Computed tomography-magnetic resonance image registration in radiotherapy treatment planning.

Magnetic resonance imaging (MRI) is being increasingly used in radiotherapy treatment planning (RTP). MRI has the potential to provide improved localisation of target volumes, leading to better tumour control rates and reduced normal tissue complications, due to capabilities including excellent soft-tissue discrimination and the ability to provide scans in which the image contrast is weighted according to different tissue properties. When computed tomography (CT)-MRI image registration is deployed, MR's advantages are combined with CT's geometrical security and its ability to provide electron density information. The quality of CT-MRI image registration can be favourably influenced by aspects of scan acquisition, including patient positioning/immobilisation and scan protocols. Appropriate protocols can ameliorate the possible presence of MR spatial distortions and other artefacts, but quality assurance of scanning remains essential. Here, the methods and quality assurance of CT-MR image registration are discussed. Developments in MRI scanner technology are progressively offering advantages for RTP, in terms of the possibility of better matching of patient positioning versus CT in a greater range of anatomical regions, while allowing thinner slices for better image quality in reformatted orthogonal planes.

MRI image-based FE modelling of the pelvis system and bladder filling.

In this study, high-resolution magnetic resonance imaging was performed in the transaxial, coronal and sagittal planes to provide comprehensive structural details of the bladder and surrounding systems. Detailed finite-element (FE) models that were specific to each participant were developed by rendering the images, and the process of bladder filling was simulated. The overall model of bladder deformation was compared with repeated images of the filled bladder that were obtained using computed tomography to validate the FE models. The relationship between the changes in the key dimensions of the bladder and the increase in bladder volume during the filling process was also investigated. The numerical results showed that the bladder dimensions increased linearly with its volume during the filling process and the predicted coefficients are comparable to some of the published clinical results.

Monte Carlo simulation and polymer gel dosimetry of 60 MeV clinical proton beams for the treatment of ocular tumours.

Monte Carlo (MCNPX) simulations of a clinical proton beam-line under a range of beam conditions have been compared with MR analysis of irradiated polymer gel (BANG-1). Gel results were found to under-estimate the height of the full energy Bragg peak relative to simulation by the order of 30%, due to increased LET in this region, which has been reported elsewhere. Comparison of narrow-beam lateral profiles suggests a slight over-prediction of lateral proton scatter in MCNPX, which has been reported previously.

Modelling concepts of proton eye radiotherapy.

Information concerning the application of proton beams in radiotherapy of ocular tumours is provided using conventional website technology by a number of treatment facilities around the world. We hypothesized, however, that many of the key concepts would be better conveyed by an interactive computer model utilizing virtual reality technology. We describe the implementation, using Virtual Reality Modelling Language (VRML), of such a model, the Proton Therapy Concepts Demonstrator (PTCD). The World-Wide-Web-accessible PTCD is intended to provide information useful both to trainee and to qualified clinical staff and also to patients. A model was created of the radiotherapy room that was linked to an interactive model depicting a simple explanation of the process of proton eye radiotherapy. This model also allows the user to explore specific elements of the treatment planning and delivery process, such as beam collimation and range modulation. A further level of detail has been provided by a dynamic model demonstrating how a specific modulated dose distribution is achieved as the time integration of discrete modulated Bragg peaks. We believe this VR-based model has the potential of enabling users to gain more rapid insight into the proton therapy process. Its development as an educational tool is continuing, following feedback collected from clinical staff and patients.

Determination of tumour regression rates during radiotherapy for cervical carcinoma by serial MRI: comparison of two measurement techniques and examination of intraobserver and interobserver variability.

