Generalized div-curl based regularization for physically constrained deformable image registration.

Variational image registration methods commonly employ a similarity metric and a regularization term that renders the minimization problem well-posed. However, many frequently used regularizations such as smoothness or curvature do not necessarily reflect the underlying physics that apply to anatomical deformations. This, in turn, can make the accurate estimation of complex deformations particularly challenging. Here, we present a new highly flexible regularization inspired from the physics of fluid dynamics which allows applying independent penalties on the divergence and curl of the deformations and/or their nth order derivative. The complexity of the proposed generalized div-curl regularization renders the problem particularly challenging using conventional optimization techniques. To this end, we develop a transformation model and an optimization scheme that uses the divergence and curl components of the deformation as control parameters for the registration. We demonstrate that the original unconstrained minimization problem reduces to a constrained problem for which we propose the use of the augmented Lagrangian method. Doing this, the equations of motion greatly simplify and become managable. Our experiments indicate that the proposed framework can be applied on a variety of different registration problems and produce highly accurate deformations with the desired physical properties.

Focused Ultrasound-Enhanced Liquid Biopsy: A Promising Diagnostic Tool for Brain Tumor Patients.

The performance of minimally invasive molecular diagnostic tools in brain tumors, such as liquid biopsy, has so far been limited by the blood-brain barrier (BBB). The BBB hinders the release of brain tumor biomarkers into the bloodstream. The use of focused ultrasound in conjunction with microbubbles has been shown to temporarily open the BBB (FUS-BBBO). This may enhance blood-based tumor biomarker levels. This systematic review provides an overview of the data regarding FUS-BBBO-enhanced liquid biopsy for primary brain tumors. A systematic search was conducted in PubMed and Embase databases with key terms "brain tumors", "liquid biopsy", "FUS" and their synonyms, in accordance with PRISMA statement guidelines. Five preclinical and two clinical studies were included. Preclinical studies utilized mouse, rat and porcine glioma models. Biomarker levels were found to be higher in sonicated groups compared to control groups. Both stable and inertial microbubble cavitation increased biomarker levels, whereas only inertial cavitation induced microhemorrhages. In clinical studies involving 14 patients with high-grade brain tumors, biomarker levels were increased after FUS-BBBO with stable cavitation. In conclusion, FUS-BBBO-enhanced liquid biopsy using stable cavitation shows diagnostic potential for primary brain tumors. Further research is imperative before integrating FUS-BBBO for liquid biopsy enhancement into clinical practice.

SOLID: a novel similarity metric for mono-modal and multi-modal deformable image registration.

Medical image registration is an integral part of various clinical applications including image guidance, motion tracking, therapy assessment and diagnosis. We present a robust approach for mono-modal and multi-modal medical image registration. To this end, we propose the novel shape operator based local image distance (SOLID) which estimates the similarity of images by comparing their second-order curvature information. Our similarity metric is rigorously tailored to be suitable for comparing images from different medical imaging modalities or image contrasts. A critical element of our method is the extraction of local features using higher-order shape information, enabling the accurate identification and registration of smaller structures. In order to assess the efficacy of the proposed similarity metric, we have implemented a variational image registration algorithm that relies on the principle of matching the curvature information of the given images. The performance of the proposed algorithm has been evaluated against various alternative state-of-the-art variational registration algorithms. Our experiments involve mono-modal as well as multi-modal and cross-contrast co-registration tasks in a broad variety of anatomical regions. Compared to the evaluated alternative registration methods, the results indicate a very favorable accuracy, precision and robustness of the proposed SOLID method in various highly challenging registration tasks.

Integration of operator-validated contours in deformable image registration for dose accumulation in radiotherapy.

