Remote EPID-based dosimetric auditing using DVH patient dose analysis.

Objective.The aim of this work was to develop and validate a method for remote dosimetric auditing that enables dose-volume histogram parameter comparisons of measured and planned dose in the patient CT volume.Approach. The method is derived by adapting and combining a remote electronic portal imaging (EPID) based auditing method (Virtual Epid based Standard Phantom Audit-VESPA) and a method to estimate 3D in-patient dose distributions from planar dosimetric measurements. The method was tested with a series of error-induced plans including monitor unit and multileaf collimator (MLC) positioning errors. A pilot audit study was conducted with eleven radiotherapy centres. IMRT plans from two clinical trials, a post-prostatectomy (RAVES trial) plan and a head and neck (HPV trial) plan were utilized. Clinically relevant DVH parameters for the planned dose and estimated measured dose were compared.Main results. The method was found to reproduce the induced dose errors within 0.5% and was sensitive to MLC positioning errors as small as 0.5 mm. For the RAVES plan audit all DVH results except one were within 3% and for the HPV plan audit all DVH results were within 3% except three with a maximum difference of 3.2%.Significance. The results from the audit method produce clinically meaningful DVH metrics for the audited plan and could enable an improved understanding of a centre's radiotherapy quality.

A high-performance method of deep learning for prostate MR-only radiotherapy planning using an optimized Pix2Pix architecture.

PURPOSE: The first aim was to generate and compare synthetic-CT (sCT) images using a conditional generative adversarial network (cGAN) method (Pix2Pix) for MRI-only prostate radiotherapy planning by testing several generators, loss functions, and hyper-parameters. The second aim was to compare the optimized Pix2Pix model with five other architectures (bulk-density, atlas-based, patch-based, U-Net, and GAN). METHODS: For 39 patients treated by VMAT for prostate cancer, T2-weighted MRI images were acquired in addition to CT images for treatment planning. sCT images were generated using the Pix2Pix model. The generator, loss function, and hyper-parameters were tuned to improve sCT image generation (in terms of imaging endpoints). The final evaluation was performed by 3-fold cross-validation. This method was compared to five other methods using the following imaging endpoints: the mean absolute error (MAE) and mean error (ME) between sCT and reference CT images (rCT) of the whole pelvis, bones, prostate, bladder, and rectum. For dose planning analysis, the dose-volume histogram metric differences and 3D gamma analysis (local, 1 %/1 mm) were calculated using the sCT and reference CT images. RESULTS: Compared with the other architectures, Pix2Pix with Perceptual loss function and generator ResNet 9 blocks showed the lowest MAE (29.5, 107.7, 16.0, 13.4, and 49.1 HU for the whole pelvis, bones, prostate, bladder, and rectum, respectively) and the highest gamma passing rates (99.4 %, using the 1 %/1mm and 10 % dose threshold criterion). Concerning the DVH points, the mean errors were -0.2% for the planning target volume V95%, 0.1 % for the rectum V70Gy, and -0.1 % for the bladder V50Gy. CONCLUSION: The sCT images generated from MRI data with the Pix2Pix architecture had the lowest image errors and similar dose uncertainties (in term of gamma pass-rate and dose-volume histogram metric differences) than other deep learning methods.

Investigation of a Novel Decision Support Metric for Head and Neck Adaptive Radiation Therapy Using a Real-Time In Vivo Portal Dosimetry System.

In adaptive radiation therapy of head and neck cancer, any significant anatomical changes observed are used to adapt the treatment plan to maintain target coverage without elevating the risk of xerostomia. However, the additional resources required for adaptive radiation therapy pose a challenge for broad-based implementation. It is hypothesized that a change in transit fluence is associated with volumetric change in the vicinity of the target and therefore can be used as a decision support metric for adaptive radiation therapy. This was evaluated by comparing the fluence with volumetric changes in 12 patients. Transit fluence was measured by an in vivo portal dosimetry system. Weekly cone beam computed tomography was used to determine volume change in the rectangular region of interest from condyloid process to C6. The integrated transit fluence through the region of interest on the day of the cone beam computed tomography scan was calculated with the first treatment as the baseline. The correlation between fluence change and volume change was determined. A logistic regression model was also used to associate the 5% region of interest volume reduction replanning trigger point and the fluence change. The model was assessed by a chi-square test. The area under the receiver-operating characteristic curve was also determined. A total of 46 pairs of measurements were obtained. The correlation between fluence and volumetric changes was found to be -0.776 (P value <.001). The negative correlation is attributed to the increase in the photon fluence transport resulting from the volume reduction. The chi-square of the logistic regression was found to be 17.4 (P value <.001). The area under the receiver-operating characteristic curve was found to be 0.88. Results indicate the change in transit fluence, which can be measured without consuming clinical resources or requiring additional time in the treatment room, can be used as a decision support metric for adaptive therapy.

