4D Monte Carlo dose reconstructions using surface motion measurements.

PURPOSE: To investigate the feasibility of a 4D Monte Carlo based dose reconstruction method to study the dosimetric impact of respiratory motion using surface motion measurements for patients undergoing VMAT treatments for Non-Small Cell Lung Cancer. METHODS: The 4Ddefdosxyznrc/EGSnrc algorithm was used to reconstruct VMAT doses delivered to the patients using machine log files and respiratory traces measured with the RADPOS 4D dosimetry system. The RADPOS sensor was adhered to the patient's abdomen prior to each treatment fraction and its position was used as a surrogate for tumour motion. Treatment log files were synchronized with the patient respiratory traces. Patient specific respiratory models were generated from deformable registration of the inhale and exhale 4DCT images and the respiratory traces. The reconstructed doses were compared to planned doses calculated with DOSXYZnrc/EGSnrc on the average-intensity and the exhale phase CT images. RESULTS: Respiratory motion measurements and log files were acquired for 2 patients over 5 treatment fractions each. The motion was predominantly along the anterior/posterior direction (A/P). The average respiratory amplitudes were 8.7 ± 2.7 mm and 10.0 ± 1.2 mm for Patient 1 and 2, respectively. Both patients displayed inter- and intra-fractional variations in the baseline position. Small inter-fractional differences were observed in the reconstructed doses for each patient. Differences between the reconstructed and planned doses were attributed to differences in organ volumes. CONCLUSION: The 4D reconstruction method was successfully implemented for the two patients studied. Small differences between the planned and reconstructed doses were observed due to the small tumour motion of these patients.

The role of glycoconjugates as receptors for insecticidal proteins.

Bacillus thuringiensis (Bt) proteins are an environmentally safe and effective alternative to chemical pesticides and have been used as biopesticides, with great commercial success, for over 50 years. Global agricultural production is predicted to require a 70% increase until 2050 to provide for an increasing population. In addition to agriculture, Bt proteins are utilized to control human vectors of disease-namely mosquitoes-which account for >700 000 deaths annually. The evolution of resistance to Bt pesticial toxins threatens the progression of sustainable agriculture. Whilst Bt protein toxins are heavily utilized, the exact mechanisms behind receptor binding and toxicity are unknown. It is critical to gain a better understanding of these mechanisms in order to engineer novel toxin variants and to predict, and prevent, future resistance evolution. This review focuses on the role of carbohydrate binding in the toxicity of the most utilized group of Bt pesticidal proteins-three domain Cry (3D-Cry) toxins.

ALERT-RA: an aperture library-enabled real-time respiratory motion adaptive framework for 4D-VMAT.

PURPOSE: To develop a framework for robust optimization of real-time respiratory motion adaptive VMAT treatment plans, and to evaluate the robustness of resulting plans to variations in tumor trajectory during delivery. METHODS: The proposed framework is called aperture library-enabled real-time robust adaptation (ALERT-RA). A patient-specific library of optimized MLC apertures is defined for each combination of gantry angle and respiratory phase. The method assumes that the tumor is tracked in real-time throughout delivery, and the aperture corresponding to the current phase and gantry angle will be delivered. The aperture library is optimized by considering all possible tumor trajectories determined by a probabilistic respiratory motion model. Plan robustness to trajectory variations was evaluated by sampling a trajectory, and determining the corresponding dose, from the respiratory model for each fraction. The cumulative dose of the full treatment course was simulated 50 times. Percentile dose-volume histograms (PDVHs) were computed from these simulated treatments. The resulting plan quality and robustness of this method were compared to other previously published motion 4D-VMAT methods, including: an optimized tracking approach that assumes reproducible tumor motion, conformal tracking with aperture deformation, and a motion-encompassing method. Two fractionation schemes were tested to determine the possible effect on robustness: a conventional fractionation of 66 Gy in 33 fractions, and an SBRT course with 60 Gy in 5 fractions. RESULTS: When considering target coverage, the ALERT-RA method was found to produce a plan which was more robust than those produced using the optimized or conformal tracking methods. Using the PDVH analysis, the 5th and 95th percentiles of the prescription dose volume for the conventionally fractioned plan were found to be (respectively) 79% and 82% for the optimized tracking approach, 81% and 83% for the conformal tracking approach, and 92% and 97% using the new ALERT-RA method. The motion-encompassing plan was slightly more robust than the ALERT-RA plan, with 5th and 95th percentiles at 94% and 95%, respectively. This came at a cost of higher dose to OARs, with the volume of lung receiving 5 Gy or more equal to 48% for the motion-encompassing plan versus 44% for the ALERT-RA plan. For the SBRT plan, the conformal tracking plan was similarly not robust, with 5th and 95th percentiles of the prescription dose volume equal to 88% and 89%. The optimized tracking SBRT plan gave values of 93% and 95%, and the motion-encompassing plan 94% and 95%, while the ALERT-RA gave values of 93% and 96%. The volume of lung receiving 20 Gy or more was slightly higher for the optimized tracking and motion-encompassing plans compared to the ALERT-RA plan, at 15%, 15%, and 14%, respectively. CONCLUSIONS: Compared to other motion-adaptive VMAT approaches, the ALERT-RA algorithm is capable of delivering high-quality plans which are robust to variations in tumor motion trajectories.

