Search

Objectives: Prior research has demonstrated that men and women emergency medicine (EM) residents receive similar numerical evaluations at the beginning of residency, but that women receive significantly lower scores than men in their final year. To better understand the emergence of this gender gap in evaluations we examined discrepancies between numerical scores and the sentiment of attached textual comments.Methods: This multicenter, longitudinal, retrospective cohort study took place at four geographically diverse academic EM training programs across the United States from July 1, 2013–July 1, 2015 using a real-time, mobile-based, direct-observation evaluation tool. We used complementary quantitative and qualitative methods to analyze 11,845 combined numerical and textual evaluations made by 151 attending physicians (94 men and 57 women) during real-time, direct observations of 202 residents (135 men and 67 women).Results: Numerical scores were more strongly positively correlated with positive sentiment of the textual comment for men (r = 0.38, P < 0.001) compared to women (r = −0.26, P < 0.04); more strongly negatively correlated with mixed (r = −0.39, P < 0.001) and negative (r = −0.46, P < 0.001) sentiment for men compared to women (r = −0.13, P < 0.28) for mixed sentiment (r = −0.22, P < 0.08) for negative; and women were around 11% more likely to receive positive comments alongside lower scores, and negative or mixed comments alongside higher scores. Additionally, on average, men received slightly more positive comments in postgraduate year (PGY)-3 than in PGY-1 and fewer mixed and negative comments, while women received fewer positive and negative comments in PGY-3 than PGY-1 and almost the same number of mixed comments.Conclusion: Women EM residents received more inconsistent evaluations than men EM residents at two levels: 1) inconsistency between numerical scores and sentiment of textual comments; and 2) inconsistency in the expected career trajectory of improvement over time. These findings reveal gender inequality in how attendings evaluate residents and suggest that attendings should be trained to provide all residents with feedback that is clear, consistent, and helpful, regardless of resident gender.

A surprising finding of recent studies in mouse is the dominance of widespread movement-related activity throughout the brain, including in early sensory areas. In awake subjects, failing to account for movement risks misattributing movement-related activity to other (e.g., sensory or cognitive) processes. In this article, we (1) review task designs for separating task-related and movement-related activity, (2) review three "case studies" in which not considering movement would have resulted in critically different interpretations of neuronal function, and (3) discuss functional couplings that may prevent us from ever fully isolating sensory, motor, and cognitive-related activity. Our main thesis is that neural signals related to movement are ubiquitous, and therefore ought to be considered first and foremost when attempting to correlate neuronal activity with task-related processes.

Study designRetrospective cohort study.ObjectivesSarcopenia is a risk factor for medical complications following spine surgery. However, the role of sarcopenia as a risk factor for proximal junctional disease (PJD) remains undefined. This study evaluates whether sarcopenia is an independent predictor of proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) following adult spinal deformity (ASD) surgery.MethodsASD patients who underwent thoracic spine to pelvis fusion with 2-year clinical and radiographic follow-up were reviewed for development of PJK and PJD. Average psoas cross-sectional area on preoperative axial computed tomography or magnetic resonance imaging at L4 was recorded. Previously described PJD risk factors were assessed for each patient, and multivariate linear regression was performed to identify independent risk factors for PJK and PJF. Disease-specific thresholds were calculated for sarcopenia based on psoas cross-sectional area.ResultsOf 32 patients, PJK and PJF occurred in 20 (62.5%) and 12 (37.5%), respectively. Multivariate analysis demonstrated psoas cross-sectional area to be the most powerful independent predictor of PJK (P = .02) and PJF (P = .009). Setting ASD disease-specific psoas cross-sectional area thresholds of

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.