Correlations between contouring similarity metrics and simulated treatment outcome for prostate radiotherapy.

Many similarity metrics exist for inter-observer contouring variation studies, however no correlation between metric choice and prostate cancer radiotherapy dosimetry has been explored. These correlations were investigated in this study. Two separate trials were undertaken, the first a thirty-five patient cohort with three observers, the second a five patient dataset with ten observers. Clinical and planning target volumes (CTV and PTV), rectum, and bladder were independently contoured by all observers in each trial. Structures were contoured on T2-weighted MRI and transferred onto CT following rigid registration for treatment planning in the first trial. Structures were contoured directly on CT in the second trial. STAPLE and majority voting volumes were generated as reference gold standard volumes for each structure for the two trials respectively. VMAT treatment plans (78 Gy to PTV) were simulated for observer and gold standard volumes, and dosimetry assessed using multiple radiobiological metrics. Correlations between contouring similarity metrics and dosimetry were calculated using Spearman's rank correlation coefficient. No correlations were observed between contouring similarity metrics and dosimetry for CTV within either trial. Volume similarity correlated most strongly with radiobiological metrics for PTV in both trials, including TCPPoisson (ρ = 0.57, 0.65), TCPLogit (ρ = 0.39, 0.62), and EUD (ρ = 0.43, 0.61) for each respective trial. Rectum and bladder metric correlations displayed no consistency for the two trials. PTV volume similarity was found to significantly correlate with rectum normal tissue complication probability (ρ = 0.33, 0.48). Minimal to no correlations with dosimetry were observed for overlap or boundary contouring metrics. Future inter-observer contouring variation studies for prostate cancer should incorporate volume similarity to provide additional insights into dosimetry during analysis.

Calpain-activated mTORC2/Akt pathway mediates airway smooth muscle remodelling in asthma.

BACKGROUND: Allergic asthma is characterized by inflammation and airway remodelling. Airway remodelling with excessive deposition of extracellular matrix (ECM) and larger smooth muscle mass are correlated with increased airway responsiveness and asthma severity. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodelling. However, the role of calpain in airway smooth muscle remodelling remains unknown. OBJECTIVE: To investigate the role of calpain in asthmatic airway remodelling as well as the underlying mechanism. METHODS: The mouse asthma model was made by ovalbumin sensitization and challenge. Calpain conditional knockout mice were studied in the model. Airway smooth muscle cells (ASMCs) were isolated from smooth muscle bundles in airway of rats. Cytokines IL-4, IL-5, TNF-α, and TGF-ß1, and serum from patients with asthma were selected to treated ASMCs. Collagen-I synthesis, cell proliferation, and phosphorylation of Akt in ASMCs were analysed. RESULTS: Inhibition of calpain using calpain knockout mice attenuated airway smooth muscle remodelling in mouse asthma models. Cytokines IL-4, IL-5, TNF-α, and TGF-ß1, and serum from patients with asthma increased collagen-I synthesis, cell proliferation, and phosphorylation of Akt in ASMCs, which were blocked by the calpain inhibitor MDL28170. Moreover, MDL28170 reduced cytokine-induced increases in Rictor protein, which is the most important component of mammalian target of rapamycin complex 2 (mTORC2). Blockage of the mTORC2 signal pathway prevented cytokine-induced phosphorylation of Akt, collagen-I synthesis, and cell proliferation of ASMCs and attenuated airway smooth muscle remodelling in mouse asthma models. CONCLUSIONS AND CLINICAL RELEVANCE: Our results indicate that calpain mediates cytokine-induced collagen-I synthesis and proliferation of ASMCs via the mTORC2/Akt signalling pathway, thereby regulating airway smooth muscle remodelling in asthma.

