An investigation into factors affecting electron density calibration for a megavoltage cone-beam CT system

There is a growing interest in the use of megavoltage cone-beam computed tomography (MV CBCT) data for radiotherapy treatment planning. To calculate accurate dose distributions, knowledge of the electron density (ED) of the tissues being irradiated is required. In the case of MV CBCT, it is necessary to determine a calibration-relating CT number to ED, utilizing the photon beam produced for MV CBCT. A number of different parameters can affect this calibration. This study was undertaken on the Siemens MV CBCT system, MVision, to evaluate the effect of the following parameters on the reconstructed CT pixel value to ED calibration: the number of monitor units (MUs) used (5, 8, 15 and 60 MUs), the image reconstruction filter (head and neck, and pelvis), reconstruction matrix size (256 by 256 and 512 by 512), and the addition of extra solid water surrounding the ED phantom. A Gammex electron density CT phantom containing EDs from 0.292 to 1.707 was imaged under each of these conditions. The linear relationship between MV CBCT pixel value and ED was demonstrated for all MU settings and over the range of EDs. Changes in MU number did not dramatically alter the MV CBCT ED calibration. The use of different reconstruction filters was found to affect the MV CBCT ED calibration, as was the addition of solid water surrounding the phantom. Dose distributions from treatment plans calculated with simulated image data from a 15 MU head and neck reconstruction filter MV CBCT image and a MV CBCT ED calibration curve from the image data parameters and a 15 MU pelvis reconstruction filter showed small and clinically insignificant differences. Thus, the use of a single MV CBCT ED calibration curve is unlikely to result in any clinical differences. However, to ensure minimal uncertainties in dose reporting, MV CBCT ED calibration measurements could be carried out using parameter-specific calibration measurements.

Near infrared (NIR) absorption spectra correlates with subchondral bone micro-CT parameters in osteoarthritic rat models

Determining the properties and integrity of subchondral bone in the developmental stages of osteoarthritis, especially in a form that can facilitate real-time characterization for diagnostic and decision-making purposes, is still a matter for research and development. This paper presents relationships between near infrared absorption spectra and properties of subchondral bone obtained from 3 models of osteoarthritic degeneration induced in laboratory rats via: (i) menisectomy (MSX); (ii) anterior cruciate ligament transaction (ACL); and (iii) intra-articular injection of mono-ido-acetate (1 mg) (MIA), in the right knee joint, with 12 rats per model group (N = 36). After 8 weeks, the animals were sacrificed and knee joints were collected. A custom-made diffuse reflectance NIR probe of diameter 5 mm was placed on the tibial surface and spectral data were acquired from each specimen in the wavenumber range 4000–12 500 cm− 1. After spectral acquisition, micro computed tomography (micro-CT) was performed on the samples and subchondral bone parameters namely: bone volume (BV) and bone mineral density (BMD) were extracted from the micro-CT data. Statistical correlation was then conducted between these parameters and regions of the near infrared spectra using multivariate techniques including principal component analysis (PCA), discriminant analysis (DA), and partial least squares (PLS) regression. Statistically significant linear correlations were found between the near infrared absorption spectra and subchondral bone BMD (R2 = 98.84%) and BV (R2 = 97.87%). In conclusion, near infrared spectroscopic probing can be used to detect, qualify and quantify changes in the composition of the subchondral bone, and could potentially assist in distinguishing healthy from OA bone as demonstrated with our laboratory rat models.

Representation of assertions in clinical free-­text using SNOMED CT

Information retrieval (IR) by clinicians in the healthcare setting is critical for informing clinical decision-making. However, a large part of this information is in the form of free-text and inhibits clinical decision support and effective healthcare services. This makes meaningful use of clinical free-­text in electronic health records (EHRs) for patient care a difficult task. Within the context of IR, given a repository of free-­text clinical reports, one might want to retrieve and analyse data for patients who have a known clinical finding.