A Comparative Analysis of Drug Therapy, Disease Phenotype, and Health Care Outcomes for Men and Women with Inflammatory Bowel Disease.

BACKGROUND: Sex and gender refer to biological and social differences between men and women. While well-evaluated in other disciplines, their roles in inflammatory bowel disease (IBD) are not well-defined. This study aimed to characterize differences in healthcare outcomes in men and women with IBD. METHODS: A retrospective single-centre cohort study was conducted to evaluate differences between men and women receiving care for Crohn's disease (CD) and ulcerative colitis (UC) at the Western University Personalized Medicine Clinic from March 2012 to September 2019. The primary endpoint was the proportion of IBD drugs used for all drug classes. Additional outcomes in healthcare utilization and disease phenotype were assessed. Student's t test and Fisher's exact test were used to assess differences RESULTS: A total of 1015 participants were included (CD = 656; UC = 359). In UC and CD, 47.9% and 59.0% were women, respectively. Overall, women were more likely prescribed budesonide than men (23.6% vs. 13.4%; p < 0.0001), while more men were exposed to prednisone for IBD management (73.5% vs. 67.4%; p = 0.04). Immunomodulator use was higher in men with CD versus women (86.6% vs. 78.3%; p = 0.008) and of those exposed, women more commonly experienced ADRs (29.5% vs. 21.2%; p = 0.01). Though no sex-related difference was identified, age was a predictor of biologic exposure in women with CD and men with UC, with those > 55 being less likely to receive biologics. CONCLUSIONS: These findings highlight differences in disease course and treatment approaches between men and women with IBD and support the consideration of sex and gender when researching disease outcomes.

Implementation and experimental validation of a robust hybrid direct aperture optimization approach for mixed-beam radiotherapy.

PURPOSE: The objectives of the work presented in this paper were to (1) implement a robust-optimization method for deliverable mixed-beam radiotherapy (MBRT) plans within a previously developed MBRT planning framework; (2) perform an experimental validation of the delivery of robust-optimized MBRT plans; and (3) compare PTV-based and robust-optimized MBRT plans in terms of target dose robustness and organs at risk (OAR) sparing for clinical head and neck and brain patient cases. METHODS: A robust-optimization method, which accounts for translational setup errors, was implemented within a previously developed treatment planning framework for MBRT. The framework uses a hybrid direct aperture optimization method combining column generation and simulated annealing. A robust plan was developed and then delivered to an anthropomorphic head phantom using the Developer Mode of a TrueBeam linac. Planar dose distributions were measured and compared to the planned dose. Robust-optimized and PTV-based plans were developed for three clinical patient cases consisting of two head and neck cases and one brain case. The plans were compared in terms of the robustness to 5 mm shifts of the target volume dose as well as in terms of OAR sparing. RESULTS: Using a gamma criterion of 3%/2 mm and a dose threshold of 10%, the agreement between film measurements and dose calculations was better than 97.7% for the total plan and better than 95.5% for the electron component of the plan. For the two head and neck patient cases, the average clinical target volume (CTV) dose homogeneity index (V95%-V107%) over all the considered setup error scenarios was on average 19% lower for the PTV-based plans and it had a larger standard deviation. The robust-optimized plans achieved, on average, a 20% reduction in the OAR doses compared to the PTV-based plans. For the brain patient case, the CTV dose homogeneity index was similar for the two plans, while the OAR doses were 22% lower, on average, for the robust-optimized plan. No clear trend in terms of electron contributions was found across the three patient cases, although robust-optimized plans tended toward higher electron beam energies. CONCLUSIONS: A framework for robust optimization of deliverable MBRT plans has been developed and validated. PTV-based MBRT were found to not be robust to setup errors, while the dose delivered by the robust-optimized plans were clinically acceptable for all considered error scenarios and had better OAR sparing. This study shows that the robust optimization is a promising alternative to conventional PTV margins for MBRT.

