Accuracy of radiotherapy dose calculations based on cone-beam CT: comparison of deformable registration and image correction based methods.

Radiotherapy dose calculations based on cone-beam CT (CBCT) images can be inaccurate due to unreliable Hounsfield units (HU) in the CBCT. Deformable image registration of planning CT images to CBCT, and direct correction of CBCT image values are two methods proposed to allow heterogeneity corrected dose calculations based on CBCT. In this paper we compare the accuracy and robustness of these two approaches. CBCT images for 44 patients were used including pelvis, lung and head & neck sites. CBCT HU were corrected using a 'shading correction' algorithm and via deformable registration of planning CT to CBCT using either Elastix or Niftyreg. Radiotherapy dose distributions were re-calculated with heterogeneity correction based on the corrected CBCT and several relevant dose metrics for target and OAR volumes were calculated. Accuracy of CBCT based dose metrics was determined using an 'override ratio' method where the ratio of the dose metric to that calculated on a bulk-density assigned version of the same image is assumed to be constant for each patient, allowing comparison to the patient's planning CT as a gold standard. Similar performance is achieved by shading corrected CBCT and both deformable registration algorithms, with mean and standard deviation of dose metric error less than 1% for all sites studied. For lung images, use of deformed CT leads to slightly larger standard deviation of dose metric error than shading corrected CBCT with more dose metric errors greater than 2% observed (7% versus 1%).

Maternal executive function, infant feeding responsiveness and infant growth during the first 3 months.

BACKGROUND: There is limited research in young infants, particularly <3 months of age, on maternal feeding practices in spite of increasing evidence that early weight gain velocity is a determinant of later obesity risk. OBJECTIVE: To examine associations between maternal executive function (cognitive control over one's own behaviour), maternal feeding decisions and infant weight and adiposity gains. METHODS: We used a checklist to assess cues mothers use to decide when to initiate and terminate infant feedings at 2 weeks and 3 months of age (N = 69). Maternal executive function was assessed using the NIH Toolbox Cognition Battery subtests for executive function and infant body composition using air displacement plethysmography. RESULTS: Mothers with higher executive function reported relying on fewer non-satiety cues at 2 weeks of age (ß = -0.29, p = 0.037) and on more infant hunger cues at 3 months of age (ß = 0.31, p = 0.018) in their decisions on initiating and terminating feedings. Responsive feeding decisions, specifically the use of infant-based hunger cues at 3 months, in turn were associated with lower gains in weight-for-length (ß = -0.30, p = 0.028) and percent body fat (ß = -0.2, p = 0.091; non-covariate adjusted ß = -0.27, p = 0.029). CONCLUSIONS: These findings show both an association between maternal executive function and responsive feeding decisions and an association between responsive feeding decisions and infant weight and adiposity gains. The causal nature and direction of these associations require further investigation.

Fast methods for training Gaussian processes on large datasets.

Gaussian process regression (GPR) is a non-parametric Bayesian technique for interpolating or fitting data. The main barrier to further uptake of this powerful tool rests in the computational costs associated with the matrices which arise when dealing with large datasets. Here, we derive some simple results which we have found useful for speeding up the learning stage in the GPR algorithm, and especially for performing Bayesian model comparison between different covariance functions. We apply our techniques to both synthetic and real data and quantify the speed-up relative to using nested sampling to numerically evaluate model evidences.

Perinatal Administration of a Selective Serotonin Reuptake Inhibitor Induces Impairments in Reproductive Function and Follicular Dynamics in Female Rat Offspring.

