PULSAR Effect: Revealing potential synergies in combined radiation therapy and immunotherapy via differential equations.

PULSAR (personalized ultrafractionated stereotactic adaptive radiotherapy) is a form of radiotherapy method where a patient is given a large dose or "pulse" of radiation a couple of weeks apart rather than daily small doses. The tumor response is then monitored to determine when the subsequent pulse should be given. Pre-clinical trials have shown better tumor response in mice that received immunotherapy along with pulses spaced 10 days apart. However, this was not the case when the pulses were 1 or 4 days apart. Therefore, a synergistic effect between immunotherapy and PULSAR is observed when the pulses are spaced out by a certain number of days. In our study, we aimed to develop a mathematical model that can capture the synergistic effect by considering a time-dependent weight function that takes into account the spacing between pulses. We determined feasible parameters by fitting murine tumor volume data of six treatment groups via simulated annealing algorithm. Applying these parameters to the model we simulated 4000 trials with varying sequencing of pulses. These simulations indicated that if pulses were spaced apart by at least 9 days the tumor volume was about 200 mm3 to 250 mm3 smaller when treated with PULSAR combined with immunotherapy. We successfully demonstrate that our model is simple to implement and can generate tumor volume data that is consistent with the pre-clinical trial data. Our model has the potential to aid in the development of clinical trials of PULSAR therapy.

Clinical experience on patient-specific quality assurance for CBCT-based online adaptive treatment plan.

PURPOSE: Ethos CBCT-based adaptive radiotherapy (ART) system can generate an online adaptive plan by re-optimizing the initial reference plan based on the patient anatomy at the treatment. The optimization process is fully automated without any room for human intervention. Due to the change in anatomy, the ART plan can be significantly different from the initial plan in terms of plan parameters such as the aperture shapes and number of monitor units (MUs). In this study, we investigated the feasibility of using calculation-based patient specific QA for ART plans in conjunction with measurement-based and calculation-based QA for initial plans to establish an action level for the online ART patient-specific QA. METHODS: A cohort of 98 cases treated on CBCT-based ART system were collected for this study. We performed measurement-based QA using ArcCheck and calculation-based QA using Mobius for both the initial plan and the ART plan for analysis. For online the ART plan, Mobius calculation was conducted prior to the delivery, while ArcCheck measurement was delivered on the same day after the treatment. We first investigated the modulation factors (MFs) and MU numbers of the initial plans and ART plans, respectively. The γ passing rates of initial and ART plan QA were analyzed. Then action limits were derived for QA calculation and measurement for both initial and online ART plans, respectively, from 30 randomly selected patient cases, and were evaluated using the other 68 patient cases. RESULTS: The difference in MF between initial plan and ART-plan was 12.9% ± 12.7% which demonstrates their significant difference in plan parameters. Based on the patient QA results, pre-treatment calculation and measurement results are generally well aligned with ArcCheck measurement results for online ART plans, illustrating their feasibility as an indicator of failure in online ART QA measurements. Furthermore, using 30 randomly selected patient cases, the γ analysis action limit derived for initial plans and ART plans are 89.6% and 90.4% in ArcCheck QA (2%/2 mm) and are 92.4% and 93.6% in Mobius QA(3%/2 mm), respectively. According to the calculated action limits, the ArcCheck measurements for all the initial and ART plans passed QA successfully while the Mobius calculation action limits flagged seven and four failure cases respectively for initial plans and ART plans, respectively. CONCLUSION: An ART plan can be substantially different from the initial plan, and therefore a separate session of ART plan QA is needed to ensure treatment safety and quality. The pre-treatment QA calculation via Mobius can serve as a reliable indicator of failure in online ART plan QA. However, given that Ethos ART system is still relatively new, ArcCheck measurement of initial plan is still in practice. It may be skipped as we gain more experience and have better understanding of the system.

Evaluating machine learning enhanced intelligent-optimization-engine (IOE) performance for ethos head-and-neck (HN) plan generation.