Hypergraph models of biological networks to identify genes critical to pathogenic viral response.

BACKGROUND: Representing biological networks as graphs is a powerful approach to reveal underlying patterns, signatures, and critical components from high-throughput biomolecular data. However, graphs do not natively capture the multi-way relationships present among genes and proteins in biological systems. Hypergraphs are generalizations of graphs that naturally model multi-way relationships and have shown promise in modeling systems such as protein complexes and metabolic reactions. In this paper we seek to understand how hypergraphs can more faithfully identify, and potentially predict, important genes based on complex relationships inferred from genomic expression data sets. RESULTS: We compiled a novel data set of transcriptional host response to pathogenic viral infections and formulated relationships between genes as a hypergraph where hyperedges represent significantly perturbed genes, and vertices represent individual biological samples with specific experimental conditions. We find that hypergraph betweenness centrality is a superior method for identification of genes important to viral response when compared with graph centrality. CONCLUSIONS: Our results demonstrate the utility of using hypergraphs to represent complex biological systems and highlight central important responses in common to a variety of highly pathogenic viruses.

Biological and therapeutic implications of a unique subtype of NPM1 mutated AML.

In acute myeloid leukemia (AML), molecular heterogeneity across patients constitutes a major challenge for prognosis and therapy. AML with NPM1 mutation is a distinct genetic entity in the revised World Health Organization classification. However, differing patterns of co-mutation and response to therapy within this group necessitate further stratification. Here we report two distinct subtypes within NPM1 mutated AML patients, which we label as primitive and committed based on the respective presence or absence of a stem cell signature. Using gene expression (RNA-seq), epigenomic (ATAC-seq) and immunophenotyping (CyToF) analysis, we associate each subtype with specific molecular characteristics, disease differentiation state and patient survival. Using ex vivo drug sensitivity profiling, we show a differential drug response of the subtypes to specific kinase inhibitors, irrespective of the FLT3-ITD status. Differential drug responses of the primitive and committed subtype are validated in an independent AML cohort. Our results highlight heterogeneity among NPM1 mutated AML patient samples based on stemness and suggest that the addition of kinase inhibitors to the treatment of cases with the primitive signature, lacking FLT3-ITD, could have therapeutic benefit.

Validation of 4D Monte Carlo dose calculations using a programmable deformable lung phantom.

PURPOSE: To validate the accuracy of 4D Monte Carlo (4DMC) simulations to calculate dose deliveries to a deforming anatomy in the presence of realistic respiratory motion traces. A previously developed deformable lung phantom comprising an elastic tumor was modified to enable programming of arbitrary motion profiles. 4D simulations of the dose delivered to the phantom were compared with the measurements. METHODS: The deformable lung phantom moving with irregular breathing patterns was irradiated using static and VMAT beam deliveries. Using the RADPOS 4D dosimetry system, point doses were measured inside and outside the tumor. Dose profiles were acquired using films along the motion path of the tumor (S-I). In addition to dose measurements, RADPOS was used to record the motion of the tumor during dose deliveries. Dose measurements were then compared against 4DMC simulations with EGSnrc/4DdefDOSXYZnrc using the recorded tumor motion. RESULTS: The agreements between dose profiles from measurements and simulations were determined to be within 2%/2 mm. Point dose agreements were within 2σ of experimental and/or positional/dose reading uncertainties. 4DMC simulations were shown to accurately predict the sensitivity of delivered dose to the starting phase of breathing motions. We have demonstrated that our 4DMC method, combined with RADPOS, can accurately simulate realistic dose deliveries to a deforming anatomy moving with realistic breathing traces. This 4DMC tool has the potential to be used as a quality assurance tool to verify treatments involving respiratory motion. Adaptive treatment delivery is another area that may benefit from the potential of this 4DMC tool.

Basolateral Amygdala Drives a GPCR-Mediated Striatal Memory Necessary for Predictive Learning to Influence Choice.

