Implementation and evaluation of a dynamic contrast-enhanced MR perfusion protocol for glioblastoma using a 0.35 T MRI-Linac system.

PURPOSE: MRI-linear accelerator (MRI-Linac) systems allow for daily tracking of MRI changes during radiotherapy (RT). Since one common MRI-Linac operates at 0.35 T, there are efforts towards developing protocols at that field strength. In this study we demonstrate the implementation of a post-contrast 3DT1-weighted (3D-T1w) and dynamic contrast-enhancement (DCE) protocol to assess glioblastoma response to RT using a 0.35 T MRI-Linac. METHODS AND MATERIALS: The protocol implemented was used to acquire 3D-T1w and DCE data from a flow phantom and two patients with glioblastoma (a responder and a non-responder) who underwent RT on a 0.35 T MRI-Linac. The detection of post-contrast-enhanced volumes was evaluated by comparing the 3DT1w images from the 0.35 T MRI-Linac to images obtained using a 3 T scanner. The DCE data were tested temporally and spatially using data from a flow phantom and patients. Ktrans maps were derived from DCE at three time points (a week before treatment-Pre RT, four weeks through treatment-Mid RT, and three weeks after treatment-Post RT) and were validated with patients' treatment outcomes. RESULTS: The 3D-T1w contrast-enhancement volumes were visually and volumetrically similar between 0.35 T MRI-Linac and 3 T. DCE images showed temporal stability, and associated Ktrans maps were consistent with patient response to treatment. On average, Ktrans values showed a 54 % decrease and 8.6 % increase for a responder and non-responder respectively when Pre RT and Mid RT images were compared. CONCLUSION: Our findings support the feasibility of obtaining post-contrast 3D-T1w and DCE data from patients with glioblastoma using a 0.35 T MRI-Linac system.

Improvement of 2D cine image quality using 3D priors and cycle generative adversarial network for low field MRI-guided radiation therapy.

BACKGROUND: Cine magnetic resonance (MR) images have been used for real-time MR guided radiation therapy (MRgRT). However, the onboard MR systems with low-field strength face the problem of limited image quality. PURPOSE: To improve the quality of cine MR images in MRgRT using prior image information provided by the patient planning and positioning MR images. METHODS: This study employed MR images from 18 pancreatic cancer patients who received MR-guided stereotactic body radiation therapy. Planning 3D MR images were acquired during the patient simulation, and positioning 3D MR images and 2D sagittal cine MR images were acquired before and during the beam delivery, respectively. A deep learning-based framework consisting of two cycle generative adversarial networks (CycleGAN), Denoising CycleGAN and Enhancement CycleGAN, was developed to establish the mapping between the 3D and 2D MR images. The Denoising CycleGAN was trained to first denoise the cine images using the time domain cine image series, and the Enhancement CycleGAN was trained to enhance the spatial resolution and contrast by taking advantage of the prior image information from the planning and positioning images. The denoising performance was assessed by signal-to-noise ratio (SNR), structural similarity index measure, peak SNR, blind/reference-less image spatial quality evaluator (BRISQUE), natural image quality evaluator, and perception-based image quality evaluator scores. The quality enhancement performance was assessed by the BRISQUE and physician visual scores. In addition, the target contouring was evaluated on the original and processed images. RESULTS: Significant differences were found for all evaluation metrics after Denoising CycleGAN processing. The BRISQUE and visual scores were also significantly improved after sequential Denoising and Enhancement CycleGAN processing. In target contouring evaluation, Dice similarity coefficient, centroid distance, Hausdorff distance, and average surface distance values were significantly improved on the enhanced images. The whole processing time was within 20 ms for a typical input image size of 512 × 512. CONCLUSION: Taking advantage of the prior high-quality positioning and planning MR images, the deep learning-based framework enhanced the cine MR image quality significantly, leading to improved accuracy in automatic target contouring. With the merits of both high computational efficiency and considerable image quality enhancement, the proposed method may hold important clinical implication for real-time MRgRT.

Dosimetry impact of distinct gating strategies in cine MR image-guided breath-hold pancreatic cancer radiotherapy.