PURPOSE: Varian Ethos utilizes novel intelligent-optimization-engine (IOE) designed to automate the planning. However, this introduced a black box approach to plan optimization and challenge for planners to improve plan quality. This study aims to evaluate machine-learning-guided initial reference plan generation approaches for head & neck (H&N) adaptive radiotherapy (ART). METHODS: Twenty previously treated patients treated on C-arm/Ring-mounted were retroactively re-planned in the Ethos planning system using a fixed 18-beam intensity-modulated radiotherapy (IMRT) template. Clinical goals for IOE input were generated using (1) in-house deep-learning 3D-dose predictor (AI-Guided) (2) commercial knowledge-based planning (KBP) model with universal RTOG-based population criteria (KBP-RTOG) and (3) an RTOG-based constraint template only (RTOG) for in-depth analysis of IOE sensitivity. Similar training data was utilized for both models. Plans were optimized until their respective criteria were achieved or DVH-estimation band was satisfied. Plans were normalized such that the highest PTV dose level received 95% coverage. Target coverage, high-impact organs-at-risk (OAR) and plan deliverability was assessed in comparison to clinical (benchmark) plans. Statistical significance was evaluated using a paired two-tailed student t-test. RESULTS: AI-guided plans were superior to both KBP-RTOG and RTOG-only plans with respect to clinical benchmark cases. Overall, OAR doses were comparable or improved with AI-guided plans versus benchmark, while they increased with KBP-RTOG and RTOG plans. However, all plans generally satisfied the RTOG criteria. Heterogeneity Index (HI) was on average <1.07 for all plans. Average modulation factor was 12.2 ± 1.9 (p = n.s), 13.1 ± 1.4 (p = <0.001), 11.5 ± 1.3 (p = n.s.) and 12.2 ± 1.9 for KBP-RTOG, AI-Guided, RTOG and benchmark plans, respectively. CONCLUSION: AI-guided plans were the highest quality. Both KBP-enabled and RTOG-only plans are feasible approaches as clinics adopt ART workflows. Similar to constrained optimization, the IOE is sensitive to clinical input goals and we recommend comparable input to an institution's planning directive dosimetric criteria.

Prediction of Type and Recurrence of Atrial Fibrillation after Catheter Ablation via Left Atrial Electroanatomical Voltage Mapping Registration and Multilayer Perceptron Classification: A Retrospective Study.

Atrial fibrillation (AF) is a common cardiac arrhythmia and affects one to two percent of the population. In this work, we leverage the three-dimensional atrial endocardial unipolar/bipolar voltage map to predict the AF type and recurrence of AF in 1 year. This problem is challenging for two reasons: (1) the unipolar/bipolar voltages are collected at different locations on the endocardium and the shapes of the endocardium vary widely in different patients, and thus the unipolar/bipolar voltage maps need aligning to the same coordinate; (2) the collected dataset size is very limited. To address these issues, we exploit a pretrained 3D point cloud registration approach and finetune it on left atrial voltage maps to learn the geometric feature and align all voltage maps into the same coordinate. After alignment, we feed the unipolar/bipolar voltages from the registered points into a multilayer perceptron (MLP) classifier to predict whether patients have paroxysmal or persistent AF, and the risk of recurrence of AF in 1 year for patients in sinus rhythm. The experiment shows our method classifies the type and recurrence of AF effectively.

Boosting radiotherapy dose calculation accuracy with deep learning.

In radiotherapy, a trade-off exists between computational workload/speed and dose calculation accuracy. Calculation methods like pencil-beam convolution can be much faster than Monte-Carlo methods, but less accurate. The dose difference, mostly caused by inhomogeneities and electronic disequilibrium, is highly correlated with the dose distribution and the underlying anatomical tissue density. We hypothesize that a conversion scheme can be established to boost low-accuracy doses to high-accuracy, using intensity information obtained from computed tomography (CT) images. A deep learning-driven framework was developed to test the hypothesis by converting between two commercially available dose calculation methods: Anisotropic analytic algorithm (AAA) and Acuros XB (AXB). A hierarchically dense U-Net model was developed to boost the accuracy of AAA dose toward the AXB level. The network contained multiple layers of varying feature sizes to learn their dose differences, in relationship to CT, both locally and globally. Anisotropic analytic algorithm and AXB doses were calculated in pairs for 120 lung radiotherapy plans covering various treatment techniques, beam energies, tumor locations, and dose levels. For each case, the CT and the AAA dose were used as the input and the AXB dose as the "ground-truth" output, to train and test the model. The mean squared errors (MSEs) and gamma passing rates (2 mm/2% & 1 mm/1%) were calculated between the boosted AAA doses and the "ground-truth" AXB doses. The boosted AAA doses demonstrated substantially improved match to the "ground-truth" AXB doses, with average (± s.d.) gamma passing rate (1 mm/1%) 97.6% (±2.4%) compared to 87.8% (±9.0%) of the original AAA doses. The corresponding average MSE was 0.11(±0.05) vs 0.31(±0.21). Deep learning is able to capture the differences between dose calculation algorithms to boost the low-accuracy algorithms. By combining a less accurate dose calculation algorithm with a trained deep learning model, dose calculation can potentially achieve both high accuracy and efficiency.

