Quantitative measurement of blood flow in paediatric brain tumours. A comparative study of dynamic susceptibility contrast and multi-timepoint arterial spin-labelled MRI

OBJECTIVE: Arterial spin-labelling (ASL) MRI uses intrinsic blood water to quantify the cerebral blood flow (CBF), removing the need for the injection of a gadolinium-based contrast agent used for conventional perfusion imaging such as dynamic susceptibility contrast (DSC). Owing to the non-invasive nature of the technique, ASL is an attractive option for use in paediatric patients. This work compared DSC and multi-timepoint ASL measures of CBF in paediatric brain tumours. METHODS: Patients (n = 23; 20 low-grade tumours and 3 high-grade tumours) had DSC and multi-timepoint ASL with and without vascular crushers (VC). VC removes the contribution from larger vessel blood flow. Mean perfusion metrics were extracted from control and T(1)-enhanced tumour regions of interest (ROIs): arterial arrival time (AAT) and CBF from the ASL images with and without VC, relative cerebral blood flow (rCBF), relative cerebral blood volume, delay time (DT) and mean transit time (MTT) from the DSC images. RESULTS: Significant correlations existed for: AAT and DT (r = 0.77, p = 0.0002) and CBF and rCBF (r = 0.56, p = 0.02) in control ROIs for ASL-noVC. No significant correlations existed between DSC and ASL measures in the tumour region. Significant differences between control and tumour ROI were found for MTT (p < 0.001) and rCBF (p < 0.005) measures. CONCLUSION: Significant correlations between ASL-noVC and DSC measures in the normal brain suggest that DSC is most sensitive to macrovascular blood flow. The absence of significant correlations within the tumour ROI suggests that ASL is sensitive to different physiological mechanisms compared with DSC measures. ADVANCES IN KNOWLEDGE: ASL provides information which is comparable with that of DSC in healthy tissues, but appears to reflect a different physiology in tumour tissues

Cellular memory of hypoxia elicits neuroblastoma metastasis and enables invasion by non-aggressive neighbouring cells

Therapies targeting cancer metastasis are challenging owing to the complexity of the metastatic process and the high number of effectors involved. Although tumour hypoxia has previously been associated with increased aggressiveness as well as resistance to radio- and chemotherapy, the understanding of a direct link between the level and duration of hypoxia and the individual steps involved in metastasis is still missing. Using live imaging in a chick embryo model, we have demonstrated that the exposure of neuroblastoma cells to 1% oxygen for 3 days was capable of (1) enabling cell migration towards blood vessels, (2) slowing down their velocity within blood vessels to facilitate extravasation and (3) promoting cell proliferation in primary and secondary sites. We have shown that cells do not have to be hypoxic anymore to exhibit these acquired capabilities as a long-term memory of prior hypoxic exposure is kept. Furthermore, non-hypoxic cells can be influenced by neighbouring hypoxic preconditioned cells and be entrained in the metastatic progression. The acquired aggressive phenotype relies on hypoxia-inducible factor (HIF)-dependent transcription of a number of genes involved in metastasis and can be impaired by HIF inhibition. Altogether, our results demonstrate the need to consider both temporal and spatial tumour heterogeneity because cells can 'remember' an earlier environment and share their acquired phenotype with their close neighbours. As a consequence, it is necessary to monitor the correct hypoxic markers to be able to predict the consequences of the cells' history on their behaviour and their potential response to therapies

p53-mediated delayed NF-κB activity enhances etoposide-induced cell death in medulloblastoma

Medulloblastoma (MB) is an embryonic brain tumour that arises in the cerebellum. Using several MB cell lines, we have demonstrated that the chemotherapeutic drug etoposide induces a p53- and caspase-dependent cell death. We have observed an additional caspase-independent cell death mechanism involving delayed nuclear factor κB (NF-κB) activity. The delayed induction was controlled by a p53-dependent transcription step and the production of death receptors (especially CD95/Fas). We further demonstrated that in both MB and glioblastoma (GM) cell lines, in which the p53 pathway was not functional, no p65 activation could be detected upon etoposide treatment. MB cell lines that have mutations in p53 or NF-κB are either less sensitive (NF-κB mutant) or even completely resistant (p53 mutant) to chemotherapeutic intervention. The optimal cell death was only achieved when both p53 and NF-κB were switched on. Taken together, our results shed light on the mechanism of NF-κB activation by etoposide in brain tumours and show that the genetic background of MB and GM cells determines their sensitivity to chemotherapy and has to be taken into account for efficient therapeutic intervention

An Evaluation of The Effectiveness of Adaptive Histogram Equalization for Contrast Enhancement

