis of nerve structure using TEM.
Conclusion
While developmental myelination of Merlin-null Schwann cells appears largely normal, the reaction of Merlin-null Schwann cells in the nerve to an injury signal (activation of the Raf-TR) is remarkably different from those of control nerves. The high levels of proliferation in Merlin-null Schwann cells may be indicative of a higher tumorigenesis potential. While the proliferation of Merlin-null cells does reduce over time in the sciatic nerve, further experiments are now testing whether there may be ongoing tumour growth at other locations in the nervous system that are associated with NF2 tumours in human patients.
Abstract
Aims
Low-grade gliomas (LGG) slowly grow and infiltrate the brain's network architecture (the connectome). Unlike strokes that acutely damage the connectome, LGGs intricately remodel it, ...leading to varying deficits in executive function (i.e. attention, concentration, working memory). By longitudinally mapping the “mesoscale” architecture of the connectome, we may begin to systematically accelerate domain-general cognitive rehabilitation in LGG patients. In this study, we pursued the following aims: 1) track cognitive and connectome trajectories following LGG surgery, 2) determine optimal time period for cognitive rehabilitation, and 3) distinguish patients with perioperative predictors of long-term cognitive deficits (>1 year).
Method
With MRI and cognitive data from n=629 individuals across the lifespan, we first validated the structural, functional, and topological relevance of the multiple demand (MD) system for higher-order cognition. Next, in n=17 patients undergoing glioma surgery, we longitudinally acquired connectome and cognitive data: pre-surgery, post-surgery Day 1, Month 3, & 12. We assessed how glioma infiltration, surgery, and rehabilitation affected MD system trajectories at the single-subject level. Deploying transcriptomic and graph theoretical analyses, we tested if perioperative connectome modularity can accurately distinguish long-term cognitive trajectories.
Results
Controlling for age and sex, the MD system’s multi-scale architecture in health was positively associated with higher-order cognition (Catell’s fluid intelligence). Pre-operative glioma infiltration into the MD system was negatively associated with the number of long-term cognitive deficits (OCS-Bridge cognitive battery), suggesting its functional reorganisation. Mixed-effects modelling demonstrated the resilience of the MD system to infiltration and resection, while the early post-operative period was critical for effective neurorehabilitation. Graph analyses revealed perioperative modularity can distinguish patients with long-term cognitive deficits at one-year follow-up. Transcriptomic analyses of inter-module connector hubs revealed increased gene expression for mitochondrial metabolism and synaptic plasticity.
Conclusion
This is the first serial functional mapping of LGG patient trajectories for domain-general cognition. By assessing the mesoscale architecture, we demonstrate how connectomics can help overcome the intrinsic heterogeneity in LGG patients and predict long-term rehabilitation trajectories. We discuss how to identify neurobiologically-grounded personalised targets for 'interventional neurorehabilitation' following LGG surgery.
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