Enabling non-isocentric dynamic trajectory radiotherapy by integration of dynamic table translations.

Objective.The purpose of this study is to develop a treatment planning process (TPP) for non-isocentric dynamic trajectory radiotherapy (DTRT) using dynamic gantry rotation, collimator rotation, table rotation, longitudinal, vertical and lateral table translations and intensity modulation and to validate the dosimetric accuracy.Approach.The TPP consists of two steps. First, a path describing the dynamic gantry rotation, collimator rotation and dynamic table rotation and translations is determined. Second, an optimization of the intensity modulation along the path is performed. We demonstrate the TPP for three use cases. First, a non-isocentric DTRT plan for a brain case is compared to an isocentric DTRT plan in terms of dosimetric plan quality and delivery time. Second, a non-isocentric DTRT plan for a craniospinal irradiation (CSI) case is compared to a multi-isocentric intensity modulated radiotherapy (IMRT) plan. Third, a non-isocentric DTRT plan for a bilateral breast case is compared to a multi-isocentric volumetric modulated arc therapy (VMAT) plan. The non-isocentric DTRT plans are delivered on a TrueBeam in developer mode and their dosimetric accuracy is validated using radiochromic films.Main results.The non-isocentric DTRT plan for the brain case is similar in dosimetric plan quality and delivery time to the isocentric DTRT plan but is expected to reduce the risk of collisions. The DTRT plan for the CSI case shows similar dosimetric plan quality while reducing the delivery time by 45% in comparison with the IMRT plan. The DTRT plan for the breast case showed better treatment plan quality in comparison with the VMAT plan. The gamma passing rates between the measured and calculated dose distributions are higher than 95% for all three plans.Significance.The versatile benefits of non-isocentric DTRT are demonstrated with three use cases, namely reduction of collision risk, reduced setup and delivery time and improved dosimetric plan quality.

Image-guided Radiotherapy to Manage Respiratory Motion: Lung and Liver.

Organ motion as a result of respiratory and cardiac motion poses significant challenges for the accurate delivery of radiotherapy to both the thorax and the upper abdomen. Modern imaging techniques during radiotherapy simulation and delivery now permit better quantification of organ motion, which in turn reduces tumour and organ at risk position uncertainty. These imaging advances, coupled with respiratory correlated radiotherapy delivery techniques, have led to the development of a range of approaches to manage respiratory motion. This review summarises the key strategies of image-guided respiratory motion management with a focus on lung and liver radiotherapy.

An interdimensional correlation framework for real-time estimation of six degree of freedom target motion using a single x-ray imager during radiotherapy.

Increasing evidence suggests that intrafraction tumour motion monitoring needs to include both 3D translations and 3D rotations. Presently, methods to estimate the rotation motion require the 3D translation of the target to be known first. However, ideally, translation and rotation should be estimated concurrently. We present the first method to directly estimate six-degree-of-freedom (6DoF) motion from the target's projection on a single rotating x-ray imager in real-time. This novel method is based on the linear correlations between the superior-inferior translations and the motion in the other five degrees-of-freedom. The accuracy of the method was evaluated in silico with 81 liver tumour motion traces from 19 patients with three implanted markers. The ground-truth motion was estimated using the current gold standard method where each marker's 3D position was first estimated using a Gaussian probability method, and the 6DoF motion was then estimated from the 3D positions using an iterative method. The 3D position of each marker was projected onto a gantry-mounted imager with an imaging rate of 11 Hz. After an initial 110° gantry rotation (200 images), a correlation model between the superior-inferior translations and the five other DoFs was built using a least square method. The correlation model was then updated after each subsequent frame to estimate 6DoF motion in real-time. The proposed algorithm had an accuracy (±precision) of -0.03 ± 0.32 mm, -0.01 ± 0.13 mm and 0.03 ± 0.52 mm for translations in the left-right (LR), superior-inferior (SI) and anterior-posterior (AP) directions respectively; and, 0.07 ± 1.18°, 0.07 ± 1.00° and 0.06 ± 1.32° for rotations around the LR, SI and AP axes respectively on the dataset. The first method to directly estimate real-time 6DoF target motion from segmented marker positions on a 2D imager was devised. The algorithm was evaluated using 81 motion traces from 19 liver patients and was found to have sub-mm and sub-degree accuracy.

Fully automatic segmentation of arbitrarily shaped fiducial markers in cone-beam CT projections.