Motion prediction in MRI-guided radiotherapy based on interleaved orthogonal cine-MRI.

In-room cine-MRI guidance can provide non-invasive target localization during radiotherapy treatment. However, in order to cope with finite imaging frequency and system latencies between target localization and dose delivery, tumour motion prediction is required. This work proposes a framework for motion prediction dedicated to cine-MRI guidance, aiming at quantifying the geometric uncertainties introduced by this process for both tumour tracking and beam gating. The tumour position, identified through scale invariant features detected in cine-MRI slices, is estimated at high-frequency (25 Hz) using three independent predictors, one for each anatomical coordinate. Linear extrapolation, auto-regressive and support vector machine algorithms are compared against systems that use no prediction or surrogate-based motion estimation. Geometric uncertainties are reported as a function of image acquisition period and system latency. Average results show that the tracking error RMS can be decreased down to a [0.2; 1.2] mm range, for acquisition periods between 250 and 750 ms and system latencies between 50 and 300 ms. Except for the linear extrapolator, tracking and gating prediction errors were, on average, lower than those measured for surrogate-based motion estimation. This finding suggests that cine-MRI guidance, combined with appropriate prediction algorithms, could relevantly decrease geometric uncertainties in motion compensated treatments.

Calculating radiotherapy margins based on Bayesian modelling of patient specific random errors.

Collected real-life clinical target volume (CTV) displacement data show that some patients undergoing external beam radiotherapy (EBRT) demonstrate significantly more fraction-to-fraction variability in their displacement ('random error') than others. This contrasts with the common assumption made by historical recipes for margin estimation for EBRT, that the random error is constant across patients. In this work we present statistical models of CTV displacements in which random errors are characterised by an inverse gamma (IG) distribution in order to assess the impact of random error variability on CTV-to-PTV margin widths, for eight real world patient cohorts from four institutions, and for different sites of malignancy. We considered a variety of clinical treatment requirements and penumbral widths. The eight cohorts consisted of a total of 874 patients and 27 391 treatment sessions. Compared to a traditional margin recipe that assumes constant random errors across patients, for a typical 4 mm penumbral width, the IG based margin model mandates that in order to satisfy the common clinical requirement that 90% of patients receive at least 95% of prescribed RT dose to the entire CTV, margins be increased by a median of 10% (range over the eight cohorts -19% to +35%). This substantially reduces the proportion of patients for whom margins are too small to satisfy clinical requirements.

Amplified Ras-MAPK signal states correlate with accelerated EGFR internalization, cytostasis and delayed HER2 tumor onset in Fer-deficient model systems.

The non-receptor tyrosine kinase Fer belongs to a distinct subfamily of F-BAR domain containing kinases implicated in vesicular trafficking and signaling downstream of adhesion and growth factor receptors. Targeted inactivation of the fer gene in a transgenic mouse model of HER2(+), breast cancer was associated with delayed tumor onset and reduced proliferative rates in tumor cells. Fer deficiency was associated with increased rates of epidermal growth factor (EGF)-induced epidermal growth factor receptor (EGFR) internalization and amplified Ras-Raf-Mek-Erk (Ras-MAPK) signaling in primary mammary tumor epithelial cells, as well as increased cytotoxic and anti-proliferative sensitivity to the dual EGFR/HER2 inhibitor Lapatinib (LPN). These observations suggest a model in which accelerated ligand-induced EGFR internalization in Fer-deficient cells hypersensitizes the Ras-MAPK pathway to EGF, resulting in MAPK signal amplification to levels that induce cytostasis, rather than proliferation. Thus, Ras-MAPK cytostatic signaling delays HER2 tumor initiation and increases LPN cytotoxicity in Fer-deficient model systems. Taken together, these data suggest that targeting Fer alone, or in combination with LPN, may be of therapeutic benefit in HER2(+) breast cancer.

A novel function of HER2/Neu in the activation of G2/M checkpoint in response to γ-irradiation.