Purpose: Studying physical activity in toddlers using accelerometers is challenging due to noncompliance with wear time (WT) and activity log (AL) instructions. The aims of this study are to examine relationships between WT and AL completion and (1) demographic and socioeconomic variables, (2) parenting style, and (3) whether sedentary time differs by AL completion. Methods: Secondary analysis was performed using baseline data from a community wellness program randomized controlled trial for parents with toddlers (12–35 mo). Parents had toddlers wear ActiGraph wGT3x accelerometers and completed ALs. Valid days included ≥600-minute WT. Analysis of variance and chi-square analyses were used. Results: The sample (n = 50) comprised racial and ethnically diverse toddlers (mean age = 27 mo, 58% male) and parents (mean age = 31.7 y, 84% female). Twenty-eight families (56%) returned valid accelerometer data with ALs. Participants in relationships were more likely to complete ALs (P <.05). Toddler sedentary time did not differ between those with ALs and those without. Conclusions: We found varied compliance with WT instructions and AL completion. Returned AL quality was poor, presenting challenges in correctly characterizing low-activity counts to improve internal validity of WT and physical activity measures. Support from marital partners may be important for adherence to study protocols. [ABSTRACT FROM AUTHOR]

Patient-reported outcomes (PROs) are used in clinical trials to provide valuable evidence on the impact of disease and treatment on patients' symptoms, function and quality of life. High-quality PRO data from trials can inform shared decision-making, regulatory and economic analyses and health policy. Recent evidence suggests the PRO content of past trial protocols was often incomplete or unclear, leading to research waste. To address this issue, international, consensus-based, PRO-specific guidelines were developed: the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)-PRO Extension. The SPIRIT-PRO Extension is a 16-item checklist which aims to improve the content and quality of aspects of clinical trial protocols relating to PRO data collection to minimise research waste, and ultimately better inform patient-centred care. This SPIRIT-PRO explanation and elaboration (E&E) paper provides information to promote understanding and facilitate uptake of the recommended checklist items, including a comprehensive protocol template. For each SPIRIT-PRO item, we provide a detailed description, one or more examples from existing trial protocols and supporting empirical evidence of the item's importance. We recommend this paper and protocol template be used alongside the SPIRIT 2013 and SPIRIT-PRO Extension paper to optimise the transparent development and review of trial protocols with PROs.

Our understanding of the neural basis of somatosensation is based largely on studies of the whisker system of mice and rats and the hands of macaque monkeys. Results across these animal models are often interpreted as providing direct insight into human somatosensation. Work on these systems has proceeded in parallel, capitalizing on the strengths of each model, but has rarely been considered as a whole. This lack of integration promotes a piecemeal understanding of somatosensation. Here, we examine the functions and morphologies of whiskers of mice and rats, the hands of macaque monkeys, and the somatosensory neuraxes of these three species. We then discuss how somatosensory information is encoded in their respective nervous systems, highlighting similarities and differences. We reflect on the limitations of these models of human somatosensation and consider key gaps in our understanding of the neural basis of somatosensation.

Ultra-high dose rate in radiotherapy (FLASH) has been shown to increase the therapeutic index with markedly reduced normal tissue toxicity and the same or better tumor cell killing. The challenge to achieve FLASH using x-rays, besides developing a high output linac, is to intensity-modulate the high-dose-rate x-rays so that the biological gain is not offset by the lack of physical dose conformity. In this study, we develop the ROtational direct Aperture optimization with a Decoupled ring-collimator (ROAD) to achieve simultaneous ultrafast delivery and complex dose modulation. The ROAD design includes a fast-rotating slip-ring linac and a decoupled collimator-ring with 75 pre-shaped multi-leaf-collimator (MLC) modules. The ring-source rotates at 1 rotation per second (rps) clockwise while the ring-collimator is either static or rotating at 1 rps counterclockwise, achieving 75 (ROAD-75) or 150 (ROAD-150) equal-angular beams for one full arc. The Direct Aperture Optimization (DAO) for ROAD was formulated to include a least-square dose fidelity, an anisotropic total variation term, and a single segment term. The FLASH dose (FD) and FLASH biological equivalent dose (FBED) were computed voxelwise, with the latter using a spatiotemporal model accounting for radiolytic oxygen depletion. ROAD was compared with clinical volumetric modulated arc therapy (VMAT) on a brain, a lung, a prostate, and a head and neck cancer patient. The mean dose rate of ROAD-75 and ROAD-150 are 76.2 Gy s-1 and 112 Gy s-1 respectively to deliver 25 Gy single-fraction dose in 1 s. With improved PTV homogeneity, ROAD-150 reduced (max, mean) OAR physical dose by (4.8 Gy, 6.3 Gy). The average R50 and integral dose of (VMAT, ROAD-75, ROAD-150) are (4.8, 3.2, 3.2) and (89, 57, 56) Gy×Liter, respectively. The FD and FBED showed model dependent FLASH effects. The novel ROAD design achieves ultrafast dose delivery and improves physical dosimetry compared with clinical VMAT, providing a potentially viable engineering solution for x-ray FLASH radiotherapy.