Background and Purpose: Deformable image registration (DIR) is a core element of adaptive radiotherapy workflows, integrating daily contour propagation and/or dose accumulation in their design. Propagated contours are usually manually validated and may be edited, thereby locally invalidating the registration result. This means the registration cannot be used for dose accumulation. In this study we proposed and evaluated a novel multi-modal DIR algorithm that incorporated contour information to guide the registration. This integrates operator-validated contours with the estimated deformation vector field and warped dose. Materials and Methods: The proposed algorithm consisted of both a normalized gradient field-based data-fidelity term on the images and an optical flow data-fidelity term on the contours. The Helmholtz-Hodge decomposition was incorporated to ensure anatomically plausible deformations. The algorithm was validated for same- and cross-contrast Magnetic Resonance (MR) image registrations, Computed Tomography (CT) registrations, and CT-to-MR registrations for different anatomies, all based on challenging clinical situations. The contour-correspondence, anatomical fidelity, registration error, and dose warping error were evaluated. Results: The proposed contour-guided algorithm considerably and significantly increased contour overlap, decreasing the mean distance to agreement by a factor of 1.3 to 13.7, compared to the best algorithm without contour-guidance. Importantly, the registration error and dose warping error decreased significantly, by a factor of 1.2 to 2.0. Conclusions: Our contour-guided algorithm ensured that the deformation vector field and warped quantitative information were consistent with the operator-validated contours. This provides a feasible semi-automatic strategy for spatially correct warping of quantitative information even in difficult and artefacted cases.

Technical note: Intensity-based quality assurance criteria for deformable image registration in image-guided radiotherapy.

BACKGROUND: Deformable image registration is increasingly used in radiotherapy to adapt the treatment plan and accumulate the delivered dose. Consequently, clinical workflows using deformable image registration require quick and reliable quality assurance to accept registrations. Additionally, for online adaptive radiotherapy, quality assurance without the need for an operator to delineate contours while the patient is on the treatment table is needed. Established quality assurance criteria such as the Dice similarity coefficient or Hausdorff distance lack these qualities and also display a limited sensitivity to registration errors beyond soft tissue boundaries. PURPOSE: The purpose of this study is to investigate the existing intensity-based quality assurance criteria structural similarity and normalized mutual information for their ability to quickly and reliably identify registration errors for (online) adaptive radiotherapy and compare them to contour-based quality assurance criteria. METHODS: All criteria were tested using synthetic and simulated biomechanical deformations of 3D MR images as well as manually annotated 4D CT data. The quality assurance criteria were scored for classification performance, for their ability to predict the registration error, and for their spatial information. RESULTS: We found that besides being fast and operator-independent, the intensity-based criteria have the highest area under the receiver operating characteristic curve and provide the best input for models to predict the registration error on all data sets. Structural similarity furthermore provides spatial information with a higher gamma pass rate of the predicted registration error than commonly used spatial quality assurance criteria. CONCLUSIONS: Intensity-based quality assurance criteria can provide the required confidence in decisions about using mono-modal registrations in clinical workflows. They thereby enable automated quality assurance for deformable image registration in adaptive radiotherapy treatments.

Towards Standardisation of a Diffuse Midline Glioma Patient-Derived Xenograft Mouse Model Based on Suspension Matrices for Preclinical Research.

Diffuse midline glioma (DMG) is an aggressive brain tumour with high mortality and limited clinical therapeutic options. Although in vitro research has shown the effectiveness of medication, successful translation to the clinic remains elusive. A literature search highlighted the high variability and lack of standardisation in protocols applied for establishing the commonly used HSJD-DIPG-007 patient-derived xenograft (PDX) model, based on animal host, injection location, number of cells inoculated, volume, and suspension matrices. This study evaluated the HSJD-DIPG-007 PDX model with respect to its ability to mimic human disease progression for therapeutic testing in vivo. The mice received intracranial injections of HSJD-DIPG-007 cells suspended in either PBS or Matrigel. Survival, tumour growth, and metastases were assessed to evaluate differences in the suspension matrix used. After cell implantation, no severe side effects were observed. Additionally, no differences were detected in terms of survival or tumour growth between the two suspension groups. We observed delayed metastases in the Matrigel group, with a significant difference compared to mice with PBS-suspended cells. In conclusion, using Matrigel as a suspension matrix is a reliable method for establishing a DMG PDX mouse model, with delayed metastases formation and is a step forward to obtaining a standardised in vivo PDX model.

A High-Throughput Image-Guided Stereotactic Neuronavigation and Focused Ultrasound System for Blood-Brain Barrier Opening in Rodents.

