Federated Learning Survival Model and Potential Radiotherapy Decision Support Impact Assessment for Non-small Cell Lung Cancer Using Real-World Data.

AIMS: The objective of this study was to develop a two-year overall survival model for inoperable stage I-III non-small cell lung cancer (NSCLC) patients using routine radiation oncology data over a federated (distributed) learning network and evaluate the potential of decision support for curative versus palliative radiotherapy. METHODS: A federated infrastructure of data extraction, de-identification, standardisation, image analysis, and modelling was installed for seven clinics to obtain clinical and imaging features and survival information for patients treated in 2011-2019. A logistic regression model was trained for the 2011-2016 curative patient cohort and validated for the 2017-2019 cohort. Features were selected with univariate and model-based analysis and optimised using bootstrapping. System performance was assessed by the receiver operating characteristic (ROC) and corresponding area under curve (AUC), C-index, calibration metrics and Kaplan-Meier survival curves, with risk groups defined by model probability quartiles. Decision support was evaluated using a case-control analysis using propensity matching between treatment groups. RESULTS: 1655 patient datasets were included. The overall model AUC was 0.68. Fifty-eight percent of patients treated with palliative radiotherapy had a low-to-moderate risk prediction according to the model, with survival times not significantly different (p = 0.87 and 0.061) from patients treated with curative radiotherapy classified as high-risk by the model. When survival was simulated by risk group and model-indicated treatment, there was an estimated 11% increase in survival rate at two years (p < 0.01). CONCLUSION: Federated learning over multiple institution data can be used to develop and validate decision support systems for lung cancer while quantifying the potential impact of their use in practice. This paves the way for personalised medicine, where decisions can be based more closely on individual patient details from routine care.

Dosimetric Impact of Delineation and Motion Uncertainties on the Heart and Substructures in Lung Cancer Radiotherapy.

AIMS: Delineation variations and organ motion produce difficult-to-quantify uncertainties in planned radiation doses to targets and organs at risk. Similar to manual contouring, most automatic segmentation tools generate single delineations per structure; however, this does not indicate the range of clinically acceptable delineations. This study develops a method to generate a range of automatic cardiac structure segmentations, incorporating motion and delineation uncertainty, and evaluates the dosimetric impact in lung cancer. MATERIALS AND METHODS: Eighteen cardiac structures were delineated using a locally developed auto-segmentation tool. It was applied to lung cancer planning CTs for 27 curative (planned dose ≥50 Gy) cases, and delineation variations were estimated by using ten mapping-atlases to provide separate substructure segmentations. Motion-related cardiac segmentation variations were estimated by auto-contouring structures on ten respiratory phases for 9/27 cases that had 4D-planning CTs. Dose volume histograms (DVHs) incorporating these variations were generated for comparison. RESULTS: Variations in mean doses (Dmean), defined as the range in values across ten feasible auto-segmentations, were calculated for each cardiac substructure. Over the study cohort the median variations for delineation uncertainty and motion were 2.20-11.09 Gy and 0.72-4.06 Gy, respectively. As relative values, variations in Dmean were between 18.7%-65.3% and 7.8%-32.5% for delineation uncertainty and motion, respectively. Doses vary depending on the individual planned dose distribution, not simply on segmentation differences, with larger dose variations to cardiac structures lying within areas of steep dose gradient. CONCLUSION: Radiotherapy dose uncertainties from delineation variations and respiratory-related heart motion were quantified using a cardiac substructure automatic segmentation tool. This predicts the 'dose range' where doses to structures are most likely to fall, rather than single DVH curves. This enables consideration of these uncertainties in cardiotoxicity research and for future plan optimisation. The tool was designed for cardiac structures, but similar methods are potentially applicable to other OARs.

Interspecies encounters with endemic health conditions: co-producing BVD and lameness with cows and sheep in the north of England.