The appearance and effects of metallic implants in CT images

Contemporary 3D radiotherapy treatment planning relies upon the use of 3D electron density maps derived from computed tomography (CT) scans of patient anatomy, to evaluate the effects of that anatomy on radiation dose distributions. Production of these electron density maps requires that the CT numbers (Hounsfield units) that quantify the attenuation of the x-ray beam by the patient’s anatomy must be reliably converted into electron densities, using a stable calibration relationship. This study investigates the fidelity of electron density assignment in the presence of metallic prostheses and implants.

Effect of CT electron density identification on Monte Carlo simulations of radiotherapeutic treatments

Introduction: The accurate identification of tissue electron densities is of great importance for Monte Carlo (MC) dose calculations. When converting patient CT data into a voxelised format suitable for MC simulations, however, it is common to simplify the assignment of electron densities so that the complex tissues existing in the human body are categorized into a few basic types. This study examines the effects that the assignment of tissue types and the calculation of densities can have on the results of MC simulations, for the particular case of a Siemen’s Sensation 4 CT scanner located in a radiotherapy centre where QA measurements are routinely made using 11 tissue types (plus air). Methods: DOSXYZnrc phantoms are generated from CT data, using the CTCREATE user code, with the relationship between Hounsfield units (HU) and density determined via linear interpolation between a series of specified points on the ‘CT-density ramp’ (see Figure 1(a)). Tissue types are assigned according to HU ranges. Each voxel in the DOSXYZnrc phantom therefore has an electron density (electrons/cm3) defined by the product of the mass density (from the HU conversion) and the intrinsic electron density (electrons /gram) (from the material assignment), in that voxel. In this study, we consider the problems of density conversion and material identification separately: the CT-density ramp is simplified by decreasing the number of points which define it from 12 down to 8, 3 and 2; and the material-type-assignment is varied by defining the materials which comprise our test phantom (a Supertech head) as two tissues and bone, two plastics and bone, water only and (as an extreme case) lead only. The effect of these parameters on radiological thickness maps derived from simulated portal images is investigated. Results & Discussion: Increasing the degree of simplification of the CT-density ramp results in an increasing effect on the resulting radiological thickness calculated for the Supertech head phantom. For instance, defining the CT-density ramp using 8 points, instead of 12, results in a maximum radiological thickness change of 0.2 cm, whereas defining the CT-density ramp using only 2 points results in a maximum radiological thickness change of 11.2 cm. Changing the definition of the materials comprising the phantom between water and plastic and tissue results in millimetre-scale changes to the resulting radiological thickness. When the entire phantom is defined as lead, this alteration changes the calculated radiological thickness by a maximum of 9.7 cm. Evidently, the simplification of the CT-density ramp has a greater effect on the resulting radiological thickness map than does the alteration of the assignment of tissue types. Conclusions: It is possible to alter the definitions of the tissue types comprising the phantom (or patient) without substantially altering the results of simulated portal images. However, these images are very sensitive to the accurate identification of the HU-density relationship. When converting data from a patient’s CT into a MC simulation phantom, therefore, all possible care should be taken to accurately reproduce the conversion between HU and mass density, for the specific CT scanner used. Acknowledgements: This work is funded by the NHMRC, through a project grant, and supported by the Queensland University of Technology (QUT) and the Royal Brisbane and Women's Hospital (RBWH), Brisbane, Australia. The authors are grateful to the staff of the RBWH, especially Darren Cassidy, for assistance in obtaining the phantom CT data used in this study. The authors also wish to thank Cathy Hargrave, of QUT, for assistance in formatting the CT data, using the Pinnacle TPS. Computational resources and services used in this work were provided by the HPC and Research Support Group, QUT, Brisbane, Australia.