Predictive learning exerts a powerful influence over choice between instrumental actions. Nevertheless, how this learning is encoded in a sufficiently stable manner to influence choices that can occur much later in time is unclear. Here, we report that the basolateral amygdala (BLA) encodes predictive learning and establishes the memory necessary for future choices by driving the accumulation of delta-opioid receptors (DOPRs) on the somatic membrane of cholinergic interneurons in the nucleus accumbens shell (NAc-S). We found that the BLA controls DOPR accumulation via its influence on substance P release in the NAc-S, and that although DOPR accumulation is not necessary for predictive learning per se, it is necessary for the influence of this learning on later choice between actions. This study uncovers, therefore, a novel GPCR-based form of memory that is established by predictive learning and is necessary for such learning to guide the selection and execution of specific actions.

Monte Carlo and analytic modeling of an Elekta Infinity linac with Agility MLC: Investigating the significance of accurate model parameters for small radiation fields.

PURPOSE: To explain the deviation observed between measured and Monaco calculated dose profiles for a small field (i.e., alternating open-closed MLC pattern). A Monte Carlo (MC) model of an Elekta Infinity linac with Agility MLC was created and validated against measurements. In addition, an analytic model which predicts the fluence at the isocenter plane was used to study the impact of multiple beam parameters on the accuracy of dose calculations for small fields. METHODS: A detailed MC model of a 6 MV Elekta Infinity linac with Agility MLC was created in EGSnrc/BEAMnrc and validated against measurements. An analytic model using primary and secondary virtual photon sources was created and benchmarked against the MC simulations and the impact of multiple beam parameters on the accuracy of the model for a small field was investigated. Both models were used to explain discrepancies observed between measured/EGSnrc simulated and Monaco calculated dose profiles for alternating open-closed MLC leaves. RESULTS: MC-simulated dose profiles (PDDs, cross- and in-line profiles, etc.) were found to be in very good agreements with measurements. The best fit for the leaf bank rotation was found to be 9 mrad to model the defocusing of Agility MLC. Moreover, a very good agreement was observed between results from the analytic model and MC simulations for a small field. Modifying the radial size of the incident electron beam in the BEAMnrc model improved the agreement between Monaco and EGSnrc calculated dose profiles by approximately 16% and 30% in the position of maxima and minima, respectively. CONCLUSION: Accurate modeling of the full-width-half-maximum (FWHM) of the primary photon source as well as the MLC leaf design (leaf bank rotation, etc.) is essential for accurate calculations of dose delivered by small radiation fields when using virtual source or MC models of the beam.

Continuous aperture dose calculation and optimization for volumetric modulated arc therapy.

Although VMAT delivery features continuous gantry rotation and leaf motion, dose calculation is often performed under the dual assumption of discrete apertures changing instantaneously from one discrete angle to the next. In this work, the validity of these two approximations is determined, as well as their impact on the quality of optimized plans. Further, an accurate method of fluence calculation is derived which does not use the discrete aperture approximation, but instead calculates the fluence as the multi-leaf collimator leaves sweep from one position to another. This continuous aperture fluence calculation is integrated in the VMAT optimization process using the open-source treatment planning system matRad. The three-step approach of VMAT optimization is used: fluence map optimization followed by leaf sequencing and direct aperture optimization, with variable leaf speed, gantry rotation speed, and MU rate. The benefit of the continuous aperture VMAT method over the discrete aperture method is determined by comparing the plan quality of discrete aperture and continuous aperture optimized plans, when the former is recalculated using the continuous aperture fluence calculation. Discrete aperture VMAT plans calculated at 4° spacing result in significant dose errors (10%-35%, depending on the anatomical site) as compared to the reference dose (continuous aperture fluence calculation at 0.5° spacing). These errors are greatly reduced (to 0.8%-2%) when the continuous aperture fluence calculation method was used at the same 4° spacing, implying that the dose error is primarily due to the discrete aperture approximation. Whereas all dose objectives were met by the discrete aperture VMAT optimized plan, many of them failed when the dose was recalculated with the continuous aperture fluence calculation. All objectives were met once again when the plan was optimized with the new continuous aperture VMAT optimization. Further, using only half of the beam angles, the continuous aperture VMAT optimization can achieve the same degree of accuracy with only 40% of the computing time as compared with the standard discrete aperture VMAT.

Development of a deformable phantom for experimental verification of 4D Monte Carlo simulations in a deforming anatomy.