Dosimetric evaluation of synthetic CT generated with GANs for MRI-only proton therapy treatment planning of brain tumors.

PURPOSE: The purpose of this study was to address the dosimetric accuracy of synthetic computed tomography (sCT) images of patients with brain tumor generated using a modified generative adversarial network (GAN) method, for their use in magnetic resonance imaging (MRI)-only treatment planning for proton therapy. METHODS: Dose volume histogram (DVH) analysis was performed on CT and sCT images of patients with brain tumor for plans generated for intensity-modulated proton therapy (IMPT). All plans were robustly optimized using a commercially available treatment planning system (RayStation, from RaySearch Laboratories) and standard robust parameters reported in the literature. The IMPT plan was then used to compute the dose on CT and sCT images for dosimetric comparison, using RayStation analytical (pencil beam) dose algorithm. We used a second, independent Monte Carlo dose calculation engine to recompute the dose on both CT and sCT images to ensure a proper analysis of the dosimetric accuracy of the sCT images. RESULTS: The results extracted from RayStation showed excellent agreement for most DVH metrics computed on the CT and sCT for the nominal case, with a mean absolute difference below 0.5% (0.3 Gy) of the prescription dose for the clinical target volume (CTV) and below 2% (1.2 Gy) for the organs at risk (OARs) considered. This demonstrates a high dosimetric accuracy for the generated sCT images, especially in the target volume. The metrics obtained from the Monte Carlo doses mostly agreed with the values extracted from RayStation for the nominal and worst-case scenarios (mean difference below 3%). CONCLUSIONS: This work demonstrated the feasibility of using sCT generated with a GAN-based deep learning method for MRI-only treatment planning of patients with brain tumor in intensity-modulated proton therapy.

Minimal mask immobilization with optical surface guidance for head and neck radiotherapy.

PURPOSE: Full face and neck thermoplastic masks provide standard-of-care immobilization for patients receiving H&N IMRT. However, these masks are uncomfortable and increase skin dose. The purpose of this pilot trial was to investigate the feasibility and setup accuracy of minimal face and neck mask immobilization with optical surface guidance. METHODS: Twenty patients enrolled onto this IRB-approved protocol. Patients were immobilized with masks securing only forehead and chin. Shoulder movement was restricted by either moldable cushion or hand held strap retractors. Positional information, including isocenter location and CT skin contours, were imported to a commercial surface image guidance system. Patients typically received standard-of-care IMRT to 60-70 Gy in 30-33 fractions. Patients were first set up to surface markings with optical image guidance referenced to regions of interest (ROIs) on simulation CT images. Positioning was confirmed by in-room CBCT. Following six-dimensional robotic couch correction, a new optical real-time surface image was acquired to track intrafraction motion and to serve as a reference surface for setup at the next treatment fraction. Therapists manually recorded total treatment time as well as couch shifts based on kV imaging. Intrafractional ROI motion tracking was automatically recorded by the optical image guidance system. Patient comfort was assessed by self-administered surveys. RESULTS: Setup error was measured as six-dimensional shifts (vertical/longitudinal/lateral/rotation/pitch/roll). Mean error values were -0.51 ± 2.42 mm, -0.49 ± 3.30 mm, 0.23 ± 2.58 mm, -0.15 ± 1.01o , -0.02 ± 1.19o , and 0.06 ± 1.08o , respectively. Average treatment time was 21.6 ± 8.4 mins). Subjective comfort during surface-guided treatment was confirmed on patient surveys. CONCLUSION: These pilot results confirm feasibility of minimal mask immobilization combined with commercially available optical image guidance. Patient acceptance of minimal mask immobilization has been encouraging. Follow-up validation, with direct comparison to standard mask immobilization, appears warranted.