This paper focuses on the relationships between people and farmed nonhuman animals, and between these animals and the farmed environments they encounter, in the enactment of interspecies endemic disease situations. It examines how the nonhuman embodied capacities, agency and subjectivities of cows and sheep on farms in the north of England make a difference to how the endemic conditions of lameness and bovine viral diarrhoea (BVD) are encountered and responded to by farmers and advisers. The paper draws on empirical research with farmers and their advisers, and explores three key, inter-related, themes: first, the importance of intersubjective relationships between people and animals on farms; second, the nonhuman components of the 'disease situations' associated with endemic diseases, including animals' embodied characteristics and behaviours and the relationships between bodies and environments on different farms; and finally the ways in which animal agency and resistance makes a difference to on-farm interventions aiming to prevent or treat lameness and BVD. The paper concludes by arguing that animals' capacities, and nonhuman difference, should be taken further into account in future policy and practice interventions in endemic disease in farmed animals.

Automated detection, delineation and quantification of whole-body bone metastasis using FDG-PET/CT images.

Non-small cell lung cancer (NSCLC) patients with the metastatic spread of disease to the bone have high morbidity and mortality. Stereotactic ablative body radiotherapy increases the progression free survival and overall survival of these patients with oligometastases. FDG-PET/CT, a functional imaging technique combining positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) and computer tomography (CT) provides improved staging and identification of treatment response. It is also associated with reduction in size of the radiotherapy tumour volume delineation compared with CT based contouring in radiotherapy, thus allowing for dose escalation to the target volume with lower doses to the surrounding organs at risk. FDG-PET/CT is increasingly being used for the clinical management of NSCLC patients undergoing radiotherapy and has shown high sensitivity and specificity for the detection of bone metastases in these patients. Here, we present a software tool for detection, delineation and quantification of bone metastases using FDG-PET/CT images. The tool extracts standardised uptake values (SUV) from FDG-PET images for auto-segmentation of bone lesions and calculates volume of each lesion and associated mean and maximum SUV. The tool also allows automatic statistical validation of the auto-segmented bone lesions against the manual contours of a radiation oncologist. A retrospective review of FDG-PET/CT scans of more than 30 candidate NSCLC patients was performed and nine patients with one or more metastatic bone lesions were selected for the present study. The SUV threshold prediction model was designed by splitting the cohort of patients into a subset of 'development' and 'validation' cohorts. The development cohort yielded an optimum SUV threshold of 3.0 for automatic detection of bone metastases using FDG-PET/CT images. The validity of the derived optimum SUV threshold on the validation cohort demonstrated that auto-segmented and manually contoured bone lesions showed strong concordance for volume of bone lesion (r = 0.993) and number of detected lesions (r = 0.996). The tool has various applications in radiotherapy, including but not limited to studies determining optimum SUV threshold for accurate and standardised delineation of bone lesions and in scientific studies utilising large patient populations for instance for investigation of the number of metastatic lesions that can be treated safety with an ablative dose of radiotherapy without exceeding the normal tissue toxicity.

Validation of a Fully Automated Hybrid Deep Learning Cardiac Substructure Segmentation Tool for Contouring and Dose Evaluation in Lung Cancer Radiotherapy.

BACKGROUND AND PURPOSE: Accurate and consistent delineation of cardiac substructures is challenging. The aim of this work was to validate a novel segmentation tool for automatic delineation of cardiac structures and subsequent dose evaluation, with potential application in clinical settings and large-scale radiation-related cardiotoxicity studies. MATERIALS AND METHODS: A recently developed hybrid method for automatic segmentation of 18 cardiac structures, combining deep learning, multi-atlas mapping and geometric segmentation of small challenging substructures, was independently validated on 30 lung cancer cases. These included anatomical and imaging variations, such as tumour abutting heart, lung collapse and metal artefacts. Automatic segmentations were compared with manual contours of the 18 structures using quantitative metrics, including Dice similarity coefficient (DSC), mean distance to agreement (MDA) and dose comparisons. RESULTS: A comparison of manual and automatic contours across all cases showed a median DSC of 0.75-0.93 and a median MDA of 2.09-3.34 mm for whole heart and chambers. The median MDA for great vessels, coronary arteries, cardiac valves, sinoatrial and atrioventricular conduction nodes was 3.01-8.54 mm. For the 27 cases treated with curative intent (planned target volume dose ≥50 Gy), the median dose difference was -1.12 to 0.57 Gy (absolute difference of 1.13-3.25%) for the mean dose to heart and chambers; and -2.25 to 4.45 Gy (absolute difference of 0.94-6.79%) for the mean dose to substructures. CONCLUSION: The novel hybrid automatic segmentation tool reported high accuracy and consistency over a validation set with challenging anatomical and imaging variations. This has promising applications in substructure dose calculations of large-scale datasets and for future studies on long-term cardiac toxicity.