Tumour regression rates of 11 patients with cervical carcinoma were estimated during external beam radiotherapy (EBRT) using serial MRI (average time interval 7 days; range 3-15 days). An average of five investigations (range 4-8) was performed per subject. Tumour volume was measured by two observers using the Cavalieri method of modern design stereology in combination with (a) planimetry and (b) point counting. The mean precision of all the volume estimates obtained by manually tracing the outline of the tumour was 6.6%. The mean precision obtained by counting an average of 176 points per investigation on the same transects was 6.7%. The intraobserver repeatability of planimetry, interobserver reproducibility of planimetry and point counting were excellent with no significant difference between the volume estimates obtained using either technique. Based on the planimetry measurements, initial tumour volumes ranged from 6.5 to 222 cm3 (mean 63 cm3, median 44 cm3). Based on the point counting measurements, initial tumour volumes ranged from 7.2 to 235 cm3 (mean 68 cm3, median 46 cm3). Tumour regression began within a few days of commencing EBRT and showed an exponential relationship with time (p < 0.01). There was good agreement between the regression rates obtained by planimetry and those obtained by point counting. No significant correlation was found between initial tumour volume and tumour regression rate for either planimetry or point counting. Planimetry measurements were, on average, obtained in about half the time taken for point counting (i.e. 30 min and 50 min, respectively). Although point counting is generally likely to be the more efficient approach, planimetry may be the preferred approach for estimating tumour volume when a purpose built track ball is available and the tumour morphology is relatively simple. Volume measurement should be obtained using the Cavalieri method to ensure that the estimates are unbiased and that their precision can be predicted. The measured tumour regression rates may have important implications for improving local tumour control, optimum timing of brachytherapy and minimizing the risk of radiation damage.

Contrast enhanced dynamic MRI of cervical carcinoma during radiotherapy: early prediction of tumour regression rate.

This prospective study investigated the relationship between changes in the MRI dynamic enhancement of cervical carcinoma early during radiotherapy, and tumour regression rate throughout radiotherapy. A total of 36 MRI examinations was performed in seven patients with cervical carcinoma, including a T2 weighted sequence weekly during radiotherapy and also a multislice dynamic Gd-DTPA enhanced sequence before and after the first 2 weeks of radiotherapy. Tumour enhancement was determined on dynamic images using a region of interest and signal-to-noise ratio method. Serial tumour volumes over time on T2 weighted images were estimated using the Cavalieri method of modern design-based stereology to obtain tumour regression rate. It was found that peak and mean enhancement prior to radiotherapy ranged from 3.0 to 13.3, and from 1.9 to 12.2, respectively. After 2 weeks of radiotherapy, peak and mean enhancement ranged from 7.5 to 13.0, and from 6.3 to 10.6, respectively. The change in peak and mean tumour enhancement between dynamic scans ranged, respectively, from -2.0 to 8.4 and from -4.5 to 8.5. Tumour volume decreased exponentially with time (p < 0.01). Tumour regression rates ranged from 2.0% to 15.2% per day, and correlated positively with changes of both peak and mean tumour enhancement (p < 0.01). It is concluded that MRI dynamic enhancement during the first 2 weeks of radiotherapy may provide early prediction of tumour regression rate, and therefore be of value in designing treatment schedules for cervical carcinoma.

Relationships between nutrient intake and progression/regression of coronary atherosclerosis as assessed by serial quantitative angiography.

To elucidate the direction and magnitude of effects of nutrition on coronary artery disease (CAD), the relation between nutrient intake and angiographic changes were examined in the course of a controlled dietary trial. Ninety men with symptomatic CAD and serum cholesterol greater than 232 mg/dL were entered into a randomized controlled trial of a lipid-lowering diet, or of diet plus cholestyramine, compared with usual cardiac care. Of those in the first and second groups, 50 patients completed the trial and are the subject of this report. Quantitative coronary angiography was performed at baseline and at 39 months. From repeated dietary assessment during the trial, mean nutrient intakes were computed, and their relationships with change of coronary artery narrowing were analyzed. Progression of coronary disease was directly, strongly and independently associated with intake of saturated fatty acids of chain length 14-18. This was not fully explained by the effects of saturated fat in raising serum cholesterol; after adjustment for low density lipoprotein cholesterol level, stearic acid (C18:0) intake remained independently predictive of progression. No 'protective' effect of linoleic, linolenic or eicosapentaenoic acid was demonstrable. Intake of trans fatty acids was directly related to progression. Together with the favourable treatment effects on angiographic appearance and clinical end-points, these findings provide further support for a causal role of saturated fats in CAD; restriction of foods containing such fats should be emphasized as part of regimens aimed to reduce progression of coronary atherosclerosis.

