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
The World Health Organisation (WHO) classification of adult gliomas has undergone significant revision in recent years, with current emphasis on the role of the molecular biomarkers ...IDH, 1p19q, ATRX, and p53 for classification of glioblastoma, astrocytoma, and oligodendroglioma. When correctly applied the T2-FLAIR mismatch sign is reported to have 100% specificity for WHO grade II or III IDH mutant 1p19q non-codeleted astrocytoma. We sought to verify this classic imaging-molecular correlate in our cohort at a single tertiary level neurosurgical referral centre in the United Kingdom.
Method
Data were gathered by searching the histopathology database for cases between 2014 and 2019 containing the keywords ‘IDH Mutant’ AND ‘Astrocytoma’ or ‘Glioblastoma’ or ‘Oligodendroglioma’ in the report. Inclusion criteria: Biopsy/resection proven IDH mutant tumours in adults (age >17). A strict application of the T2-FLAIR mismatch sign was used when evaluating MRI. Native T2 signal was required to be homogenous or near homogenous, with hypointense signal on T2 weighted FLAIR except for a hyperintense peripheral rim. In addition, the T2-FLAIR mismatch sign was not applied to tumours showing any unequivocal contrast enhancement or macrocystic change.
Results
66/185 cases were excluded for reasons of insufficient imaging, duplication, 1p19q partial deletion/unknown + ATRX wild type/unknown, IDH wild type/negative, Grade IV histology. 119 cases fit the inclusion criteria, all IDH positive. Group 1 comprised 49 (39%) 1p19q codeleted tumours, or oligodendrogliomas. ATRX was wild type (78%), unknown (18%), or mutated (<1%). Group 2 comprised 37 (29%) 1p19q non-codeleted tumours, or astrocytomas. ATRX was mutated (70%), unknown (22%), wild type (5%), or equivocal (3%). Group 3 comprised 41 (32%) 1p19q unknown tumours, all ATRX mutated, p53 expressed (83%). When p53 status was unaltered/equivocal, microscopy was convincingly astrocytic. Groups 2 and 3 comprised the astrocytomas (61%). T2-FLAIR mismatch was positive in 5 1p19q non-codeleted astrocytomas, 5 1p19q unknown ATRX mutant astrocytomas, and no 1p19q co-deleted oligodendrogliomas. Test sensitivity and specificity was 14% and 100% for 1p19q non-codeletion, 13% and 100% for ATRX mutation.
Conclusion
Although relatively uncommon, when present and correctly applied we confirm 100% specificity of the T2-FLAIR mismatch sign for IDH mutant 1p19q non-codeleted astrocytoma. However, if 1p19q status is unknown, clear astrocytic histology and ATRX mutation and/or p53 overexpression is also considered sufficient to diagnose astrocytoma. When 1p19q status is unavailable we also report 100% specificity of T2-FLAIR mismatch for ATRX mutated astrocytomas. T2-FLAIR mismatch was not observed in any 1p19q codeleted oligodendrogliomas or ATRX wild type tumours. More accurate methods of non-invasive glioma diagnosis will help improve neurohistopathological correlation, prognostication, and guide the tempo of the pre-operative planning phase.
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.
Abstract
Aims
Ependymomas (tumours arising from ependymal cells) are rare in the adult population and therefore there is limited class 1 evidence on the treatment and management of these patients. We ...present our experience from a large single center. We address whether management should be undertaken by sub-specialised surgeons with high volume experience.
Method
Retrospective comparative study.
Results
High volume surgeons operated on larger volume (16.14 mm3, 8.31mm3, p=0.10) and more complex tumours (multi-centric cases p=0.10). We find a non-significant improvement in complication rate (p=0.77), extent of gross total resection (70.8% against 65.7%) and a positive change in performance status for high volume surgeons (p=0.84). Length of hospital stay is significantly prolonged when complications occur (14.2 and 48.4 days, p<0.05).
Conclusion
Surgeons who have higher case load of ependymomas operate on more complex tumours. In addition, our results indicate there is a technical advantage of high volume surgeons compared to low volume surgeons, which translates into improved clinical outcomes for patients. We show that this has a significant impact on length of hospital stay, as well as the associated economical implications. For rare tumours such as ependymomas, super-specialisation and referral to surgeons with higher case volume will likely improve patient outcomes.
We call for a multi-centre, prospective studies to combine data in demonstrating statistical significance (power calculation for complication rate, N=150, p=0.05).
