research reports
University of Hull
2005/6
Centre for Magnetic Resonance Investigations
Director: Professor L W Turnbull
Achievements during 2005 - 2006
Since the installation of the GE LX whole body 3 Tesla MR system in May 2004, work has continued to develop specific protocols related to accurate and reproducible assessment of the pathophysiology of tumours. Although the system provides twice the field strength of currently employed magnetic resonance machines, important technical issues which have been overcome include dielectric effect, reduced radio-frequency penetration and limited receiver coil availability. Advanced imaging protocols are now in place including multi-flip, 3D dynamic contrast-enhanced volume acquisitions for contrast uptake assessment and multi-nuclear spectroscopy, providing chemical information about tissues. This translates into improved cancer patient diagnosis and optimised patient management.
The research programmes include breast, prostate and gynaecological malignancy, radiotherapy planning and a recent move into bone imaging related to cancer and cancer therapy. The development of surrogate biomarkers continues and with pathological input required, joint work with the University of Leeds has been instigated, hopefully within the context of the proposed Leeds Bradford Hull York Experimental Cancer Medicine Centre.
Breast Programme
The clinical utility of multiparametric quantitative MRI in breast cancer patients undergoing neoadjuvant chemotherapy for primary inoperable breast is the focus of current research. This uses a combination of data obtained from pharmacokinetic modelling of contrast-enhanced data, T2 and ADC mapping, and spectroscopy. To predict eventual treatment outcome early in the course of treatment a functional rather than morphological approach has been undertaken, examining parameters that reflect delivery of blood and oxygen, hypoxic status and tissue microstructure. Significant differences between eventual responders and non-responders has been demonstrated, both early in the course of treatment and at baseline.
Pharmacokinetic modelling of contrast uptake, shape descriptors and textural analysis of high resolution images, have been utilised to aid lesion discrimination. We have developed 2-dimensional textural analysis software and morphological software based on moment theory. Since neural networks often suffer from over-learning, robust ensemble methods have been developed using the above parameters as inputs. The diagnostic and prognostic potential of these networks is being assessed. Software development is currently focussing on an extension of textural analysis to 3-dimensions and the development of shape analysis tools.
For the purpose of automation software for the morphometric analysis of breast tumours has been developed and the efficacy of different shape parameters for the discrimination of lesions assessed. This semi-automated processing method has the potential to reduce analysis time. With large and/or multi-focal tumours volume determination is an extremely laborious and tedious process. An algorithm for semi-automatic estimation of tumour volume has been generated by 3D segmentation of the DCE-MRI data, using a fuzzy c-means clustering algorithm.
Gynaecology Programme
This program incorporates studies to optimise the differentiation of benign from malignant pelvic masses; comparison of surgical findings with pre-operative MR staging to determine accuracy; assessment of operability essential for optimisation of initial management; assessment of response to treatment in both the neoadjuvant and adjuvant settings; and the detection of tumour recurrence using conventional imaging and MR spectroscopy.
The ability of MR to predict response to neoadjuvant chemotherapy or chemoradiotherpay is being investigated using pharmacokinetic modelling of contrast-enhanced data, R2 and ADC mapping, and single voxel proton spectroscopy. This incorporates tumours of the cervix uteri and endometrium as well as ovarian and peritoneal primary tumours. For less advanced tumours of the cervix uteri the role of endovaginal imaging for the assessment of parametrial tissues is underway, in comparison with whole mounted Wertheim hysterectomy specimens.
Prostate Program
Current research in prostate cancer at 3 Tesla includes quantification of MR derived functional information, particularly the apparent diffusion coefficient of water, metabolite concentrations, and blood flow within reasonable scan times. The use of a prototype endo-rectal receiver coil is in progress to optimise morphological information important for tumour staging. The dynamic contrast-enhanced sequence incorporates multiple separate acquired pre-contrast series allowing the determination of tissue T1 values and hence the estimation of tissue Gadolinium concentrations throughout the subsequently acquired dynamic series. Parallel imaging available at 3T, allows measurement of an arterial input function and an increase in temporal resolution. Software tools have been developed to produce absolute values for Ktrans on a pixel-by-pixel basis thus creating maps of lesion extent potentially useful for tumour volume determination. The diagnostic potential of these parameters is being assessed via comparison with appropriate pathological parameters, such as cell and microvessel density, obtained from radical prostatectomy specimens. Appropriate immunohistochemical techniques are used to confirm the underlying mechanisms of action. We have previously shown that reduced diffusion in the peripheral zone is indicative of prostatic carcinoma. Differences in fractional anisotropy between regions of cancerous and normal peripheral zone have also been found. The repeatability of diffusion imaging in the prostate has been quantified with a view to assessing the certainty of treatment induced changes.