PURPOSE: To investigate the dosimetry effects of different gating strategies in cine magnetic resonance imaging (MRI)-guided breath-hold pancreatic cancer radiotherapy. METHODS: Two cine MRI-based gating strategies were investigated： a tumor contour-based gating strategy at a gating threshold of 0-5% and a tumor displacement-based gating strategy at a gating threshold of 3-5 mm. The cine MRI videos were obtained from 17 pancreatic cancer patients who received MRI-guided radiation therapy. We calculated the tumor displacement in each cine MR frame that satisfied the gating threshold and obtained the proportion of frames with different displacements. We generated IMRT and VMAT plans using a 33 Gy prescription, and motion plans were generated by adding up all isocenter-shift plans corresponding to different tumor displacements. The dose parameters of GTV, PTV, and organs at risk (OAR) were compared between the original and motion plans. RESULTS: In both gating strategies, the difference was significant in PTV coverage but not in GTV coverage between the original and motion plans. OAR dose parameters deteriorate with increasing gating threshold. The beam duty cycle increased from 19.5±14.3% (median 18.0%) to 60.8±15.6% (61.1%) for gating thresholds from 0% to 5% in tumor contour-based gating and from 51.7±11.5% (49.7%) to 67.3±12.4% (67.1%) for gating thresholds from 3 to 5 mm in tumor displacement-based gating. CONCLUSION: In tumor contour-based gating strategy, the dose delivery accuracy deteriorates while the dose delivery efficiency improves with increasing gating thresholds. To ensure treatment efficiency, the gating threshold might be no less than 3%. A threshold up to 5% may be acceptable in terms of the GTV coverage. The displacement-based gating strategy may serve as a potential alternative to the tumor contour based gating strategy, in which the gating threshold of approximately 4 mm might be a good choice for reasonably balancing the dose delivery accuracy and efficiency.

Implementation and evaluation of a dynamic contrast enhanced MR perfusion protocol for glioblastoma using a 0.35T MRI-Linac system.

Purpose: MRI-linear accelerator (MRI-Linac) systems allow for daily tracking of MRI changes during radiotherapy (RT). Since one common MRI-Linac operates at 0.35T, there are efforts towards developing protocols at that field strength. In this study we demonstrate the implementation of a post-contrast 3DT1-weighted (3DT1w) and dynamic contrast enhancement (DCE) protocol to assess glioblastoma response to RT using a 0.35T MRI-Linac. Methods and materials: The protocol implemented was used to acquire 3DT1w and DCE data from a flow phantom and two patients with glioblastoma (a responder and a non-responder) who underwent RT on a 0.35T-MRI-Linac. The detection of post-contrast enhanced volumes was evaluated by comparing the 3DT1w images from the 0.35T-MRI-Linac to images obtained using a 3T-standalone scanner. The DCE data were tested temporally and spatially using data from the flow phantom and patients. Ktrans maps were derived from DCE at three time points (a week before treatment-Pre RT, four weeks through treatment-Mid RT, and three weeks after treatment-Post RT) and were validated with patients' treatment outcomes. Results: The 3D-T1 contrast enhancement volumes were visually and volumetrically similar (±0.6-3.6%) between 0.35T MRI-Linac and 3T. DCE images showed temporal stability, and associated Ktrans maps were consistent with patient response to treatment. On average, Ktrans values showed a 54% decrease and 8.6% increase for a responder and non-responder respectively when Pre RT and Mid RT images were compared. Conclusion: Our findings support the feasibility of obtaining post-contrast 3DT1w and DCE data from patients with glioblastoma using a 0.35T MRI-Linac system.

Simulated Adaptive Radiotherapy for Shrinking Glioblastoma Resection Cavities on a Hybrid MRI-Linear Accelerator.

During radiation therapy (RT) of glioblastoma, daily MRI with combination MRI-linear accelerator (MRI-Linac) systems has demonstrated significant anatomic changes, including evolving post-surgical cavity shrinkage. Cognitive function RT for brain tumors is correlated with radiation doses to healthy brain structures, especially the hippocampi. Therefore, this study investigates whether adaptive planning to the shrinking target could reduce normal brain RT dose with the goal of improving post-RT function. We evaluated 10 glioblastoma patients previously treated on a 0.35T MRI-Linac with a prescription of 60 Gy delivered in 30 fractions over six weeks without adaptation ("static plan") with concurrent temozolomide chemotherapy. Six weekly plans were created per patient. Reductions in the radiation dose to uninvolved hippocampi (maximum and mean) and brain (mean) were observed for weekly adaptive plans. The dose (Gy) to the hippocampi for static vs. weekly adaptive plans were, respectively: max 21 ± 13.7 vs. 15.2 ± 8.2 (p = 0.003) and mean 12.5 ± 6.7 vs. 8.4 ± 4.0 (p = 0.036). The mean brain dose was 20.6 ± 6.0 for static planning vs. 18.7 ± 6.8 for weekly adaptive planning (p = 0.005). Weekly adaptive re-planning has the potential to spare the brain and hippocampi from high-dose radiation, possibly reducing the neurocognitive side effects of RT for eligible patients.

Boosted Radiation Bystander Effect of PSMA-Targeted Gold Nanoparticles in Prostate Cancer Radiosensitization.