Convolution-based modified Clarkson integration (CMCI) for electron cutout factor calculation.

Electron therapy is widely used to treat shallow tumors because of its characteristic sharp dose fall-off beyond a certain range. A customized cutout is typically applied to block radiation to normal tissues. Determining the final monitor unit (MU) for electron treatment requires an output factor for the cutout, which is usually generated by measurement, especially for highly irregular cutouts. However, manual measurement requires a lengthy quality assurance process with possible errors. This work presents an accurate and efficient cutout output factor prediction model, convolution-based modified Clarkson integration (CMCI), to replace patient-specific output factor measurement. Like the Clarkson method, we decompose the field into basic sectors. Unlike the Clarkson integration method, we use annular sectors for output factor estimation. This decomposition method allows calculation via convolution. A 2D distribution of fluence is generated, and the output factor at any given point can be obtained. We applied our method to 10 irregularly shaped cutouts for breast patients for 6E, 9E, and 15E beams and compared the results with measurements and the electron Monte Carlo (eMC) calculation using the Eclipse planning system. While both the CMCI and eMC methods showed good agreement with chamber measurements and film measurements in relative distributions at the nominal source to surface distance (SSD) of 100 cm, eMC generated larger errors than the CMCI method at extended SSDs, with up to -9.28% deviations from the measurement for 6E beam. At extended SSD, the mean absolute errors of our method relative to measurements were 0.92 and 1.14, while the errors of eMC were 1.42 and 1.79 for SSD 105 cm and 110 cm, respectively. These results indicate that our method is more accurate than eMC, especially for low-energy beams, and can be used for MU calculation and as a QA tool for electron therapy.

Moving GPU-OpenCL-based Monte Carlo dose calculation toward clinical use: Automatic beam commissioning and source sampling for treatment plan dose calculation.

We have previously developed a GPU-based Monte Carlo (MC) dose engine on the OpenCL platform, named goMC, with a built-in analytical linear accelerator (linac) beam model. In this paper, we report our recent improvement on goMC to move it toward clinical use. First, we have adapted a previously developed automatic beam commissioning approach to our beam model. The commissioning was conducted through an optimization process, minimizing the discrepancies between calculated dose and measurement. We successfully commissioned six beam models built for Varian TrueBeam linac photon beams, including four beams of different energies (6 MV, 10 MV, 15 MV, and 18 MV) and two flattening-filter-free (FFF) beams of 6 MV and 10 MV. Second, to facilitate the use of goMC for treatment plan dose calculations, we have developed an efficient source particle sampling strategy. It uses the pre-generated fluence maps (FMs) to bias the sampling of the control point for source particles already sampled from our beam model. It could effectively reduce the number of source particles required to reach a statistical uncertainty level in the calculated dose, as compared to the conventional FM weighting method. For a head-and-neck patient treated with volumetric modulated arc therapy (VMAT), a reduction factor of ~2.8 was achieved, accelerating dose calculation from 150.9 s to 51.5 s. The overall accuracy of goMC was investigated on a VMAT prostate patient case treated with 10 MV FFF beam. 3D gamma index test was conducted to evaluate the discrepancy between our calculated dose and the dose calculated in Varian Eclipse treatment planning system. The passing rate was 99.82% for 2%/2 mm criterion and 95.71% for 1%/1 mm criterion. Our studies have demonstrated the effectiveness and feasibility of our auto-commissioning approach and new source sampling strategy for fast and accurate MC dose calculations for treatment plans.

Data correlation based noise level estimation for cone beam projection data.