In response to γ-irradiation (IR)-induced DNA damage, activation of cell cycle checkpoints results in cell cycle arrest, allowing time for DNA repair before cell cycle re-entry. Human cells contain G1 and G2 cell cycle checkpoints. While G1 checkpoint is defective in most cancer cells, commonly due to mutations and/or alterations in the key regulators of G1 checkpoint (for example, p53, cyclin D), G2 checkpoint is rarely impaired in cancer cells, which is important for cancer cell survival. G2 checkpoint activation involves activation of ataxia telangiectasia-mutated (ATM)/ATM- and rad3-related (ATR) signalings, which leads to the inhibition of Cdc2 kinase and subsequent G2/M cell cycle arrest. Previous studies from our laboratory show that G2 checkpoint activation following IR exposure of MCF-7 breast cancer cells is dependent on the activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signaling. As HER receptor tyrosine kinases (RTKs), which have important roles in cell proliferation and survival, have been shown to activate ERK1/2 signaling in response to various stimuli, we investigated the role of HER RTKs in IR-induced G2/M checkpoint response in breast cancer cells. Results of the present studies indicate that IR exposure resulted in a striking increase in the phosphorylation of HER1, HER2, HER3 and HER4 in MCF-7 cells, indicative of activation of these proteins. Furthermore, specific inhibition of HER2 using an inhibitor, short hairpin RNA and dominant-negative mutant HER2 abolished IR-induced activation of ATM/ATR signaling, phosphorylation of Cdc2-Y15 and subsequent induction of G2/M arrest. Moreover, the inhibition of HER2 also abrogated IR-induced ERK1/2 phosphorylation. In contrast, inhibition of HER1 using specific inhibitors or decreasing expression of HER3 or HER4 using short hairpin RNAs did not block the induction of G2/M arrest following IR. These results suggest an important role of HER2 in the activation of G2/M checkpoint response following IR.

Calpain cleavage within dysferlin exon 40a releases a synaptotagmin-like module for membrane repair.

Dysferlin and calpain are important mediators of the emergency response to repair plasma membrane injury. Our previous research revealed that membrane injury induces cleavage of dysferlin to release a synaptotagmin-like C-terminal module we termed mini-dysferlinC72. Here we show that injury-activated cleavage of dysferlin is mediated by the ubiquitous calpains via a cleavage motif encoded by alternately spliced exon 40a. An exon 40a-specific antibody recognizing cleaved mini-dysferlinC72 intensely labels the circumference of injury sites, supporting a key role for dysferlinExon40a isoforms in membrane repair and consistent with our evidence suggesting that the calpain-cleaved C-terminal module is the form specifically recruited to injury sites. Calpain cleavage of dysferlin is a ubiquitous response to membrane injury in multiple cell lineages and occurs independently of the membrane repair protein MG53. Our study links calpain and dysferlin in the calcium-activated vesicle fusion of membrane repair, placing calpains as upstream mediators of a membrane repair cascade that elicits cleaved dysferlin as an effector. Of importance, we reveal that myoferlin and otoferlin are also cleaved enzymatically to release similar C-terminal modules, bearing two C2 domains and a transmembrane domain. Evolutionary preservation of this feature highlights its functional importance and suggests that this highly conserved C-terminal region of ferlins represents a functionally specialized vesicle fusion module.

MR simulation for prostate radiation therapy: effect of coil mounting position on image quality.

OBJECTIVE: To eliminate the effects of body deformation for MR-based prostate treatment planning, coil mounts are essential. In this study, we evaluated the effect of the coil set-up on image quality. METHODS: A custom-designed pelvic-shaped phantom was scanned by systematically increasing the anterior body-to-coil (BTC) distance from 30 to 90 mm. The image quality near the organs of interest was determined in order to characterize the relationship between image quality and BTC distance at the critical organ structures. The half intensity reduction (HIR) was calculated to determine the sensitivity of each organ structure to the BTC distance change. RESULTS: As the BTC distance increased, the uniformity reduced at 3% per millimetre. The HIR value indicated that the bladder signal is most sensitive to the change in BTC distance. By maintaining a constant BTC distance set-up, the intensity uniformity was improved by 28% along the B0 directions. CONCLUSION: Positioning the MRI coil on mounts can reduce body deformation but adversely degrades the image quality. The magnitude of this effect has been quantified for prostate MR simulation scanning. The coil needs to be positioned not only with a minimal but also uniform BTC distance in order to maximize image quality. ADVANCES IN KNOWLEDGE: A method to characterize the effect on image quality due to the use of coil mounts was demonstrated. Coil mounts whose height can be adjusted individually to keep BTC distance constant are necessary to maintain a uniform image across the entire field of view.

