Multiparametric analysis of magnetic resonance images for glioma grading and patient survival time prediction.

BACKGROUND: A systematic comparison of magnetic resonance imaging (MRI) options for glioma diagnosis is lacking. PURPOSE: To investigate multiple MR-derived image features with respect to diagnostic accuracy in tumor grading and survival prediction in glioma patients. MATERIAL AND METHODS: T1 pre- and post-contrast, T2 and dynamic susceptibility contrast scans of 74 glioma patients with histologically confirmed grade were acquired. For each patient, a set of statistical features was obtained from the parametric maps derived from the original images, in a region-of-interest encompassing the tumor volume. A forward stepwise selection procedure was used to find the best combinations of features for grade prediction with a cross-validated logistic model and survival time prediction with a cox proportional-hazards regression. RESULTS: Presence/absence of enhancement paired with kurtosis of the FM (first moment of the first-pass curve) was the feature combination that best predicted tumor grade (grade II vs. grade III-IV; median AUC = 0.96), with the main contribution being due to the first of the features. A lower predictive value (median AUC = 0.82) was obtained when grade IV tumors were excluded. Presence/absence of enhancement alone was the best predictor for survival time, and the regression was significant (P < 0.0001). CONCLUSION: Presence/absence of enhancement, reflecting transendothelial leakage, was the feature with highest predictive value for grade and survival time in glioma patients.

In vitro cytotoxicity of low-dose-rate radioimmunotherapy by the alpha-emitting radioimmunoconjugate Thorium-227-DOTA-rituximab.

PURPOSE: To determine whether the low-dose-rate alpha-particle-emitting radioimmunoconjugate (227)Th-1,4,7,10-p-isothiocyanato-benzyl-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-rituximab can be used to inactivate lymphoma cells growing as single cells and small colonies. METHODS AND MATERIALS: CD20-positive lymphoma cell lines were treated with (227)Th-DOTA-rituximab for 1-5 weeks. To simulate the in vivo situation with continuous but decreasing supply of radioimmunoconjugates from the blood pool, the cells were not washed after incubation with (227)Th-DOTA-rituximab, but half of the medium was replaced with fresh medium, and cell concentration and cell-bound activity were determined every other day after start of incubation. A microdosimetric model was established to estimate the average number of hits in the nucleus for different localizations of activity. RESULTS: There was a specific targeted effect on cell growth of the (227)Th-DOTA-rituximab treatment. Although the cells were not washed after incubation with (227)Th-DOTA-rituximab, the average contribution of activity in the medium to the mean dose was only 6%, whereas the average contribution from activity on the cells' own surface was 78%. The mean dose rates after incubation with 800 Bq/mL (227)Th-DOTA-rituximab varied from 0.01 to 0.03 cGy/min. The average delay in growing from 10(5) to 10(7) cells/mL was 15 days when the cells were treated with a mean absorbed radiation dose of 2 Gy alpha-particle radiation from (227)Th-DOTA-rituximab, whereas it was 11 days when the cells were irradiated with 6 Gy of X-radiation. The relative biologic effect of the treatment was estimated to be 2.9-3.4. CONCLUSIONS: The low-dose-rate radioimmunoconjugate (227)Th-DOTA-rituximab is suitable for inactivation of single lymphoma cells and small colonies of lymphoma cells.

Multispectral analysis of multimodal images.

INTRODUCTION: An increasing number of multimodal images represent a valuable increase in available image information, but at the same time it complicates the extraction of diagnostic information across the images. Multispectral analysis (MSA) has the potential to simplify this problem substantially as unlimited number of images can be combined, and tissue properties across the images can be extracted automatically. MATERIALS AND METHODS: We have developed a software solution for MSA containing two algorithms for unsupervised classification, an EM-algorithm finding multinormal class descriptions and the k-means clustering algorithm, and two for supervised classification, a Bayesian classifier using multinormal class descriptions and a kNN-algorithm. The software has an efficient user interface for the creation and manipulation of class descriptions, and it has proper tools for displaying the results. RESULTS: The software has been tested on different sets of images. One application is to segment cross-sectional images of brain tissue (T1- and T2-weighted MR images) into its main normal tissues and brain tumors. Another interesting set of images are the perfusion maps and diffusion maps, derived images from raw MR images. The software returns segmentations that seem to be sensible. DISCUSSION: The MSA software appears to be a valuable tool for image analysis with multimodal images at hand. It readily gives a segmentation of image volumes that visually seems to be sensible. However, to really learn how to use MSA, it will be necessary to gain more insight into what tissues the different segments contain, and the upcoming work will therefore be focused on examining the tissues through for example histological sections.