INTRODUCTION: Up to 10% of pregnant women take antidepressants, of which selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed. Using a rodent model, we investigated the reproductive impacts of perinatal SSRI treatment on reproductive cyclicity and function in female offspring. METHODS: Virgin Wistar rats were given oral vehicle (n = 10) or fluoxetine hydrochloride (FLX, 10 mg/kg/d; n = 11) from 2 weeks prior to mating until weaning. Pubertal onset and reproductive cyclicity in offspring were assessed. Blood and ovarian tissues were collected for measures of reproductive function. RESULTS: Perinatal FLX tends to induce irregular reproductive cycles in adult offspring, which most commonly manifest as a prolonged estrus phase (FLX 34% vs control [CON] 10%) relative to CON offspring. The FLX offspring tended to have longer cycles (P = .052), had more secondary follicles (P = .0067), more total follicles (P = .0310), and increased apoptotic ovarian cells (P < .001). Prenatally exposed FLX offspring demonstrated elevated ovarian messenger RNA (mRNA) levels of ERß (P = .008), Cry1 (P = .043), and tryptophan hydroxylase 2 (P = .024), independent of stage of cycle. Ovarian mRNA levels of brain and muscle Arnt-like protein 1 (P = .046) and Pet-1 (P = .021) were increased in FLX offspring a manner that was reproductive cycle stage dependent. CONCLUSIONS: This is the first study to investigate the postnatal effects of maternal perinatal exposure to FLX on adult offspring reproduction. We show that genes that regulate serotonin signaling and action in the ovary are altered in prenatally FLX-exposed offspring, which when coupled with increased expression of components of the core Circadian Locomotor Output Cycles Kaput (CLOCK) gene regulatory loop may suggest an interaction between serotonergic signaling and clock gene signaling pathways leading to the altered reproductive phenotype.

Antagonism of corticotrophin-releasing factor type 1 receptors attenuates caloric intake of free feeding subordinate female rhesus monkeys in a rich dietary environment.

Social subordination in macaque females is a known chronic stressor and previous studies have shown that socially subordinate female rhesus monkeys consume fewer kilocalories than dominant animals when a typical laboratory chow diet is available. However, in a rich dietary environment that provides access to chow in combination with a more palatable diet (i.e. high in fat and refined sugar), subordinate animals consume significantly more daily kilocalories than dominant conspecifics. Substantial literature is available supporting the role of stress hormone signals in shaping dietary preferences and promoting the consumption of palatable, energy-dense foods. The present study was conducted using stable groups of adult female rhesus monkeys to test the hypothesis that pharmacological treatment with a brain penetrable corticotrophin-releasing factor type 1 receptor (CRF1) antagonist would attenuate the stress-induced consumption of a palatable diet among subordinate animals in a rich dietary environment but would be without effect in dominant females. The results show that administration of the CRF1 receptor antagonist significantly reduced daily caloric intake of both available diets among subordinate females compared to dominant females. Importantly, multiple regression analyses showed that the attenuation in caloric intake in response to Antalarmin (Sigma-Aldrich, St Louis, MO, USA) was significantly predicted by the frequency of submissive and aggressive behaviour emitted by females, independent of social status. Taken together, the findings support the involvement of activation of CRF1 receptors in the stress-induced consumption of excess calories in a rich dietary environment and also support the growing literature concerning the importance of CRF for sustaining emotional feeding.

Controlling colloidal stability of silica nanoparticles during bioconjugation reactions with proteins and improving their longer-term stability, handling and storage.

Despite the potential of antibody-coated nanoparticles (Ab-NPs) in many biological applications, there are very few successful, commercially available examples in which the carefully engineered nanomaterial has made it beyond the laboratory bench. Herein we explore the robustness and cost of protein-nanoparticle conjugation. Using multivalent polyamidoamine (PAMAM) dendrimers and dextran as crosslinkers, it was possible to retain colloidal stability during (i) NP-linker binding and (ii) the subsequent conjugation reaction between linker-coated NPs and proteins to generate monodisperse Ab-NPs. This was attributed to the physicochemical properties of the linkers, which were inherited by the NPs and thus benefited colloidal stability. Attaching negatively charged, EDC/sulfo-NHS-activated PAMAM to the NPs contributed to overall negative charge of particles, and in turn led to high electrostatic attraction between the protein and PAMAM-coated NPs during the reaction conditions. In contrast, using an uncharged, EDC/NHS-activated PAMAM dendrimer led to NP aggregation and lower protein binding efficiency. Dextran as a cost-effective, uncharged macromolecule allowed for steric repulsions between neighbouring particles during protein binding, thus inducing NP stability in solution, and also produced monodisperse Ab-NPs. By freeze-drying Ab-NPs from a 1% BSA solution it is possible to reconstitute the solid-form colloid back to a stable state by adding solvent and simply shaking the sample vial by hand. The consequences of the different surface chemistries and freeze-drying stabilizers on the colloidal stability of the NPs were probed by dynamic light scattering. The performance of Ab-NPs was compared in a simple fluorescence linked immunoassay in whole serum. Interestingly, the signal-to-noise ratios were similar for Ab-NPs using PAMAM and dextran, despite dextran binding fewer Abs per NP. We believe this work provides researchers with the tools and strategies for reliably generating Ab-NPs that can be used for a variety of biological applications.