Simulation of real-time EPID images during IMRT using Monte-Carlo.

This study is part of a project concerned with real-time EPID-based verification of the incremental dose delivered during IMRT radiation treatments. Three automated Monte-Carlo methods are devised to calculate the differential dose delivered to the EPID during treatment. All methods break down the normalized total monitor units into a number of equally spaced segments. A method models the dynamic simulation as a series of static fields, each field corresponding to an IMRT segment or a sub-segment. Another method models each segment as a separate dynamic IMRT file. A third method, which modifies the DYNVMLC module of the BEAMnrc code, uses the full-MLC file. The MLC positions for the simulated photons are sequentially selected within DYNVMLC to correspond to individual segments of the delivery. A bash script calls the BEAM shared-library to calculate and store the EPID dose for each segment. Validation is performed by comparing the average dose contributed by all segments with the dose predicted by a canonical dynamic IMRT simulation that uses the same MLC file. The best results are achieved by the methods based on dynamic simulations (where leaf positions within a segment are interpolated for simulated photons) whose normalized root mean square error is at the most 0.2% over the focal area. EPID images can be predicted for individual segments (or smaller intervals) of an IMRT delivery using Monte-Carlo methods. The MLC file can be externally spliced or a simple modification of the DYNVMLC code can achieve accurate results.

Model-based prediction of portal dose images during patient treatment.

PURPOSE: Dosimetric verification of radiation therapy is crucial when delivering complex treatments like intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT. Pretreatment verification, characterized by methods applied without the patient present and before the treatment start date, is typically carried out at most centers. In vivo dosimetric verification, characterized by methods applied with the patient present, is not commonly carried out in the clinic. This work presents a novel, model-based EPID dosimetry method that could be used for routine clinical in vivo patient treatment verification. METHODS: The authors integrated a detailed fluence model with a patient scatter prediction model that uses a superposition of scatter energy fluence kernels, generated via Monte Carlo techniques, to determine patient scatter fluence delivered to the EPID. The total dose to the EPID was calculated using the sum of convolutions of the calculated energy fluence distribution entering the EPID with monoenergetic dose kernels, specific to the a-Si EPID. Measured images with simple, square fields delivered to slab phantoms were validated against predicted images. Measured and predicted images acquired during the delivery of IMRT fields to slabs and an anthropomorphic phantom were compared using the χ-comparison for 3% dose difference and 3 mm distance-to-agreement criteria. RESULTS: Predicted and measured images of the square fields with slabs in the field agreed within 2.5%. Predicted portal dose images of clinical IMRT fields delivered to slabs and an anthropomorphic phantom agreed with measured images within 3% and 3 mm for an average of at least 97% of the infield pixels (defined as >10% maximum field dose) for each case, over all fields. CONCLUSIONS: This work presents the first validation of the integration of a comprehensive fluence model with a patient and EPID radiation transport model that accounts for patient transmission, including complex factors such as patient scatter and the energy response of the a-Si detector. The portal dose image prediction model satisfies the 3% and 3 mm criteria for IMRT fields delivered to slab phantoms and could be used for patient treatment verification.

Finding the optimal statistical model to describe target motion during radiotherapy delivery--a Bayesian approach.

Early approaches to characterizing errors in target displacement during a fractionated course of radiotherapy assumed that the underlying fraction-to-fraction variability in target displacement, known as the 'treatment error' or 'random error', could be regarded as constant across patients. More recent approaches have modelled target displacement allowing for differences in random error between patients. However, until recently it has not been feasible to compare the goodness of fit of alternate models of random error rigorously. This is because the large volumes of real patient data necessary to distinguish between alternative models have only very recently become available. This work uses real-world displacement data collected from 365 patients undergoing radical radiotherapy for prostate cancer to compare five candidate models for target displacement. The simplest model assumes constant random errors across patients, while other models allow for random errors that vary according to one of several candidate distributions. Bayesian statistics and Markov Chain Monte Carlo simulation of the model parameters are used to compare model goodness of fit. We conclude that modelling the random error as inverse gamma distributed provides a clearly superior fit over all alternatives considered. This finding can facilitate more accurate margin recipes and correction strategies.