PurposeA previously developed ordinary differential equation (ODE) that models the dynamic interaction and distinct radiosensitivity between cancer stem cells (CSC) and differentiated cancer cells (DCC) was used to explain the definitive treatment failure in Glioblastoma Multiforme (GBM) for conventionally and hypo-fractionated treatments. In this study, optimization of temporal dose modulation based on the ODE equation is performed to explore the feasibility of improving GBM treatment outcome.MethodsA non-convex optimization problem with the objective of minimizing the total cancer cell number while maintaining the normal tissue biological effective dose (BEDnormal) at 100 Gy, equivalent to the conventional 2 Gy × 30 dosing scheme was formulated. With specified total number of dose fractions and treatment duration, the optimization was performed using a paired simulated annealing algorithm with fractional doses delivered to the CSC and DCC compartments and time intervals between fractions as variables. The recurrence time, defined as the time point at which the total tumor cell number regrows to 2.8×109 cells, was used to evaluate optimization outcome. Optimization was performed for conventional treatment time frames equivalent to currently and historically utilized fractionation schemes, in which limited improvement in recurrence time delay was observed. The efficacy of a super hyperfractionated approach with a prolonged treatment duration of one year was therefore tested, with both fixed regular and optimized variable time intervals between dose fractions corresponding to total number of fractions equivalent to weekly, bi-weekly, and monthly deliveries (n = 53, 27, 13). Optimization corresponding to BEDnormal of 150 Gy was also obtained to evaluate the possibility in further recurrence delay with dose escalation.ResultsFor the super hyperfractionated schedules with dose fraction number equivalent to weekly, bi-weekly, and monthly deliveries, the recurrence time points were found to be 430.5, 423.9, and 413.3 days, respectively, significantly delayed compared with the recurrence time of 250.3 days from conventional fractionation. Results show that optimal outcome was achieved by first delivering infrequent fractions followed by dense once per day fractions in the middle and end of the treatment course, with sparse and low dose treatments in the between. The dose to the CSC compartment was held relatively constant throughout while larger dose fractions to the DCC compartment were observed in the beginning and final fractions that preceded large time intervals. Dose escalation to BEDnormal of 150 Gy was shown capable of further delaying recurrence time to 452 days.ConclusionThe development and utilization of a temporal dose fractionation optimization framework in the context of CSC dynamics have demonstrated that substantial delay in GBM local tumor recurrence could be achieved with a super hyperfractionated treatment approach. Preclinical and clinical studies are needed to validate the efficacy of this novel treatment delivery method.

Background: This study describes a method for harmonizing data collected with different tools to compute a rating of compliance with national recommendations for school physical activity (PA) and nutrition environments. Methods: We reviewed questionnaire items from 84 elementary schools that participated in the Childhood Obesity Research Demonstration (CORD) project, which was 3 distinct childhood obesity prevention projects in 7 communities in California, Massachusetts, and Texas. Each project used tools specific to its programs, schools, and communities. While this approach increased the feasibility of data collection, it created a challenge with the need to combine data across projects. We evaluated all questionnaire items and retained only those items that assessed one or more recommendations and constructed several items to indicate compliance or noncompliance with the respective associated recommendations. Results: Ten constructed items covered 11 of the 20 recommendations. Analysis indicated that the scores detected variability in compliance both among communities and among school within communities. Conclusions: The scores captured differences in compliance with the national recommendations at multiple levels. Our method, designed for creating common scores, may be useful in integrated data analysis, systematic reviews, or future studies requiring harmonizing of data collected via different tools.