Oestradiol differentially influences feeding behaviour depending on diet composition in female rhesus monkeys.

In females, cyclical changes in the ovarian hormone oestradiol are known to modulate feeding behaviour. However, what is less clear is how these behavioural effects of oestradiol are modified by the macronutrient content of a diet. In the present study, we report data showing that oestradiol treatment results in both significantly smaller meals and a reduced total calorie intake in ovariectomised, socially-housed female rhesus macaques when only chow diet is available. Conversely, during a choice dietary condition where both palatable and chow options are available, oestradiol treatment had no observable, attenuating effect on calorie intake. During this choice dietary phase, all animals consumed more of the palatable diet than chow diet; however, oestradiol treatment appeared to further increase preference for the palatable diet. Finally, oestradiol treatment increased snacking behaviour (i.e. the consumption of calories outside of empirically defined meals), regardless of diet condition. These findings illustrate how oestradiol differentially influences feeding behaviour depending on the dietary environment and provides a framework in which we can begin to examine the mechanisms underlying these observed changes.

Quantitative comparison of 3D and 2.5D gamma analysis: introducing gamma angle histograms.

Comparison of dose distributions using the 3D gamma method is anticipated to provide better indicators for the quality assurance process than the 2.5D (stacked 2D slice-by-slice) gamma calculation, especially for advanced radiotherapy technologies. This study compares the accuracy of the 3D and 2.5D gamma calculation methods. 3D and 2.5D gamma calculations were carried out on four reference/evaluation 3D dose sample pairs. A number of analysis methods were used, including average gamma and gamma volume histograms. We introduce the concept of gamma-angle histograms. Noise sensitivity tests were also performed using two different noise models. The advantage of the 3D gamma method showed up as a higher proportion of points passing the tolerance criteria of 3% dose difference and 3 mm distance-to-agreement (DTA), with considerably lower average gamma values, a lower influence of the DTA criterion, and a higher noise tolerance. The 3D gamma approach is more reliable than the 2.5D approach in terms of providing comprehensive quantitative results, which are needed in quality assurance procedures for advanced radiotherapy methods.

Automated delineation of radiotherapy volumes: are we going in the right direction?

Rapid and accurate delineation of target volumes and multiple organs at risk, within the enduring International Commission on Radiation Units and Measurement framework, is now hugely important in radiotherapy, owing to the rapid proliferation of intensity-modulated radiotherapy and the advent of four-dimensional image-guided adaption. Nevertheless, delineation is still generally clinically performed with little if any machine assistance, even though it is both time-consuming and prone to interobserver variation. Currently available segmentation tools include those based on image greyscale interrogation, statistical shape modelling and body atlas-based methods. However, all too often these are not able to match the accuracy of the expert clinician, which remains the universally acknowledged gold standard. In this article we suggest that current methods are fundamentally limited by their lack of ability to incorporate essential human clinical decision-making into the underlying models. Hybrid techniques that utilise prior knowledge, make sophisticated use of greyscale information and allow clinical expertise to be integrated are needed. This may require a change in focus from automated segmentation to machine-assisted delineation. Similarly, new metrics of image quality reflecting fitness for purpose would be extremely valuable. We conclude that methods need to be developed to take account of the clinician's expertise and honed visual processing capabilities as much as the underlying, clinically meaningful information content of the image data being interrogated. We illustrate our observations and suggestions through our own experiences with two software tools developed as part of research council-funded projects.

Real-time optical measurement of the dynamic body surface for use in guided radiotherapy.