Other studies
The efficacy of incorporating dynamic contrast enhanced (DCE) imaging into the treatment planning of head / neck tumour is under investigation. Software has been developed to enable functional and anatomical images to be fused in a DICOM compliant format for input into the radiotherapy planning system. In addition, this software produces morphologically optimised enhancement data which is more suitable for contouring and planning radiotherapy distributions. On going work is utilising these images to obtain conformal plans which demonstrate our strategy of improving tumour control and reducing side effects by boosting dose to the vascular part of the planning target volume. In parallel gel dosimetry (in collaboration with York University) is being used to verify these complex dose distributions for which routine film dosimetry is no longer suitable. Computer-generated IMRT planned head / neck treatment data has been compared to MR dose maps and good accuracy has been demonstrated. The techniques developed in this study are being translated into other areas (e.g. prostate) and will continue to have wide reaching implications for the efficacy of advanced MRI in radiotherapy of cancer.
For brain tumours a multi-imaging strategy for combining 3D Diffusion Tensor Imaging (DTI), Magnetic Resonance Spectroscopy (MRSI) and functional Magnetic Resonance Imaging (fMRI), to aid diagnosis and treatment (both surgical and radiotherapy) of brain neoplasm is being developed. Dedicated software for the analysis of three-dimensional (3D) Magnetic Resonance Spectroscopic Imaging (MRSI) has been written, including features for exporting spectroscopic data onto Radiotherapy planning systems as well as statistical tools for the analysis of 3D metabolic information.
A new project has begun exploring the use of MR Spectroscopy for investigating normal bone marrow composition and techniques developed therein will be applied to follow late osteoporotic effects in cancer patients during the course of their treatment. In addition, the increased spatial resolution afforded by our high field scanner will enable an improved visualisation and correlation of trabecular structure with this metabolic data. Initial pilot data has shown great promise and will form the basis of a PhD studentship later this year.
MRI in the Delivery and Verification of Intensity Modulated Radiotherapy (IMRT)
G.P. Liney, L.W. Turnbull and R. Garcia-Alvarez
We have embarked upon a study to examine the efficacy of incorporating dynamic contrast enhanced (DCE) imaging into the treatment planning of head and neck tumours. This is a particularly challenging area of the body in which to acquire this data with patient motion and poor signal-to-noise causing problems.
Software has been developed to enable functional and anatomical images to be fused in a Digital Imaging Communications in Medicine compliant format so that it can be input into the planning system. In addition, this software produces morphologically optimised enhancement data which is more suitable for contouring and planning radiotherapy distributions.
On-going work is utilising these images to obtain conformal plans which demonstrate our strategy of improving tumour control and reducing side effects by boosting dose to the vascular part of the planning target volume.
In parallel with the main part of the work, gel dosimetry (in collaboration with York University) is being used to verify these complex dose distributions for which routine film dosimetry is no longer suitable. Computer-generated Intensity Modulated Radiotherapy planned head and neck treatment data has been compared to MR dose maps and good accuracy has been demonstrated.
The techniques developed in this study are being translated into other areas (e.g. prostate) and will continue to have wide reaching implications for the efficacy of advanced MRI in radiotherapy of cancer.
School of Pharmacy and Chemistry
Head of Department: Professor J. E. Brown
Structure-activity studies on novel DNA affinic compounds incorporating oestrogen-receptor ligand, polyamine and antineoplastic moieties
Dr. S. Carrington, Prof. J. E. Brown and Ms. H. Mackay
Healthy breast tissue requires a constant supply of oestrogens for growth and maintenance. Consequently it has been shown that up to 65% of breast cancers in pre-menopausal women are also dependent on oestrogens to sustain growth. We aim to target oestrogen receptors in such tumour cells with drug conjugates to produce selective therapies.
We have begun investigating structure-activity relationships between compounds consisting of an oestrogenic ligand, a polyamine and a cytotoxic DNA-binding moiety. Such conjugates are designed to target, and exhibit selective cytotoxicity towards breast cancers. We have already shown that linking oestrone to doxorubicin can confer selective cytotoxicity towards cells expressing oestrogen receptors (ER). By including a polyamine we aim to increase cellular uptake via the polyamine transport mechanism and to demonstrate increased cytotoxicity by enhanced polyamine associated DNA-binding. Compounds are being synthesised by established methodologies and then assayed in three areas: (i) Preclinical evaluation by in vitro MTT assay utilising ER-positive and ER-negative cell lines. (ii) Mechanistic studies including thermodenaturation, spectrophotometric titrations, and topoisomerase assays to characterise DNA interactions. (iii) Analytical HPLC and microscopy studies to determine compound stability and fate in the cell. Together the data from these assays will inform the design of further compounds.
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