Pixel value to electron density conversion for a Megavoltage Cone Beam CT System

Introduction: The motivation for developing megavoltage (and kilovoltage) cone beam CT (MV CBCT) capabilities in the radiotherapy treatment room was primarily based on the need to improve patient set-up accuracy. There has recently been an interest in using the cone beam CT data for treatment planning. Accurate treatment planning, however, requires knowledge of the electron density of the tissues receiving radiation in order to calculate dose distributions. This is obtained from CT, utilising a conversion between CT number and electron density of various tissues. The use of MV CBCT has particular advantages compared to treatment planning with kilovoltage CT in the presence of high atomic number materials and requires the conversion of pixel values from the image sets to electron density. Therefore, a study was undertaken to characterise the pixel value to electron density relationship for the Siemens MV CBCT system, MVision, and determine the effect, if any, of differing the number of monitor units used for acquisition. If a significant difference with number of monitor units was seen then pixel value to ED conversions may be required for each of the clinical settings. The calibration of the MV CT images for electron density offers the possibility for a daily recalculation of the dose distribution and the introduction of new adaptive radiotherapy treatment strategies. Methods: A Gammex Electron Density CT Phantom was imaged with the MVCB CT system. The pixel value for each of the sixteen inserts, which ranged from 0.292 to 1.707 relative electron density to the background solid water, was determined by taking the mean value from within a region of interest centred on the insert, over 5 slices within the centre of the phantom. These results were averaged and plotted against the relative electron densities of each insert with a linear least squares fit was preformed. This procedure was performed for images acquired with 5, 8, 15 and 60 monitor units. Results: The linear relationship between MVCT pixel value and ED was demonstrated for all monitor unit settings and over a range of electron densities. The number of monitor units utilised was found to have no significant impact on this relationship. Discussion: It was found that the number of MU utilised does not significantly alter the pixel value obtained for different ED materials. However, to ensure the most accurate and reproducible MV to ED calibration, one MU setting should be chosen and used routinely. To ensure accuracy for the clinical situation this MU setting should correspond to that which is used clinically. If more than one MU setting is used clinically then an average of the CT values acquired with different numbers of MU could be utilized without loss in accuracy. Conclusions: No significant differences have been shown between the pixel value to ED conversion for the Siemens MV CT cone beam unit with change in monitor units. Thus as single conversion curve could be utilised for MV CT treatment planning. To fully utilise MV CT imaging for radiotherapy treatment planning further work will be undertaken to ensure all corrections have been made and dose calculations verified. These dose calculations may be either for treatment planning purposes or for reconstructing the delivered dose distribution from transit dosimetry measurements made using electronic portal imaging devices. This will potentially allow the cumulative dose distribution to be determined through the patient’s multi-fraction treatment and adaptive treatment strategies developed to optimize the tumour response.

An X chromosome association scan of the Norfolk Island genetic isolate provides evidence for a novel migraine susceptibility locus at Xq12

Migraine is a common and debilitating neurovascular disorder with a complex envirogenomic aetiology. Numerous studies have demonstrated a preponderance of women affected with migraine and previous pedigree linkage studies in our laboratory have identified susceptibility loci on chromosome Xq24-Xq28. In this study we have used the genetic isolate of Norfolk Island to further analyse the X chromosome for migraine susceptibility loci. An association approach was employed to analyse 14,124 SNPs spanning the entire X chromosome. Genotype data from 288 individuals comprising a large core-pedigree, of which 76 were affected with migraine, were analysed. Although no SNP reached chromosome-wide significance (empirical α = 1×10−5) ranking by P-value revealed two primary clusters of SNPs in the top 25. A 10 SNP cluster represents a novel migraine susceptibility locus at Xq12 whilst a 11 SNP cluster represents a previously identified migraine susceptibility locus at Xq27. The strongest association at Xq12 was seen for rs599958 (OR = 1.75, P = 8.92×10−4), whilst at Xq27 the strongest association was for rs6525667 (OR = 1.53, P = 1.65×10−4). Further analysis of SNPs at these loci was performed in 5,122 migraineurs from the Women’s Genome Health Study and provided additional evidence for association at the novel Xq12 locus (P<0.05). Overall, this study provides evidence for a novel migraine susceptibility locus on Xq12. The strongest effect SNP (rs102834, joint P = 1.63×10−5) is located within the 5′UTR of the HEPH gene, which is involved in iron homeostasis in the brain and may represent a novel pathway for involvement in migraine pathogenesis.