PURPOSE: To verify the accuracy of 4D Monte Carlo (MC) simulations, using the 4DdefDOSXYZnrc user code, in a deforming anatomy. We developed a tissue-equivalent and reproducible deformable lung phantom and evaluated 4D simulations of delivered dose to the phantom by comparing calculations against measurements. METHODS: A novel deformable phantom consisting of flexible foam, emulating lung tissue, inside a Lucite external body was constructed. A removable plug, containing an elastic tumor that can hold film and other dosimeters, was inserted in the phantom. Point dose and position measurements were performed inside and outside the tumor using RADPOS 4D dosimetry system. The phantom was irradiated on an Elekta Infinity linac in both stationary and moving states. The dose delivery was simulated using delivery log files and the phantom motion recorded with RADPOS. RESULTS: Reproducibility of the phantom motion was determined to be within 1 mm. The phantom motion presented realistic features like hysteresis. MC calculations and measurements agreed within 2% at the center of tumor. Outside the tumor agreements were better than 5% which were within the positional/dose reading uncertainties at the measurement points. More than 94% of dose points from MC simulations agreed within 2%/2 mm compared to film measurements. CONCLUSION: The deformable lung phantom presented realistic and reproducible motion characteristics and its use for verification of 4D dose calculations was demonstrated. Our 4DMC method is capable of accurate calculations of the realistic dose delivered to a moving and deforming anatomy during static and dynamic beam delivery techniques.

AML refractory to primary induction with Ida-FLAG has a poor clinical outcome.

We evaluated outcomes of 100 patients with high risk AML treated with Ida-FLAG induction as first-line therapy. 72 achieved remission with one cycle; 19 did not. High risk cytogenetics and TP53 mutations were associated with failure to achieve remission. In those reaching remission, allogeneic bone marrow transplantation was associated with better relapse-free and overall survival. Those not achieving remission with induction therapy were extremely unlikely to reach remission with further therapy and had a dismal prognosis. Exploratory molecular analysis confirmed persistence of the dominant genetic mutations identified at diagnosis. Ex vivo chemosensitivity did not demonstrate significant differences between responders and non-responders. Thus, Ida-FLAG induction has a high chance of inducing remission in patients with high risk AML. Those achieving remission require allogeneic transplantation to achieve cure; those not achieving remission rarely respond to salvage chemotherapy and have a dismal outcome. Alternatives to conventional chemotherapy must be considered in this group.

Substance P and dopamine interact to modulate the distribution of delta-opioid receptors on cholinergic interneurons in the striatum.

It has been recently demonstrated that predictive learning induces a persistent accumulation of delta-opioid receptors (DOPrs) at the somatic membrane of cholinergic interneurons (CINs) in the nucleus accumbens shell (Nac-S). This accumulation is required for predictive learning to influence subsequent choice between goal-directed actions. The current experiments investigated the local neurochemical events responsible for this translocation. We found that (1) local administration of substance P into multiple striatal sub-territories induced DOPr translocation and (2) that this effect was mediated by the NK1 receptor, likely through its expression on CINs. Interestingly, whereas intrastriatal infusion of the D1 agonist chloro-APB reduced the DOPr translocation on CINs and infusion of the D2 agonist quinpirole had no effect, co-administration of both agonists again generated DOPr translocation, suggesting the effect of the D1 agonist alone was due to receptor internalisation. In support of this, local administration of cocaine was found to increase DOPr translocation as was chloro-APB when co-administered with the DOPr antagonist naltrindole. These studies provide the first evidence of delta-opioid receptor translocation in striatal cholinergic interneurons outside of the accumbens shell and suggest that, despite differences in local striatal neurochemical microenvironments, a similar molecular mechanism - involving an interaction between dopamine and SP signalling via NK1R - regulates DOPr translocation in multiple striatal regions. To our knowledge, this represents a novel mechanism by which DOPr distribution is regulated that may be particularly relevant to learning-induced DOPr trafficking.

RECORDS: improved Reporting of montE CarlO RaDiation transport Studies: Report of the AAPM Research Committee Task Group 268.