Radio-opaque fiducial markers of different shapes are often implanted in or near abdominal or thoracic tumors to act as surrogates for the tumor position during radiotherapy. They can be used for real-time treatment adaptation, but this requires a robust, automatic segmentation method able to handle arbitrarily shaped markers in a rotational imaging geometry such as cone-beam computed tomography (CBCT) projection images and intra-treatment images. In this study, we propose a fully automatic dynamic programming (DP) assisted template-based (TB) segmentation method. Based on an initial DP segmentation, the DPTB algorithm generates and uses a 3D marker model to create 2D templates at any projection angle. The 2D templates are used to segment the marker position as the position with highest normalized cross-correlation in a search area centered at the DP segmented position. The accuracy of the DP algorithm and the new DPTB algorithm was quantified as the 2D segmentation error (pixels) compared to a manual ground truth segmentation for 97 markers in the projection images of CBCT scans of 40 patients. Also the fraction of wrong segmentations, defined as 2D errors larger than 5 pixels, was calculated. The mean 2D segmentation error of DP was reduced from 4.1 pixels to 3.0 pixels by DPTB, while the fraction of wrong segmentations was reduced from 17.4% to 6.8%. DPTB allowed rejection of uncertain segmentations as deemed by a low normalized cross-correlation coefficient and contrast-to-noise ratio. For a rejection rate of 9.97%, the sensitivity in detecting wrong segmentations was 67% and the specificity was 94%. The accepted segmentations had a mean segmentation error of 1.8 pixels and 2.5% wrong segmentations.

Pulmonary resection of colorectal metastases in patients with or without a history of hepatic metastases.

INTRODUCTION: In selected patients with isolated colorectal lung or liver metastases resection can provide an increase in overall survival and even cure. Here, we evaluate whether also patients with combined or sequential metastatic disease to liver and lung may still be candidates for surgical resection. METHODS: From 1997 till 2006 39 patients underwent pulmonary metastasectomy. Two subgroups were identified: resection of pulmonary metastases only (PM) and resection of hepatic and later pulmonary metastases (LPM). RESULTS: Patient characteristics were identical in both groups. Median follow-up in group PM was 35 months and 38 months in group LPM. Two-year survival in group PM was 61%, and in group LPM 81% (p=NS). Five-year survival was 30% and 20% in PM and LPM groups, respectively (p=NS). The median disease free survival was 12 months in the PM group and 13 months in the LPM group. The extent of pulmonary resection had no impact on survival. Complications occurred in seven patients in the PM group and two patients in the LPM group. Complication rate and severity were related to the extent of pulmonary resection. A small group of patients underwent repeated pulmonary resection without serious complications. CONCLUSION: Resection of pulmonary colorectal metastases may improve survival, even in patients who underwent hepatic resection for colorectal liver metastases at an earlier stage.

Hippocampal morphology and open-field behavior in Mus musculus domesticus and Mus spretus inbred mice.

Mus spretus is extensively used in interspecific mouse backcross analyses employed to generate genetic linkage maps. However, little is known about its behavior and neuroanatomy, phenotypes for which large interstrain differences have been observed in Mus musculus domesticus. Behavioral and hippocampal neuroanatomical variables were measured in adult male mice from the inbred strains C57BL/6J (Mus musculus domesticus) and SEG (Mus spretus). Clear differences were found for behavioral responses to novelty in an open field, SEG being much less active than C57BL/6J. Morphometrical analysis of hippocampal terminal fields, visualized with Timm's stain, revealed strain differences only for the size of the intra- and infrapyramidal mossy fiber terminal fields, which were about 3 x larger in C57BL/6J than in SEG. In addition, absolute left-right differences were larger in SEG for the stratum radiatum and stratum oriens. In spite of these behavioral and neuroanatomical differences, the phenotypical scores obtained for SEG do not exceed the range observed for Mus musculus domesticus inbred strains.

Age-related morphological changes in the hippocampus in two mouse strains.

The granule cell number (nGR) in the dentate gyrus (DG) has been reported to vary considerably among inbred strains of mice, thus providing proof of some genetically associated components to this variation. Furthermore, several authors have described age-related morphological changes in the DG in both humans and animals, but there is no general agreement in the literature about the occurrence of such changes. The purpose of this study was to investigate for strain differences in hippocampal structure changes in old C57BL/6J (B) and DBA/2J (D) mice as compared with younger ones. The nGR in the DG, as well as other structural parameters of the hippocampus, were determined in female B and D mice of 4 and 24 months. The two-way analysis of variance indicated a significant interaction between 'strain' and 'age' for the nGR, suggesting that this parameter changes differently with age in B and D mice. This finding indicates that these strains could present a differential susceptibility in granule cell aging raising the possibility that age effects on the granule cell population in the DG could be influenced by some hereditary factors.

Neuroanatomical divergence between two substrains of C57BL/6J inbred mice entails differential radial-maze learning.

Compared to the parental strain C57BL/6J, male mice from the mutated substrain C57BL/6JNmg show smaller hippocampal intra- and infrapyramidal mossy fiber projections and a correlated inability to master a simple spatial radial-maze task. Possibly, these two substrains differ for only one single gene, making them a valuable model to investigate the physiological pathways leading from genotype to neurobehavioral phenotype.

Hippocampal mossy fiber changes in mice transgenic for the human copper-zinc superoxide dismutase gene.