TU-E-BRA-02: A Method to Remove Support Arm Backscatter from EPID Images.

PURPOSE: To develop a method for removing the effect of support arm backscatter from Varian electronic portal imaging devices (EPIDs), improving the dosimetric abilities of the imager. METHODS: A physical, kernel based model of the backscatter signal produced during an exposure was developed. The model parameters were determined through an optimization process, comparing measured images without arm backscatter (EPID removed from arm) to measured images that include arm backscatter. The backscatter model was used to develop a backscatter correction process that removes the support arm backscatter from measured EPID images. The correction process was tested by applying the method to measured images of 17 rectangular asymmetric fields and comparing the Result to off-arm images. The same process was repeated with 42 IMRT fields. RESULTS: The backscatter removal process was able to effectively remove the arm backscatter from all of the measured images and accurately predict the measured off-arm images. Comparing the corrected images to the measured off-arm images, the mean absolute difference at the centre of each rectangular field was 0.29% (standard deviation 0.18%). This is an improvement over the uncorrected images which gave a mean difference of 1.01% (standard deviation 0.73%). The largest discrepancy observed with the corrected images was 0.6%, compared to 2.8% for the uncorrected images. Comparing the corrected IMRT images to the measured off-arm images, an overall mean gamma value of 0.28 (standard deviation 0.04) was found using 2%, 2mm criteria. Comparison of the uncorrected images to the measured off-arm images resulted in an overall mean gamma of 0.40 (standard deviation 0.10). CONCLUSIONS: A method for accurately and reliably removing the effect of support arm backscatter from EPID images has been developed and extensively tested. The method can be applied to any measured EPID image and does not require any additional information about the exposure.

SU-E-J-179: Requirements for the Accuracy of Electron Density Data Planning for MRI Based Cervix Cancer Treatment Planning.

PURPOSE: A sensitivity analysis of the effect of variations in electron density data (ED) on dose calculation accuracy for MRI based cervical cancer treatment planning. METHODS: Five cervical cancer patients were analysed in this work. Planning CT scans represented gold standard ED data. Standard four field 3DCRT plans (prescription 45Gy) were designed on these CT scans. The CT data was then manipulated to simulate the following methods of assigning ED to MRI; (1) homogenous bulk density corrections, (2) Bulk density correction to bones, (3) rigid image registration of CT to MR, and (4) regression analysis based pseudo CT. Plans were then generated on the manipulated data sets, and compared to the plans generated on the original. Dose was analysed using Chi analysis and equivalent uniform dose (EUD). Data was analysed to quantify (A) the effect on plan design (called optimisation error), and (B) the effect on dose calculation accuracy (systematic error). RESULTS: Analysis of the averaged patient results showed that for 3DCRT, the use of imperfect electron density data had minimal impact on plan design for all tested data sets. Analysis of systematic error showed minimal errors for cases (1), (2) and (3), where average errors of less than 0.3 Gy in EUD were recorded and Chi analysis showed that over 95% of points within the high dose region (D>36Gy) were within 2% or 2mm of the original dose. For case (4), errors greater than .5 Gy in EUD were recorded; these were not considered acceptable errors. CONCLUSIONS: Using imperfect electron density data for 3DCRT treatment planning for cervical cancer patients is feasible for appropriately considered choices of electron density assignment. Further analysis is needed to test this result for IMRT, and is ongoing.

SU-E-I-109: Sensitivity Analysis of an Electronic Portal Imaging Device Monte Carlo Model to Variations in Optical Transport Parameters.