A virtual reality solution for evaluation of radiotherapy plans.

This report presents a VR system for evaluation of treatment plans used in radiotherapy (RT), developed to improve the understanding of the spatial relationships between the patient anatomy and the calculated dose distribution. The VR system offers visualization through interactive volume rendering of RT dose distribution and computed tomography (CT) and surface and line rendering of RT structures such as target volumes and organs at risk. The VR system has been installed and networked in a hospital room used for the daily RT conferences, making stereoscopic viewing of treatment planning data for clinical cases possible.

Planning organ at risk volume margins for organ motion of the intestine.

BACKGROUND AND PURPOSE: To account for internal organ motion and set-up uncertainties around organs at risk (OR) in radiotherapy (RT), the ICRU report no 62 introduced the planning organ at risk volume (PRV). In the present study, we have quantified PRV margins for the intestine, which is an important OR in pelvic RT. MATERIALS AND METHODS: The present study was based on intestine contours outlined in a total of 149 CT scans of 20 male bladder cancer patients (20 planning scans, 129 during treatment). From these data, we created location probability maps of the intestine for each patient. A commercial treatment planning system was used to add 3D isotropic intestine PRV margins (from 5 to 30 mm, in intervals of 5 mm) around the intestine planning outline. We then derived the fraction of patients for which a given PRV encompassed various degrees of intestine motion (85%, 90% and 95% of volumes with different probabilities of intestinal occupancy). As a measure of the specificity of the PRV, we also derived the fraction of the PRV containing volumes with zero probability of intestinal occupancy. RESULTS: Isotropic margins of up to 30 mm are required to account for all intestine motion in 90% of the patients, while isotropic margins of 5 - 10 mm will encompass 85 - 95% of the volumes having a probability of intestinal occupancy of > or = 75% in the same fraction of patients. Intestine PRVs are not very specific and will also include volumes where the intestine will rarely or never be located. CONCLUSIONS: Large intestinal motion was found, but isotropic PRV margins of 5-10 mm will include the major part of volumes with a large probability of intestinal occupancy in most patients.

The impact of organ motion on intestine doses and complication probabilities in radiotherapy of bladder cancer.

BACKGROUND AND PURPOSE: The intestine is an organ at risk during irradiation of tumours in the abdomen and pelvis, and it is therefore of interest to predict the risk for complications when planning the treatment. However, this organ displays considerable temporal variations in volume and shape. The aim of this investigation was to investigate the uncertainties caused by organ motion in dose-volume histograms (DVHs) and normal-tissue-complication probabilities (NTCP's). PATIENTS AND METHODS: Between 6 and 8 weekly repeat CT scans were acquired for 10 patients with muscle invading urinary bladder cancer. The intestine was delineated in all scans, and the coordinates of the outlines were transferred to the planning CT using the appropriate transformation. Using the actual treatment plan, the DVHs for each of these 6-8 instances of the intestine as well as the corresponding NTCP estimates were calculated. Also, for each patient, a 3D matrix was created that contained the number of scans where the intestine occupied the voxels represented by the elements of the matrix. From this matrix additional information about the organ movements were extracted. RESULTS: The mean values (across scans for individual patients) for the volume receiving at least 30.8 Gy, V30.8, ranged from 77 to 336 cm3, from 52 to 250 cm3 for V49.5 and from 38 to 243 cm3 for V53.5. The corresponding relative standard deviations were 0.45, 0.45, and 0.51, respectively. The relative standard deviations (over repeat scans for each patient) had ranges 0.065-0.45, 0.10-0.53, and 0.10-0.54 and the mean relative deviations were 0.20, 0.24, and 0.26, approximately half the magnitude of the variation between the mean values for the patients. For 6 out of 10 patients, the volume occupied by the intestine in only one of the CT scans was larger than the volume occupied in all CT scans, thus illustrating the very mobile nature of this organ. CONCLUSIONS: The movements of the small intestine cause large uncertainties in the DVH and calculated NTCP for the individual patient, and the usefulness of dose constraints for this organ may be questioned. Still, the inter-patient variation was larger, and it may be that the DVH can be useful for judging which patients have the greatest risk for radiation injury.

