Sustained and Localized Drug Depot Release Using Radiation-Activated Scintillating Nanoparticles.

Clinical treatment of cancer commonly incorporates X-ray radiation therapy (XRT), and developing spatially precise radiation-activatable drug delivery strategies may improve XRT efficacy while limiting off-target toxicities associated with systemically administered drugs. Nevertheless, achieving this has been challenging thus far because strategies typically rely on radical species with short lifespans, and the inherent nature of hypoxic and acidic tumor microenvironments may encourage spatially heterogeneous effects. It is hypothesized that the challenge could be bypassed by using scintillating nanoparticles that emit light upon X-ray absorption, locally forming therapeutic drug depots in tumor tissues. Thus a nanoparticle platform (Scintillating nanoparticle Drug Depot; SciDD) that enables the local release of cytotoxic payloads only after activation by XRT is developed, thereby limiting off-target toxicity. As a proof-of-principle, SciDD is used to deliver a microtubule-destabilizing payload MMAE (monomethyl auristatin E). With as little as a 2 Gy local irradiation to tumors, MMAE payloads are released effectively to kill tumor cells. XRT-mediated drug release is demonstrated in multiple mouse cancer models and showed efficacy over XRT alone (p < 0.0001). This work shows that SciDD can act as a local drug depot with spatiotemporally controlled release of cancer therapeutics.

Online adaptive planning methods for intensity-modulated radiotherapy.

Online adaptive radiation therapy aims at adapting a patient's treatment plan to their current anatomy to account for inter-fraction variations before daily treatment delivery. As this process needs to be accomplished while the patient is immobilized on the treatment couch, it requires time-efficient adaptive planning methods to generate a quality daily treatment plan rapidly. The conventional planning methods do not meet the time requirement of online adaptive radiation therapy because they often involve excessive human intervention, significantly prolonging the planning phase. This article reviews the planning strategies employed by current commercial online adaptive radiation therapy systems, research on online adaptive planning, and artificial intelligence's potential application to online adaptive planning.

Technical note: Progressive deep learning: An accelerated training strategy for medical image segmentation.

BACKGROUND: Recent advancements in Deep Learning (DL) methodologies have led to state-of-the-art performance in a wide range of applications especially in object recognition, classification, and segmentation of medical images. However, training modern DL models requires a large amount of computation and long training times due to the complex nature of network structures and the large number of training datasets involved. Moreover, it is an intensive, repetitive manual process to select the optimized configuration of hyperparameters for a given DL network. PURPOSE: In this study, we present a novel approach to accelerate the training time of DL models via the progressive feeding of training datasets based on similarity measures for medical image segmentation. We term this approach Progressive Deep Learning (PDL). METHODS: The two-stage PDL approach was tested on the auto-segmentation task for two imaging modalities: CT and MRI. The training datasets were ranked according to similarity measures between each sample based on Mean Square Error (MSE), Peak Signal-to-Noise Ratio (PSNR), Structural Similarity Index (SSIM), and the Universal Quality Image Index (UQI) values. At the start of the training process, a relatively coarse sampling of training datasets with higher ranks was used to optimize the hyperparameters of the DL network. Following this, the samples with higher ranks were used in step 1 to yield accelerated loss minimization in early training epochs and the total dataset was added in step 2 for the remainder of training. RESULTS: Our results demonstrate that the PDL approach can reduce the training time by nearly half (∼49%) and can predict segmentations (CT U-net/DenseNet dice coefficient: 0.9506/0.9508, MR U-net/DenseNet dice coefficient: 0.9508/0.9510) without major statistical difference (Wilcoxon signed-rank test) compared to the conventional DL approach. The total training times with a fixed cutoff at 0.95 DSC for the CT dataset using DenseNet and U-Net architectures, respectively, were 17 h, 20 min and 4 h, 45 min in the conventional case compared to 8 h, 45 min and 2 h, 20 min with PDL. For the MRI dataset, the total training times using the same architectures were 2 h, 54 min and 52 min in the conventional case and 1 h, 14 min and 25 min with PDL. CONCLUSION: The proposed PDL training approach offers the ability to substantially reduce the training time for medical image segmentation while maintaining the performance achieved in the conventional case.

