Cambridge Brain Tumour Imaging Laboratory

The Cambridge Brain Tumour Imaging Laboratory uses advanced multimodal MR and PET imaging to understand the heterogeneity of gliomas (high and low grade) in individual patients. We know that gliomas are among the most heterogeneous tumours but still do not have a method of detecting this heterogeneity. Tissue markers cannot impact surgically based therapies. Imaging provides a non-invasive method of assessing tumour pathology.

Our work focuses on two areas:

1. Intertumoural heterogeneity (i.e. differences between individuals). Especially heterogeneity of tumour invasion. Post-mortem studies show there is variation in tumour invasion with 20-25% of GBMs extend <1cm from the edge of the tumour mass, with another 20% extending >3 centimetres.

2. Intratumoural heterogeneity (i.e. differences within a tumour in an individual patient). Our work studies variation of response to chemotherapy/radiotherapy and drug uptake. We are developing [3-N-11C-methyl]-temozolomide a PET tracer to correlate response with drug uptake.

Imaging is central to the management of patients with brain tumours. We use it to make the diagnosis, plan treatment and determine response to therapy. Yet we know that the conventional MRI is not sensitive enough to identify the full extent of tumours and is not specific enough to identify pathological changes in the tumour or surrounding normal brain. Advanced MRI methods have been developed that probe the pathological changes in the tumour, but at present these methods have not translated into routine clinical practice as there is lack of evidence that they impact on clinical treatment.

The Cambridge Brain Tumour Imaging Laboratory is the first dedicated brain tumour image processing and analysis laboratory in the UK. The aims are to validate new imaging biomarkers, determine their clinical utility to implement them into routine clinical practice and use these methods to guide surgical resection using our StealthViz workstation that incorporates this imaging into our image-guidance systems in the adjacent operating theatres. Our current interest are:

UNDERSTANDING SPATIAL HETEROGENEITY IN GLIOMAS:

Figure 1: Areas of increased cellularity (low ADC) and increased vascularity (high rCBV) are shown in purple. These can be seen in both enhancing and non-enhancing tumour. From Radiology (2017) 284(1):180-190.

We know that there is spatial heterogeneity in glioblastomas (GBMs) that impact on diagnosis and drug uptake and response. Sampling less aggressive tumour regions may lead to under-treatment. Our aim is to apply advanced methods to study this variation. By combining two simple imaging biomarkers – ADC from diffusion MRI (reflects cellularity) and rCBV (a measure of vascularity), Dr Natalie Boonzaier (former PhD student) could show areas of high cellularity and high vascularity exist in all GBMs.

These regions had MR spectroscopy evidence suggesting they were biologically very aggressive and correlated with survival. Most interestingly we found that these regions in both the enhancing and non-enhancing components of the tumour suggesting our current focus on the enhancing tumour may miss these aggressive areas. This work has been taken up by Chao Li (PhD student) who has defined further regions – including areas of high cellularity and low vascularity suggestive of a hypoxic stem-cell niche. These regions have different spectroscopic patterns. We are now planning to biopsy these regions to assess histological features in these areas.

IMAGING OCCULT INVASION OF THE PERITUMOURAL BRAIN

Our main interest is studying the peritumoural brain. As surgery aims to remove the enhancing compartment of the tumour, residual tumour in the peritumoural area is a major factor leading tumours progressing adjacent to the resection cavity. We have developed a method using diffusion tensor MRI (DTI) that can detect subtle disruption of white matter tracts. We developed a novel analysis method that was originally devise to calculate stress-strain patterns in the soil around skyscrapers and could show abnormalities not seen on conventional imaging. Subsequent studies have shown biopsy of these abnormalities could identify invasive tumour and these areas predicted sites of tumour progression. This has led to a multicentre CRUK funded study – PRaM-GBM that aims to qualify our methods as a biomarker that predicts the site of tumour progression at initial presentation. Interestingly, we have identified about 20% of patients with minimally invasive tumours – these include the less aggressive IDH-1 mutated tumours. This will allow us to direct and individualise surgical resection and change how we plan radiotherapy to maximise tumour kill and minimise injury to normal brain. A retrospective analysis by Jiun-Lin Yan (PhD student) has shown that the extent of resection of our DTI regions is a strong predictor of outcome.

Our results have shown there is great variation in the extent of invasiveness in glioblastomas. What we don’t know is if the impact of the extent of resection will vary between patients with differing amounts of tumour invasion. By developing markers of ‘invasive behaviour’ we can assess the efficacy of local therapies for these tumours.

By better understanding where tumours will progress will allow us to refine our surgical and radiotherapy treatment volumes. We plan to develop early phase clinical trials to explore this.

THE IMPACT OF TUMOURS AND TREATMENT ON THE NORMAL BRAIN

Unlike other tumours, brain tumours cannot be removed with a margin of normal tissue. Understanding impact of treatment on the normal brain is important and not understood. We focus on neurological deficits but need to understand how this impacts on patient functioning and quality of life. We have looked at the effect of radiotherapy in the normal brain and have shown a radiotherapy-dose related reduction in blood volume in the peritumoural brain. We are now interested in the impact of surgery on brain function and are looking at changes in neurocognitive function (Rohit Sinha, MPhil student). We are particularly interested in effect of surgery on brain networks (Mike Hart, PhD student working with John Suckling in psychiatry).

To understand the objective effects of treatments needs collection of quality of life data. Working with Alexis Joannides (Clinical Lecturer in Neurosurgery) and ORION we have used the DAMSEL tool to routinely collect quality of life data during a patient’s treatment. We have shown it can be collected routinely, and that this method is able to collect more patient concerns than is identified by clinicians.

Our aim is to develop an ‘individualised’ target for surgery that will allow us to maximise the amount of tumour removed but minimise damage to normal brain that causes deterioration in quality of life. This will require us to bring these imaging methods into the operating theatre to change how we manage patients.