Quantitative coronary cineangiography for the study of atherosclerosis.

Angiography is the definitive procedure for characterising the extent and course of coronary artery disease. We describe the methodology required to measure, with optimal resolving power, angiographic changes in coronary artery disease. We utilised recent technological developments in image digitization, storage and analysis. The measures of change quantified both diffuse and focal atherosclerosis. Frames from angiographic cine films were digitized at high resolution (1024 x 1024 pixels, 8 bit grey scale) and archived on optical disk. Four radiographic projections were stored to ensure good visualization of as many as possible of a set of ten major arterial segments. Edges of segments and catheter were automatically delineated by computer using a dynamic programming algorithm involving a cost function which contained terms based on edge strength and on continuity. For every digitized radiographic projection, delineation was repeated in three adjacent frames, to improve precision. Edge points for each coronary segment were stored on disk. From these we computed the mean width along the segment (pixels). Scaling to obtain the Mean Absolute Width of the Segment (MAWS, mm) was achieved using catheter dimensions known from micrometry, systematic error due to imaging system line-spread function being corrected using data from computer simulations and phantom studies. Correction for geometric image intensifier distortion was also applied. We used the methodology in a randomized, controlled trial of the effect of lipid-lowering therapy, the St Thomas' Atherosclerosis Regression Study. The fundamental measure of change of disease in each segment was the change in MAWS (delta MAWS). Using in-vitro and in-vivo studies we established that the overall resolving power for one segment delta MAWS was 0.10 mm at 2 mm width and 0.14 mm at 4 mm width. Subsidiary end-points were the change (delta) in minimum absolute width of segment (MinAWS), edge irregularity index (EII) and percent diameter stenosis (%DS). Delta%DS (the conventional angiographic measure of coronary disease) was significantly correlated with change in all indices, closest correlation being seen with delta EII (r = 0.94, p < 0.001).

Metabolic determinants of the course of coronary artery disease in men.

We examined associations between metabolic variables and changes in coronary artery disease (CAD) in the St. Thomas' Atherosclerosis Regression Study (STARS). The course of CAD over 3 years was measured continually by quantitative coronary angiography, i.e., as the per patient change in the mean absolute width of coronary segments (delta MAWS). The decrease in MAWS (progression of CAD) was significantly correlated with in-trial plasma concentrations of cholesterol (P = 0.002), low-density lipoprotein (LDL) cholesterol (P = 0.001), apolipoprotein B (apoB) (P = 0.008), and lipoprotein(a) [Lp(a)] (P = 0.004); no significant associations were found with high-density lipoprotein (HDL) cholesterol, apoA-I, vitamin E, thyroid hormones, fibrinogen, von Willebrand factor, or post-load plasma glucose and insulin concentrations. By multiple regression analysis, LDL cholesterol was the best predictor of delta MAWS, the adjusted model explaining 22% of the variance (P = 0.04). Thus, in men with symptomatic CAD the most important metabolic predictor of change in CAD is plasma LDL cholesterol, there being no advantage in measuring other variables, in particular, apoB or Lp(a).

Nutrient intake and progression of coronary artery disease.

