Synthetic CT for the planning of MR-HIFU treatment of bone metastases in pelvic and femoral bones: a feasibility study

Objectives: Visualization of the bone distribution is an important prerequisite for MRI-guided high-intensity focused ultrasound (MRI-HIFU) treatment planning of bone metastases. In this context, we evaluated MRI-based synthetic CT (sCT) imaging for the visualization of cortical bone. Methods: MR and CT images of nine patients with pelvic and femoral metastases were retrospectively analyzed in this study. The metastatic lesions were osteolytic, osteoblastic or mixed. sCT were generated from pre-treatment or treatment MR images using a UNet-like neural network. sCT was qualitatively and quantitatively compared to CT in the bone (pelvis or femur) containing the metastasis and in a region of interest placed on the metastasis itself, through mean absolute difference (MAD), mean difference (MD), Dice similarity coefficient (DSC), and root mean square surface distance (RMSD). Results: The dataset consisted of 3 osteolytic, 4 osteoblastic and 2 mixed metastases. For most patients, the general morphology of the bone was well represented in the sCT images and osteolytic, osteoblastic and mixed lesions could be discriminated. Despite an average timespan between MR and CT acquisitions of 61 days, in bone, the average (± standard deviation) MAD was 116 ± 26 HU, MD − 14 ± 66 HU, DSC 0.85 ± 0.05, and RMSD 2.05 ± 0.48 mm and, in the lesion, MAD was 132 ± 62 HU, MD − 31 ± 106 HU, DSC 0.75 ± 0.2, and RMSD 2.73 ± 2.28 mm. Conclusions: Synthetic CT images adequately depicted the cancellous and cortical bone distribution in the different lesion types, which shows its potential for MRI-HIFU treatment planning. Key Points: • Synthetic computed tomography was able to depict bone distribution in metastatic lesions. • Synthetic computed tomography images intrinsically aligned with treatment MR images may have the potential to facilitate MR-HIFU treatment planning of bone metastases, by combining visualization of soft tissues and cancellous and cortical bone

Ultrasound-directed enzyme-prodrug therapy (UDEPT) using self-immolative doxorubicin derivatives

Background: Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly heterogeneous in different tumor types and patients, we propose ultrasound-directed enzyme-prodrug therapy (UDEPT) as a means to increase enzyme access and availability for prodrug activation locally. Methods: We synthesized β-glucuronidase-sensitive self-immolative doxorubicin prodrugs with different spacer lengths between the active drug moiety and the capping group. We evaluated drug conversion, uptake and cytotoxicity in the presence and absence of the activating enzyme β-glucuronidase. To trigger the cell release of β-glucuronidase, we used high-intensity focused ultrasound to aid in the conversion of the prodrugs into their active counterparts. Results: More efficient enzymatic activation was observed for self-immolative prodrugs with more than one aromatic unit in the spacer. In the absence of β-glucuronidase, the prodrugs showed significantly reduced cellular uptake and cytotoxicity compared to the parent drug. High-intensity focused ultrasound-induced mechanical destruction of cancer cells resulted in release of intact β-glucuronidase, which activated the prodrugs, restored their cytotoxicity and induced immunogenic cell death. Conclusion: These findings shed new light on prodrug design and activation, and they contribute to novel UDEPT-based mechanochemical combination therapies for the treatment of cancer

Cavitation-enhanced back projection for acoustic detection of attenuating structures

Current methodology for the detection of attenuating structures in abdominal HIFU interventions requires lengthy, elaborate image analysis, which is undesired in a clinical setting. In this work, a method for the acoustic detection of attenuating structures in the beam path of the therapeutic HIFU array is described. The proposed method is used to determine binary apodizations that can be applied to the HIFU transducer for intercostal shot positions. Such a binary apodization was determined in vivo on an anesthetized pig under controlled breathing. Validation of the proposed method was done by comparing the binary apodization based on the proposed method to a binary apodization obtained using methodology based on MR image analysis and a collision detection algorithm. The proposed acoustical method provided a binary apodization that was over 90% similar to the apodization obtained using the image analysis-based method. Additionally, the proposed method can provide a measure of the amount of attenuation that each respective transducer element encounters in its beam path towards the focus