The blood-brain barrier (BBB) has been a major hurdle for the treatment of various brain diseases. Endothelial cells, connected by tight junctions, form a physiological barrier preventing large molecules (>500 Da) from entering the brain tissue. Microbubble-mediated focused ultrasound (FUS) can be used to induce a transient local BBB opening, allowing larger drugs to enter the brain parenchyma. In addition to large-scale clinical devices for clinical translation, preclinical research for therapy response assessment of drug candidates requires dedicated small animal ultrasound setups for targeted BBB opening. Preferably, these systems allow high-throughput workflows with both high-spatial precision as well as integrated cavitation monitoring, while still being cost effective in both initial investment and running costs. Here, we present a bioluminescence and X-ray guided stereotactic small animal FUS system that is based on commercially available components and fulfills the aforementioned requirements. A particular emphasis has been placed on a high degree of automation facilitating the challenges typically encountered in high-volume preclinical drug evaluation studies. Examples of these challenges are the need for standardization in order to ensure data reproducibility, reduce intra-group variability, reduce sample size and thus comply with ethical requirements and decrease unnecessary workload. The proposed BBB system has been validated in the scope of BBB opening facilitated drug delivery trials on patient-derived xenograft models of glioblastoma multiforme and diffuse midline glioma.

Biomechanical quality assurance criteria for deformable image registration algorithms used in radiotherapy guidance.

Image-guided radiation therapy (IGRT) allows radiation dose deposition with a high degree of geometric accuracy. Previous studies have demonstrated that such therapies may benefit from the employment of deformable image registration (DIR) algorithms, which allow both the automatic tracking of anatomical changes and accumulation of the delivered radiation dose over time. In order to ensure patient care and safety, however, the estimated deformations must be subjected to stringent quality assurance (QA) measures. In the present study we propose to extend the state-of-the-art methodology for QA of DIR algorithms by a set of novel biomechanical criteria. The proposed biomechanical criteria imply the calculation of the normal and shear mechanical stress, which would occur within the observed tissues as a result of the estimated deformations. The calculated stress is then compared to plausible physiological limits, providing thus the anatomical plausibility of the estimated deformations. The criteria were employed for the QA of three DIR algorithms in the context of abdominal conebeam computed tomography and magnetic resonance radiotherapy guidance. An initial evaluation of organ boundary alignment capabilities indicated that all three algorithms perform similarly. However, an analysis of the deformations within the organ boundaries with respect to the proposed biomechanical QA criteria revealed different degrees of anatomical plausibility. Additionally, it was demonstrated that violations of these criteria are also indicative of errors within the dose accumulation process. The proposed QA criteria, therefore, provide a tissue-dependent assessment of the anatomical plausibility of the deformations estimated by DIR algorithms, showcasing potential in ensuring patient safety for future adaptive IGRT treatments.

High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.

PURPOSE: Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically "cold" tumors into responsive "hot" tumors. EXPERIMENTAL DESIGN: We treated <2% of tumor volume in previously unresponsive, large, refractory murine neuroblastoma tumors with mechanical HIFU and assessed systemic immune response using flow cytometry, ELISA, and gene sequencing. In addition, we combined this treatment with αCTLA-4 and αPD-L1 to study its effect on the immune response and long-term survival. RESULTS: Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances antitumor response, improving survival from 0% to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL2, IFNγ, and DAMPs, whereas immune regulators like CD4+Foxp3+, IL10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4+, CD8α+, and CD8α+CD11c+ cells, CD11c+ in regional lymph nodes, and decrease in circulating IL10 compared with untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared with tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival, P < 0.0001). This combination treatment significantly also induces CD4+CD44+hiCD62L+low and CD8α+CD44+hiCD62L+low population and is adoptively transferable, imparting immunity, slowing subsequent de novo tumor engraftment. CONCLUSIONS: Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model and promises a novel yet efficacious immunoadjuvant modality to overcome therapeutic resistance.

Evaluating the benefit of PBS vs. VMAT dose distributions in terms of dosimetric sparing and robustness against inter-fraction anatomical changes for pediatric abdominal tumors.