PurposeTo develop and demonstrate the efficacy of a novel head-and-neck multimodality image registration technique using deep-learning-based cross-modality synthesis.Methods and materialsTwenty-five head-and-neck patients received magnetic resonance (MR) and computed tomography (CT) (CTaligned ) scans on the same day with the same immobilization. Fivefold cross validation was used with all of the MR-CT pairs to train a neural network to generate synthetic CTs from MR images. Twenty-four of 25 patients also had a separate CT without immobilization (CTnon-aligned ) and were used for testing. CTnon-aligned 's were deformed to the synthetic CT, and compared to CTnon-aligned registered to MR. The same registrations were performed from MR to CTnon-aligned and from synthetic CT to CTnon-aligned . All registrations used B-splines for modeling the deformation, and mutual information for the objective. Results were evaluated using the 95% Hausdorff distance among spinal cord contours, landmark error, inverse consistency, and Jacobian determinant of the estimated deformation fields.ResultsWhen large initial rigid misalignment is present, registering CT to MRI-derived synthetic CT aligns the cord better than a direct registration. The average landmark error decreased from 9.8 ± 3.1 mm in MR→CTnon-aligned to 6.0 ± 2.1 mm in CTsynth →CTnon-aligned deformable registrations. In the CT to MR direction, the landmark error decreased from 10.0 ± 4.3 mm in CTnon-aligned →MR deformable registrations to 6.6 ± 2.0 mm in CTnon-aligned →CTsynth deformable registrations. The Jacobian determinant had an average value of 0.98. The proposed method also demonstrated improved inverse consistency over the direct method.ConclusionsWe showed that using a deep learning-derived synthetic CT in lieu of an MR for MR→CT and CT→MR deformable registration offers superior results to direct multimodal registration.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PurposeTo achieve more translatable preclinical research results, small animal irradiation needs to more closely simulate human radiotherapy. Although the clinical gold standard is intensity-modulated radiation therapy (IMRT), the direct translation of this method for small animals is impractical. In this study we describe the treatment planning system for a novel dose modulation device to address this challenge.MethodsUsing delineated target and avoidance structures, a rectangular aperture optimization (RAO) problem was formulated to penalize deviations from a desired dose distribution and limit the number of selected rectangular apertures. RAO was used to create IMRT plans with highly concave targets in the mouse brain, and the plan quality was compared to that using a hypothetical miniaturized multileaf collimator (MLC). RAO plans were also created for a realistic application of mouse whole liver irradiation and for a highly complex two-dimensional (2D) dose distribution as a proof-of-principle. Beam commissioning data, including output and off-axis factors and percent depth dose (PDD) curves, were acquired for our small animal irradiation system and incorporated into the treatment planning system. A plan post-processing step was implemented for aperture size-specific dose recalculation and aperture weighting reoptimization.ResultsThe first RAO test case achieved highly conformal doses to concave targets in the brain, with substantially better dose gradient, conformity, and target dose homogeneity than the hypothetical miniaturized MLC plans. In the second test case, a highly conformal dose to the liver was achieved with significant sparing of the kidneys. RAO also successfully replicated a complex 2D dose distribution with three prescription dose levels. Energy spectra for field sizes 1 to 20 mm were calculated to match the measured PDD curves, with maximum and mean dose deviations of 4.47 ± 0.30% and 1.71 ± 0.18%. The final reoptimization of aperture weightings for the complex RAO test plan was able to reduce the maximum and mean dose deviations between the optimized and recalculated dose distributions from 10.3% to 6.6% and 4.0% to 2.8%, respectively.ConclusionsUsing the advanced optimization techniques, complex IMRT plans were achieved using a simple dose modulation device. Beam commissioning data were incorporated into the treatment planning process to more accurately predict the resulting dose distribution. This platform substantially reduces the gap in treatment plan quality between clinical and preclinical radiotherapy, potentially increasing the value and flexibility of small animal studies.