A genome-wide scan provides evidence for loci influencing a severe heritable form of common migraine

Migraine is a prevalent neurovascular disease with a significant genetic component. Linkage studies have so far identified migraine susceptibility loci on chromosomes 1, 4, 6, 11, 14, 19 and X. We performed a genome-wide scan of 92 Australian pedigrees phenotyped for migraine with and without aura and for a more heritable form of “severe” migraine. Multipoint non-parametric linkage analysis revealed suggestive linkage on chromosome 18p11 for the severe migraine phenotype (LOD*=2.32, P=0.0006) and chromosome 3q (LOD*=2.28, P=0.0006). Excess allele sharing was also observed at multiple different chromosomal regions, some of which overlap with, or are directly adjacent to, previously implicated migraine susceptibility regions. We have provided evidence for two loci involved in severe migraine susceptibility and conclude that dissection of the “migraine” phenotype may be helpful for identifying susceptibility genes that influence the more heritable clinical (symptom) profiles in affected pedigrees. Also, we concluded that the genetic aetiology of the common (International Headache Society) forms of the disease is probably comprised of a number of low to moderate effect susceptibility genes, perhaps acting synergistically, and this effect is not easily detected by traditional single-locus linkage analyses of large samples of affected pedigrees.

Prospects for whole genome linkage disequilibrium mapping in domestic dog breeds

Linkage disequilibrium (LD) mapping is commonly used as a fine mapping tool in human genome mapping and has been used with some success for initial disease gene isolation in certain isolated in-bred human populations. An understanding of the population history of domestic dog breeds suggests that LD mapping could be routinely utilized in this species for initial genome-wide scans. Such an approach offers significant advantages over traditional linkage analysis. Here, we demonstrate, using canine copper toxicosis in the Bedlington terrier as the model, that LD mapping could be reasonably expected to be a useful strategy in low-resolution, genome-wide scans in pure-bred dogs. Significant LD was demonstrated over distances up to 33.3 cM. It is very unlikely, for a number of reasons discussed, that this result could be extrapolated to the rest of the genome. It is, however, consistent with the expectation given the population structure of canine breeds and, in this breed at least, with the hypothesis that it may be possible to utilize LD in a genome-wide scan. In this study, LD mapping confirmed the location of the copper toxicosis in Bedlington terrier gene (CT-BT) and was able to do so in a population that was refractory to traditional linkage analysis.

Characterisation of microvasulature changes after closed soft tissue trauma by contrast enhanced micro-CT imaging

INTRODUCTION It is known that the vascular morphology and functionality are changed following closed soft tissue trauma (CSTT) [1], and bone fractures [2]. The disruption of blood vessels may lead to hypoxia and necrosis. Currently, most clinical methods for the diagnosis and monitoring of CSTT with or without bone fractures are primarily based on qualitative measures or practical experience, making the diagnosis subjective and inaccurate. There is evidence that CSTT and early vascular changes following the injury delay the soft tissue tissue and bone healing [3]. However, a precise qualitative and quantitative morphological assessment of vasculature changes after trauma is currently missing. In this research, we aim to establish a diagnostic framework to assess the 3D vascular morphological changes after standardized CSTT in a rat model qualitatively and quantitatively using contrast-enhanced micro-CT imaging. METHODS An impact device was used for the application of a controlled reproducible CSTT to the left thigh (Biceps Femoris) of anaesthetized male Wistar rats. After euthanizing the animals at 6 hours, 24 hours, 3 days, 7 days, or 14 days after trauma, CSTT was qualitatively evaluated by macroscopic visual observation of the skin and muscles. For visualization of the vasculature, the blood vessels of sacrificed rats were flushed with heparinised saline and then perfused with a radio-opaque contrast agent (Microfil, MV 122, Flowtech, USA) using an infusion pump. After allowing the contrast agent to polymerize overnight, both hind-limbs were dissected, and then the whole injured and contra-lateral control limbs were imaged using a micro-CT scanner (µCT 40, Scanco Medical, Switzerland) to evaluate the vascular morphological changes. Correlated biopsy samples were also taken from the CSTT region of both injured and control legs. The morphological parameters such as the vessel volume ratio (VV/TV), vessel diameter (V.D), spacing (V.Sp), number (V.N), connectivity (V.Conn) and the degree of anisotropy (DA) were then quantified by evaluating the scans of biopsy samples using the micro-CT imaging system. RESULTS AND DISCUSSION A qualitative evaluation of the CSTT has shown that the developed impact protocols were capable of producing a defined and reproducible injury within the region of interest (ROI), resulting in a large hematoma and moderate swelling in both lateral and medial sides of the injured legs. Also, the visualization of the vascular network using 3D images confirmed the ability to perfuse the large vessels and a majority of the microvasculature consistently (Figure 1). Quantification of the vascular morphology obtained from correlated biopsy samples has demonstrated that V.D and V.N and V.Sp were significantly higher in the injured legs 24 hours after impact in comparison with the control legs (p<0.05). The evaluation of the other time points is currently progressing. CONCLUSIONS The findings of this research will contribute to a better understanding of the changes to the vascular network architecture following traumatic injuries and during healing process. When interpreted in context of functional changes, such as tissue oxygenation, this will allow for objective diagnosis and monitoring of CSTT and serve as validation for future non-invasive clinical assessment modalities.