Studies involving Monte Carlo simulations are common in both diagnostic and therapy medical physics research, as well as other fields of basic and applied science. As with all experimental studies, the conditions and parameters used for Monte Carlo simulations impact their scope, validity, limitations, and generalizability. Unfortunately, many published peer-reviewed articles involving Monte Carlo simulations do not provide the level of detail needed for the reader to be able to properly assess the quality of the simulations. The American Association of Physicists in Medicine Task Group #268 developed guidelines to improve reporting of Monte Carlo studies in medical physics research. By following these guidelines, manuscripts submitted for peer-review will include a level of relevant detail that will increase the transparency, the ability to reproduce results, and the overall scientific value of these studies. The guidelines include a checklist of the items that should be included in the Methods, Results, and Discussion sections of manuscripts submitted for peer-review. These guidelines do not attempt to replace the journal reviewer, but rather to be a tool during the writing and review process. Given the varied nature of Monte Carlo studies, it is up to the authors and the reviewers to use this checklist appropriately, being conscious of how the different items apply to each particular scenario. It is envisioned that this list will be useful both for authors and for reviewers, to help ensure the adequate description of Monte Carlo studies in the medical physics literature.

Evaluation of a Machine-Learning Algorithm for Treatment Planning in Prostate Low-Dose-Rate Brachytherapy.

PURPOSE: This work presents the application of a machine learning (ML) algorithm to automatically generate high-quality, prostate low-dose-rate (LDR) brachytherapy treatment plans. The ML algorithm can mimic characteristics of preoperative treatment plans deemed clinically acceptable by brachytherapists. The planning efficiency, dosimetry, and quality (as assessed by experts) of preoperative plans generated with an ML planning approach was retrospectively evaluated in this study. METHODS AND MATERIALS: Preimplantation and postimplantation treatment plans were extracted from 100 high-quality LDR treatments and stored within a training database. The ML training algorithm matches similar features from a new LDR case to those within the training database to rapidly obtain an initial seed distribution; plans were then further fine-tuned using stochastic optimization. Preimplantation treatment plans generated by the ML algorithm were compared with brachytherapist (BT) treatment plans in terms of planning time (Wilcoxon rank sum, α = 0.05) and dosimetry (1-way analysis of variance, α = 0.05). Qualitative preimplantation plan quality was evaluated by expert LDR radiation oncologists using a Likert scale questionnaire. RESULTS: The average planning time for the ML approach was 0.84 ± 0.57 minutes, compared with 17.88 ± 8.76 minutes for the expert planner (P=.020). Preimplantation plans were dosimetrically equivalent to the BT plans; the average prostate V150% was 4% lower for ML plans (P=.002), although the difference was not clinically significant. Respondents ranked the ML-generated plans as equivalent to expert BT treatment plans in terms of target coverage, normal tissue avoidance, implant confidence, and the need for plan modifications. Respondents had difficulty differentiating between plans generated by a human or those generated by the ML algorithm. CONCLUSIONS: Prostate LDR preimplantation treatment plans that have equivalent quality to plans created by brachytherapists can be rapidly generated using ML. The adoption of ML in the brachytherapy workflow is expected to improve LDR treatment plan uniformity while reducing planning time and resources.

Experimental verification of 4D Monte Carlo simulations of dose delivery to a moving anatomy.

PURPOSE: To evaluate a novel 4D Monte Carlo simulation tool by comparing calculations to physical measurements using a respiratory motion phantom. METHODS: We used a dynamic Quasar phantom in both stationary and breathing states (sinusoidal motion of amplitude of 1.8 cm and period of 3.3 s) for dose measurements on an Elekta Agility linear accelerator. Gafchromic EBT3 film and the RADPOS 4D dosimetry system were placed inside the lung insert of the phantom to measure dose profiles and point-dose values at the center of the spherical tumor inside the insert. Both a static 4 × 4 cm2 field and a VMAT plan were delivered. Static and 4D Monte Carlo simulations of the treatment deliveries were performed using DOSXYZnrc and a modified version of the defDOSXYZnrc user code that allows modeling of the continuous motion of both machine and patient. DICOM treatment plan files and linac delivery log files were used to generate corresponding input files. The phantom motion recorded by RADPOS during beam delivery was incorporated into the input files for the 4DdefDOSXYZnrc simulations. RESULTS: For stationary phantom simulations, all point-dose values from MC simulations at the tumor center agreed within 1% with film and within 2% with RADPOS. More than 98% of the voxels from simulated dose profiles passed a 1D gamma of 2%/2-mm criteria against measured dose profiles. Similar results were observed when applying a 2D gamma analysis with a 2%/2-mm criteria to compare 2D dose distributions of Monte Carlo simulations against measurements. For simulations on the moving phantom, MC-calculated dose values at the center of the tumor were found to be within 1% of film and within 2σ of experimental uncertainties which are 2.8% of the RADPOS measurements. 1D gamma comparisons of the dose profiles were better than 91%, and 2D gamma comparisons of the 2D dose distributions were found to be better than 94%. CONCLUSION: Our 4D Monte Carlo method using defDOSXYZnrc can be used to accurately calculate the dose distribution in continuously moving anatomy for various treatment techniques. This work, if extended to deformable anatomies, can be used to reconstruct patient delivered dose for use in adaptive radiation therapy.