PurposeNon-coplanar 4π radiotherapy generalizes intensity modulated radiation therapy (IMRT) to automate beam geometry selection but requires complicated hyperparameter tuning to attain superior plan quality, which can be tedious and inconsistent. In this study, a fully automated 4π treatment planning was developed using evolving knowledge-base (EKB) planning guided by dose prediction.MethodsTwenty 4π lung and twenty 4π head and neck (HN) cases were included. A statistical voxel dose learning model was initially trained on low-quality plans created using generic hyperparameter templates without manual tuning. To improve the automated plan quality without being limited by the training data quality, a new 4π optimization problem was formulated to include a one-sided penalty on the organ-at-risk (OAR) dose deviation from the predicted dose. This directional OAR penalty encourages superior OAR sparing. The fast iterative shrinkage-thresholding algorithm (FISTA) was used to solve the large-scale beam orientation optimization problem. With the improved plans, new predictions were created to guide the next loop of EKB planning for a total of 10 loops. Plan quality was evaluated using a plan quality metric (PQM) points system based on clinical dose constraints and compared with automated planning approaches guided by manual high-quality plans using all non-coplanar beams, automated plans using individually evolved targeted dose, and manually created 4π plans.ResultsFor the lung cases, the final EKB plans had significantly higher PQM than manually created 4π (+2.60%). The improvements plateaued after the third loop. The final HN EKB plans and manually created 4π plans had comparable PQMs, but had lower PQM compared to automated plans using a high-quality training set (-3.00% and -4.44%, respectively). The PQM consistently increased up to the sixth loop. Individually evolved plans were able to improve the plan quality from initial condition due to the one-sided cost function but the 60% of them were trapped in undesired local minima that were substantially worse than their corresponding EKB plans.ConclusionEvolving knowledge-base planning is a novel automated planning technique guided by the predicted three-dimensional dose distribution, which can evolve from low-quality plans. EKB allows new beams to be used in the automated planning workflow for superior plan quality.

The intra-renal dopamine (DA) system is highly expressed in the proximal tubule and contributes to Na+ and blood pressure homeostasis, as well as to the development of nephropathy. In the kidney, the enzyme DOPA Decarboxylase (DDC) originating from the circulation. We used a twin/family study design, followed by polymorphism association analysis at DDC locus to elucidate heritable influences on renal DA production. Dense single nucleotide polymorphism (SNP) genotyping across the DDC locus on chromosome 7p12 was analyzed by re-sequencing guided by trait-associated genetic markers to discover the responsible genetic variation. We also characterized kinetics of the expressed DDC mutant enzyme. Systematic polymorphism screening across the 15-Exon DDC locus revealed a single coding variant in Exon-14 that was associated with DA excretion and multiple other renal traits indicating pleiotropy. When expressed and characterized in eukaryotic cells, the 462Gln variant displayed lower Vmax (maximal rate of product formation by an enzyme) (21.3 versus 44.9 nmol/min/mg) and lower Km (substrate concentration at which half-maximal product formation is achieved by an enzyme.)(36.2 versus 46.8 μM) than the wild-type (Arg462) allele. The highly heritable DA excretion trait is substantially influenced by a previously uncharacterized common coding variant (Arg462Gln) at the DDC gene that affects multiple renal tubular and glomerular traits, and predicts accelerated functional decline in chronic kidney disease.