Testing the new ICRU 62 'Planning Organ at Risk Volume' concept for the rectum.

BACKGROUND AND PURPOSE: To study the impact of the new ICRU 62 'Planning organ at Risk Volume' (PRV) concept on the relationship between rectum dose-volume histogram (DVH) data and toxicity. PATIENTS AND METHODS: The acute gastro-intestinal (GI) RTOG toxicity in 127 prostate cancer patients prescribed a total dose of 70 Gy with conformal irradiation to either the prostate, the prostate and seminal vesicles or the whole pelvis (initial 50 Gy only) were analysed. DVHs were derived for the rectum only and for rectum extended with six PRV margin sets (narrow/intermediate/wide; anterior/anterior and posterior). The data was analysed using permutation tests, logistic regression and effective uniform dose (EUD) calculations. RESULTS: Acute Grade 2 GI toxicity was seen in 22 of 127 cases (17%). Permutation tests showed that the difference between DVHs for patients with and without Grade 2 effects was significant, both for rectum only and rectum PRVs (P-value range: 0.02-0.04), with generally lower P-values for the PRVs. In the logistic regression, the fractional DVH variables (i.e. volumes) were significantly related to toxicity, with approximately 2-3 times as many significant dose levels for the PRVs as for rectum only. E.g. with wide anterior and posterior margins (16 and 11 mm, respectively) the relation was significant at 26 different dose levels (6-7, 13-14, 35-43, 60-71 and 73 Gy), compared to nine levels (38-40, 43-44 and 71-74 Gy) for rectum only. EUDs were significantly different for patients with and without Grade 2 effects both for rectum only and the PRVs (95% confidence interval for EUD increase with Grade 2 effects: 0.1-3.1 Gy). CONCLUSIONS: All statistical methods applied indicated a small, but definite difference in DVH parameters between patients with versus those without Grade 2 effects. The difference was most pronounced when margins of 16 mm anterior and 11 mm posterior were applied.

Measurements and treatment planning calculations of electron dose distributions below bolus edges.

Electron dose distributions below bolus edges of various thicknesses and angles were measured using a diode in a water phantom. The measurements were compared with treatment planning calculations using the gamma method. Below 5 mm boluses, the dose variations were acceptable for all angles, while for boluses thicker than 5mm, the lowest edge gave the smallest dose variations. The calculated dose distributions agreed well with the measured dose distributions.

A Monte Carlo study of the impact of the choice of rectum volume definition on estimates of equivalent uniform doses and the volume parameter.

Calculations of normal tissue complication probability (NTCP) values for the rectum are difficult because it is a hollow, non-rigid, organ. Finding the true cumulative dose distribution for a number of treatment fractions requires a CT scan before each treatment fraction. This is labour intensive, and several surrogate distributions have therefore been suggested, such as dose wall histograms, dose surface histograms and histograms for the solid rectum, with and without margins. In this study, a Monte Carlo method is used to investigate the relationships between the cumulative dose distributions based on all treatment fractions and the above-mentioned histograms that are based on one CT scan only, in terms of equivalent uniform dose. Furthermore, the effect of a specific choice of histogram on estimates of the volume parameter of the probit NTCP model was investigated. It was found that the solid rectum and the rectum wall histograms (without margins) gave equivalent uniform doses with an expected value close to the values calculated from the cumulative dose distributions in the rectum wall. With the number of patients available in this study the standard deviations of the estimates of the volume parameter were large, and it was not possible to decide which volume gave the best estimates of the volume parameter, but there were distinct differences in the mean values of the values obtained.

Evaluation of a new method for calculation of cumulative doses in the rectum wall using repeat CT scans.