Abstract
Aims
There are approximately four thousand neuro-oncology procedures in the UK per annum. Many of these result in tissue and biofluid specimens that are surplus to diagnostic requirement and ...can be collected as standard of clinical care. However, developing technologies and treatments for precision medicine require access to a range of individualised biospecimens paired with deep clinical phenotyping data. Here, we present Brain Surgical Tissue for Advanced Tumour Models (BRAINSTAT) programme, an infrastructure that has been established between Queen Elizabeth Hospital, Birmingham and the University of Birmingham, to collect, structure and store these resources and also maximise their value for research over the long-term. Using this approach our aim is to provide high-quality, annotated resources to help develop novel treatments for patients with brain tumours.
Method
BRAINSTAT infrastructure allows:
Prospective consent
Biospecimens, including tumour tissue (brain and other primary in the case of metastasis), cyst fluid, dura, skin, CSF, blood (matched “germ-line” and for circulating cell free tumour DNA analysis), urine and saliva can be collected. Consent for long term follow-up, is either via clinic or NHS digital. More limited consent for non-oncological neurosurgical cohorts (e.g. epilepsy or vascular) and healthy volunteers allow healthy access-tissue and biofluids to be collected.
B. Rapid transfer of fresh surgical tissue samples:
Strong collaborative links and close physical proximity between operating theatre and laboratory allows rapid transfer of biospecimens minimising transit time.
C. Standardised annotation across disciplines
The RedCAP database system allows granular control over data-access, and each specialist research team is provided access only to the sub-sections relevant to them. All users must have Good Clinical Practice certification and GDPR training, prior to access of the BRAINSTAT database.
Results
Between 25/11/2019-16/03/2020 and 27/07/2020-16/11/2020, 65 patients were consented for BRAINSTAT at the weekly neurosurgical oncology clinic. (Recruitment gaps due to the SARS-COVID 19 pandemic). Pathological diagnosis of surplus tissue collected included: 37 high grade glioma, 3 low grade glioma and 16 brain metastasis including: (6 lung, 6 breast, 2 colorectal, 1 oesophageal, 1 endometrial). Meningioma (5 WHO I; 1 WHO III) 1 patient undergoing anterior temporal lobectomy for hippocampal sclerosis contributed access tissue from the lateral neocortex. 1 patient had a non- neoplastic, non-diagnostic sample. All patients had matched “germ-line” blood samples.
Median time from resection to arrival in the laboratory was 10 minutes (range 4-31). Standardised operating protocols to optimise this have been developed.
Glioblastoma and breast-brain metastasis tumourspheres and cerebral organoids are currently being validated.
Conclusion
Despite the challenges of the pandemic we have established a viable tissue pipeline from neurosurgical operating theatre to our university laboratories. We are developing clinically annotated human brain tumour cell lines, stem cells and 3D organoid models, principally for commonly encountered brain tumours such as glioma and metastasis.
The research sets the foundation for a multitude of downstream applications including:
- Building more complex organoid cultures e.g. by including other cell types such as healthy brain cells and endothelial cells allowing future experiments to more accurately model tumour growth.
- Developing high-throughput, patient-specific drug screens of novel drugs and drug combinations using these 3D tumour models aiming to more effectively treat tumour proliferation and spread. These patient avatars will help inform and test more “stratified” personal medical treatments and will provide opportunities to allow earlier intervention with the aim of improving survival, coupled with a better quality of life.
Abstract
Aims
Circulating tumour DNA (ctDNA), shed from solid cancers in to the plasma, represents an exciting analyte for diagnosis and monitoring of disease in cancer patients. However, its use in ...glioma brain cancer patients represents a challenge, due to reduced permeability of the blood brain barrier.
This pilot study sought to investigate the practical aspects and clinical utility of using cell-free DNA (cfDNA) in glioma tests in a NHS diagnostic laboratory. Firstly, we investigated the potential of ctDNA as a proxy for the brain cancer biopsy; where cfDNA analysis was compared to the paired FFPE brain specimen for relevant glioma genetic biomarkers. Secondly, ctDNA constitutes a portion of the overall cfDNA and there is evidence cfDNA metrics per se may also be of value as prognostic tools and surrogates of tumour burden. Additionally, we investigated a potential role for cfDNA metrics in prognostic impact; linking cfDNA concentrations to clinical outcome measures.