PurposeProton dose distribution is sensitive to uncertainties in range estimation and patient positioning. Currently, the proton robustness is managed by worst-case scenario optimization methods, which are computationally inefficient. To overcome these challenges, we develop a novel intensity-modulated proton therapy (IMPT) optimization method that integrates dose fidelity with a sensitivity term that describes dose perturbation as the result of range and positioning uncertainties.MethodsIn the integrated optimization framework, the optimization cost function is formulated to include two terms: a dose fidelity term and a robustness term penalizing the inner product of the scanning spot sensitivity and intensity. The sensitivity of an IMPT scanning spot to perturbations is defined as the dose distribution variation induced by range and positioning errors. To evaluate the sensitivity, the spatial gradient of the dose distribution of a specific spot is first calculated. The spot sensitivity is then determined by the total absolute value of the directional gradients of all affected voxels. The fast iterative shrinkage-thresholding algorithm is used to solve the optimization problem. This method was tested on three skull base tumor (SBT) patients and three bilateral head-and-neck (H&N) patients. The proposed sensitivity-regularized method (SenR) was implemented on both clinic target volume (CTV) and planning target volume (PTV). They were compared with conventional PTV-based optimization method (Conv) and CTV-based voxel-wise worst-case scenario optimization approach (WC).ResultsUnder the nominal condition without uncertainties, the three methods achieved similar CTV dose coverage, while the CTV-based SenR approach better spared organs at risks (OARs) compared with the WC approach, with an average reduction of [Dmean, Dmax] of [4.72, 3.38]  GyRBE for the SBT cases and [2.54, 3.33] GyRBE for the H&N cases. The OAR sparing of the PTV-based SenR method was comparable with the WC method. The WC method, and SenR approaches all improved the plan robustness from the conventional PTV-based method. On average, under range uncertainties, the lowest [D95%, V95%, V100%] of CTV were increased from [93.75%, 88.47%, 47.37%] in the Conv method, to [99.28%, 99.51%, 86.64%] in the WC method, [97.71%, 97.85%, 81.65%] in the SenR-CTV method and [98.77%, 99.30%, 85.12%] in the SenR-PTV method, respectively. Under setup uncertainties, the average lowest [D95%, V95%, V100%] of CTV were increased from [95.35%, 94.92%, 65.12%] in the Conv method, to [99.43%, 99.63%, 87.12%] in the WC method, [96.97%, 97.13%, 77.86%] in the SenR-CTV method, and [98.21%, 98.34%, 83.88%] in the SenR-PTV method, respectively. The runtime of the SenR optimization is eight times shorter than that of the voxel-wise worst-case method.ConclusionWe developed a novel computationally efficient robust optimization method for IMPT. The robustness is calculated as the spot sensitivity to both range and shift perturbations. The dose fidelity term is then regularized by the sensitivity term for the flexibility and trade-off between the dosimetry and the robustness. In the stress test, SenR is more resilient to unexpected uncertainties. These advantages in combination with its fast computation time make it a viable candidate for clinical IMPT planning.

Existing volumetric modulated arc therapy (VMAT) optimization using coplanar arcs is highly efficient but usually dosimetrically inferior to intensity modulated radiation therapy (IMRT) with optimized non-coplanar beams. To achieve both dosimetric quality and delivery efficiency, we proposed in this study, a novel integrated optimization method for non-coplanar VMAT (4πVMAT). 4πVMAT with direct aperture optimization (DAO) was achieved by utilizing a least square dose fidelity objective, along with an anisotropic total variation term for regularizing the fluence smoothness, a single segment term for imposing simple apertures, and a group sparsity term for selecting beam angles. Continuous gantry/couch angle trajectories were selected using the Dijkstra's algorithm, where the edge and node costs were determined based on the maximal gantry rotation speed and the estimated fluence map at the current iteration, respectively. The couch-gantry-patient collision space was calculated based on actual machine geometry and a human subject 3D surface. Beams leading to collision are excluded from the DAO and beam trajectory selection (BTS). An alternating optimization strategy was implemented to solve the integrated DAO and BTS problem. The feasibility of 4πVMAT using one full-arc or two full-arcs was tested on nine patients with brain, lung, or prostate cancer. The plan was compared against a coplanar VMAT (2πVMAT) plan using one additional arc and collimator rotation. Compared to 2πVMAT, 4πVMAT reduced the average maximum and mean organs-at-risk dose by 9.63% and 3.08% of the prescription dose with the same target coverage. R50 was reduced by 23.0%. Maximum doses to the dose limiting organs, such as the brainstem, the major vessels, and the proximal bronchus, were reduced by 8.1 Gy (64.8%), 16.3 Gy (41.5%), and 19.83 Gy (55.5%), respectively. The novel 4πVMAT approach affords efficient delivery of non-coplanar arc trajectories that lead to dosimetric improvements compared with coplanar VMAT using more arcs.