The rectum wall is an important organ at risk during irradiation of the prostate, the bladder and other organs in the pelvis. It is therefore of great interest to be able reliably to predict normal tissue complication probabilities (NTCPs) for this organ. Because the rectum wall is a hollow organ capable of large deformations between fractions, dose estimates from a single CT are unreliable, and thereby also NTCP estimates. In this study two methods for calculations of cumulative dose distributions from repetitive CT scans are compared. The first is a method presented in this article that uses tracking of volume elements for a direct summation of the doses delivered in the treatment fractions. The other, presented earlier (1), is based on information from dose-volume histograms. The comparisons were made in terms of equivalent uniform doses (EUDs) and NTCPs. The methods were also compared with mean values of EUD and NTCP values from individual CT scans. The study showed that with the relatively symmetric beam arrangements normally used for treatment of prostate and bladder cancer, it is not necessary to use the more laborious method of element tracking. However, an introduction of artificial lateral rectum movements revealed that element tracking is necessary in less symmetric situations.

On the use of margins for geometrical uncertainties around the rectum in radiotherapy planning.

BACKGROUND AND PURPOSE: To derive planning organ at risk volume (PRV) margins for the rectum and to analyse the impact of such margins on rectum dose volume histograms (DVHs). PATIENTS AND METHODS: Weekly repeat computer tomography (CT) scans of 19 bladder cancer patients acquired during a conformal radiotherapy course were registered with the corresponding planning CT scans. From these scans, the internal rectal motion was quantified, and the margins that had to be added to the rectum contour in the planning scan to encompass the observed span of rectum motion were determined. These margins were compared to the margins derived using a recent PRV margin recipe. To illustrate the impact of margins on rectum DVHs, the margins were applied in treatment plans of six prostate cancer patients. RESULTS: Altogether 141 CT scans were analysed. On average 24% of the repeat scan rectum volume was displaced outside the planning scan contours, and wall movements of up to 30 mm were observed. Margins of 16 mm anterior and 11 mm posterior encompassed all rectal motion except for the two most displaced rectum walls in each of these directions, in 89% of the patients. Using a recently published statistics-based recipe, margins of 6 mm anterior and 5 mm posterior accounted for the systematic rectum variation, i.e. the average wall position, in 90% of the patients. Adding anterior margin only caused consistent increases (up to 20%) in the fraction of the volume inside the high-dose region (40-70 Gy) compared to the DVH of rectum only. When using both anterior and posterior margins only small shifts (<5%) in the volume fractions were observed. CONCLUSIONS: Rectum PRV margins of 5-6 mm will encompass the systematic component of rectum motion, while margins up to 16 mm are required to also account for most of the random variation. Use of anterior margins only caused large shifts in the DVHs in the clinically significant dose range, while only minor shifts were seen when using both anterior and posterior margins.

A method for measurement of the uptake patterns of two beta-emitting radionuclides in the same tissue section with a digital silicon detector: application to a study of 89SrCl2 and 153Sm-EDTMP in a dog with spontaneous osteosarcoma.

The biological effect of a radiopharmaceutical depends heavily on the heterogeneity of the uptake in the various tissues. A comparative study of two radiopharmaceuticals should therefore include a comparison of the uptake patterns in different tissues. To eliminate the problems caused by variation in kinetics and tumour characteristics between individuals, such a comparison should be based on measured distributions of the radiopharmaceuticals in the same tissue sample. The excellent linearity between activity and counts in images obtained with a digital silicon strip detector allows such distributions to be derived from two autoradiographs acquired at different time points. This method was applied in a comparison of the uptake patterns of 153Sm-EDTMP and 89SrCl2 in sections obtained from a dog with spontaneous osteosarcoma, containing both tumour and normal bone tissues. As the areas of the section were larger than the detector area, the section had to be cut into smaller parts. Images of these were later merged by means of image processing techniques. There were significant differences in the uptake patterns of the two nuclides. In the primary tumour, the uptake of 153Sm was highly heterogeneous, while 89Sr was more uniformly distributed. In trabecular bone, the accumulation of 153Sm was higher than that of 89Sr. In solid cortical bone, 89Sr had the highest uptake.