Metal nanoparticles are effective radiosensitizers that locally enhance radiation doses in targeted cancer cells. Compared with other metal nanoparticles, gold nanoparticles (GNPs) exhibit high biocompatibility, low toxicity, and they increase secondary electron scatter. Herein, we investigated the effects of active-targeting GNPs on the radiation-induced bystander effect (RIBE) in prostate cancer cells. The impact of GNPs on the RIBE presents implications for secondary cancers or spatially fractionated radiotherapy treatments. Anti-prostate-specific membrane antigen (PSMA) antibodies were conjugated with PEGylated GNPs through EDC-NHS chemistry. The media transfer technique was performed to induce the RIBE on the non-irradiated bystander cells. This study focused on the LNCaP cell line, because it can model a wide range of stages relating to prostate cancer progression, including the transition from androgen dependence to castration resistance and bone metastasis. First, LNCaP cells were pretreated with phosphate buffered saline (PBS) or PSMA-targeted GNPs (PGNPs) for 24 h and irradiated with 160 kVp X-rays (0-8 Gy). Following that, the collected culture media were filtered (sterile 0.45 µm polyethersulfone) in order to acquire PBS- and PGNP- conditioned media (CM). Then, PBS- and PGNP-CM were transferred to the bystander cells that were loaded with/without PGNPs. MTT, γ-H2AX, clonogenic assays and reactive oxygen species assessments were performed to compare RIBE responses under different treatments. Compared with 2 Gy-PBS-CM, 8 Gy-PBS-CM demonstrated a much higher RIBE response, thus validating the dose dependence of RIBE in LNCaP cells. Compared with PBS-CM, PGNP-CM exhibited lower cell viability, higher DNA damage, and a smaller survival fraction. In the presence of PBS-CM, bystander cells loaded with PGNPs showed increased cell death compared with cells that did not have PGNPs. These results demonstrate the PGNP-boosted expression and sensitivity of RIBE in prostate cancer cells.

A novel edge gradient distance metric for automated evaluation of deformable image registration quality.

PURPOSE: To develop a new registration quality metric, based on the distance between image edges, for automated evaluation and comparison of DIR algorithms. METHODS: Canny filter is used to create binary gradient images from input images to be compared. A small subregion of one binary image is translated relative to the other. The translational distance maximizing overlap of edges in the subregion is the local edge gradient distance to agreement (EGDTA); repeating over all subregions provides an EGDTA map. The method was tested on phantom and pelvic CT images, by applying a known deformable vector field (DVF). The method was then applied to evaluate two DIR algorithms (SICLE and Demons) for pelvic CTs from five patients. Three SICLE variants were used: Grayscale-driven (G), Contour-driven (C), and Grayscale + Contour-driven (G + C). For each patient, a planning CT was registered to three repeat CTs using the above DIR algorithms. Mean EGDTA values in concentric ring regions of interest close to and far away from the pelvic organ contours were compared. RESULTS: EGDTA maps and imposed DVF deformations on phantom and CT images demonstrated agreement. In comparison of the three variants of SICLE: C had lower EGDTA values close to the pelvic organs, while G showed much better performance in the regions distant from the organs compared to C; and G + C registration exhibited the lowest or comparable EGDTA value among three variants. Demons achieved the lowest EGDTA values. CONCLUSIONS: The EGDTA metric shows potential as an automated means of evaluating and comparing DIR algorithms.

Dosimetry impact of gating latency in cine magnetic resonance image guided breath-hold pancreatic cancer radiotherapy.

Objective.We investigated dosimetry effect of gating latency in cine magnetic resonance image (cine MRI) guided breath-hold pancreatic cancer radiotherapy.Approach.The gating latency was calculated based on cine MRI obtained from 17 patients who received MRI guided radiotherapy. Because of the cine MRI-related latency, beam overshoot occurs when beam remains on while the tracking target already moves out of the target boundary. The number of beam on/off events was calculated from the cine MRI data. We generated both IMRT and VMAT plans for all 17 patients using 33 Gy prescription, and created motion plans by applying isocenter shift that corresponds to motion-induced tumor displacement. The GTV and PTV coverage and dose to nearby critical structures were compared between the motion and original plan to evaluate the dosimetry change caused by cine MRI latency.Main results.The time ratio of cine MRI imaging latency over the treatment duration is 6.6 ± 3.1%, the mean and median percentage of beam-on events <4 s are 67.0 ± 14.3% and 66.6%. When a gating boundary of 4 mm and a target-out threshold of 5% is used, there is no significant difference for GTV V33Gy between the motion and original plan (p = 0.861 and 0.397 for IMRT and VMAT planning techniques, respectively). However, the PTV V33Gy and stomach Dmax for the motion plans are significantly lower; duodenum V12.5 Gy and V18Gy are significantly higher when compared with the original plans, for both IMRT and VMAT planning techniques.Significance.The cine MRI gating latency can significantly decrease the dose delivered to the PTV, and increase the dose to the nearby critical structures. However, no significant difference is observed for the GTV coverage. The dosimetry impact can be mitigated by implementing additional beam-on control techniques which reduces unnecessary beam on events and/or by using faster cine MRI sequences which reduces the latency period.