PURPOSE: To investigate the sensitivity of a Monte Carlo (MC) model of a standard clinical amorphous silicon (a-Si) electron portal imaging device (EPID) to variations in optical photon transport parameters. METHODS: The Geant4 MC toolkit was used to develop a comprehensive model of an indirect-detection a-Si EPID incorporating x-ray and optical photon transport. The EPID was modeled as a series of uniform layers with properties specified by the manufacturer (PerkinElmer, Santa Clara, CA) of a research EPID at our centre. Optical processes that were modeled include bulk absorption, Rayleigh scattering, and boundary processes (reflection and refraction). Model performance was evaluated by scoring optical photons absorbed by the a-Si photodiode as a function of radial distance from a point source of x-rays on an event-by-event basis (0.025 mm resolution). Primary x-ray energies were sampled from a clinical 6 MV photon spectrum. Simulations were performed by varying optical transport parameters and the resulting point spread functions (PSFs) were compared. The optical parameters investigated include: x-ray transport cutoff thresholds; absorption path length; optical energy spectrum; refractive indices; and the 'roughness' of boundaries within phosphor screen layers. RESULTS: The transport cutoffs and refractive indices studied were found to minimally affect resulting PSFs. A monoenergetic optical spectrum slightly broadened the PSF in comparison with the use of a polyenergetic spectrum. The absorption path length only significantly altered the PSF when decreased drastically. Variations in the treatment of boundaries noticeably broadened resulting PSFs. CONCLUSIONS: Variation in optical transport parameters was found to affect resulting PSF calculations. Current work is focusing on repeating this analysis with a coarser resolution more typical of a commercial a-Si EPID to observe if these effects continue to alter the EPID PSF. Experimental measurement of the EPID line spread function to validate these results is also underway. Cancer Institute NSW Research Equipment Grants 10/REG/1-20 and 10/REG/1-10 Cancer Council NSW Grant, ID RG 11-06 NHMRC Project Grant, ID569211 The University of Sydney Postgraduate Research Scholarship in Medical Physics SWSCS Radiation Oncology Student Scholarship, 2012.

Long-term two-dimensional pixel stability of EPIDs used for regular linear accelerator quality assurance.

The long-term stability of three clinical electronic portal imaging devices (EPIDs) was studied to determine if longer times between calibrations can be justified. This would make alternatives to flood-field calibration of EPIDs clinically feasible, allowing for more effective use of EPIDs for dosimetry. Images were acquired monthly for each EPID as part of regular clinical quality assurance over a time period of approximately 3 years. The images were analysed to determine (1) the long-term stability of the EPID positioning system, (2) the dose response of the central pixels and (3) the long term stability of each pixel in the imager. The position of the EPID was found to be very repeatable with variations less than 0.3 pixels (0.27 mm) for all imagers (1 standard deviation). The central axis dose response was found to reliably track ion chamber measurements to better than 0.5%. The mean variation in pixel response (1 standard deviation), averaged over all pixels in the EPID, was found to be at most 0.6% for the three EPIDs studied over the entire period. More than 99% of pixels in each EPID showed less than 1% variation. Since the EPID response was found to be very stable over long periods of time, an annual calibration should be sufficient in most cases. More complex dosimetric calibrations should be clinically feasible.

The respiratory pathology in infants with sudden unexpected deaths in whom respiratory specimens were initially PCR-positive or PCR-negative for Bordetella pertussis.

BACKGROUND: In a previous controlled study, we investigated the relationship between Bordetella pertussis infections and sudden unexpected deaths among German infants (sudden infant death syndrome, SIDS). In this present study, we investigated further the respiratory pathology in a subset of infants in the original study. METHODS: Originally, there were 234 infants with SIDS and, of these, 12 had either a nasopharyngeal swab (NPS) or a tracheal swab specimen (TS) that was positive for B. pertussis by polymerase chain reaction (PCR). Here, tissue specimens from eight infants who were originally PCR-positive were compared with tissue specimens from seven infants in whom the original PCR studies were negative. RESULTS: The histopathologic diagnoses were as follows: 14 of 15 had pulmonary edema and the remaining case had early diffuse alveolar damage. Although 14 of 15 cases had some histologic or clinical evidence suggesting respiratory tract infection, the features were more consistent with a viral etiology, and in none were the findings typical of respiratory disease attributable to B. pertussis. CONCLUSIONS: The findings in this present investigation do not support a direct role of B. pertussis at the site of infection (ciliated epithelium) in the causation of SIDS. The clinical aspects of this study were carried out in the 1990s when pertussis was widespread in Germany. Therefore, the original finding of some PCR-positive cases is not surprising. The possibility that B. pertussis infection could still be a factor in some SIDS cases, e.g., by a systemic release of toxins, cannot be definitely ruled out.