Mathematical Modelling of Glioblastomas Invasion within the Brain:A 3D Multi-Scale Moving-Boundary Approach

International audienceBrain-related experiments are limited by nature, and so biological insights are often limited or absent. This is particularly problematic in the context of brain cancers, which have very poor survival rates. To generate and test new biological hypotheses, researchers have started using mathematical models that can simulate tumour evolution. However, most of these models focus on single-scale 2D cell dynamics, and cannot capture the complex multi-scale tumour invasion patterns in 3D brains. A particular role in these invasion patterns is likely played by the distribution of micro-fibres. To investigate the explicit role of brain micro-fibres in 3D invading tumours, in this study, we extended a previously introduced 2D multi-scale moving-boundary framework to take into account 3D multi-scale tumour dynamics. T1 weighted and DTI scans are used as initial conditions for our model, and to parametrise the diffusion tensor. Numerical results show that including an anisotropic diffusion term may lead in some cases (for specific micro-fibre distributions) to significant changes in tumour morphology, while in other cases, it has no effect. This may be caused by the underlying brain structure and its microscopic fibre representation, which seems to influence cancer-invasion patterns through the underlying cell-adhesion process that overshadows the diffusion process

Automated brain tumour identification using magnetic resonance imaging:a systematic review and meta-analysis

BACKGROUND: Automated brain tumor identification facilitates diagnosis and treatment planning. We evaluate the performance of traditional machine learning (TML) and deep learning (DL) in brain tumor detection and segmentation, using MRI. METHODS: A systematic literature search from January 2000 to May 8, 2021 was conducted. Study quality was assessed using the Checklist for Artificial Intelligence in Medical Imaging (CLAIM). Detection meta-analysis was performed using a unified hierarchical model. Segmentation studies were evaluated using a random effects model. Sensitivity analysis was performed for externally validated studies. RESULTS: Of 224 studies included in the systematic review, 46 segmentation and 38 detection studies were eligible for meta-analysis. In detection, DL achieved a lower false positive rate compared to TML; 0.018 (95% CI, 0.011 to 0.028) and 0.048 (0.032 to 0.072) (P < .001), respectively. In segmentation, DL had a higher dice similarity coefficient (DSC), particularly for tumor core (TC); 0.80 (0.77 to 0.83) and 0.63 (0.56 to 0.71) (P < .001), persisting on sensitivity analysis. Both manual and automated whole tumor (WT) segmentation had “good” (DSC ≥ 0.70) performance. Manual TC segmentation was superior to automated; 0.78 (0.69 to 0.86) and 0.64 (0.53 to 0.74) (P = .014), respectively. Only 30% of studies reported external validation. CONCLUSIONS: The comparable performance of automated to manual WT segmentation supports its integration into clinical practice. However, manual outperformance for sub-compartmental segmentation highlights the need for further development of automated methods in this area. Compared to TML, DL provided superior performance for detection and sub-compartmental segmentation. Improvements in the quality and design of studies, including external validation, are required for the interpretability and generalizability of automated models

Simulating photodynamic therapy for the treatment of glioblastoma using Monte Carlo radiative transport

Funding: LF acknowledges financial support from the UK Research and Innovation (UKRI) Engineering and Physical Sciences Research Council (EPSRC) Centre for Doctoral Training in Applied Photonics (Grant No. EP/S022821/1) and the Laser Research and Therapy Fund (Grant No. SC030850).Significance Glioblastoma (GBM) is a rare but deadly form of brain tumor with a low median survival rate of 14.6 months, due to its resistance to treatment. An independent simulation of the INtraoperative photoDYnamic therapy for GliOblastoma (INDYGO) trial, a clinical trial aiming to treat the GBM resection cavity with photo- dynamic therapy (PDT) via a laser coupled balloon device, is demonstrated. Aim To develop a framework providing increased understanding for the PDT treatment, its parameters, and their impact on the clinical outcome. Approach We use Monte Carlo radiative transport techniques within a computational brain model containing a GBM to simulate light path and PDT effects. Treatment parameters (laser power, photosensitizer concentration, and irradiation time) are considered, as well as PDT’s impact on brain tissue temperature.  Results The simulation suggests that 39% of post-resection GBM cells are killed at the end of treatment when using the standard INDYGO trial protocol (light fluence = 200 J∕cm2 at balloon wall) and assuming an initial photosensitizer concentration of 5 μM. Increases in treatment time and light power (light fluence = 400 J∕cm2 at balloon wall) result in further cell kill but increase brain cell temperature, which potentially affects treatment safety. Increasing the p hotosensitizer concentration produces the most significant increase in cell kill, with 61% of GBM cells killed when doubling concentration to 10 μM and keeping the treatment time and power the same. According to these simulations, the standard trial protocol is reasonably well optimized with improvements in cell kill difficult to achieve without potentially dangerous increases in temperature. To improve treatment outcome, focus should be placed on improving the photosensitizer.  Conclusions With further development and optimization, the simulation could have potential clinical benefit and be used to help plan and optimize intraoperative PDT treatment for GBM.Peer reviewe