BACKGROUND AND PURPOSE: To evaluate the dosimetric sparing and robustness against inter-fraction anatomical changes between photon and proton dose distributions for children with abdominal tumors. MATERIAL AND METHODS: Volumetric modulated arc therapy (VMAT) and intensity-modulated pencil beam scanning (PBS) proton dose distributions were calculated for 20 abdominal pediatric cases (average 3, range 1-8 years). VMAT plans were based on a full-arc while PBS plans on 2-3 posterior-oblique irradiation fields. Plans were robustly optimized on a patient-specific internal target volume (ITV) using a uniform 5 mm set-up uncertainty. Additionally, for the PBS plans a ± 3% proton range uncertainty was accounted for. Fractional dose re-calculations were performed using the planning computed tomography (CT) deformably registered to the daily cone-beam CT (CBCT) images. Fractional doses were accumulated rigidly. Planned and CBCT accumulated VMAT and PBS dose distributions were compared using dose-volume histogram (DVH) parameters. RESULTS: Significant better sparing of the organs at risk with a maximum reduction in the mean dose of 40% was achieved with PBS. Mean ITV DVH parameters differences between planned and CBCT accumulated dose distributions were smaller than 0.5% for both VMAT and PBS. However, the ITV coverage (V95% > 99%) was not reached for one patient for the accumulated VMAT dose distribution. CONCLUSIONS: For pediatric patients with abdominal tumors, improved dosimetric sparing was obtained with PBS compared to VMAT. In addition, PBS delivered by posterior-oblique irradiation fields demonstrated to be robust against anatomical inter-fraction changes. Compared to PBS, daily anatomical changes proved to affect the target coverage of VMAT dose distributions to a higher extent.

Non-rigid CT/CBCT to CBCT registration for online external beam radiotherapy guidance.

Image-guided external beam radiotherapy (EBRT) allows radiation dose deposition with a high degree of accuracy and precision. Guidance is usually achieved by estimating the displacements, via image registration, between cone beam computed tomography (CBCT) and computed tomography (CT) images acquired at different stages of the therapy. The resulting displacements are then used to reposition the patient such that the location of the tumor at the time of treatment matches its position during planning. Moreover, ongoing research aims to use CBCT-CT image registration for online plan adaptation. However, CBCT images are usually acquired using a small number of x-ray projections and/or low beam intensities. This often leads to the images being subject to low contrast, low signal-to-noise ratio and artifacts, which ends-up hampering the image registration process. Previous studies addressed this by integrating additional image processing steps into the registration procedure. However, these steps are usually designed for particular image acquisition schemes, therefore limiting their use on a case-by-case basis. In the current study we address CT to CBCT and CBCT to CBCT registration by the means of the recently proposed EVolution registration algorithm. Contrary to previous approaches, EVolution does not require the integration of additional image processing steps in the registration scheme. Moreover, the algorithm requires a low number of input parameters, is easily parallelizable and provides an elastic deformation on a point-by-point basis. Results have shown that relative to a pure CT-based registration, the intrinsic artifacts present in typical CBCT images only have a sub-millimeter impact on the accuracy and precision of the estimated deformation. In addition, the algorithm has low computational requirements, which are compatible with online image-based guidance of EBRT treatments.

A framework for continuous target tracking during MR-guided high intensity focused ultrasound thermal ablations in the abdomen.

BACKGROUND: During lengthy magnetic resonance-guided high intensity focused ultrasound (MRg-HIFU) thermal ablations in abdominal organs, the therapeutic work-flow is frequently hampered by various types of physiological motion occurring at different time-scales. If left un-addressed this can lead to an incomplete therapy and/or to tissue damage of organs-at-risk. While previous studies focus on correction schemes for displacements occurring at a particular time-scale within the work-flow of an MRg-HIFU therapy, in the current work we propose a motion correction strategy encompassing the entire work-flow. METHODS: The proposed motion compensation framework consists of several linked components, each being adapted to motion occurring at a particular time-scale. While respiration was addressed through a fast correction scheme, long term organ drifts were compensated using a strategy operating on time-scales of several minutes. The framework relies on a periodic examination of the treated area via MR scans which are then registered to a reference scan acquired at the beginning of the therapy. The resulting displacements were used for both on-the-fly re-optimization of the interventional plan and to ensure the spatial fidelity between the different steps of the therapeutic work-flow. The approach was validated in three complementary studies: an experiment conducted on a phantom undergoing a known motion pattern, a study performed on the abdomen of 10 healthy volunteers and during 3 in-vivo MRg-HIFU ablations on porcine liver. RESULTS: Results have shown that, during lengthy MRg-HIFU thermal therapies, the human liver and kidney can manifest displacements that exceed acceptable therapeutic margins. Also, it was demonstrated that the proposed framework is capable of providing motion estimates with sub-voxel precision and accuracy. Finally, the 3 successful animal studies demonstrate the compatibility of the proposed approach with the work-flow of an MRg-HIFU intervention under clinical conditions. CONCLUSIONS: In the current study we proposed an image-based motion compensation framework dedicated to MRg-HIFU thermal ablations in the abdomen, providing the possibility to re-optimize the therapy plan on-the-fly with the patient on the interventional table. Moreover, we have demonstrated that even under clinical conditions, the proposed approach is fully capable of continuously ensuring the spatial fidelity between the different phases of the therapeutic work-flow.