The copper-zinc superoxide dismutase (SOD-1) gene, located on chromosome 21 and triplicated in Down's syndrome (DS), is suspected to be involved in the neuropathology observed in Alzheimer's disease (AD), DS and physiological aging. In order to explore the effect of an overproduction of SOD-1 in the mouse hippocampus, we investigated the Timm-stained mossy fiber (MF) innervation in the hippocampus of transgenic mice for the human SOD-1 gene (hSOD-1 mice). The results showed a decrease of the MF projection area in the hSOD-1 mice overexpressing the SOD-1 protein. These findings suggest that free radicals could play a role in this particular synaptic loss.

No aging effect on hippocampal type II glucocorticoid receptors in two inbred mouse strains.

We report here on the type II glucocorticoid receptor concentration in the hippocampal cytosol of two inbred strains of mice, C57BL/6J and DBA/2J, aged 2 and 24 months. Glucocorticoid receptors are usually considered as mediating cytotoxic effects of glucocorticoids on hippocampal neurons and modulating hippocampus-dependent behaviors. Either a decrease in glucocorticoid receptors with aging or no effect of aging have been reported previously. In order to test whether strain differences may explain these conflicting results, we have measured, using [3H]RU 28362, the hippocampal glucocorticoid receptor concentrations in two inbred strains of mice showing differential modifications of some hippocampus-dependent behaviors with aging. Our results show that there is neither a strain nor an age effect.

Spatial and non-spatial spontaneous alternation and hippocampal mossy fibre distribution in nine inbred mouse strains.

Ten male mice from each one of nine inbred strains were tested for spontaneous alternation in a T-maze, which was placed in a spatially richly structured room. Each test consisted of two trials, the first choice to be made was forced, the second one free. By turning the maze 180 degrees between choices during 8 of the 16 tests, 3 variables could be measured: total alternation, spatial alternation, and non-spatial alternation. After Timm's staining, the sizes of the intra- and infrapyramidal mossy fibre terminal fields (iip-MF) were measured. Significant strain differences were found for all variables, but none of the behavioural variables correlated with hippocampal variation. These results disagree with earlier experiments, where large correlations between the iip-MF and spatial working memory were found. Some hypotheses to explain this discrepancy are presented.

No correlations between spatial and non-spatial reference memory in a T-maze task and hippocampal mossy fibre distribution in the mouse.

Two reference memory tasks were tested in a T-maze, which was placed in a spatially richly structured environment and turned 180 degrees between trials following a semi-random schedule. Male mice from 9 different inbred strains were either trained always to go to the same place (spatial task) or always to make the same turn (non-spatial task). Animals were subsequently processed for Timm's stain and the sizes of their intra- and infrahippocampal mossy fibre terminal fields (ipp-MF) were measured. Significant strain differences were found for this variable and in both learning tasks, but learning and hippocampal variation did not correlate. This disagrees with earlier findings in a radial maze, where significant correlations between the iipMF and spatial reference memory were obtained. Two hypotheses are brought forward to explain this discrepancy. First, in radial mazes (multiple choices) different memory capabilities might be used than in T-mazes (only two choices). Second, a considerable amount of stress appeared to be present in our subjects, possibly induced by the large size of the T-maze. This might have interfered negatively with acquisition. Further experiments will be needed to test these hypotheses.

Proliferative activity and cell migration in the adrenal cortex of fetal and neonatal rats: an autoradiographic study.

The aim of this experiment was to examine, using autoradiograhic techniques, proliferative activity in the adrenal cortex of rats on day 20 of fetal life, and to follow the fate of labelled cells 48, 168, 336 and 672 h after injection of [3H]thymidine. On day 20 of fetal life, labelled cells were more numerous in the zona glomerulosa than in the other zones. The fate of the labelled cells in each cell compartment showed centripetal migration, but their displacement from day 20 of pregnancy up to 5 days post partum, combined with a reduction in the size of the adrenal gland, suggested a real migration. The centripetal movement was found in the cortex when growth had effectively ceased.

[Proliferative activity of the rat adrenal cortex during the estrous cycle and at the end of gestation]. / Activité proliférative du cortex surrénal de la ratte au cours du cycle oestrien et en fin de gestation.

The cell proliferation in the female Rat adrenal cortex undergoes rhythmic modifications which appear to be related to the estrous cycle. Significant variations appear likewise at the end of pregnancy. Such fluctuations of the proliferative activity raise the question of a possible endocrine regulation.

[Autoradiographic study of proliferative activity and cell migration in the adrenal cortex in fetal and neonatal rats]. / Etude autoradiographique de l'activité proliférative et de la migration cellulaire dans le cortex surrénal du foetus de Rat et du Rat nouveau-né.

On the 20th day of fetal life the cell proliferation is higher in the zona glomerulosa. The fate of marked cells in each cell compartment shows centripetal migration. Their displacement, from the 20th day of pregnancy up to five days post-partum, while at that time the adrenal growth is slowered down, suggests a real migration.