Cavitation-enhanced back projection for acoustic detection of attenuating structures

Current methodology for the detection of attenuating structures in abdominal HIFU interventions requires lengthy, elaborate image analysis, which is undesired in a clinical setting. In this work, a method for the acoustic detection of attenuating structures in the beam path of the therapeutic HIFU array is described. The proposed method is used to determine binary apodizations that can be applied to the HIFU transducer for intercostal shot positions. Such a binary apodization was determined in vivo on an anesthetized pig under controlled breathing. Validation of the proposed method was done by comparing the binary apodization based on the proposed method to a binary apodization obtained using methodology based on MR image analysis and a collision detection algorithm. The proposed acoustical method provided a binary apodization that was over 90% similar to the apodization obtained using the image analysis-based method. Additionally, the proposed method can provide a measure of the amount of attenuation that each respective transducer element encounters in its beam path towards the focus

Development and validation of a deep learning-based method for automatic measurement of uterus, fibroid, and ablated volume in MRI after MR-HIFU treatment of uterine fibroids

Introduction: The non-perfused volume divided by total fibroid load (NPV/TFL) is a predictive outcome parameter for MRI-guided high-intensity focused ultrasound (MR-HIFU) treatments of uterine fibroids, which is related to long-term symptom relief. In current clinical practice, the MR-HIFU outcome parameters are typically determined by visual inspection, so an automated computer-aided method could facilitate objective outcome quantification. The objective of this study was to develop and evaluate a deep learning-based segmentation algorithm for volume measurements of the uterus, uterine fibroids, and NPVs in MRI in order to automatically quantify the NPV/TFL. Materials and Methods: A segmentation pipeline was developed and evaluated using expert manual segmentations of MRI scans of 115 uterine fibroid patients, screened for and/or undergoing MR-HIFU treatment. The pipeline contained three separate neural networks, one per target structure. The first step in the pipeline was uterus segmentation from contrast-enhanced (CE)-T1w scans. This segmentation was subsequently used to remove non-uterus background tissue for NPV and fibroid segmentation. In the following step, NPVs were segmented from uterus-only CE-T1w scans. Finally, fibroids were segmented from uterus-only T2w scans. The segmentations were used to calculate the volume for each structure. Reliability and agreement between manual and automatic segmentations, volumes, and NPV/TFLs were assessed. Results: For treatment scans, the Dice similarity coefficients (DSC) between the manually and automatically obtained segmentations were 0.90 (uterus), 0.84 (NPV) and 0.74 (fibroid). Intraclass correlation coefficients (ICC) were 1.00 [0.99, 1.00] (uterus), 0.99 [0.98, 1.00] (NPV) and 0.98 [0.95, 0.99] (fibroid) between manually and automatically derived volumes. For manually and automatically derived NPV/TFLs, the mean difference was 5% [-41%, 51%] (ICC: 0.66 [0.32, 0.85]). Conclusion: The algorithm presented in this study automatically calculates uterus volume, fibroid load, and NPVs, which could lead to more objective outcome quantification after MR-HIFU treatments of uterine fibroids in comparison to visual inspection. When robustness has been ascertained in a future study, this tool may eventually be employed in clinical practice to automatically measure the NPV/TFL after MR-HIFU procedures of uterine fibroids

Spatiotemporal control of gene expression in bone-marrow derived cells of the tumor microenvironment induced by MRI guided focused ultrasound