BACKGROUND: In regularized iterative reconstruction algorithms, the selection of regularization parameter depends on the noise level of cone beam projection data. OBJECTIVE: Our aim is to propose an algorithm to estimate the noise level of cone beam projection data. METHODS: We first derived the data correlation of cone beam projection data in the Fourier domain, based on which, the signal and the noise were decoupled. Then the noise was extracted and averaged for estimation. An adaptive regularization parameter selection strategy was introduced based on the estimated noise level. Simulation and real data studies were conducted for performance validation. RESULTS: There exists an approximately zero-energy double-wedge area in the 3D Fourier domain of cone beam projection data. As for the noise level estimation results, the averaged relative errors of the proposed algorithm in the analytical/MC/spotlight-mode simulation experiments were 0.8%, 0.14% and 0.24%, respectively, and outperformed the homogeneous area based as well as the transformation based algorithms. Real studies indicated that the estimated noise levels were inversely proportional to the exposure levels, i.e., the slopes in the log-log plot were -1.0197 and -1.049 with respect to the short-scan and half-fan modes. The introduced regularization parameter selection strategy could deliver promising reconstructed image qualities. CONCLUSIONS: Based on the data correlation of cone beam projection data in Fourier domain, the proposed algorithm could estimate the noise level of cone beam projection data accurately and robustly. The estimated noise level could be used to adaptively select the regularization parameter.

Dosimetric comparison of Acuros XB with collapsed cone convolution/superposition and anisotropic analytic algorithm for stereotactic ablative radiotherapy of thoracic spinal metastases.

The aim of this study is to compare the recent Eclipse Acuros XB (AXB) dose calculation engine with the Pinnacle collapsed cone convolution/superposition (CCC) dose calculation algorithm and the Eclipse anisotropic analytic algorithm (AAA) for stereotactic ablative radiotherapy (SAbR) treatment planning of thoracic spinal (T-spine) metastases using IMRT and VMAT delivery techniques. The three commissioned dose engines (CCC, AAA, and AXB) were validated with ion chamber and EBT2 film measurements utilizing a heterogeneous slab-geometry water phantom and an anthropomorphic phantom. Step-and-shoot IMRT and VMAT treatment plans were developed and optimized for eight patients in Pinnacle, following our institutional SAbR protocol for spinal metastases. The CCC algorithm, with heterogeneity corrections, was used for dose calculations. These plans were then exported to Eclipse and recalculated using the AAA and AXB dose calculation algorithms. Various dosimetric parameters calculated with CCC and AAA were compared to that of the AXB calculations. In regions receiving above 50% of prescription dose, the calculated CCC mean dose is 3.1%-4.1% higher than that of AXB calculations for IMRT plans and 2.8%-3.5% higher for VMAT plans, while the calculated AAA mean dose is 1.5%-2.4% lower for IMRT and 1.2%-1.6% lower for VMAT. Statistically significant differences (p < 0.05) were observed for most GTV and PTV indices between the CCC and AXB calculations for IMRT and VMAT, while differences between the AAA and AXB calculations were not statistically significant. For T-spine SAbR treatment planning, the CCC calculations give a statistically significant overestimation of target dose compared to AXB. AAA underestimates target dose with no statistical significance compared to AXB. Further study is needed to determine the clinical impact of these findings.

A method for generating large datasets of organ geometries for radiotherapy treatment planning studies.

BACKGROUND: With the rapidly increasing application of adaptive radiotherapy, large datasets of organ geometries based on the patient's anatomy are desired to support clinical application or research work, such as image segmentation, re-planning, and organ deformation analysis. Sometimes only limited datasets are available in clinical practice. In this study, we propose a new method to generate large datasets of organ geometries to be utilized in adaptive radiotherapy. METHODS: Given a training dataset of organ shapes derived from daily cone-beam CT, we align them into a common coordinate frame and select one of the training surfaces as reference surface. A statistical shape model of organs was constructed, based on the establishment of point correspondence between surfaces and non-uniform rational B-spline (NURBS) representation. A principal component analysis is performed on the sampled surface points to capture the major variation modes of each organ. RESULTS: A set of principal components and their respective coefficients, which represent organ surface deformation, were obtained, and a statistical analysis of the coefficients was performed. New sets of statistically equivalent coefficients can be constructed and assigned to the principal components, resulting in a larger geometry dataset for the patient's organs. CONCLUSIONS: These generated organ geometries are realistic and statistically representative.

Rethinking the potential role of dose painting in personalized ultra-fractionated stereotactic adaptive radiotherapy.