Mid-treatment Fluorodeoxyglucose Positron Emission Tomography in Human Papillomavirus-related Oropharyngeal Squamous Cell Carcinoma Treated with Primary Radiotherapy: Nodal Metabolic Response Rate can Predict Treatment Outcomes.

AIMS: To evaluate whether biomarkers derived from fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) performed prior to (prePET) and during the third week (interim PET; iPET) of radiotherapy can predict treatment outcomes in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPC). MATERIALS AND METHODS: This retrospective analysis included 46 patients with newly diagnosed OPC treated with definitive (chemo)radiation and all patients had confirmed positive HPV status (HPV+OPC) based on p16 immunohistochemistry. The maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV) and total lesional glycolysis (TLG) of primary, index node (node with the highest TLG) and total lymph nodes and their median percentage (≥50%) reductions in iPET were analysed, and correlated with 5-year Kaplan-Meier and multivariable analyses (smoking, T4, N2b-3 and AJCC stage IV), including local failure-free survival, regional failure-free survival, locoregional failure-free survival (LRFFS), distant metastatic failure-free survival (DMFFS), disease-free survival (DFS) and overall survival. RESULTS: There was no association of outcomes with prePET parameters observed on multivariate analysis. A complete metabolic response of primary tumour was seen in 13 patients; the negative predictive value for local failure was 100%. More than a 50% reduction in total nodal MTV provided the best predictor of outcomes, including LRFFS (88% versus 47.1%, P = 0.006, hazard ratio = 0.153) and DFS (78.2% versus 41.2%, P = 0.01, hazard ratio = 0.234). More than a 50% reduction in index node TLG was inversely related to DMFFS: a better nodal response was associated with a higher incidence of distant metastatic failure (66.7% versus 100%, P = 0.009, hazard ratio = 3.0). CONCLUSION: The reduction (≥50%) of volumetric nodal metabolic burden can potentially identify a subgroup of HPV+OPC patients at low risk of locoregional failure but inversely at higher risk of distant metastatic failure and may have a role in individualised adaptive radiotherapy and systemic therapy.

Quantitative MRI: Defining repeatability, reproducibility and accuracy for prostate cancer imaging biomarker development.

INTRODUCTION: Quantitative MRI (qMRI) parameters have been increasingly used to develop predictive models to accurately monitor treatment response in prostate cancer after radiotherapy. To reliably detect changes in signal due to treatment response, predictive models require qMRI parameters with high repeatability and reproducibility. The purpose of this study was to measure qMRI parameter uncertainties in both commercial and in-house developed phantoms to guide the development of robust predictive models for monitoring treatment response. MATERIALS AND METHODS: ADC, T1, and R2* values were acquired across three 3 T scanners with a prostate-specific qMRI protocol using the NIST/ISMRM system phantom, RSNA/NIST diffusion phantom, and an in-house phantom. A B1 field map was acquired to correct for flip angle inhomogeneity in T1 maps. All sequences were repeated in each scan to assess within-session repeatability. Weekly scans were acquired on one scanner for three months with the in-house phantom. Between-session repeatability was measured with test-retest scans 6-months apart on all scanners with all phantoms. Accuracy, defined as percentage deviation from reference value for ADC and T1, was evaluated using the system and diffusion phantoms. Repeatability and reproducibility coefficients of variation (%CV) were calculated for all qMRI parameters on all phantoms. RESULTS: Overall, repeatability CV of ADC was <2.40%, reproducibility CV was <3.98%, and accuracy ranged between -8.0% to 2.7% across all scanners. Applying B1 correction on T1 measurements significantly improved the repeatability and reproducibility (p<0.05) but increased error in accuracy (p<0.001). Repeatability and reproducibility of R2* was <4.5% and <7.3% respectively in the system phantom across all scanners. CONCLUSION: Repeatability, reproducibility, and accuracy in qMRI parameters from a prostate-specific protocol was estimated using both commercial and in-house phantoms. Results from this work will be used to identify robust qMRI parameters for use in the development of predictive models to longitudinally monitor treatment response for prostate cancer in current and future clinical trials.

