Molecular, genetic, patient and surgical factors involved in the development and outcome of central nervous system tumours

Prognostic factors come in a variety of forms and may be patient, tumour or environmental related. This thesis examines the interaction of prognostic factors for a variety of tumour types. It particularly focuses on single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) gene. The first section on meningiomas describes the frequency of sex steroid receptors in meningiomas. In this study, absence of progesterone receptors is associated with high tumour grade and male gender. Tumours that are progesterone receptor negative have an odds ratio for recurrence of 5.Choroid plexus carcinomas are aggressive malignant tumours generally occurring in young children. Gross total surgical resection has been shown to be a highly significant factor in tumour recurrence and survival. This study describes a treatment paradigm of neoadjuvant ICE chemotherapy in these children which decreases the vascularity and increase the chance of a complete removal. The operative blood loss with this regimen is reduced to 0.22 blood volumes from 1.11 blood volumes without neoadjuvant chemotherapy. The VEGF gene is highly polymorphic and SNPs of the region have previously been shown to influence VEGF protein expression. This study looks at cohorts of both adult gliomas and a variety of paediatric brain tumours; comparing them to controls. There are several associations described between the development of certain tumours and specific SNP genotypes. In addition to this, certain genotypes and haplotypes have an influence on survival of adult grade 2 astrocytomas and paediatric medulloblastomas and ependymomas. There are consistent themes to the prognostic genotypes throughout both the adult and the paediatric tumours.Prognostic factors come in a variety forms as described in this thesis. It is vital to understand the complex interaction between factors to best utilise them for the benefit of patients.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Molecular, genetic, patient and surgical factors involved in the development and outcome of central nervous system tumours

Prognostic factors come in a variety of forms and may be patient, tumour or environmental related. This thesis examines the interaction of prognostic factors for a variety of tumour types. It particularly focuses on single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) gene. The first section on meningiomas describes the frequency of sex steroid receptors in meningiomas. In this study, absence of progesterone receptors is associated with high tumour grade and male gender. Tumours that are progesterone receptor negative have an odds ratio for recurrence of 5.Choroid plexus carcinomas are aggressive malignant tumours generally occurring in young children. Gross total surgical resection has been shown to be a highly significant factor in tumour recurrence and survival. This study describes a treatment paradigm of neoadjuvant ICE chemotherapy in these children which decreases the vascularity and increase the chance of a complete removal. The operative blood loss with this regimen is reduced to 0.22 blood volumes from 1.11 blood volumes without neoadjuvant chemotherapy. The VEGF gene is highly polymorphic and SNPs of the region have previously been shown to influence VEGF protein expression. This study looks at cohorts of both adult gliomas and a variety of paediatric brain tumours; comparing them to controls. There are several associations described between the development of certain tumours and specific SNP genotypes. In addition to this, certain genotypes and haplotypes have an influence on survival of adult grade 2 astrocytomas and paediatric medulloblastomas and ependymomas. There are consistent themes to the prognostic genotypes throughout both the adult and the paediatric tumours.Prognostic factors come in a variety forms as described in this thesis. It is vital to understand the complex interaction between factors to best utilise them for the benefit of patients.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A Tablet-based Virtual Environment for Neurosurgery Training

Published in Presence: Teleoperators and Virtual Environments, Spring 2015No. 2, Pages 155-162 Posted Online October 15, 2015. doi:10.1162/PRES_a_00224The requirement for training surgical procedures without exposing the patient to additional risk is well accepted and is part of a national drive in the UK and internationally. Computer-based simulations are important in this context, including neurosurgical resident training. The objective of this study is to evaluate the effectiveness of a custom built virtual environment in assisting training of a ventriculostomy procedure. The training tool (called VCath) has been developed as an app for a tablet platform to provide easy access and availability to trainees. The study was conducted at the first boot camp organized for all year one trainees in neurosurgery in the UK. The attendees were randomly distributed between the VCath training group and the Control group. Efficacy of performing ventriculostomy for both groups was assessed at the beginning and end of the study using a simulated insertion task. Statistically significant changes in performance of selecting the burr hole entry point, the trajectory length and duration metrics for the VCath group, together with a good indicator of improved normalized jerk (representing the speed and smoothness of arm motion), all suggest that there has been a higher level cognitive benefit to using VCath. The app is successful as it is focused on the cognitive task of ventriculostomy, encouraging the trainee to rehearse the entry point and use anatomical landmarks to create a trajectory to the target. In straight-line trajectory procedures such as ventriculostomy, cognitive task based education is a useful adjunct to traditional methods and may reduce the learning curve and ultimately improve patient safety