The relation between nutrient intake and progression of coronary artery disease was examined in 50 men receiving a lipid-lowering diet or usual care in the St. Thomas' Atherosclerosis Regression Study. Nutrient intake was assessed by diet history. Changes in coronary angiograms were measured by quantitative image analysis. In univariate linear regression analysis progression of disease over 39 months, as measured by decrease in minimum absolute width of coronary segments, was directly related to dietary energy (p < 0.001) and to the absolute intakes of total fat (p < 0.001), saturated fat (p < 0.001), monounsaturated fat (p = 0.016) and cholesterol (p = 0.06). No significant associations were seen with polyunsaturated fat, carbohydrate, protein, fiber, alcohol or with the ratio of intakes of polyunsaturated fatty acids to saturated fatty acids. In multiple linear regression analysis the associations of change in minimum absolute width of coronary segments with total or saturated fat persisted when adjusted for plasma low-density lipoprotein cholesterol concentration, age, weight, blood pressure, smoking or treatment group assignment. The findings suggest that in middle-aged men, progression of CAD is strongly influenced by intake of saturated fatty acids, an effect mediated in part by mechanisms other than the influence of this nutrient on plasma cholesterol and low-density lipoprotein cholesterol.

Independent associations between plasma lipoprotein subfraction levels and the course of coronary artery disease in the St. Thomas' Atherosclerosis Regression Study (STARS).

Associations between plasma lipoprotein subfractions and changes in coronary artery diseases (CAD) were examined in 74 men who completed the St. Thomas' Atherosclerosis Regression Study (STARS). Plasma lipoproteins were isolated by stepwise, preparative ultracentrifugation at repeated intervals during the 38-month trial. Paired coronary angiograms were quantitatively analyzed by a computerized method. In univariate linear regression analysis, changes in mean absolute width (delta MAWS) and minimum absolute with (delta MinAWS) of coronary segments were significantly correlated with in-trial concentrations of cholesterol in intermediate-density lipoprotein ([IDL] d = 1.006 to 1.019 kg/L), low-density lipoprotein ([LDL2] d = 1.019 to 1.040 kg/L; LDL3, d = 1.040 to 1.063 kg/L), and high-density lipoprotein ([HDL3] d = 1.125 to 1.210 kg/L) subfractions; no significant associations were found with other lipoproteins. IDL, LDL3, and HDL3 cholesterol were then selected for multiple linear regression analysis because these variables were not co-correlated and because they attained a significance of P less than or equal to .1 in univariate regression. In this analysis, only LDL3 cholesterol level was a significant negative predictor (P < .05) of both delta MAWS and delta MinAWS; a positive association between delta MinAWS and HDL3 cholesterol level just failed to reach conventional statistical significance (P = .066). Correlations between changes in coronary luminal dimensions and LDL3 cholesterol level were independent of age, smoking, weight, and blood pressure. Most patients showing regression of coronary atherosclerosis had an LDL3 cholesterol level of less than 1.8 mmol/L. The findings suggest that LDL3 is the plasma lipoprotein subfraction that exerts the single most powerful effect on the course of CAD in middle-aged men with hypercholesterolemia.

Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS)

To assess the effect of dietary reduction of plasma cholesterol concentrations on coronary atherosclerosis, we set up a randomised, controlled, end-point-blinded trial based on quantitative image analysis of coronary angiograms in patients with angina or past myocardial infarction. Another intervention group received diet and cholestyramine, to determine the effect of a greater reduction in circulating cholesterol concentrations. 90 men with coronary heart disease (CHD), who had a mean (SD) plasma cholesterol of 7.23 (0.77) mmol/l were randomised to receive usual care (U, controls), dietary intervention (D), or diet plus cholestyramine (DC), with angiography at baseline and at 39 (SD 3.5) months. Mean plasma cholesterol during the trial period was 6.93 (U), 6.17 (D), and 5.56 (DC) mmol/l. The proportion of patients who showed overall progression of coronary narrowing was significantly reduced by both interventions (U 46%, D 15%, DC 12%), whereas the proportion who showed an increase in luminal diameter rose significantly (U 4%, D 38%, DC 33%). The mean absolute width of the coronary segments (MAWS) studied decreased by 0.201 mm in controls, increased by 0.003 mm in group D, and increased by 0.103 mm in group DC (p less than 0.05), with improvement also seen in the minimum width of segments, percentage diameter stenosis, and edge-irregularity index in intervention groups. The change in MAWS was independently and significantly correlated with LDL cholesterol concentration and LDL/HDL cholesterol ratio during the trial period. Both interventions significantly reduced the frequency of total cardiovascular events. Dietary change alone retarded overall progression and increased overall regression of coronary artery disease, and diet plus cholestyramine was additionally associated with a net increase in coronary lumen diameter. These findings support the use of a lipid-lowering diet, and if necessary of appropriate drug treatment, in men with CHD who have even mildly raised serum cholesterol concentrations.