Development and optimisation of in vitro sonodynamic therapy for glioblastoma

Sonodynamic therapy (SDT) is currently on critical path for glioblastoma therapeutics. SDT is a non-invasive approach utilising focused ultrasound to activate photosensitisers like 5-ALA to impede tumour growth. Unfortunately, the molecular mechanisms underlying the therapeutic functions of SDT remain enigmatic. This is primarily due to the lack of intricately optimised instrumentation capable of modulating SDT delivery to glioma cells in vitro. Consequently, very little information is available on the effects of SDT on glioma stem cells which are key drivers of gliomagenesis and recurrence. To address this, the current study has developed and validated an automated in vitro SDT system to allow the application and mapping of focused ultrasound fields under varied exposure conditions and setup configurations. The study optimizes ultrasound frequency, intensity, plate base material, thermal effect, and the integration of live cells. Indeed, in the presence of 5-ALA, focused ultrasound induces apoptotic cell death in primary patient-derived glioma cells with concurrent upregulation of intracellular reactive oxygen species. Intriguingly, primary glioma stem neurospheres also exhibit remarkably reduced 3D growth upon SDT exposure. Taken together, the study reports an in vitro system for SDT applications on tissue culture-based disease models to potentially benchmark the novel approach to the current standard-of-care.</p

Studies on axonal regeneration in the CNS and peripheral nerves

This thesis examines the roles of inflammation and the chondroitin sulphate proteoglycan NG2 in regeneration of injured axons in the adult mammalian nervous system, against a background suggesting that inflammation around the cell bodies of axotomised neurons enhances axonal regeneration and that NG2 is a major inhibitor of CNS axonal regeneration. 1) Lipopolysaccharide was placed on / injected in motor cortex of rats, with or without concomitant injury of the cervical corticospinal tract (CST). The inflammatory response and expression of the growth-associated genes c-jun, ATF3, SCGIO and GAP-43 was investigated by immunohistochemistry or in situ hybridisation. Retrograde labelling identified CST neuron cell bodies, and anterograde tracing of CST axons identified axonal sprouting / regeneration. Lipopolysaccharide-induced inflammation promoted upregulation of GAP-43 (briefly), c-jun and SCG 10 (for two weeks) in CST neurons, but did not enhance regeneration of injured CST axons. 2) Axonal regeneration was examined in the CNS and PNS ofNG2 knockout mice. CNS regeneration was assessed following dorsal column injury in ascending axons with cholera toxin-conjugated horseradish peroxidase (CT-HRP) and in descending CST axons with anterograde labelling with BDA, as well as transganglionic labelling of transected dorsal roots with CT-HRP. PNS regeneration after sciatic nerve crush was assessed anatomically by: retrograde labelling (from the hindpaw) ofL4/5 dorsal root ganglion cells; immunohistochemistry to detect sensory axons in hindpaw skin; silver-cholinesterase staining of soleus motor axons / end plates; EM counts of tibial and digital nerves. Functional recovery was assessed by the (motor) toe spreading reflex and (sensory) responses to von Frey hairs. There was neither anatomical nor functional evidence for significant effects on CNS or PNS axonal regeneration in the knockout mice. These findings suggest that NG2 is not a major inhibitory factor in the failure of CNS regeneration and is not important for successful axonal regeneration in the PNS.EThOS - Electronic Theses Online ServiceGBUnited Kingdo