A novel characterisation model for microvasulature changes following closed soft tissue trauma using micro-CT imaging

INTRODUCTION There is evidence that the reduction of blood perfusion caused by closed soft tissue trauma (CSTT) delays the healing of the affected soft tissues and bone [1]. We hypothesise that the characterisation of vascular morphology changes (VMC) following injury allows us to determine the effect of the injury on tissue perfusion and thereby the severity of the injury. This research therefore aims to assess the VMC following CSTT in a rat model using contrast-enhanced micro-CT imaging. METHODOLOGY A reproducible CSTT was created on the left leg of anaesthetized rats (male, 12 weeks) with an impact device. After euthanizing the animals at 6 and 24 hours following trauma, the vasculature was perfused with a contrast agent (Microfil, Flowtech, USA). Both hind-limbs were dissected and imaged using micro-CT for qualitative comparison of the vascular morphology and quantification of the total vascular volume (VV). In addition, biopsy samples were taken from the CSTT region and scanned to compare morphological parameters of the vasculature between the injured and control limbs. RESULTS AND DISCUSSION While the visual observation of the hindlimb scans showed consistent perfusion of the microvasculature with microfil, enabling the identification of all major blood vessels, no clear differences in the vascular architecture were observed between injured and control limbs. However, overall VV within the region of interest (ROI)was  measured to be higher for the injured limbs after 24h. Also, scans of biopsy samples demonstrated that vessel diameter and density were higher in the injured legs 24h after impact. CONCLUSION We believe these results will contribute to the development of objective diagnostic methods for CSTT based on changes to the microvascular morphology as well as aiding in the validation of future non-invasive clinical assessment modalities.

Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer

INTRODUCTION: Performance status (PS) 2 patients with non-small cell lung cancer (NSCLC) experience more toxicity, lower response rates, and shorter survival times than healthier patients treated with standard chemotherapy. Paclitaxel poliglumex (PPX), a macromolecule drug conjugate of paclitaxel and polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel and may lead to increased concentrations in tumors due to enhanced vascular permeability. METHODS: Chemotherapy-naive PS 2 patients with advanced NSCLC were randomized to receive carboplatin (area under the curve = 6) and either PPX (210 mg/m/10 min without routine steroid premedication) or paclitaxel (225 mg/m/3 h with standard premedication) every 3 weeks. The primary end point was overall survival. RESULTS: A total of 400 patients were enrolled. Alopecia, arthralgias/myalgias, and cardiac events were significantly less frequent with PPX/carboplatin, whereas grade ≥3 neutropenia and grade 3 neuropathy showed a trend of worsening. There was no significant difference in the incidence of hypersensitivity reactions despite the absence of routine premedication in the PPX arm. Overall survival was similar between treatment arms (hazard ratio, 0.97; log rank p = 0.769). Median and 1-year survival rates were 7.9 months and 31%, for PPX versus 8 months and 31% for paclitaxel. Disease control rates were 64% and 69% for PPX and paclitaxel, respectively. Time to progression was similar: 3.9 months for PPX/carboplatin versus 4.6 months for paclitaxel/carboplatin (p = 0.210). CONCLUSION: PPX/carboplatin failed to provide superior survival compared with paclitaxel/carboplatin in the first-line treatment of PS 2 patients with NSCLC, but the results with respect to progression-free survival and overall survival were comparable and the PPX regimen was more convenient. © 2008International Association for the Study of Lung Cancer.