Pelvic organ motion and dosimetric implications during horizontal patient rotation for prostate radiation therapy.

PURPOSE: Gantry-free radiation therapy systems utilizing patient rotation would be simpler and more cost effective than the conventional gantry-based systems. Such a system could enable the expansion of radiation therapy to meet global demand and reduce capital costs. Recent advances in adaptive radiation therapy could potentially be applied to correct for gravitational deformation during horizontal patient rotation. This study aims to quantify the pelvic organ motion and the dosimetric implications of horizontal rotation for prostate intensity-modulated radiation therapy (IMRT) treatments. METHODS: Eight human participants who previously received prostate radiation therapy were imaged in a clinical magnetic resonance imaging (MRI) scanner using a bespoke patient rotation system (PRS). The patients were imaged every 45 degrees during a full roll rotation (0-360 degrees). Whole pelvic bone, prostate, rectum, and bladder motion were compared to the supine position using dice similarity coefficient (DSC) and mean absolute surface distance (MASD). Prostate centroid motion was compared in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) direction prior to and following pelvic bone-guided rigid registration. Seven-field prostate IMRT treatment plans were generated for each patient rotation angles under three adaption scenarios: No plan adaption, rigid planning target volume (PTV)-guided alignment to the prostate, and plan re-optimization. Prostate, rectum, and bladder doses were compared for each adaption scenario. RESULTS: Pelvic bone motion within the PRS of up to 53 mm relative to the supine position was observed for some participants. Internal organ motion was greatest at the 180-degree PRS couch angle (prone), with prostate centroid motion range < 2 mm LR, 0 mm to 14 mm SI, and -11 mm to 4 mm AP. Rotation with no adaption of the treatment plan resulted in an underdose to the PTV -- in some instances up to 75% (D95%: 78 ± 0.3 Gy at supine to 20 ± 15.0 Gy at the 225-degree PRS couch angle). Bladder dose was reduced during the rotation by up to 98% (V60 Gy: 15.0 ± 9.4% supine to 0.3 ± 0.5% at the 225-degree PRS couch angle). In some instances, the rectum dose increased during rotation (V60Gy: 20.0 ± 4.5% supine to 25.0 ± 15.0% at the 135-degree PRS couch angle). Rigid PTV-guided alignment resulted in PTV coverage which, though statistically lower (P < 0.05 for all D95% values), was within 1 Gy of the supine plans. Plan re-optimization resulted in a statistically equivalent PTV coverage compared to the supine plans (P > 0.05 for all D95% metrics and all within ±0.4 Gy). For both rigid PTV-guided alignment and plan re-optimization, rectum dose volume metrics were reduced compared to the supine position between the 90- and 225-degree PRS couch angles (P < 0.05). Bladder dose volume metrics were not impacted by rotation. CONCLUSION: Pelvic bone and internal organ motion are present during patient rotation. Rigid PTV-guided alignment to the prostate will be a requirement if prostate IMRT is to be safely delivered using patient rotation. Plan re-optimization for each PRS couch angle to account for anatomical deformations further improves the PTV coverage.

Anatomical deformation due to horizontal rotation: towards gantry-free radiation therapy.