The measurement of blood flow waveforms from X-ray angiography. Part 1: Principles of the method and preliminary validation.

The principles and implementation of a method for measurement of blood flow waveforms from X-ray angiography are described. Contrast medium mass values are obtained at multitudinous positions along individual vessels and from numerous images in a time sequence. These values are represented as a matrix of grey levels in a parametric image. This image is normalized to represent contrast medium concentration, and the movement over time of isoconcentration portions of the contrast bolus is recovered to determine blood flow. Preliminary validation has been undertaken using parametric images generated in two ways: synthesis from a computer model of vascular pulsatile flow and analysis of cine-angiograms of physical models (plastic and perspex tubes) carrying known pulsatile flows. Two distinct methods for interrogation of parametric images by digital image processing were employed; both provided accurate flow measurements.

The measurement of blood flow waveforms from X-ray angiography. Part 2: Application to video recordings of digital subtraction angiography.

A method of measuring blood flow from X-ray angiograms recorded on cine film, by obtaining contrast mass values at numerous positions along individual vessels and at multiple instants of time, has been previously reported. In the present work it was hypothesized that the signal-to-noise limitations of recordings on video tape could be overcome by recording already-subtracted angiograms from a digital subtraction angiographic (DSA) system and that the spatial resolution of video was adequate to use a similar measurement method. Validation experiments were recorded, in which flows measured using a calibrated electromagnetic flowmeter passed through tubes of 4-7 mm diameter, during injections of 2-5 ml contrast medium. The video sequences were computer analysed and produced angiographic flow measurements agreeing with the electromagnetic flows to within 5 per cent. A case study of a clinical carotid artery DSA in a patient with secondary carcinoma metastases in the brain is described. It is concluded that accurate flow measurements can be made from DSA video recordings.

Treatment of hyperlipidaemia retards progression of symptomatic femoral atherosclerosis. A randomised controlled trial.

The effect of plasma lipid reduction on the progression of femoral atherosclerosis was studied in hyperlipidaemic patients with stable intermittent claudication. 24 patients were randomly assigned to treatment and usual-care groups, the former receiving dietary advice and cholestyramine, nicotinic acid, or clofibrate depending on their lipoprotein phenotype. Biplanar arteriography was performed when the study began and after a mean period of 19 months. Angiograms were assessed visually, with blinding, and by computerised image analysis. Therapy reduced mean plasma total cholesterol by 25%, mean low density lipoprotein (LDL) cholesterol by 28%, and mean plasma triglycerides by 45%. Significantly fewer arterial segments showed detectable progression of atherosclerosis in the treatment group. The mean increase in plaque area (mm2/segment/year) in the treatment group was only one third of that in the usual-care group. The mean increase in edge irregularity index (a measure of the severity of disease) in the treatment group was only 40% of that in the usual care group. Twice as many arterial segments showed improvement in the treatment group. In both groups changes in edge irregularity index were directly related to plasma LDL cholesterol concentration. This study, the first randomised controlled trial of its type, provides evidence that effective treatment of hyperlipidaemia favourably influences the natural history of symptomatic peripheral atherosclerosis.

Computerised image analysis of split-drop micropuncture data.

A technique is described for rapid and reproducible analysis of split-drop micropuncture sequences recorded on film. Automatic identification of the droplet menisci in each cine frame, and subsequent evaluation is performed by a computerised T.V. image analysis system. In comparison with a more conventional technique, the improvement in reproducibility of the analysis is achieved without loss of accuracy and is accompanied by a three fold increase in speed.