PURPOSE:Intensity-Modulated Proton Therapy (IMPT) is the state-of-the-art method of delivering proton radiotherapy. Previous research has been mainly focused on optimization of scanning spots with manually selected beam angles. Due to the computational complexity, the potential benefit of simultaneously optimizing beam orientations and spot pattern could not be realized. In this study, we developed a novel integrated beam orientation optimization (BOO) and scanning-spot optimization algorithm for intensity-modulated proton therapy (IMPT). METHODS:A brain chordoma and three unilateral head-and-neck patients with a maximal target size of 112.49 cm3 were included in this study. A total number of 1162 noncoplanar candidate beams evenly distributed across 4π steradians were included in the optimization. For each candidate beam, the pencil-beam doses of all scanning spots covering the PTV and a margin were calculated. The beam angle selection and spot intensity optimization problem was formulated to include three terms: a dose fidelity term to penalize the deviation of PTV and OAR doses from ideal dose distribution; an L1-norm sparsity term to reduce the number of active spots and improve delivery efficiency; a group sparsity term to control the number of active beams between 2 and 4. For the group sparsity term, convex L2,1-norm and nonconvex L2,1/2-norm were tested. For the dose fidelity term, both quadratic function and linearized equivalent uniform dose (LEUD) cost function were implemented. The optimization problem was solved using the Fast Iterative Shrinkage-Thresholding Algorithm (FISTA). The IMPT BOO method was tested on three head-and-neck patients and one skull base chordoma patient. The results were compared with IMPT plans created using column generation selected beams or manually selected beams. RESULTS:The L2,1-norm plan selected spatially aggregated beams, indicating potential degeneracy using this norm. L2,1/2-norm was able to select spatially separated beams and achieve smaller deviation from the ideal dose. In the L2,1/2-norm plans, the [mean dose, maximum dose] of OAR were reduced by an average of [2.38%, 4.24%] and[2.32%, 3.76%] of the prescription dose for the quadratic and LEUD cost function, respectively, compared with the IMPT plan using manual beam selection while maintaining the same PTV coverage. The L2,1/2 group sparsity plans were dosimetrically superior to the column generation plans as well. Besides beam orientation selection, spot sparsification was observed. Generally, with the quadratic cost function, 30%~60% spots in the selected beams remained active. With the LEUD cost function, the percentages of active spots were in the range of 35%~85%.The BOO-IMPT run time was approximately 20 min. CONCLUSION:This work shows the first IMPT approach integrating noncoplanar BOO and scanning-spot optimization in a single mathematical framework. This method is computationally efficient, dosimetrically superior and produces delivery-friendly IMPT plans.

Conventional beam orientation optimization (BOO) algorithms for IMRT assume that the same set of beam angles is used for all treatment fractions. In this paper we present a BOO formulation based on group sparsity that simultaneously optimizes non-coplanar beam angles for all fractions, yielding a fraction-variant (FV) treatment plan. Beam angles are selected by solving a multi-fraction fluence map optimization problem involving 500-700 candidate beams per fraction, with an additional group sparsity term that encourages most candidate beams to be inactive. The optimization problem is solved using the fast iterative shrinkage-thresholding algorithm. Our FV BOO algorithm is used to create five-fraction treatment plans for digital phantom, prostate, and lung cases as well as a 30-fraction plan for a head and neck case. A homogeneous PTV dose coverage is maintained in all fractions. The treatment plans are compared with fraction-invariant plans that use a fixed set of beam angles for all fractions. The FV plans reduced OAR mean dose and D 2 values on average by 3.3% and 3.8% of the prescription dose, respectively. Notably, mean OAR dose was reduced by 14.3% of prescription dose (rectum), 11.6% (penile bulb), 10.7% (seminal vesicle), 5.5% (right femur), 3.5% (bladder), 4.0% (normal left lung), 15.5% (cochleas), and 5.2% (chiasm). D 2 was reduced by 14.9% of prescription dose (right femur), 8.2% (penile bulb), 12.7% (proximal bronchus), 4.1% (normal left lung), 15.2% (cochleas), 10.1% (orbits), 9.1% (chiasm), 8.7% (brainstem), and 7.1% (parotids). Meanwhile, PTV homogeneity defined as D 95/D 5 improved from .92 to .95 (digital phantom), from .95 to .98 (prostate case), and from .94 to .97 (lung case), and remained constant for the head and neck case. Moreover, the FV plans are dosimetrically similar to conventional plans that use twice as many beams per fraction. Thus, FV BOO offers the potential to reduce delivery time for non-coplanar IMRT.