Ethnic differences in adiposity and diabetes risk - insights from genetic studies.

Type 2 diabetes is more common in non-Europeans and starts at a younger age and at lower BMI cut-offs. This review discusses the insights from genetic studies about pathophysiological mechanisms which determine risk of disease with a focus on the role of adiposity and body fat distribution in ethnic disparity in risk of type 2 diabetes. During the past decade, genome-wide association studies (GWAS) have identified more than 400 genetic variants associated with the risk of type 2 diabetes. The Eurocentric nature of these genetic studies has made them less effective in identifying mechanisms that make non-Europeans more susceptible to higher risk of disease. One possible mechanism suggested by epidemiological studies is the role of ethnic difference in body fat distribution. Using genetic variants associated with an ability to store extra fat in a safe place, which is subcutaneous adipose tissue, we discuss how different ethnic groups could be genetically less susceptible to type 2 diabetes by developing a more favourable fat distribution.

MAPPED study design: a 6 month randomised controlled study to evaluate the effect of dutasteride on prostate cancer volume using magnetic resonance imaging.

OBJECTIVE: To evaluate the percentage change in volume of prostate cancer, as assessed by T2-weighted MRI, following exposure to dutasteride (Avodart) 0.5mg daily for six months. PATIENTS AND METHODS: MRI in Primary Prostate cancer after Exposure to Dutasteride (MAPPED) is a double-blind, placebo-controlled trial, supported by GlaxoSmithKline (GSK). Men with prostate cancer suitable for active surveillance (low-intermediate risk prostate cancer on biopsy), and a visible lesion on T2-weighted MRI of at least 0.2 cc, were eligible for consideration. Forty-two men were randomised to 6 months of daily dutasteride 0.5mg or placebo. Multi-parametric MRI (mpMRI) scans were performed at baseline, 3 and 6 months. The percentage changes in cancer volume over time will be compared between the dutasteride and placebo groups. Planned analyses will examine the association between tumour volume and characteristics (perfusion and contrast washout) as seen on mpMRI, HistoScan ultrasound and biopsy histopathology in both groups. DISCUSSION: MAPPED is the first randomised controlled trial to use mpMRI to look at the effect of dutasteride on the volume of prostate cancer. If dutasteride is shown to reduce the volume of prostate cancer, it might be considered as an adjunct for men on active surveillance. Analysis of the placebo arm will allow us to comment on the short-term natural variability of the MR appearance in men who are not receiving any treatment. CONCLUSION: MAPPED will evaluate the short-term effect of dutasteride on prostate cancer volume, as assessed by mpMRI, in men undergoing active surveillance for low or intermediate risk prostate cancer. The study completed recruitment in January 2012.

Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.

Many therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines.

DCE-MRI biomarkers of tumour heterogeneity predict CRC liver metastasis shrinkage following bevacizumab and FOLFOX-6.

BACKGROUND: There is limited evidence that imaging biomarkers can predict subsequent response to therapy. Such prognostic and/or predictive biomarkers would facilitate development of personalised medicine. We hypothesised that pre-treatment measurement of the heterogeneity of tumour vascular enhancement could predict clinical outcome following combination anti-angiogenic and cytotoxic chemotherapy in colorectal cancer (CRC) liver metastases. METHODS: Ten patients with 26 CRC liver metastases had two dynamic contrast-enhanced MRI (DCE-MRI) examinations before starting first-line bevacizumab and FOLFOX-6. Pre-treatment biomarkers of tumour microvasculature were computed and a regression analysis was performed against the post-treatment change in tumour volume after five cycles of therapy. The ability of the resulting linear model to predict tumour shrinkage was evaluated using leave-one-out validation. Robustness to inter-visit variation was investigated using data from a second baseline scan. RESULTS: In all, 86% of the variance in post-treatment tumour shrinkage was explained by the median extravascular extracellular volume (v(e)), tumour enhancing fraction (E(F)), and microvascular uniformity (assessed with the fractal measure box dimension, d(0)) (R(2)=0.86, P<0.00005). Other variables, including baseline volume were not statistically significant. Median prediction error was 12%. Equivalent results were obtained from the second scan. CONCLUSION: Traditional image analyses may over-simplify tumour biology. Measuring microvascular heterogeneity may yield important prognostic and/or predictive biomarkers.

Image analysis and statistical inference in neuroimaging with R.