Evaluation of accuracy and precision in polymer gel dosimetry.

PURPOSE: To assess the overall reproducibility and accuracy of an X-ray computed tomography (CT) polymer gel dosimetry (PGD) system and investigate what effects the use of generic, interbatch, and intrabatch gel calibration have on dosimetric and spatial accuracy. METHODS: A N-isopropylacrylamide (NIPAM)-based gel formulation optimized for X-ray CT gel dosimetry was used, and the results over four different batches of gels were analyzed. All gels were irradiated with three 6 MV beams in a calibration pattern at both the bottom and top of the dosimeter. Postirradiation CT images of the gels were processed using background subtraction, image averaging, adaptive mean filtering, and remnant artifact removal. The gel dose distributions were calibrated using a Monte Carlo (Vancouver Island Monte Carlo system) calculated dose distribution of the calibration pattern. Using the calibration results from all gels, an average or "generic" calibration curve was calculated and this generic calibration curve was used to calibrate each of the gels within the sample. For each of the gels, the irradiation pattern at the bottom of the dosimeter was also calibrated using the irradiation pattern at the top of the dosimeter to evaluate intragel calibration. RESULTS: Comparison of gel measurements with Monte Carlo dose calculations found excellent dosimetric accuracy when using an average (or generic) calibration with a mean dose discrepancy of 1.8% in the low-dose gradient region which compared to a "best-case scenario" self-calibration method with a mean dose discrepancy of 1.6%. The intragel calibration method investigated produced large dose discrepancies due to differences in dose response at the top and bottom of the dosimeter, but the use of a dose-dependent correction reduced these dose errors. Spatial accuracy was found to be excellent for the average calibration method with a mean distance-to-agreement (DTA) of 0.63 mm and 99.6% of points with a DTA < 2 mm in high-dose gradient regions. This compares favorably to the self-calibration method which produced a mean DTA of 0.61 mm and 99.8% of points with a DTA < 2 mm. Gamma analysis using a 3%/3 mm criterion also found good agreement between the gel measurement and Monte Carlo dose calculation when using either the average calibration or self-calibration methods (96.8% and 98.2%, respectively). CONCLUSIONS: An X-ray CT PGD system was evaluated and found to have excellent dosimeteric and spatial accuracy when compared to Monte Carlo dose calculations and the use of generic and interbatch calibration methods were found to be effective. The establishment of the accuracy and reproducibility of this system provides important information for clinical implementation.

Robustness assessment of a novel IMRT planning method for lung radiotherapy.

PURPOSE: Conventional radiotherapy treatment planning for lung cancer accounts for tumour motion by increasing the beam apertures. We recently developed an IMRT planning strategy which uses reduced beam apertures in combination with an edge enhancing boost to compensate for loss of coverage due to respiration. Previous results showed that this approach ensures target coverage while reducing lung dose. The current study evaluated the robustness of this boost volume (BV) technique to changes in respiratory motion, including amplitude and time spent in each respiratory phase. METHODS: ITV and BV plans were generated for one NSCLC patient with respiratory motion amplitude of 0.9cm. Dose was accumulated for three different weightings of the 4DCT phases. Nine numerical phantoms were created with tumour sizes of 3cm, 5cm and 6.5cm and motion amplitudes of 7mm, 10mm and 14mm. The robustness of BV and ITV plans to variations in motion amplitude was assessed. The relative contributions of the width of the boost volume and the boost dose to plans efficacy and robustness were investigated. RESULTS: The BV plans were robust to typical variations in the time spent at each respiratory phase. Both ITV and BV plans were robust to 3mm amplitude decreases but not to 3mm amplitude increases. Increasing the boost dose from 110% to 120% of the prescription dose had negligible effect in improving tumour coverage. CONCLUSION: To improve the robustness of this technique the width of the boost volume needs to be increased.