Fractionated radiotherapy was established in the 1920s based upon two principles: (1) delivering daily treatments of equal quantity, unless the clinical situation requires adjustment, and (2) defining a specific treatment period to deliver a total dosage. Modern fractionated radiotherapy continues to adhere to these century-old principles, despite significant advancements in our understanding of radiobiology. At UT Southwestern, we are exploring a novel treatment approach called PULSAR (Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy). This method involves administering tumoricidal doses in a pulse mode with extended intervals, typically spanning weeks or even a month. Extended intervals permit substantial recovery of normal tissues and afford the tumor and tumor microenvironment ample time to undergo significant changes, enabling more meaningful adaptation in response to the evolving characteristics of the tumor. The notion of dose painting in the realm of radiation therapy has long been a subject of contention. The debate primarily revolves around its clinical effectiveness and optimal methods of implementation. In this perspective, we discuss two facets concerning the potential integration of dose painting with PULSAR, along with several practical considerations. If successful, the combination of the two may not only provide another level of personal adaptation ("adaptive dose painting"), but also contribute to the establishment of a timely feedback loop throughout the treatment process. To substantiate our perspective, we conducted a fundamental modeling study focusing on PET-guided dose painting, incorporating tumor heterogeneity and tumor control probability (TCP).

An AI-based approach for modeling the synergy between radiotherapy and immunotherapy.

Personalized, ultra-fractionated stereotactic adaptive radiotherapy (PULSAR) is designed to administer tumoricidal doses in a pulsed mode with extended intervals, spanning weeks or months. This approach leverages longer intervals to adapt the treatment plan based on tumor changes and enhance immune-modulated effects. In this investigation, we seek to elucidate the potential synergy between combined PULSAR and PD-L1 blockade immunotherapy using experimental data from a Lewis Lung Carcinoma (LLC) syngeneic murine cancer model. Employing a long short-term memory (LSTM) recurrent neural network (RNN) model, we simulated the treatment response by treating irradiation and anti-PD-L1 as external stimuli occurring in a temporal sequence. Our findings demonstrate that: (1) The model can simulate tumor growth by integrating various parameters such as timing and dose, and (2) The model provides mechanistic interpretations of a "causal relationship" in combined treatment, offering a completely novel perspective. The model can be utilized for in-silico modeling, facilitating exploration of innovative treatment combinations to optimize therapeutic outcomes. Advanced modeling techniques, coupled with additional efforts in biomarker identification, may deepen our understanding of the biological mechanisms underlying the combined treatment.

Quality assurance for online adaptive radiotherapy: a secondary dose verification model with geometry-encoded U-Net.

In online adaptive radiotherapy (ART), quick computation-based secondary dose verification is crucial for ensuring the quality of ART plans while the patient is positioned on the treatment couch. However, traditional dose verification algorithms are generally time-consuming, reducing the efficiency of ART workflow. This study aims to develop an ultra-fast deep-learning (DL) based secondary dose verification algorithm to accurately estimate dose distributions using computed tomography (CT) and fluence maps (FMs). We integrated FMs into the CT image domain by explicitly resolving the geometry of treatment delivery. For each gantry angle, an FM was constructed based on the optimized multi-leaf collimator apertures and corresponding monitoring units. To effectively encode treatment beam configuration, the constructed FMs were back-projected to 30 cm away from the isocenter with respect to the exact geometry of the treatment machines. Then, a 3D U-Net was utilized to take the integrated CT and FM volume as input to estimate dose. Training and validation were performed on 381 prostate cancer cases, with an additional 40 testing cases for independent evaluation of model performance. The proposed model can estimate dose in ∼ 15 ms for each patient. The average γ passing rate ( 3 % / 2 mm , 10 % threshold) for the estimated dose was 99.9% ± 0.15% on testing patients. The mean dose differences for the planning target volume and organs at risk were 0.07 % ± 0.34 % and 0.48 % ± 0.72 % , respectively. We have developed a geometry-resolved DL framework for accurate dose estimation and demonstrated its potential in real-time online ART doses verification.

Zero-Shot Medical Image Translation via Frequency-Guided Diffusion Models.

