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.
In the era of "Internet plus," the world economy is becoming more and more globalized and informationalized. China's enterprises are facing unprecedented opportunities for their operation and ...development. However, it is also facing the financial uncertainties brought about by the fluctuations of the general economic environment, and the company is facing increasing financial risks. The reason why most enterprises encounter a serious financial crisis or even close down in the later stage is that they do not pay full attention to the initial financial problems and do not take effective measures to deal with the crisis in time. Financial risk warning has become an important part of modern enterprise financial management. This paper mainly puts forward the optimized BP neural system as the financial early warning model and ensures its high prediction accuracy. In the research, the operation principle and related reasoning process of the model are described, its shortcomings are analyzed, and solutions are put forward. Through the financial risk analysis of listed companies from 2017 to 2020, we find that the correct rate of the prediction results of the financial distress of normal companies in the selected companies based on the optimized BPNN has reached more than 80%, which proves the effectiveness of the optimized BPNN.
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
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
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
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
Glioblastoma (GBM) is currently an incurable malignancy with a very poor prognosis for the majority of patients. Many patients undergo debulking surgery, radiotherapy and chemotherapy ...however therapeutic options are limited, and this can lead to patients sourcing their own treatments. There is some evidence that cannabinoids have the effect of inhibiting GBM tumour growth through a variety of pathways, some of which include CB2 cannabinoid receptor pathway activation. We undertook a patient questionnaire to understand what alternative therapies patients are accessing and why, with a focus on cannabinoid use.
Method
We undertook a prospective observational questionnaire based qualitative study of 50 … consecutive patients undergoing treatment for glioblastoma at our centre.
Results
43 patients responded to our questionnaire. 33% of patients were taking some kind of supplementary therapy with 25% taking cannabis derivatives, mainly CBD oil. There were no clear discriminators amongst our cohort including age or sex when considering the likelihood of taking cannabis derivatives. 6 out of 11 (55%) patients taking cannabis derivatives reported some positive effects with improved sleep and general wellbeing being most commonly reported. Patients reported spending between £10-£300 per month with an average of £42 per month. Cannabis products were obtained via the internet or from friends.
Conclusion
This small cohort of patients indicates that a significant proportion of glioblastoma patients investigate and use alternative therapies, in particular cannabis oil. NICE guidance for clinicians simply notes there is insufficient evidence to support the use of cannabis oil in the treatment of this disease. Given the publicity and interest in the utility of cannabis oil to treat cancers this leaves patients to research the use of these agents without access to robust clinical data to guide their use or indeed to conclude they are not beneficial. The accessing of these compounds, potentially by a sizeable number of patients, leaves them vulnerable to unregulated perhaps unscrupulous drug sources. This small study has further highlighted the unmet need for information and guidance on supplementary treatments for glioma patients and this poses a challenge to all those treating this group of patients to answer a question our patients are clearly wanting answered.
Abstract
Aims
Meningioma is the most common primary intracranial tumour. Although ~80% are benign WHO grade I and show high rates of recurrence. Surgery is the main therapeutic approach, yet location ...can hamper complete resection and chemotherapies are ineffective. Moreover, accurate biomarkers for clinical management are lacking. Approximately 60% sporadic meningiomas harbour mutations in the NF2gene, while mutations in genes including TRAF7, KLF4, AKT1, SMO and PIK3CAhave been identified majority in the NF2-positive low grade-tumours. Moreover, mutations in TRAF7 mostly co-occur with a KLF4K409Q or with AKT1E17K mutation. The mutations and their molecular manifestations consequently affect the signalling pathways at the protein level. The molecular mechanisms behind meningioma tumourigenesis are still obscure and the identification of specific biomarker is necessary to enable their implementation in routine diagnostics and therapeutics. Therefore, we aim to identify novel biomarkers and therapeutic targets of genetically stratified low-grade meningioma by characterising the proteomic landscape.
Method
Frozen tumour samples have already been analysed for NF2-/- by next generation sequencing and genotyped for common mutational hotspots in non-NF2 meningioma such as TRAF7, KLF4 and AKT1 and grouped in to three different mutational groups: AKT1E17K/TRAF7, KLF4K409Q/TRAF7and NF2-/- and all these mutations will be compared to normal healthy meninges. For global proteomics, proteins were separated by SDS-PAGE followed by in-gel tryptic digestion and sample preparation for LC-MS/MS analysis. Raw mass spectrometry data files were processed by MaxQuant (1.6.2.10) and Perseus software (1.6.1.3). Quantitative phospho-proteomics was performed using TMT 10plex labelling approach followed by motif analysis using motif-X algorithm. GO enrichment analyses were performed using (DAVID) v6.8 against all human proteins. Potential candidates from expression data analysis will be validated via Western Blot and immunohistochemistry.
Results
We have quantified 4162 proteins across all mutational meningioma subgroups and normal meninges (n=31). Hierarchical clustering analysis showed distinct proteomic profiles of mutational subgroups revealing clusters of differentially expressed proteins. Comparative analysis showed 10 proteins were commonly significantly upregulated (log2 fold-change≥1; p<0.05) among all mutational subtypes vs. normal meninges, indicating proteomic landscapes of mutational subtypes to be highly variable. In contrast, 257 proteins were commonly significantly downregulated (log2 fold-change≤-1; p<0.05) and enriched with molecular functions including aldehyde dehydrogenase and oxido-reductase. Mutational subtype-specific analysis identified 162 proteins significantly upregulated in AKT1E17K/TRAF7 vs. remaining sample groups to be enriched in the oxidative phosphorylation pathway. However, only 14 and 7 proteins were commonly significantly upregulated in KLF4K409Q/TRAF7 and NF2-/- mutant meningioma subtypes respectively. Several of these up-regulated proteins including ANNEXIN-3, CRABP2, CLIC3 and Endoglin were already verified via WB. Lastly, analyses of 6600 phospho-sites (n=8) predicted regulatory kinases including CHEK1, CHEK2 and LCK.
Conclusion
Global proteomic and phos-phoproteomics analysis has led to the identification of proteins differentially expressed in mutant subtypes. Results of this study to date suggest that a proteomic approach is an effective tool to identify distinct patterns in genetically distinct meningioma subgroups. Further validation and functional verification (with inhibitory or knockdown approaches) of potential candidates will allow us to identify potential drug targets/biomarkers for meningiomas.
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