R is a language and environment for statistical computing and graphics. It can be considered an alternative implementation of the S language developed in the 1970s and 1980s for data analysis and graphics (Becker and Chambers, 1984; Becker et al., 1988). The R language is part of the GNU project and offers versions that compile and run on almost every major operating system currently available. We highlight several R packages built specifically for the analysis of neuroimaging data in the context of functional MRI, diffusion tensor imaging, and dynamic contrast-enhanced MRI. We review their methodology and give an overview of their capabilities for neuroimaging. In addition we summarize some of the current activities in the area of neuroimaging software development in R.

Reproducibility of fMRI in the clinical setting: implications for trial designs.

With expanding potential clinical applications of functional magnetic resonance imaging (fMRI) it is important to test how reliable different measures of fMRI activation are between subjects and sessions and between centres. This study compared variability across 17 patients with multiple sclerosis (MS) and 22 age-matched healthy controls (HC) in 5 European centres performing an fMRI block design with hand tapping. We recruited subjects from sites using 1.5 T scanners from different manufacturers. 5 healthy volunteers also were studied at each of 4 of the centres. We found that reproducibility between runs and sessions for single individuals was consistently much greater than between individuals. There was greater run-to-run variability for MS patients than for HC. Measurements of maximum signal change (MSC) appeared to provide higher reproducibility within individuals and greater sensitivity to differences between individuals than region of interest (ROI) suprathreshold voxel counts. The variability in measurements between centres was not as great as that between individuals. Consistent with these observations, we estimated that power should not be reduced substantially with use of multi-, as opposed to single-, centre study designs with similar numbers of subjects. Multi-centre interventional studies in which fMRI is used as an outcome measure thus appear practical even when implemented in conventional clinical environments.

Quantifying heterogeneity in dynamic contrast-enhanced MRI parameter maps.

Simple summary statistics of Dynamic Contrast-Enhanced MRI (DCE-MRI) parameter maps (e.g. the median) neglect the spatial arrangement of parameters, which appears to carry important diagnostic and prognostic information. This paper describes novel statistics that are sensitive to both parameter values and their spatial arrangement. Binary objects are created from 3-D DCE-MRI parameter maps by "extruding" each voxel into a fourth dimension; the extrusion distance is proportional to the voxel's value. The following statistics are then computed on these 4-D binary objects: surface area, volume, surface area to volume ratio, and box counting (fractal) dimension. An experiment using 4 low and 5 high grade gliomas showed significant differences between the two grades for box counting dimension computed for extruded v(e) maps, surface area of extruded K(trans) and v(e) maps and the volume of extruded v(e) maps (all p < 0.05). An experiment using 18 liver metastases imaged before and after treatment with a vascular endothelial growth factor (VEGF) inhibitor showed significant differences for surface area to volume ratio computed for extruded K(trans) and v(e) maps (p = 0.0013 and p = 0.045 respectively).

Treatment of recurrent eosinophilic granuloma of the mandible following radiation therapy.

A case of recurrent eosinophilic granuloma of the mandible following radiation therapy is presented. The lesion was curetted and immediately reconstructed with autogenous bone for strength and lower border continuity. Since radiation therapy in low doses is normally curative for this disease, few recurrences have been reported. It is emphasized that polyostotic disease may have a greater propensity for recurrence and that patients presenting with multiple lesions should be followed up closely, regardless of the mode of therapy.

A leaded apron for use in panoramic dental radiography.

The leaded aprons currently available for use during dental radiography do not protect the thyroid gland from radiation. Conventional aprons may produce artifacts when used with panoramic dental x-ray units. This study measures the dose reduction obtained with an experimental leaded apron designed for use with panoramic dental x-ray units. Skin exposures measured at the thyroid and at the sternum were reduced with the use of the apron. Films produced during the study were free from apron artifacts.

Leaded shields for thyroid dose reduction in intraoral dental radiography.

This study evaluated the radiation dose reduction, operator acceptance, and patient acceptance of two types of leaded thyroid shields designed for use during intraoral dental radiography. Exposure levels were measured with thermoluminescent dosimeters on three groups of 20 patients undergoing complete mouth (20-film) surveys. Skin entrance dose to the thyroid was 20 mR per complete mouth survey without a shield in place, 12 mR per complete mouth survey with the experimental shield in place, and 9 mR with the commercial shield. Patients and radiologic technologist were surveyed to determine patient comfort and operator acceptability. Patient and operator acceptability were higher for the experimental shield than for the commercial shield.