Optical measurements are increasingly used in radiotherapy. In this paper we present, in detail, the design and implementation of a multi-channel optical system optimized for fast, high spatial resolution, dynamic body surface measurement in guided therapy. We include all algorithmic modifications and calibration procedures required to create a robust, practical system for clinical use. Comprehensive static and dynamic phantom validation measurements in the radiotherapy treatment room show: conformance with simultaneously measured cone beam CT data to within 1 mm over 62% ± 8% of the surface and 2 mm over 90% ± 3%; agreement with the measured radius of a precision geometrical phantom to within 1 mm; and true real-time performance with image capture through to surface display at 23 Hz. An example patient dataset is additionally included, indicating similar performance in the clinic.

Reduction of motion artefacts in on-board cone beam CT by warping of projection images.

OBJECTIVE: We describe the development and testing of a motion correction method for flat panel imager-based cone beam CT (CBCT) based on warping of projection images. METHODS: Markers within or on the surface of the patient were tracked and their mean three-dimensional (3D) position calculated. The two-dimensional (2D) cone beam projection images were then warped before reconstruction to place each marker at the projection from its mean 3D position. The motion correction method was tested using simulated cone beam projection images of a deforming virtual phantom, real CBCT images of a moving breast phantom and clinical CBCT images of a patient with breast cancer and another with pancreatic cancer undergoing radiotherapy. RESULTS: In phantom studies, the method was shown to greatly reduce motion artefacts in the locality of the radiotherapy target and allowed the true surface shape to be accurately recovered. The breast phantom motion-compensated surface was within 1 mm of the true surface shape for 90% of surface points and greater than 2 mm from the true surface at only 2% of points. Clinical CBCT images showed improved image quality in the locality of the radiotherapy target after motion correction. CONCLUSION: The proposed method is effective in reducing motion artefacts in CBCT images.

Chemical detoxification vs mechanical removal of host plant toxins in Eucalyptus feeding sawfly larvae (Hymenoptera: Pergidae).

The essential oils that characterize the eucalypts and related Myrtaceae pose a challenge for herbivores. Phytophagous insects that feed on oil-rich Myrtaceae have developed specific mechanisms to deal with these oils, some of which are notoriously toxic (e.g. 1,8-cineole). Some of the eight Australian subfamilies in the sawfly family Pergidae are associated exclusively with Eucalyptus and Melaleuca species that often have high concentrations of essential oils. Unexpectedly, the Perginae and Pterygophorinae use different mechanisms to deal with the same toxic components in their respective host plants. Larvae of the Perginae have the inner surface of their mandibles equipped with soft brush-like structures that are unique among phytophagous insects in general. The proposed role of these ancillary mandibular structures in separating leaf oils from nutritive plant matter could be confirmed in experiments with larvae of two pergine species. The oil sequestration is, however, incomplete and chemical gut content analyses by gas-chromatography (GC) revealed that 1,8-cineole does enter the midgut and is metabolised to hydroxycineole. Although the related Pterygophorinae also feed mainly on oil-rich Myrtaceae, they do not sequester the oil and lack morphological structures on their mandibles. Chemical analysis of the gut content of two pterygophorine species showed that they rely solely on chemical detoxification of the relevant plant compounds, with GC demonstrating that the 1,8-cineole is removed far more rapidly and completely than in the pergine species.

New iterative cone beam CT reconstruction software: parameter optimisation and convergence study.

Cone beam computed tomography (CBCT) provides a volumetric image reconstruction from tomographic projection data. Image quality is the main concern for reconstruction in comparison to conventional CT. The reconstruction algorithm used is clearly important and should be carefully designed, developed and investigated before it can be applied clinically. The Multi-Instrument Data Analysis System (MIDAS) tomography software originally designed for geophysical applications has been modified to CBCT image reconstruction. In CBCT reconstruction algorithms, iterative methods offer the potential to generate high quality images and would be an advantage especially for down-sampling projection data. In this paper, studies of the CBCT iterative algorithms implemented in MIDAS are presented. Stability, convergence rate, quality of reconstructed image and edge recovery are suggested as the main criteria for monitoring reconstructive performance. Accordingly, the selection of relaxation parameter and number of iterations are studied in detail. Results are presented, where images are reconstructed from full and down-sampled cone beam CT projection data using iterative algorithms. Various iterative algorithms have been implemented and the best selection of the iteration number and relaxation parameters are investigated for ART. Optimal parameters are chosen where the errors in projected data as well as image errors are minimal.