Gantry-free radiation therapy systems may be simpler and more cost effective, particularly for MRI-guided photon or hadron therapy. This study aims to understand and quantify anatomical deformations caused by horizontal rotation with scan sequences sufficiently short to facilitate integration into an MRI-guided workflow. Rigid and non-rigid pelvic deformations due to horizontal rotation were quantified for a cohort of 8 healthy volunteers using a bespoke patient rotation system and a clinical MRI scanner. For each volunteer a reference scan was acquired at 0° followed by sequential faster scans in 45° increments through to 360°. All fast scans were registered to the 0° image via a three-step process: first, images were aligned using MR visible couch markers. Second, the scans were pre-processed then rigidly registered to the 0° image. Third, the rigidly registered scans were non-rigidly registered to the 0° image to assess soft tissue deformation. The residual differences after rigid and non-rigid registration were determined from the transformation matrix and the deformation vector field, respectively. The rigid registration yielded mean rotations of ⩽2.5° in all cases. The average 3D translational magnitudes range was 5.8 ± 2.9 mm-30.0 ± 11.0 mm. Translations were most significant in the left-right (LR) direction. Smaller translations were observed in the anterior-posterior (AP) and superior-inferior (SI) directions. The maximum deformation magnitudes range was: 10.0 ± 0.9 mm-28.0 ± 2.8 mm and average deformation magnitudes range: 2.3 ± 0.6 mm-7.5 ± 1.0 mm. Average non-rigid deformation magnitude was correlated with BMI (correlation coefficient 0.84, p  = 0.01). Rigid pelvic deformations were most significant in the LR direction but could be accounted for with on-line adjustments. Non-rigid deformations can be significant and will need to be accounted for in order to facilitate the delivery of gantry-free therapy with an automated patient rotation system.

Comparison of multi-institutional pre-treatment verification for VMAT of nasopharynx with delivery errors.

PURPOSE: Measurement-based pre-treatment verification with phantoms frequently uses gamma analysis to assess acceptable delivery accuracy. This study evaluates the sensitivity of a commercial system to simulated machine errors for three different institutions' Volumetric Modulated Arc Therapy (VMAT) planning approaches. METHODS: VMAT plans were generated for ten patients at three institutions using each institution's own protocol (manually-planned at institution 1; auto-planned at institutions 2 and 3). Errors in Multi-Leaf Collimator (MLC) field size (FS), MLC shift (S), and collimator angle (C) of -5, -2, -1, 1, 2 and 5 mm or degrees were introduced. Dose metric constraints discriminated which error magnitudes were considered unacceptable. The smallest magnitude error treatment plans deemed clinically unacceptable (typically for a 5% dose change) were delivered to the ArcCHECK for all institutions, and with a high-dose point ion chamber measurement in 2 institutions. Error detection for different gamma analysis criteria was compared. RESULTS: Not all deliberately introduced VMAT plan errors were detected using a typical 3D 3%/3 mm global gamma pass rate of 95%. Considering all institutions, gamma analysis was least sensitive to negative FS errors. The most sensitive was a 2%/2 mm global analysis for institution 1, whilst for institution 2 it was 3%/3 mm global analysis. The majority of errors (58/59 for institution 1, 54/60 for institution 3) were detected using ArcCHECK and ion chamber measurements combined. CONCLUSIONS: Not all clinically unacceptable errors are detected. Combining ion chamber measurements with gamma analysis improved sensitivity and is recommended. Optimum gamma settings varied across institutions.

A simple model for transit dosimetry based on a water equivalent EPID.

PURPOSE: The aim of this study was to demonstrate a new model for implementing a transit dosimetry system as a means of in vivo dose verification with a water equivalent electronic portal imaging device (WE-EPID) and a conventional treatment planning system (TPS). METHOD AND MATERIALS: A standard amorphous silicon (a-Si) EPID was modified to a WE-EPID configuration by replacing the metal-plate/phosphor screen situated above the photodiode detector with a 3 cm thick water equivalent plastic x ray converter material. A clinical TPS was used to calculate dose to the WE-EPID in its conventional EPID position behind the phantom/patient. The "extended phantom" concept was used to facilitate dose calculation at the EPID position, which is outside the CT field of view (FOV). The CT images were manipulated from 512 × 512 into 1024 × 1024 and padded pixels were assigned the density of air before importing to the TPS. The virtual WE-EPID was added as an RT structure of water density at the EPID plane. The accuracy of TPS dose calculations at the EPID plane in transit geometry was first evaluated for different field sizes and thickness of object in the beam by comparison with the dose measured using a 2D ion chamber array (ICA) and the WE-EPID. Following basic dose response tests, clinical fields including direct single fields (open and wedged) and modulated fields (integrated or control point by control point doses for VMAT) were measured for 6 MV photons with varying of solid water thickness or an anthropomorphic phantom present in beam. The EPID images were corrected for dark signal and pixel sensitivity and converted to dose using a single dose calibration factor. The 2D dose evaluation was conducted using 3%/3 and 2%/2 mm gamma-index criteria. RESULTS: The measured dose-response with the ICA and WE-EPID for all basic dose-response tests agreed with TPS dose calculations to within 1.5%. The maximum difference in dose profiles for the largest measured field size of 25 × 25 cm2 was 2.5%. Gamma evaluation showed at least 94% (3%/3 mm criteria) and 90% (2%/2 mm) agreement in both integrated and control-point doses for all clinical fields acquired by the WE-EPID and ICA when compared with TPS-calculated portal dose images. CONCLUSION: A new approach to transit dose verification has been demonstrated utilizing a water equivalent EPID and a commercial TPS. The accuracy of dose calculations at the EPID plane using a commercial TPS beam model was experimentally confirmed. The model proposed in this study provides an accurate method to directly verify doses delivered during treatment without the additional uncertainties inherent in modelling the complex dose-response of standard EPIDs.