Ensemble learning and personalized training for the improvement of unsupervised deep learning-based synthetic CT reconstruction.

BACKGROUND: The growing adoption of magnetic resonance imaging (MRI)-guided radiation therapy (RT) platforms and a focus on MRI-only RT workflows have brought the technical challenge of synthetic computed tomography (sCT) reconstruction to the forefront. Unpaired-data deep learning-based approaches to the problem offer the attractive characteristic of not requiring paired training data, but the gap between paired- and unpaired-data results can be limiting. PURPOSE: We present two distinct approaches aimed at improving unpaired-data sCT reconstruction results: a cascade ensemble that combines multiple models and a personalized training strategy originally designed for the paired-data setting. METHODS: Comparisons are made between the following models: (1) the paired-data fully convolutional DenseNet (FCDN), (2) the FCDN with the Intentional Deep Overfit Learning (IDOL) personalized training strategy, (3) the unpaired-data CycleGAN, (4) the CycleGAN with the IDOL training strategy, and (5) the CycleGAN as an intermediate model in a cascade ensemble approach. Evaluation of the various models over 25 total patients is carried out using a five-fold cross-validation scheme, with the patient-specific IDOL models being trained for the five patients of fold 3, chosen at random. RESULTS: In both the paired- and unpaired-data settings, adopting the IDOL training strategy led to improvements in the mean absolute error (MAE) between true CT images and sCT outputs within the body contour (mean improvement, paired- and unpaired-data approaches, respectively: 38%, 9%) and in regions of bone (52%, 5%), the peak signal-to-noise ratio (PSNR; 15%, 7%), and the structural similarity index (SSIM; 6%, <1%). The ensemble approach offered additional benefits over the IDOL approach in all three metrics (mean improvement over unpaired-data approach in fold 3; MAE: 20%; bone MAE: 16%; PSNR: 10%; SSIM: 2%), and differences in body MAE between the ensemble approach and the paired-data approach are statistically insignificant. CONCLUSIONS: We have demonstrated that both a cascade ensemble approach and a personalized training strategy designed initially for the paired-data setting offer significant improvements in image quality metrics for the unpaired-data sCT reconstruction task. Closing the gap between paired- and unpaired-data approaches is a step toward fully enabling these powerful and attractive unpaired-data frameworks.

Intentional deep overfit learning (IDOL): A novel deep learning strategy for adaptive radiation therapy.

PURPOSE: Applications of deep learning (DL) are essential to realizing an effective adaptive radiotherapy (ART) workflow. Despite the promise demonstrated by DL approaches in several critical ART tasks, there remain unsolved challenges to achieve satisfactory generalizability of a trained model in a clinical setting. Foremost among these is the difficulty of collecting a task-specific training dataset with high-quality, consistent annotations for supervised learning applications. In this study, we propose a tailored DL framework for patient-specific performance that leverages the behavior of a model intentionally overfitted to a patient-specific training dataset augmented from the prior information available in an ART workflow-an approach we term Intentional Deep Overfit Learning (IDOL). METHODS: Implementing the IDOL framework in any task in radiotherapy consists of two training stages: (1) training a generalized model with a diverse training dataset of N patients, just as in the conventional DL approach, and (2) intentionally overfitting this general model to a small training dataset-specific the patient of interest ( N + 1 ) generated through perturbations and augmentations of the available task- and patient-specific prior information to establish a personalized IDOL model. The IDOL framework itself is task-agnostic and is, thus, widely applicable to many components of the ART workflow, three of which we use as a proof of concept here: the autocontouring task on replanning CTs for traditional ART, the MRI super-resolution (SR) task for MRI-guided ART, and the synthetic CT (sCT) reconstruction task for MRI-only ART. RESULTS: In the replanning CT autocontouring task, the accuracy measured by the Dice similarity coefficient improves from 0.847 with the general model to 0.935 by adopting the IDOL model. In the case of MRI SR, the mean absolute error (MAE) is improved by 40% using the IDOL framework over the conventional model. Finally, in the sCT reconstruction task, the MAE is reduced from 68 to 22 HU by utilizing the IDOL framework. CONCLUSIONS: In this study, we propose a novel IDOL framework for ART and demonstrate its feasibility using three ART tasks. We expect the IDOL framework to be especially useful in creating personally tailored models in situations with limited availability of training data but existing prior information, which is usually true in the medical setting in general and is especially true in ART.