Method
10ml peripheral blood was collected in specialist preservative tubes and cfDNA isolated using an extraction kit (Qiagen MinElute ccfDNA kit). cfDNA concentration and purity was assessed using chip-based automated electrophoresis.
Where relevant (12/39 cases), cfDNA samples were run though laboratory tests of IDH variant detection, 1p19q co-deletion assessment and MGMT promoter methylation analysis. Results were compared with ‘standard of care’ brain biopsy tests.
A potential correlate of cfDNA concentration and clinical outcomes data were assessed in a sub-cohort of glioblastoma patients (n=32). The cohort was divided in to 2 groups – high cfDNA vs. low cfDNA - based on whether a subject’s extracted sample cfDNA concentration fell above or below the mean. Comparison of overall survival in months between subjects was checked for normal distribution using the Shapiro-Wilk t-test. The test of equity of survival distributions for the high cfDNA vs. low cfDNA was then analysed as a Kaplan-Meier curve.
Results
The protocol delivered cfDNA of high purity, averaging 91%, within the plasma nucleic acid fraction, however the cfDNA concentrations (mean ≈1ng µl-1) fell below the conventional limit of detection of the laboratory tests. In spite of the low concentration, cfDNA samples did generate test PCR amplicon; however results reflected the germline DNA profile rather than the new somatic changes of the tumour. The cfDNA analysis did not pick up the tumour biomarkers seen in the paired tumour biopsy sample.
In a second part of the study, cfDNA concentrations for the glioblastoma cohort were assessed in the context of their clinical outcomes data. The data showed a correlate where high cfDNA concentration in the extracted sample was independently associated with inferior outcome in terms of overall survival, with Log Rank significance p=0.014 (Figure 1).
Conclusion
The cfDNA yields from a 10ml blood sample were consistently too low to meet the limit of detection requirements of the standard laboratory neuropathology genetic tests and glioma tumour profile could not be picked up against the germline background. Thus, in spite of the considerable advantages to glioma plasma molecular testing, using cfDNA as a proxy for a brain biopsy would currently not be possible in our routine diagnostic environment.
However, within the limitations of the pilot project testing strategy, the data showed an interesting correlate where high cfDNA concentration was independently associated with inferior outcome in terms of overall survival for glioblastoma patients. Given the simplicity of obtaining this quantifiable metric, there are grounds for further investigations as to its utility; not only with survival outcomes, but also potential correlation with the clinical assessment of tumour burden, blood brain barrier integrity and disease pseudoprogression.
Abstract
Aims
Objective: Active acromegaly is associated with increased mortality. While surgery is the mainstay of treatment, it is not always curative. In selected cases, CyberKnife stereotactic ...radiosurgery (CK SRS) can be used as adjuvant treatment in patients with persistent disease.
Method
Methodology: Biochemical response was measured using serum IGF-1 levels, calculated as a percentage of the upper limit of normal (% ULN). Levels were recorded prior to treatment, at 6-12 months post-treatment and at the most recent follow-up. Anterior pituitary hormone deficits were assessed before and after treatment. Tumour size was followed-up using MRI.
Results
10 patients (7 male, mean age 36 yrs +/- 12.6, SD) with acromegaly were treated with CK SRS. 9 were treated following failure to attain biochemical remission with TSS. 1 had primary CK SRS. 2 had previous conventional fractionated external beam radiotherapy.
Median tumour diameter was 6 mm (IQR 5.2-10.5 mm), with cavernous sinus invasion in 2 cases. The dose was 20-24Gy/1#. 4 patients were on dopamine agonist, 4 on somatostatin analogue and 2 on pegvisomant. Mean follow-up 31.6 months (+/- 13.5 months, SD).
Median IGF-1 % ULN was 146% pre-treatment (IQR 126.5-208.5), 109% at 6-12 months (IQR 76.5-131%) and 71% (IQR 59-91%) at last follow-up. Mean radiological follow-up 16.6 months (+/- 15.9 months, SD). No cases showed tumour enlargement.
One patient developed secondary hypothyroidism. Side-effects: headache (7 patients), blurred vision (1 patient), fatigue/nausea (1 patient). No new visual fields defects, cranial nerve palsies, cerebrovascular events or secondary tumours.
Conclusion
Conclusions: CK SRS appears safe and effective in selected patients with acromegaly, when there is failure to attain biochemical cure with surgery and in patients intolerant or resistant to medical treatment.
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