Prostate Cancer Targeted X-Ray Fluorescence Imaging via Gold Nanoparticles Functionalized With Prostate-Specific Membrane Antigen (PSMA).

PURPOSE: The gold nanoparticle (GNP) as a promising theranostic probe has been increasingly studied. The tumor-targeting efficiency of GNPs is crucial to increase the therapeutic ratio. In this study, we developed PSMA-targeted GNPs to enhance GNP uptake in prostate cancer and developed an x-ray fluorescence imaging system to noninvasively monitor and assess GNP delivery. METHODS AND MATERIALS: For targeted therapy of prostate cancer, anti-prostate-specific membrane antigen (PSMA) antibodies were conjugated onto PEGylated GNPs through 1-ethyl-3-(-3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) (EDC/NHS) chemistry. In vivo imaging was implemented using an in-house-developed dual-modality computed tomography (CT) and x-ray fluorescence CT (XFCT) system on mice bearing subcutaneous LNCaP prostate tumors. After intravenous administration of GNPs (15 mg/mL, 200 µL), the x-ray fluorescence signals from the tumor were collected at various time points (5 minutes to approximately 30 hours) for GNP pharmacokinetics analysis. At 24 hours after administration, x-ray fluorescence projection (XRFproj) and XFCT imaging were conducted to evaluate the prostate tumor uptake of active- and passive-targeting GNPs. Inductively coupled plasma mass spectrometry analysis was adopted as a benchmark to verify the quantification accuracy of XRFproj/XFCT imaging. RESULTS: Fluorescence microscopic imaging confirmed the enhanced (approximately 4 times) targeting efficiency of PSMA-targeted GNPs in vitro. The pharmacokinetics analysis showed enhanced tumor uptake/retention of PSMA-targeted GNPs and revealed that the peak tumor accumulation appeared at approximately 24 hours after intravenous administration. Both XRFproj and XFCT imaging presented their accuracy in quantifying GNPs within tumors noninvasively. Moreover, XFCT imaging verified its unique capabilities to simultaneously determine the heterogeneous spatial distribution and the concentration of GNPs within tumors in vivo. CONCLUSIONS: In conjunction with PSMA-targeted GNPs, XRFproj/XFCT would be a highly sensitive tool for targeted imaging of prostate cancer, benefiting the elucidation of mechanisms of GNP-assisted prostate-cancer therapy.

Advantages of Radiation Therapy Simulation with 0.35 Tesla Magnetic Resonance Imaging for Stereotactic Ablation of Spinal Metastases.

The hybrid 0.35T magnetic resonance imaging (MRI) and radiation therapy system functions in part as a simulation platform for treatment planning. We have found that the images generated are particularly helpful for planning of stereotactic radiation therapy for spinal metastases. Advantages include the following: (1) Low-field MRI mitigates magnetic susceptibility artifacts caused by spinal hardware. (2) Volumetric pulse sequence provides isotropic images for improved target delineation. (3) Wide-bore MRI in the radiation oncology department allows for easy simulation in treatment position for accurate fusion across imaging modalities. (4) When patients are treated on the MRI and radiation therapy hybrid device, adaptive radiation therapy is available for special situations to avoid mobile organs at risk.

Evaluation of radiomic texture feature error due to MRI acquisition and reconstruction: A simulation study utilizing ground truth.

The purpose of this study was to examine the dependence of image texture features on MR acquisition parameters and reconstruction using a digital MR imaging phantom. MR signal was simulated in a parallel imaging radiofrequency coil setting as well as a single element volume coil setting, with varying levels of acquisition noise, three acceleration factors, and four image reconstruction algorithms. Twenty-six texture features were measured on the simulated images, ground truth images, and clinical brain images. Subtle algorithm-dependent errors were observed on reconstructed phantom images, even in the absence of added noise. Sources of image error include Gibbs ringing at image edge gradients (tissue interfaces) and well-known artifacts due to high acceleration; two of the iterative reconstruction algorithms studied were able to mitigate these image errors. The difference of the texture features from ground truth, and their variance over reconstruction algorithm and parallel imaging acceleration factor, were compared to the clinical "effect size", i.e., the feature difference between high- and low-grade tumors on T1- and T2-weighted brain MR images of twenty glioma patients. The measured feature error (difference from ground truth) was small for some features, but substantial for others. The feature variance due to reconstruction algorithm and acceleration factor were generally smaller than the clinical effect size. Certain texture features may be preserved by MR imaging, but adequate precautions need to be taken regarding their validity and reliability. We present a general simulation framework for assessing the robustness and accuracy of radiomic textural features under various MR acquisition/reconstruction scenarios.