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.

Deformable image registration for cervical cancer brachytherapy dose accumulation: Organ at risk dose-volume histogram parameter reproducibility and anatomic position stability.

PURPOSE: The purpose of this study was to determine the effect of deformable image registration (DIR) on cumulative organ at risk dose-volume histogram (DVH) parameter summation for more than three brachytherapy fractions. The reproducibility of different methods of DIR was tested. DIR was then used to assess the stability of the anatomic position of the DVH parameters within the bladder and rectum. METHODS AND MATERIALS: DIR was completed for 39 consecutive cervical cancer brachytherapy patients' planning CTs. Accumulated DVH parameters (D2cc and D0.1cc) for bladder and rectum were compared with dose summation without DIR. Reproducibility of DIR results was assessed for different methods of implementation based on adding contour biases added to the DIR algorithm. VolD2cc and VolD0.1cc structures were created from the overlap of the D2cc and D0.1cc isodose and the bladder or rectum, respectively. The overlap of VolD2cc and VolD0.1cc structures was calculated using the Dice similarity coefficient. RESULTS: DIR accumulated D2cc and D0.1cc decreased by an average of 2.9% and 4.2% for bladder and 5.08% and 2.8% for rectum compared with no DIR. DIR was most reproducible when the bladder or rectum contour was masked. The average Dice similarity coefficient was 0.78 and 0.61 for the bladder D2cc and D0.1cc as well as 0.83 and 0.62 for rectal D2cc and D0.1cc, respectively. CONCLUSIONS: Dose decreases were observed for accumulated DVH parameters using DIR. Adding contour-based biases to the algorithm increases the reproducibility of D2cc and D0.1cc accumulation. The anatomic position of VolD2cc was more stable than VolD0.1cc.

Defining and assessing an anisotropic delineation margin for modern radiotherapy.

PURPOSE: Uncertainty in target volume delineation for modern radiotherapy impacts dosimetry and patient outcomes. Delineation uncertainty is generally overlooked in practice as a source of error, potentially since historically, other uncertainties have been the main focus. This work defined and assessed an anisotropic delineation margin in both polar and spherical coordinate systems in order to account for the spatially varying nature of this uncertainty using a whole breast radiotherapy cohort as a proof of concept. METHODS: A cohort of 21 whole breast radiotherapy patient datasets with clinical target volumes delineated by eight independent observers was utilized. Patients were divided into categories based on target volume and laterality. An anisotropic delineation margin for each category was determined by multiplying the average standard deviation in observer contours in each category by a factor of two. Standard deviation was determined in both polar and spherical coordinates at angular increments. This anisotropic approach was compared to a conventional clinical approach, where the delineation margin was applied in the cardinal directions only. The assessment of the delineation margin was undertaken by comparing the encompassment of the observer volumes by the target volume with added margin. The extra, presumed healthy tissue included in the margin and the malignant tissue missed by the margin were determined. RESULTS: The proposed delineation margin is effective at accounting for inter-observer variation, producing >95% coverage of all CTVs for polar, spherical, and Cartesian margins in 82%, 79%, and 92% of cases, respectively. Additionally, <1% malignant tissue was missed for 65%, 70%, and 91% of cases and <37% healthy tissue was included in 95%, 89%, and 97% of cases. A conventional delineation margin approach is most appropriate for small and gold standard target volumes. However, for large target volumes, an anisotropic margin is necessary, producing significantly greater coverage of CTVs, including significantly less presumed healthy tissue and missing significantly less malignant tissue. CONCLUSIONS: All delineation margin methods that account for target volume and laterality proved to be adequate, with appropriate encompassment of interobserver variation and minimal inclusion of extra excess healthy tissue and exclusion of possible malignant tissue. The anisotropic approach was found to be superior to a conventional approach for target volumes >1400 cm3 only with significantly greater encompassment of interobserver variation, less missed malignant tissue and less included healthy tissue. This methodology has been validated for a whole breast radiotherapy cohort as a proof of concept, however could be applied to other anatomical sites.