The Use of Stereoscopy in a Neurosurgery Training Virtual Environment

Published in Presence: Teleoperators and Virtual EnvironmentsWe have previously investigated the effectiveness of a custom built virtual environment in assisting training of a ventriculostomy procedure, which is a commonly performed procedure by a neurosurgeon and a core task for trainee surgeons. The training tool (called VCath) was initially developed as a low fidelity app for a tablet platform to provide easy access and availability to trainees. Subsequently we have developed a high fidelity version of VCath that uses a stereoscopic display to immerse the trainee in the virtual environment. This paper reports on two studies that have been carried out to compare the low and high fidelity versions of VCath, particularly to assess the value of stereoscopy. Study 1 was conducted at the second annual boot camp organized for all year one trainees in neurosurgery in the UK. Study 2 was performed on lay people, with no surgical experience. Our hypothesis was that using stereoscopy in the training task would be beneficial. Results from Study 1 demonstrated that performance improved for both the control group and the group trained with the tablet version of VCath. The group trained on the high fidelity version of VCath with a stereoscopic display showed no performance improvement. The indication is that our hypothesis is false. In Study 2, six different conditions were investigated that covered the use of training with VCath on a tablet, a mono display at two different sizes, a stereo display at two different sizes, and a control group who received no training. Results from this study with lay people show that stereoscopy can make a significant improvement to the accuracy of needle placement. The possible reasons for these results and the apparent contradiction between the two studies are discussed

Outcomes with respect to extent of surgical resection for pediatric atypical teratoid rhabdoid tumors

Purpose To evaluate overall survival for atypical teratoid rhabdoid tumors (ATRTs) in relation to extent of surgical resection. Methods The neurosurgical tumor databases from three UK Pediatric centers (University Hospital of Wales, Alder Hey and Royal Manchester Children’s Hospital) were analyzed. Patients with a diagnosis of ATRT were identified between 2000 and 2018. Data was collected regarding demographics, extent of resection, complications, and overall survival. Results Twenty-four patients diagnosed with ATRT underwent thirty-eight operations. The age range was 20 days to 147 months (median 17.5 months). The most common location for the tumor was the posterior fossa (nine patients; 38%). Six patients (25%) underwent a complete total resection (CTR), seven (29%) underwent a near total resection (NTR), eight (33.3%) underwent a subtotal resection (STR), and three patients (12.5%) had biopsy only. Two-thirds of patients who underwent a CTR are still alive, as of March 2019, compared to 29% in the NTR and 12.5% in the STR groups. Out of the thirty-eight operations, there were a total of twenty-two complications, of which the most common was pseudomeningocele (27%). The extent of surgical resection (p = 0.021), age at surgery (p = 0.00015), and the presence of metastases at diagnosis (0.015) significantly affected overall survival. Conclusions Although these patients are a highly vulnerable group, maximal resection is recommended where possible, for the best chance of long-term survival. However, near total resections are likely beneficial when compared with subtotal resections and biopsy alone. Maximal surgical resection should be combined with adjuvant therapies for the best long-term outcomes

A non-myeloablative chimeric mouse model accurately defines microglia and macrophage contribution in glioma.

Resident and peripherally-derived glioma associated microglia/macrophages (GAMM) play a key role in driving tumour progression, angiogenesis, invasion, and attenuating host immune responses. Differentiating these cells' origins is challenging and current pre-clinical models such as irradiation-based adoptive transfer, parabiosis and transgenic mice have limitations. We aimed to develop a novel non-myeloablative transplantation (NMT) mouse model that permits high levels of peripheral chimerism without blood-brain barrier (BBB) damage or brain infiltration prior to tumour implantation.NMT dosing was determined in C57BL/6J or Pep3/CD45.1 mice conditioned with concentrations of busulfan ranging from 25mg/kg to 125mg/kg. Donor haematopoietic cells labelled with eGFP or CD45.2 were injected via tail vein. Donor chimerism was measured in peripheral blood, bone marrow and spleen using flow cytometry. BBB integrity was assessed with anti-IgG and anti-fibrinogen antibodies. Immunocompetent chimerised animals were orthotopically implanted with murine glioma GL-261 cells. Central and peripheral cell contributions were assessed using immunohistochemistry and flow cytometry. GAMM subpopulation analysis of peripheral cells was performed using Ly6C/MHCII/MerTK/CD64.NMT achieves >80% haematopoietic chimerism by 12 weeks without BBB damage and normal life span. Bone marrow derived cells (BMDC) and peripheral macrophages accounted for approximately 45% of the GAMM population in GL-261 implanted tumours. Existing markers such as CD45 high/low proved inaccurate to determine central and peripheral populations while Ly6C/MHCII/MerTK/CD64 reliably differentiated GAMM subpopulations in chimerised and unchimerised mice.NMT is a powerful method for dissecting tumour microglia and macrophage subpopulations and can guide further investigation of BMDC subsets in glioma and neuro-inflammatory diseases. This article is protected by copyright. All rights reserved

Comparative analysis of endoscopic third ventriculostomy trajectories in pediatric cases.