Can SNOMED CT as implemented in New South Wales, Australia be used for road trauma injury surveillance in emergency departments?

The introduction of Systematized Nomenclature of Medicine - Clinical Terms (Snomed CT) for diagnosis coding in emergency departments (EDs) in New South Wales (NSW) has implications for injury surveillance abilities. This study aimed to assess the consequences of its introduction, as implemented as part of the ED information system in NSW, for identifying road trauma-related injuries in EDs. It involved a retrospective analysis of road trauma-related injuries identified in linked police, ED and mortality records during March 2007 to December 2009. Between 53.7% to 78.4% of all Snomed CT classifications in the principal provisional diagnosis field referred to the type of injury or symptom experienced by the individual. Of the road users identified by police, 3.2% of vehicle occupants, 6% of motorcyclists, 10.0% of pedal cyclists and 5.2% of pedestrians were identified using Snomed CT classifications in the principal provisional diagnosis field. The introduction of Snomed CT may provide flexible terminologies for clinicians. However, unless carefully implemented in information systems, its flexibility can lead to mismatches between the intention and actual use of defined data fields. Choices available in Snomed CT to indicate either symptoms, diagnoses, or injury mechanisms need to be controlled and these three concepts need to be retained in separate data fields to ensure a clear distinction between their classification in the ED.

Automatic classification of free-text radiology reports to identify limb fractures using machine learning and the SNOMED CT ontology

Objective To develop and evaluate machine learning techniques that identify limb fractures and other abnormalities (e.g. dislocations) from radiology reports. Materials and Methods 99 free-text reports of limb radiology examinations were acquired from an Australian public hospital. Two clinicians were employed to identify fractures and abnormalities from the reports; a third senior clinician resolved disagreements. These assessors found that, of the 99 reports, 48 referred to fractures or abnormalities of limb structures. Automated methods were then used to extract features from these reports that could be useful for their automatic classification. The Naive Bayes classification algorithm and two implementations of the support vector machine algorithm were formally evaluated using cross-fold validation over the 99 reports. Result Results show that the Naive Bayes classifier accurately identifies fractures and other abnormalities from the radiology reports. These results were achieved when extracting stemmed token bigram and negation features, as well as using these features in combination with SNOMED CT concepts related to abnormalities and disorders. The latter feature has not been used in previous works that attempted classifying free-text radiology reports. Discussion Automated classification methods have proven effective at identifying fractures and other abnormalities from radiology reports (F-Measure up to 92.31%). Key to the success of these techniques are features such as stemmed token bigrams, negations, and SNOMED CT concepts associated with morphologic abnormalities and disorders. Conclusion This investigation shows early promising results and future work will further validate and strengthen the proposed approaches.

Using pulse transit delay in Z-scan to discriminate between excited-state absorption and other nonlinear processes in ZnO nanocones

We report a new approach that uses the single beam Z-scan technique, to discriminate between excited state absorption (ESA) and two and three photon nonlinear absorption. By measuring the apparent delay or advance of the pulse in reaching the detector, the nonlinear absorption can be unambiguously identified as either instantaneous or transient. The simple method does not require a large range of input fluences or sophisticated pulse-probe experimental apparatus. The technique is easily extended to any absorption process dependent on pulse width and to nonlinear refraction measurements. We demonstrate in particular, that the large nonlinear absorption in ZnO nanocones when exposed to nanosecond 532 nm pulses, is due mostly to ESA, not pure two-photon absorption.