Technical Note: Experimental results from a prototype high-field inline MRI-linac.

PURPOSE: The pursuit of real-time image guided radiotherapy using optimal tissue contrast has seen the development of several hybrid magnetic resonance imaging (MRI)-treatment systems, high field and low field, and inline and perpendicular configurations. As part of a new MRI-linac program, an MRI scanner was integrated with a linear accelerator to enable investigations of a coupled inline MRI-linac system. This work describes results from a prototype experimental system to demonstrate the feasibility of a high field inline MR-linac. METHODS: The magnet is a 1.5 T MRI system (Sonata, Siemens Healthcare) was located in a purpose built radiofrequency (RF) cage enabling shielding from and close proximity to a linear accelerator with inline (and future perpendicular) orientation. A portable linear accelerator (Linatron, Varian) was installed together with a multileaf collimator (Millennium, Varian) to provide dynamic field collimation and the whole assembly built onto a stainless-steel rail system. A series of MRI-linac experiments was performed to investigate (1) image quality with beam on measured using a macropodine (kangaroo) ex vivo phantom; (2) the noise as a function of beam state measured using a 6-channel surface coil array; and (3) electron contamination effects measured using Gafchromic film and an electronic portal imaging device (EPID). RESULTS: (1) Image quality was unaffected by the radiation beam with the macropodine phantom image with the beam on being almost identical to the image with the beam off. (2) Noise measured with a surface RF coil produced a 25% elevation of background intensity when the radiation beam was on. (3) Film and EPID measurements demonstrated electron focusing occurring along the centerline of the magnet axis. CONCLUSIONS: A proof-of-concept high-field MRI-linac has been built and experimentally characterized. This system has allowed us to establish the efficacy of a high field inline MRI-linac and study a number of the technical challenges and solutions.

The application of thermoluminescence dosimetry in X-ray energy discrimination.

Clinical dosimetry requires an understanding of radiation energy to accurately determine the delivered dose. For many situations this is known, however there are also many situations where the radiation energy is not well known, thus limiting dosimetric accuracy. This is the case in personnel dosimetry where thermo luminescent (TL) dosimetry is the method of choice. Traditionally beam energy characteristics in personnel dosimetry are determined through discrimination with the use of various filters fitted within a radiation monitor. The presence of scattered and characteristic radiation produced by these metallic filters, however, can compromise the results. In this study the TL response of five materials TLD100, TLD100H, TLD200, TLD400 and TLD500, was measured at various X-ray energies. The TL sensitivity ratio for various combinations of materials as a function of X-ray energy was calculated. The results indicate that in personal dosimetry a combination of three or more TL detector system has a better accuracy of estimation of effective radiation energy of an X-ray beam than some of the current method of employed for energy estimation and has the potential to improve the accuracy in dose determination in a variety of practical situations. The development of this method also has application in other fields including quality assurance of the orthovoltage therapy machines, dosimetry intercomparisons of kilovoltage X-ray beams, and measurement of the dose to critical organs outside a treatment field of a megavoltage therapy beam.

An assessment of image distortion and CT number accuracy within a wide-bore CT extended field of view.