OBJECT Endoscopic third ventriculostomy (ETV) has become a widely used method for CSF diversion when treating obstructive hydrocephalus. There are multiple recommendations on the transcortical ETV entry points, and some are specifically designed to provide a trajectory that avoids displacement to the eloquent periventricular structures. However, the morphology of the ventricular system is highly variable in hydrocephalus, and therefore a single best ETV trajectory may not be applicable to all cases. In the current study, 3 frequently quoted ETV entry points are compared in a cohort of pediatric cases with different degrees of ventriculomegaly. METHODS The images of 30 consecutive pediatric patients with varying degrees of ventriculomegaly were reviewed. Three-dimensional models were created using radiological analysis of anatomical detail and preoperative MRI scans in order to simulate 3 frequently quoted ETV trajectories for rigid neuroendoscopes. These trajectories were characterized based on the frequency and depth of tissue displacement to structures such as the fornix, caudate nucleus, genu of the internal capsule, and thalamus. The results are stratified based on ventricle size using the frontal horn ratio (FHR). RESULTS Eloquent areas were displaced in nearly all analyzed entry points (97%–100%). Stratifying the data based on ventricle size revealed that 1) lateral structures were more likely to be displaced in cases of intermediate ventriculomegaly (FHR &lt; 0.4) using all 3 trajectories, whereas 2) the fornix was less likely to be displaced using more posteriorly placed trajectories for severe ventriculomegaly (FHR &gt; 0.4). Allowing for minimal (2.4 mm) tissue displacement, a more posterior entry point was less traumatic for severe ventriculomegaly. CONCLUSIONS There is no single best ETV trajectory that fully avoids displacement of the eloquent periventricular structures. Larger ventricles require a more posteriorly placed entry point in order to reduce injury to the eloquent structures, and intermediate ventricles would dictate a medial entry point. These results suggest that the optimal entry point should be selected on a case-by-case basis after incorporating ventricle size.</jats:sec

Operative planning aid for optimal endoscopic third ventriculostomy trajectories in pediatric cases

OBJECT: Endoscopic third ventriculostomy (ETV) uses anatomical spaces of the ventricular system to reach the third ventricle floor and create an alternative pathway for cerebrospinal fluid flow. Optimal ETV trajectories have been previously proposed in the literature, designed to grant access to the third ventricle floor without a displacement of eloquent periventricular structures. However, in hydrocephalus, there is a significant variability to the configuration of the ventricular system, implying that the optimal ETV trajectory and cranial entry point needs to be planned on a case-by-case basis. In the current study, we created a mathematical model, which tailors the optimal ETV entry point to the individual case by incorporating the ventricle dimensions. METHODS: We retrospectively reviewed the imaging of 30 consecutive pediatric patients with varying degrees of ventriculomegaly. Three dimensional radioanatomical models were created using preoperative MRI scans to simulate the optimal ETV trajectory and entry point for each case. The surface location of cranial entry points for individual ETV trajectories was recorded as Cartesian coordinates centered at Bregma. The distance from the Bregma in the coronal plane represented as “x”, and the distance from the coronal suture in the sagittal plane represented as “y”. The correlation between the ventricle dimensions and the x, y coordinates were tested using linear regression models. RESULTS: The distance of the optimal ETV entry point from the Bregma in the coronal plane (“x”) and from the coronal suture in the sagittal plane (“y”) correlated well with the frontal horn ratio (FHR). The coordinates for x and y were fitted along the following linear equations: x = 85.8 FHR−13.3 (r (2) = 0.84, p < 0.001) and y = −69.6 FHR + 16.7 (r (2) = 0.83, p < 0.001). CONCLUSION: The surface location of the optimal cranial ETV entry point correlates well with the ventricle size. We provide the first model that can be used as a surgical planning aid for a case specific ETV entry site with the incorporation of the ventricle size

The role of artificial intelligence in paediatric neuroradiology

Imaging plays a fundamental role in the managing childhood neurologic, neurosurgical and neuro-oncological disease. Employing multi-parametric MRI techniques, such as spectroscopy and diffusion- and perfusion-weighted imaging, to the radiophenotyping of neuroradiologic conditions is becoming increasingly prevalent, particularly with radiogenomic analyses correlating imaging characteristics with molecular biomarkers of disease. However, integration into routine clinical practice remains elusive. With modern multi-parametric MRI now providing additional data beyond anatomy, informing on histology, biology and physiology, such metric-rich information can present as information overload to the treating radiologist and, as such, information relevant to an individual case can become lost. Artificial intelligence techniques are capable of modelling the vast radiologic, biological and clinical datasets that accompany childhood neurologic disease, such that this information can become incorporated in upfront prognostic modelling systems, with artificial intelligence techniques providing a plausible approach to this solution. This review examines machine learning approaches than can be used to underpin such artificial intelligence applications, with exemplars for each machine learning approach from the world literature. Then, within the specific use case of paediatric neuro-oncology, we examine the potential future contribution for such artificial intelligence machine learning techniques to offer solutions for patient care in the form of decision support systems, potentially enabling personalised medicine within this domain of paediatric radiologic practice