Recently, the diffusion model has emerged as a superior generative model that can produce high quality and realistic images. However, for medical image translation, the existing diffusion models are deficient in accurately retaining structural information since the structure details of source domain images are lost during the forward diffusion process and cannot be fully recovered through learned reverse diffusion, while the integrity of anatomical structures is extremely important in medical images. For instance, errors in image translation may distort, shift, or even remove structures and tumors, leading to incorrect diagnosis and inadequate treatments. Training and conditioning diffusion models using paired source and target images with matching anatomy can help. However, such paired data are very difficult and costly to obtain, and may also reduce the robustness of the developed model to out-of-distribution testing data. We propose a frequency-guided diffusion model (FGDM) that employs frequency-domain filters to guide the diffusion model for structure-preserving image translation. Based on its design, FGDM allows zero-shot learning, as it can be trained solely on the data from the target domain, and used directly for source-to-target domain translation without any exposure to the source-domain data during training. We evaluated it on three cone-beam CT (CBCT)-to-CT translation tasks for different anatomical sites, and a cross-institutional MR imaging translation task. FGDM outperformed the state-of-the-art methods (GAN-based, VAE-based, and diffusion-based) in metrics of Fréchet Inception Distance (FID), Peak Signal-to-Noise Ratio (PSNR), and Structural Similarity Index Measure (SSIM), showing its significant advantages in zero-shot medical image translation.

Fast Monte Carlo dose calculation in proton therapy.

This article examines the critical role of fast Monte Carlo (MC) dose calculations in advancing proton therapy techniques, particularly in the context of increasing treatment customization and precision. As adaptive radiotherapy and other patient-specific approaches evolve, the need for accurate and precise dose calculations, essential for techniques like proton-based stereotactic radiosurgery, becomes more prominent. These calculations, however, are time-intensive, with the treatment planning/optimization process constrained by the achievable speed of dose computations. Thus, enhancing the speed of MC methods is vital, as it not only facilitates the implementation of novel treatment modalities but also leads to more optimal treatment plans. Today, the state-of-the-art in MC dose calculation speeds is 106-107protons per second. This review highlights the latest advancements in fast MC dose calculations that have led to such speeds, including emerging artificial intelligence-based techniques, and discusses their application in both current and emerging proton therapy strategies.

Utilizing Large Language Models for Enhanced Clinical Trial Matching: A Study on Automation in Patient Screening.

Background Clinical trial matching, essential for advancing medical research, involves detailed screening of potential participants to ensure alignment with specific trial requirements. Research staff face challenges due to the high volume of eligible patients and the complexity of varying eligibility criteria. The traditional manual process, both time-consuming and error-prone, often leads to missed opportunities. Recently, large language models (LLMs), specifically generative pre-trained transformers (GPTs), have become impressive and impactful tools. Utilizing such tools from artificial intelligence (AI) and natural language processing (NLP) may enhance the accuracy and efficiency of this process through automated patient screening against established criteria. Methods Utilizing data from the National NLP Clinical Challenges (n2c2) 2018 Challenge, we utilized 202 longitudinal patient records. These records were annotated by medical professionals and evaluated against 13 selection criteria encompassing various health assessments. Our approach involved embedding medical documents into a vector database to determine relevant document sections and then using an LLM (OpenAI's GPT-3.5 Turbo and GPT-4) in tandem with structured and chain-of-thought prompting techniques for systematic document assessment against the criteria. Misclassified criteria were also examined to identify classification challenges. Results This study achieved an accuracy of 0.81, sensitivity of 0.80, specificity of 0.82, and a micro F1 score of 0.79 using GPT-3.5 Turbo, and an accuracy of 0.87, sensitivity of 0.85, specificity of 0.89, and micro F1 score of 0.86 using GPT-4. Notably, some criteria in the ground truth appeared mislabeled, an issue we couldn't explore further due to insufficient label generation guidelines on the website. Conclusion Our findings underscore the potential of AI and NLP technologies, including LLMs, in the clinical trial matching process. The study demonstrated strong capabilities in identifying eligible patients and minimizing false inclusions. Such automated systems promise to alleviate the workload of research staff and improve clinical trial enrollment, thus accelerating the process and enhancing the overall feasibility of clinical research. Further work is needed to determine the potential of this approach when implemented on real clinical data.