Although wide bore computed tomography (CT) scanners provide increased space for patients, the scan field of view (sFOV) remains considerably smaller than the bore size. Consequently, patient anatomy which spans beyond the sFOV is truncated and the information is lost. As a solution, some manufacturers provide the capacity to reconstruct CT images from a partial dataset at an extended field of view (eFOV). To assess spatial distortion within this eFOV three phantoms were considered a 30 × 30 × 20 cm(3) slab of solid water, the Gammex electron density CT phantom and a female anthropomorphic phantom. For each phantom, scans were taken centrally within the sFOV as a reference image and with the phantom edge extended at 1 cm intervals from 0 to 5 cm beyond the sFOV into the eFOV. To assess CT number accuracy various tissue equivalent materials were scanned in the eFOV and resulting CT numbers were compared to inserts scanned within the sFOV. For all phantom geometries, objects within the eFOV were geometrically overestimated with elongation of phantom shapes into the eFOV. The percentage increase in size ranged from 0.22 to 15.94 % over all phantoms considered. The difference between eFOV and sFOV CT numbers was dependent upon insert density. The eFOV underestimated CT numbers in the range of -127 to -230 HU for soft tissue densities and -278 to -640 for bone densities. This trend reversed for low tissue densities with the CT numbers in the eFOV being overestimated by 100-130 HU for lung equivalent inserts. Initial correlation between eFOV and sFOV CT numbers was seen and a correction function was successfully applied to better estimate the CT number representative of that seen within the sFOV.

Quantitative evaluation of diffusion-weighted imaging techniques for the purposes of radiotherapy planning in the prostate.

OBJECTIVE: Diffusion-weighted imaging (DWI) is an important technique for the localization of prostate cancer, and its response assessment during treatment with radiotherapy (RT). However, it has known limitations in terms of distortions and artefacts using standard acquisition techniques. This study evaluates two alternative methods that offer the promise of improved image quality and the potential for more reliable and consistent diffusion data. METHODS: Three DWI techniques were investigated; single-shot echoplanar imaging (EPI), EPI combined with reduced volume excitation (ZOOMit; Siemens Healthcare, Erlangen, Germany) and read-out segmentation with navigator-echo correction (RESOLVE; Siemens Healthcare). Daily measurements of apparent diffusion coefficient (ADC) value were made in a quality assurance phantom to assess the repeatability of each sequence. In order to evaluate the geometric integrity of these sequences, ten normal volunteers were scanned, and the prostate was contoured to compare its similarity with T2 weighted images. RESULTS: Phantom ADC values were significantly higher using the standard EPI sequence than those of the other two sequences. Differences were also observed between sequences in terms of repeatability, with RESOLVE and EPI performing better than ZOOMit. Overall, the RESOLVE sequence provided the best agreement for the in vivo data with smaller differences in volume and higher contour similarity than T2 weighted imaging. CONCLUSION: Important differences have been observed between each of the three techniques investigated with RESOLVE performing the best overall. We have adopted this sequence for routine RT simulation of prostate patients at Liverpool Cancer Therapy Centre. ADVANCES IN KNOWLEDGE: This work will be of interest to the increasing number of centres wanting to incorporate quantitative DWI in a clinical setting.

Alpha-thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation - c.109C>T (p.R37X).

Alpha-thalassemia intellectual disability, one of the recognizable X-linked disability syndromes, is characterized by short stature, microcephaly, distinctive facies, hypotonic appearance, cardiac and genital anomalies, and marked skewing of X-inactivation in female carriers. With the advent of next generation sequencing, mutations have been identified that result in less severe phenotypes lacking one or more of these phenotypic manifestations. Here we report five unrelated kindreds in which a c.109C>T (p.R37X) mutation segregates with a variable but overall milder phenotype. The distinctive facial appearance of alpha-thalassemia intellectual disability was present in only one of the 18 affected males evaluated beyond the age of puberty, although suggestive facial appearance was present in several during infancy or early childhood. Although the responsible genetic alteration is a nonsense mutation in exon 2 of ATRX, the phenotype appears to be partially rescued by the production of alternative transcripts and/or other molecular mechanisms.