The tumor microenvironment is an interesting target for anticancer therapies but modifying this compartment is challenging. Here, we demonstrate the feasibility of a gene therapy strategy that combined targeting to bone marrow-derived tumor microenvironment using genetically modified bone-marrow derived cells and control of transgene expression by local hyperthermia through a thermo-inducible promoter. Chimera were obtained by engraftment of bone marrow from transgenic mice expressing reporter genes under transcriptional control of heat shock promoter and inoculated sub-cutaneously with tumors cells. Heat shocks were applied at the tumor site using a water bath or magnetic resonance guided high intensity focused ultrasound device. Reporter gene expression was followed by bioluminescence and fluorescence imaging and immunohistochemistry. Bone marrow-derived cells expressing reporter genes were identified to be mainly tumor-associated macrophages. We thus provide the proof of concept for a gene therapy strategy that allows for spatiotemporal control of transgenes expression by macrophages targeted to the tumor microenvironment

Field drift correction of proton resonance frequency shift temperature mapping with multichannel fast alternating nonselective free induction decay readouts

Purpose: To demonstrate that proton resonance frequency shift MR thermometry (PRFS-MRT) acquisition with nonselective free induction decay (FID), combined with coil sensitivity profiles, allows spatially resolved B0 drift-corrected thermometry. Methods: Phantom experiments were performed at 1.5T and 3T. Acquisition of PRFS-MRT and FID were performed during MR-guided high-intensity focused ultrasound heating. The phase of the FIDs was used to estimate the change in angular frequency δωdrift per coil element. Two correction methods were investigated: (1) using the average δωdrift over all coil elements (0th-order) and (2) using coil sensitivity profiles for spatially resolved correction. Optical probes were used for independent temperature verification. In-vivo feasibility of the methods was evaluated in the leg of 1 healthy volunteer at 1.5T. Results: In 30 minutes, B0 drift led to an apparent temperature change of up to –18°C and –98°C at 1.5T and 3T, respectively. In the sonicated area, both corrections had a median error of 0.19°C at 1.5T and –0.54°C at 3T. At 1.5T, the measured median error with respect to the optical probe was –1.28°C with the 0th-order correction and improved to 0.43°C with the spatially resolved correction. In vivo, without correction the spatiotemporal median of the apparent temperature was at –4.3°C and interquartile range (IQR) of 9.31°C. The 0th-order correction had a median of 0.75°C and IQR of 0.96°C. The spatially resolved method had the lowest median at 0.33°C and IQR of 0.80°C. Conclusion: FID phase information from individual receive coil elements allows spatially resolved B0 drift correction in PRFS-based MRT

Field drift correction of proton resonance frequency shift temperature mapping with multichannel fast alternating nonselective free induction decay readouts

Purpose: To demonstrate that proton resonance frequency shift MR thermometry (PRFS-MRT) acquisition with nonselective free induction decay (FID), combined with coil sensitivity profiles, allows spatially resolved B0 drift-corrected thermometry. Methods: Phantom experiments were performed at 1.5T and 3T. Acquisition of PRFS-MRT and FID were performed during MR-guided high-intensity focused ultrasound heating. The phase of the FIDs was used to estimate the change in angular frequency δωdrift per coil element. Two correction methods were investigated: (1) using the average δωdrift over all coil elements (0th-order) and (2) using coil sensitivity profiles for spatially resolved correction. Optical probes were used for independent temperature verification. In-vivo feasibility of the methods was evaluated in the leg of 1 healthy volunteer at 1.5T. Results: In 30 minutes, B0 drift led to an apparent temperature change of up to –18°C and –98°C at 1.5T and 3T, respectively. In the sonicated area, both corrections had a median error of 0.19°C at 1.5T and –0.54°C at 3T. At 1.5T, the measured median error with respect to the optical probe was –1.28°C with the 0th-order correction and improved to 0.43°C with the spatially resolved correction. In vivo, without correction the spatiotemporal median of the apparent temperature was at –4.3°C and interquartile range (IQR) of 9.31°C. The 0th-order correction had a median of 0.75°C and IQR of 0.96°C. The spatially resolved method had the lowest median at 0.33°C and IQR of 0.80°C. Conclusion: FID phase information from individual receive coil elements allows spatially resolved B0 drift correction in PRFS-based MRT