Abdominal synthetic CT reconstruction with intensity projection prior for MRI-only adaptive radiotherapy.

Objective. Owing to the superior soft tissue contrast of MRI, MRI-guided adaptive radiotherapy (ART) is well-suited to managing interfractional changes in anatomy. An MRI-only workflow is desirable, but producing synthetic CT (sCT) data through paired data-driven deep learning (DL) for abdominal dose calculations remains a challenge due to the highly variable presence of intestinal gas. We present the preliminary dosimetric evaluation of our novel approach to sCT reconstruction that is well suited to handling intestinal gas in abdominal MRI-only ART.Approach. We utilize a paired data DL approach enabled by the intensity projection prior, in which well-matching training pairs are created by propagating air from MRI to corresponding CT scans. Evaluations focus on two classes: patients with (1) little involvement of intestinal gas, and (2) notable differences in intestinal gas presence between corresponding scans. Comparisons between sCT-based plans and CT-based clinical plans for both classes are made at the first treatment fraction to highlight the dosimetric impact of the variable presence of intestinal gas.Main results. Class 1 patients (n= 13) demonstrate differences in prescribed dose coverage of the PTV of 1.3 ± 2.1% between clinical plans and sCT-based plans. Mean DVH differences in all structures for Class 1 patients are found to be statistically insignificant. In Class 2 (n= 20), target coverage is 13.3 ± 11.0% higher in the clinical plans and mean DVH differences are found to be statistically significant.Significance. Significant deviations in calculated doses arising from the variable presence of intestinal gas in corresponding CT and MRI scans result in uncertainty in high-dose regions that may limit the effectiveness of adaptive dose escalation efforts. We have proposed a paired data-driven DL approach to sCT reconstruction for accurate dose calculations in abdominal ART enabled by the creation of a clinically unavailable training data set with well-matching representations of intestinal gas.

Development of Volumetric Independent Dose Calculation System for Verification of the Treatment Plan in Image-Guided Adaptive Brachytherapy.

Purpose: This study aimed to develop a volumetric independent dose calculation (vIDC) system for verification of the treatment plan in image-guided adaptive brachytherapy (IGABT) and to evaluate the feasibility of the vIDC in clinical practice with simulated cases. Methods: The vIDC is based on the formalism of TG-43. Four simulated cases of cervical cancer were selected to retrospectively evaluate the dose distributions in IGABT. Some reference point doses, such as points A and B and rectal points, were calculated by vIDC using absolute coordinate. The 3D dose volume was also calculated to acquire dose-volume histograms (DVHs) with grid resolutions of 1.0 × 1.0 (G1.0), 2.5 × 2.5 (G2.5), and 0.5 × 0.5 mm2 (G0.5). Dosimetric parameters such as D90% and D2cc doses covering 90% of the high-risk critical target volume (HR-CTV) and 2 cc of the organs at risk (OARs) were obtained from DVHs. D90% also converted to equivalent dose in 2-Gy fractions (EQD2) to produce the same radiobiological effect as external beam radiotherapy. In addition, D90% was obtained in two types with or without the applicator volume to confirm the effect of the applicator itself. Validation of the vIDC was also performed using gamma evaluation by comparison with Monte Carlo simulation. Results: The average percentage difference of point doses was <2.28%. The DVHs for the HR-CTV and OARs showed no significant differences between the vIDC and the treatment planning system (TPS). Without considering the applicator volume, the D90% of the HR-CTV calculated by the vIDC decreases with a decreasing calculated dose-grid size (32.4, 5.65, and -2.20 cGy in G2.5, G1.0, and G0.5, respectively). The overall D90% is higher when considering the applicator volume. The converted D90% by EQD2 ranged from -1.29 to 1.00%. The D2cc of the OARs showed that the averaged dose deviation is <10 cGy regardless of the dose-grid size. Based on gamma analysis, the passing rate was 98.81% for 3%/3-mm criteria. Conclusion: The vIDC was developed as an independent dose verification system for verification of the treatment plan in IGABT. We confirmed that the vIDC is suitable for second-check dose validation of the TPS under various conditions.