An analysis of breast motion using high-frequency, dense surface points captured by an optical sensor during radiotherapy treatment delivery.

Patient motion is an important factor affecting the quality of external beam radiotherapy in breast patients. We analyse the motion of a dense set of surface points on breast patients throughout their treatment schedule to assess the magnitude and stability of motion, in particular, with respect to breast volume. We use an optical sensor to measure the surface motion of 13 breast cancer patients. Patients were divided into two cohorts dependent upon breast volume. Measurements were made during radiotherapy treatment beam delivery for an average of 12 fractions per patient (total 158 datasets). The motion of each surface point is parameterized in terms of its period, amplitude and relative phase. Inter-comparison of the motion parameters across treatment schedules and between patients is made through the creation of corresponding regions on the breast surfaces. The motion period is spatially uniform and is similar in both patient groups (mean 4 s), with the small volume cohort exhibiting greater inter-fraction period variability. The mean motion amplitude is also similar in both groups with a range between 2 mm and 4 mm and an inter-fraction variability generally less than 1 mm. There is a phase lag of up to 0.4 s across the breast, led by the sternum. Breast patient motion is reasonably stable between and during treatment fractions, with the large volume cohort exhibiting greater repeatability than the small volume one.

Shading correction algorithm for improvement of cone-beam CT images in radiotherapy.

Cone-beam CT (CBCT) images have recently become an established modality for treatment verification in radiotherapy. However, identification of soft-tissue structures and the calculation of dose distributions based on CBCT images is often obstructed by image artefacts and poor consistency of density calibration. A robust method for voxel-by-voxel enhancement of CBCT images using a priori knowledge from the planning CT scan has been developed and implemented. CBCT scans were enhanced using a low spatial frequency grey scale shading function generated with the aid of a planning CT scan from the same patient. This circumvents the need for exact correspondence between CBCT and CT and the process is robust to the appearance of unshared features such as gas pockets. Enhancement was validated using patient CBCT images. CT numbers in regions of fat and muscle tissue in the processed CBCT were both within 1% of the values in the planning CT, as opposed to 10-20% different for the original CBCT. Visual assessment of processed CBCT images showed improvement in soft-tissue visibility, although some cases of artefact introduction were observed.

Early clinical evaluation of a novel three-dimensional structure delineation software tool (SCULPTER) for radiotherapy treatment planning.

Modern radiotherapy treatment planning (RTP) necessitates increased delineation of target volumes and organs at risk. Conventional manual delineation is a laborious, time-consuming and subjective process. It is prone to inconsistency and variability, but has the potential to be improved using automated segmentation algorithms. We carried out a pilot clinical evaluation of SCULPTER (Structure Creation Using Limited Point Topology Evidence in Radiotherapy) - a novel prototype software tool designed to improve structure delineation for RTP. Anonymized MR and CT image datasets from patients who underwent radiotherapy for bladder or prostate cancer were studied. An experienced radiation oncologist used manual and SCULPTER-assisted methods to create clinically acceptable organ delineations. SCULPTER was also tested by four other RTP professionals. Resulting contours were compared by qualitative inspection and quantitatively by using the volumes of the structures delineated and the time taken for completion. The SCULPTER tool was easy to apply to both MR and CT images and diverse anatomical sites. SCULPTER delineations closely reproduced manual contours with no significant volume differences detected, but SCULPTER delineations were significantly quicker (p<0.05) in most cases. In conclusion, clinical application of SCULPTER resulted in rapid and simple organ delineations with equivalent accuracy to manual methods, demonstrating proof-of-principle of the SCULPTER system and supporting its potential utility in RTP.

Measurement of inter and intra fraction organ motion in radiotherapy using cone beam CT projection images.