Adaptive Histogram Equalization (AHE), a method of contrast enhancement which is sensitive to local spatial information in an image, has been proposed as a solution to the problem of the inability of ordinary display devices to depict the full dynamic intensity range in some medical images. This method is automatic, reproducible, and simultaneously displays most of the information contained in the grey-scale contrast of the image. However, it has not been known whether the use of AHE causes the loss of diagnostic information relative to the commonly-used method intensity windowing. In the current work, AHE and intensity windowing are compared using psychophysical observer studies. In studies performed at North Carolina Memorial Hospital, experienced radiologists were shown clinical CT images of the chest. Into some of the images, appropriate artificial lesion were introduced; the physicians were then shown the images processed with both AHE and intensity windowing. They were asked to assess the probability that as given image contained the artificial lesion, and their accurate was measured. The results of these experiments shown that for this particular diagnostic task, there was no significant difference in the ability of the two methods to depict luminance contrast; thus, further evaluation of AHE using controlled clinical trials is indicated

Longitudinal assessment of ataxia in children following surgical resection of posterior fossa tumours

OBJECTIVES To report the natural history of ataxia in the first two years following surgical resection of a posterior fossa tumour (PFT). METHODS 20 children (mean age 9.9 years, range 5-15 years) who had undergone resection of a posterior fossa tumour were assessed using the Scale for the Assessment and Rating of Ataxia (SARA), Brief Ataxia Rating Scale (BARS) and the Pediatric Evaluation of Disability Index (PEDI) at the following time points; initial post-operative period, then at 3 months, 1 and 2 years post operatively. RESULTS The assessments demonstrated a rapid improvement in ataxia between initial and 3 months post-operative assessments, quantified by both the SARA and BARS (mean reduction in scores 4.8, 4.6 respectively). There were additional gradual improvements at 1 year (mean reduction SARA 0.6, BARS 0.2) and 2 years post operatively (mean reduction SARA 0.9, BARS 0.9). Return of function behaved similarly, quantified by a rapid increase in PEDI scores between initial and 3 month assessments (mean increase in score 26) and gradual increases at 1 and 2 years (mean increase 2, 2.5 respectively). There was a trend for children with medulloblastoma to demonstrate higher ataxia scores than children with low grade gliomas (mean initial post-operative scores 13.4 and 8.5 respectively). CONCLUSIONS The largest change in ataxia scores and functional mobility scores (PEDI) is demonstrated within the first 3 months post operatively. Ongoing gradual improvement in ataxia and mobility function was observed at 2 years. These results have implications for management of children with PFT

Skeletal Shape Correspondence Through Entropy

We present a novel approach for improving the shape statistics of medical image objects by generating correspondence of skeletal points. Each object's interior is modeled by an s-rep, i.e., by a sampled, folded, two-sided skeletal sheet with spoke vectors proceeding from the skeletal sheet to the boundary. The skeleton is divided into three parts: the up side, the down side, and the fold curve. The spokes on each part are treated separately and, using spoke interpolation, are shifted along that skeleton in each training sample so as to tighten the probability distribution on those spokes' geometric properties while sampling the object interior regularly. As with the surface/boundary-based correspondence method of Cates et al., entropy is used to measure both the probability distribution tightness and the sampling regularity, here of the spokes' geometric properties. Evaluation on synthetic and real world lateral ventricle and hippocampus data sets demonstrate improvement in the performance of statistics using the resulting probability distributions. This improvement is greater than that achieved by an entropy-based correspondence method on the boundary points

E-Survey of current international physiotherapy practice for children with ataxia following surgical resection of posterior fossa tumour

OBJECTIVE – To determine current international practice regarding physiotherapy input for children with posterior fossa tumours. METHODS – An e-survey primarily composed of closed questions covering the following domains; participant demographics, treatment and intervention, virtual training, intensity/timing of treatment, aims and outcomes of physiotherapy was piloted and refined. It was distributed internationally to physiotherapists via 6 key groups; (Paediatric Oncology Physiotherapy Network (POPs), Association of Paediatric Chartered Physiotherapists (APCP), European Paediatric Neurology Society (EPNS), International Society of Paediatric Oncology (SIOP)-Europe Brain Tumour Group, Posterior fossa society (PFS), Pediatric Oncology Special Interest Group (American Physical Therapy Association). Data were descriptively analysed. RESULTS – 84 physiotherapists participated: UK (n=53), rest of Europe (n=22), USA/Canada (n=9). The most common physiotherapy interventions used were balance exercises, proximal control activities, gait re-education, and task specific training. The most frequently used adjuncts to treatment were mobility aids and orthotics. A lack of clinical guidelines and research evidence in this area was highlighted. Frequent challenges raised regarding physiotherapy treatment in this area were; reduced availability of physiotherapy input following discharge from the acute setting, lack of evidence, impact of adjuvant treatment (e.g. chemotherapy/radiotherapy), and psychosocial impact. CONCLUSIONS – This e-survey provides an initial scoping review of international physiotherapy practice in this area. It demonstrates the wide range of intervention types used and highlights the lack of clinical evidence in this area. The results raise the need for further research in this field to help with the development of physiotherapy guidelines in children with posterior fossa tumours