MRI super-resolution reconstruction for MRI-guided adaptive radiotherapy using cascaded deep learning: In the presence of limited training data and unknown translation model.

PURPOSE: Deep learning (DL)-based super-resolution (SR) reconstruction for magnetic resonance imaging (MRI) has recently been receiving attention due to the significant improvement in spatial resolution compared to conventional SR techniques. Challenges hindering the widespread implementation of these approaches remain, however. Low-resolution (LR) MRIs captured in the clinic exhibit complex tissue structures obfuscated by noise that are difficult for a simple DL framework to handle. Moreover, training a robust network for a SR task requires abundant, perfectly matched pairs of LR and high-resolution (HR) images that are often unavailable or difficult to collect. The purpose of this study is to develop a novel SR technique for MRI based on the concept of cascaded DL that allows for the reconstruction of high-quality SR images in the presence of insufficient training data, an unknown translation model, and noise. METHODS: The proposed framework, based on the concept named cascaded deep learning, consists of three components: (a) a denoising autoencoder (DAE) trained using clinical LR noisy MRI scans that have been processed with a nonlocal means filter that generates denoised LR data; (b) a down-sampling network (DSN) trained with a small amount of paired LR/HR data from volunteers that allows for the generation of perfectly paired LR/HR data for the training of a generative model; and (c) the proposed SR generative model (p-SRG) trained with data generated by the DSN that maps from LR inputs to HR outputs. After training, LR clinical images may be fed through the DAE and p-SRG to yield SR reconstructions of the LR input. The application of this framework was explored in two settings: 3D breath-hold MRI axial SR reconstruction from LR axial scans (<3 sec/vol) and in the enhancement of the spatial resolution of LR 4D-MRI acquisitions (0.5 sec/vol). RESULTS: The DSN produces LR scans from HR inputs with a higher fidelity to true, LR clinical scans compared to conventional k-space down-sampling methods based on the metrics of root mean square error (RMSE) and structural similarity index (SSIM). Furthermore, HR outputs generated by the p-SRG exhibit improved scores in the peak signal-to-noise ratio, normalized RMSE, SSIM, and in the blind/reference-less image spatial quality evaluator assessment compared to conventional approaches to MRI SR. CONCLUSIONS: The robust, SR reconstruction method for MRI based on the novel cascaded deep learning framework is an end-to-end method for producing detail-preserving SR reconstructions from noisy, LR clinical MRI scans. Fourfold enhancements in spatial resolution facilitate target delineation and motion management during radiation therapy, enabling precise MRI-guided radiation therapy with 3D LR breath-hold MRI and 4D-MRI in a clinically feasible time frame.

Synthetic CT reconstruction using a deep spatial pyramid convolutional framework for MR-only breast radiotherapy.