A method is presented for extraction of intra and inter fraction motion of seeds/markers within the patient from cone beam CT (CBCT) projection images. The position of the marker is determined on each projection image and fitted to a function describing the projection of a fixed point onto the imaging panel at different gantry angles. The fitted parameters provide the mean marker position with respect to the isocentre. Differences between the theoretical function and the actual projected marker positions are used to estimate the range of intra fraction motion and the principal motion axis in the transverse plane. The method was validated using CBCT projection images of a static marker at known locations and of a marker moving with known amplitude. The mean difference between actual and measured motion range was less than 1 mm in all directions, although errors of up to 5 mm were observed when large amplitude motion was present in an orthogonal direction. In these cases it was possible to calculate the range of motion magnitudes consistent with the observed marker trajectory. The method was shown to be feasible using clinical CBCT projections of a pancreas cancer patient.

Mating activity of Bactrocera cacuminata (Hering) (Diptera: Tephritidae) on its larval host plant Solanum mauritianum Scopoli in southeast Queensland.

A detailed study was conducted on the mating behaviour of Bactrocera cacuminata (Hering) (Diptera: Tephritidae) in nature. Plant tissues from Solanum mauritianum Scopoli, the primary larval host for B. cacuminata, were also analysed for methyl eugenol content. In the field, over a 15 month period, 44,171 observations of adult B. cacuminata individuals were made including 1109 mating pairs on S. mauritianum. Calling behaviour consisting of wing fanning and anus beating by males was also consistently observed on the underside of leaves of S. mauritianum after sunset. Female flies that arrived into these groups of 10-15 calling males were mated and often remained coupled until dawn. No methyl eugenol was detected from the analysis of leaves, flowers and fruits of S. mauritianum. Thus, B. cacuminata does not need to aggregate at sites where methyl eugenol is present and the hypothesis that this chemical plays a role in the selection of mating sites by B. cacuminata is not supported by the current study. It is concluded that S. mauritianum is the primary site of mating for B. cacuminata in nature and that the concept that the larval host plant is the centre of activity for dacine fruit flies remains robust, being fully supported by the results of this study.

A method to calculate coverage probability from uncertainties in radiotherapy via a statistical shape model.

In this paper we describe a technique that may be used to model the geometric uncertainties that accrue during the radiotherapy process. Using data from in-treatment cone beam CT scans, we simultaneously analyse non-uniform observer delineation variability and organ motion together with patient set-up errors via the creation of a point distribution model (PDM). We introduce a novel method of generating a coverage probability matrix, that may be used to determine treatment margins and calculate uncertainties in dose, from this statistical shape model. The technique does not assume rigid body motion and can extrapolate shape variability in a statistically meaningful manner. In order to construct the PDM, we generate corresponding surface points over a set of delineations. Correspondences are established at a set of points in parameter space on spherically parameterized and canonical aligned outlines. The method is demonstrated using rectal delineations from serially acquired in-treatment cone beam CT image volumes of a prostate patient (44 image volumes total), each delineated by a minimum of two observers (maximum six). Two PDMs are constructed, one with set-up errors included and one without. We test the normality assumptions of the PDMs and find the distributions to be Gaussian in nature. The rectal PDM variability is in general agreement with data in the literature. The two resultant coverage probability matrices show differences as expected.

Developments in and experience of kilovoltage X-ray cone beam image-guided radiotherapy.

This paper offers a realistic review of kilovoltage X-ray cone beam tomography integrated with the treatment machine for image-guided radiotherapy in the light of experience taking a commercial system from prototype development into clinical use. It shows that key practicalities cannot be ignored, in particular the regular characterization of mechanical flex during gantry rotation, the mapping of defects in flat panel image transducers and their response to X-ray exposure. The number of X-ray projections and the doses required for clinically useful cone beam reconstruction at different therapy sites are considered in the context of imaging that is fit for purpose. Three roles for cone beam tomography in radiotherapy are identified: patient setup in three dimensions (3D), where even low dose cone beam tissue detail is superior to megavoltage imaging; disease targeting where, despite wide field scatter and slow scanning, it is possible to generate images that are suitable for tumour delineation even at challenging sites; adaptive treatment planning, where calibrated cone beam images have been shown to provide sufficient target detail to support "plan of the day" selection and have the potential for planning with bulk corrections. With frequent use in mind, the need to limit patient dose during setup, yet maximize much needed image quality in the target zone, is considered. Finally, it is noted that the development of cone beam tomography for radiotherapy is far from complete, with X-ray source, image transducer, reconstruction algorithms and techniques for image profile collection still being researched.