Can input reconstruction be used to directly estimate uncertainty of a dose prediction U-Net model?

BACKGROUND: The reliable and efficient estimation of uncertainty in artificial intelligence (AI) models poses an ongoing challenge in many fields such as radiation therapy. AI models are intended to automate manual steps involved in the treatment planning workflow. We focus in this study on dose prediction models that predict an optimal dose trade-off for each new patient for a specific treatment modality. They can guide physicians in the optimization, be part of automatic treatment plan generation or support decision in treatment indication. Most common uncertainty estimation methods are based on Bayesian approximations, like Monte Carlo dropout (MCDO) or Deep ensembling (DE). These two techniques, however, have a high inference time (i.e., require multiple inference passes) and might not work for detecting out-of-distribution (OOD) data (i.e., overlapping uncertainty estimate for in-distribution (ID) and OOD). PURPOSE: In this study, we present a direct uncertainty estimation method and apply it for a dose prediction U-Net architecture. It can be used to flag OOD data and give information on the quality of the dose prediction. METHODS: Our method consists in the addition of a branch decoding from the bottleneck which reconstructs the CT scan given as input. The input reconstruction error can be used as a surrogate of the model uncertainty. For the proof-of-concept, our method is applied to proton therapy dose prediction in head and neck cancer patients. A dataset of 60 oropharyngeal patients was used to train the network using a nested cross-validation approach with 11 folds (training: 50 patients, validation: 5 patients, test: 5 patients). For the OOD experiment, we used 10 extra patients with a different head and neck sub-location. Accuracy, time-gain, and OOD detection are analyzed for our method in this particular application and compared with the popular MCDO and DE. RESULTS: The additional branch did not reduce the accuracy of the dose prediction model. The median absolute error is close to zero for the target volumes and less than 1% of the dose prescription for organs at risk. Our input reconstruction method showed a higher Pearson correlation coefficient with the prediction error (0.620) than DE (0.447) and MCDO (between 0.599 and 0.612). Moreover, our method allows an easier identification of OOD (no overlap for ID and OOD data and a Z-score of 34.05). The uncertainty is estimated simultaneously to the regression task, therefore requires less time and computational resources. CONCLUSIONS: This study shows that the error in the CT scan reconstruction can be used as a surrogate of the uncertainty of the model. The Pearson correlation coefficient with the dose prediction error is slightly higher than state-of-the-art techniques. OOD data can be more easily detected and the uncertainty metric is computed simultaneously to the regression task, therefore faster than MCDO or DE. The code and pretrained model are available on the gitlab repository: https://gitlab.com/ai4miro/ct-reconstruction-for-uncertainty-quatification-of-hdunet.

Progressive auto-segmentation for cone-beam computed tomography-based online adaptive radiotherapy.

Background and purpose: Accurate and automated segmentation of targets and organs-at-risk (OARs) is crucial for the successful clinical application of online adaptive radiotherapy (ART). Current methods for cone-beam computed tomography (CBCT) auto-segmentation face challenges, resulting in segmentations often failing to reach clinical acceptability. Current approaches for CBCT auto-segmentation overlook the wealth of information available from initial planning and prior adaptive fractions that could enhance segmentation precision. Materials and methods: We introduce a novel framework that incorporates data from a patient's initial plan and previous adaptive fractions, harnessing this additional temporal context to significantly refine the segmentation accuracy for the current fraction's CBCT images. We present LSTM-UNet, an innovative architecture that integrates Long Short-Term Memory (LSTM) units into the skip connections of the traditional U-Net framework to retain information from previous fractions. The models underwent initial pre-training with simulated data followed by fine-tuning on a clinical dataset. Results: Our proposed model's segmentation predictions yield an average Dice similarity coefficient of 79% from 8 Head & Neck organs and targets, compared to 52% from a baseline model without prior knowledge and 78% from a baseline model with prior knowledge but no memory. Conclusions: Our proposed model excels beyond baseline segmentation frameworks by effectively utilizing information from prior fractions, thus reducing the effort of clinicians to revise the auto-segmentation results. Moreover, it works together with registration-based methods that offer better prior knowledge. Our model holds promise for integration into the online ART workflow, offering precise segmentation capabilities on synthetic CT images.