PURPOSE: The superior soft-tissue contrast achieved using magnetic resonance imaging (MRI) compared to x-ray computed tomography (CT) has led to the popularization of MRI-guided radiation therapy (MR-IGRT), especially in recent years with the advent of first and second generation MRI-based therapy delivery systems for MR-IGRT. The expanding use of these systems is driving interest in MRI-only RT workflows in which MRI is the sole imaging modality used for treatment planning and dose calculations. To enable such a workflow, synthetic CT (sCT) data must be generated based on a patient's MRI data so that dose calculations may be performed using the electron density information derived from CT images. In this study, we propose a novel deep spatial pyramid convolutional framework for the MRI-to-CT image-to-image translation task and compare its performance to the well established U-Net architecture in a generative adversarial network (GAN) framework. METHODS: Our proposed framework utilizes atrous convolution in a method named atrous spatial pyramid pooling (ASPP) to significantly reduce the total number of parameters required to describe the model while effectively capturing rich, multi-scale structural information in a manner that is not possible in the conventional framework. The proposed framework consists of a generative model composed of stacked encoders and decoders separated by the ASPP module, where atrous convolution is applied at increasing rates in parallel to encode large-scale features. The performance of the proposed method is compared to that of the conventional GAN framework in terms of the time required to train the model and the image quality of the generated sCT as measured by the root mean square error (RMSE), structural similarity index (SSIM), and peak signal-to-noise ratio (PSNR) depending on the size of the training data set. Dose calculations based on sCT data generated using the proposed architecture are also compared to clinical plans to evaluate the dosimetric accuracy of the method. RESULTS: Significant reductions in training time and improvements in image quality are observed at every training data set size when the proposed framework is adopted instead of the conventional framework. Over 1042 test images, values of 17.7 ± 4.3 HU, 0.9995 ± 0.0003, and 71.7 ± 2.3 are observed for the RMSE, SSIM, and PSNR metrics, respectively. Dose distributions calculated based on sCT data generated using the proposed framework demonstrate passing rates equal to or greater than 98% using the 3D gamma index with a 2%/2 mm criterion. CONCLUSIONS: The deep spatial pyramid convolutional framework proposed here demonstrates improved performance compared to the conventional GAN framework that has been applied to the image-to-image translation task of sCT generation. Adopting the method is a first step toward an MRI-only RT workflow that enables widespread clinical applications for MR-IGRT including online adaptive therapy.

Optimization of treatment planning workflow and tumor coverage during daily adaptive magnetic resonance image guided radiation therapy (MR-IGRT) of pancreatic cancer.

BACKGROUND: To simplify the adaptive treatment planning workflow while achieving the optimal tumor-dose coverage in pancreatic cancer patients undergoing daily adaptive magnetic resonance image guided radiation therapy (MR-IGRT). METHODS: In daily adaptive MR-IGRT, the plan objective function constructed during simulation is used for plan re-optimization throughout the course of treatment. In this study, we have constructed the initial objective functions using two methods for 16 pancreatic cancer patients treated with the ViewRay™ MR-IGRT system: 1) the conventional method that handles the stomach, duodenum, small bowel, and large bowel as separate organs at risk (OARs) and 2) the OAR grouping method. Using OAR grouping, a combined OAR structure that encompasses the portions of these four primary OARs within 3 cm of the planning target volume (PTV) is created. OAR grouping simulation plans were optimized such that the target coverage was comparable to the clinical simulation plan constructed in the conventional manner. In both cases, the initial objective function was then applied to each successive treatment fraction and the plan was re-optimized based on the patient's daily anatomy. OAR grouping plans were compared to conventional plans at each fraction in terms of coverage of the PTV and the optimized PTV (PTV OPT), which is the result of the subtraction of overlapping OAR volumes with an additional margin from the PTV. RESULTS: Plan performance was enhanced across a majority of fractions using OAR grouping. The percentage of the volume of the PTV covered by 95% of the prescribed dose (D95) was improved by an average of 3.87 ± 4.29% while D95 coverage of the PTV OPT increased by 3.98 ± 4.97%. Finally, D100 coverage of the PTV demonstrated an average increase of 6.47 ± 7.16% and a maximum improvement of 20.19%. CONCLUSIONS: In this study, our proposed OAR grouping plans generally outperformed conventional plans, especially when the conventional simulation plan favored or disregarded an OAR through the assignment of distinct weighting parameters relative to the other critical structures. OAR grouping simplifies the MR-IGRT adaptive treatment planning workflow at simulation while demonstrating improved coverage compared to delivered pancreatic cancer treatment plans in daily adaptive radiation therapy.