An Adaptive Non-Local-Means Filter for Real-Time MR-Thermometry.

Proton resonance frequency shift-based magnetic resonance thermometry is a currently used technique for monitoring temperature during targeted thermal therapies. However, in order to provide temperature updates with very short latency times, fast MR acquisition schemes are usually employed, which in turn might lead to noisy temperature measurements. This will, in general, have a direct impact on therapy control and endpoint detection. In this paper, we address this problem through an improved non-local filtering technique applied on the temperature images. Compared with previous non-local filtering methods, the proposed approach considers not only spatial information but also exploits temporal redundancies. The method is fully automatic and designed to improve the precision of the temperature measurements while at the same time maintaining output accuracy. In addition, the implementation was optimized in order to ensure real-time availability of the temperature measurements while having a minimal impact on latency. The method was validated in three complementary experiments: a simulation, an ex-vivo and an in-vivo study. Compared to the original non-local means filter and two other previously employed temperature filtering methods, the proposed approach shows considerable improvement in both accuracy and precision of the filtered data. Together with the low computational demands of the numerical scheme, the proposed filtering technique shows great potential for improving temperature measurements during real-time MR thermometry dedicated to targeted thermal therapies.

Improved intercostal HIFU ablation using a phased array transducer based on Fermat's spiral and Voronoi tessellation: A numerical evaluation.

PURPOSE: A major complication for abdominal High Intensity Focused Ultrasound (HIFU) applications is the obstruction of the acoustic beam path by the thoracic cage, which absorbs and reflects the ultrasonic energy leading to undesired overheating of healthy tissues in the pre-focal area. Prior work has investigated the determination of optimized transducer apodization laws, which allow for a reduced rib exposure whilst (partially) restoring focal point intensity through power compensation. Although such methods provide an excellent means of reducing rib exposure, they generally increase the local energy density in the pre-focal area, which similarly can lead to undesired overheating. Therefore, this numerical study aimed at evaluating whether a novel transducer design could provide improvement for intercostal HIFU applications, in particular with respect to the pre-focal area. METHODS: A combination of acoustic and thermal simulations was used to evaluate 2 mono-element transducers, 2 clinical phased array transducers, and 4 novel transducers based on Fermat's Spiral (FS), two of which were Voronoi-tessellated (VTFS). Binary apodizations were determined for the phased array transducers using a collision detection algorithm. A tissue geometry was modeled to represent an intercostal HIFU sonication in the liver at 30 and 50 mm behind the ribs, including subsequent layers of gel pad, skin, subcutaneous fat, muscle, and liver tissue. Acoustic simulations were then conducted using propagation of the angular spectrum of plane waves (ASPW). The results of these simulations were used to evaluate pre-focal intensity levels. Subsequently, a finite difference scheme based on the Pennes bioheat equation was used for thermal simulations. The results of these simulations were used to calculate both the energy density in the pre-focal skin, fat, and muscle layers, as well as the energy exposure of the ribs. RESULTS: The acoustic simulations showed that for a sonication in a single point without beamsteering, comparing the best performing clinical phased array in this study to an equivalent VTFS transducer, the maximum intensity in the focal point was increased from 19.0 to 27.0 W/mm2 for the sonication 30 mm behind the ribs, while the rib area exposed to ≥20 J/cm2 was reduced from 0.88 to 0.14 cm2 . For the sonication 50 mm behind the ribs, the maximum focal point intensity was increased from 13.4 to 21.5 W/mm2 , while the rib area exposed to ≥40 J/cm2 was lowered from 2.71 to 0.01 cm2 . The thermal simulations showed that for a circular sonication cell of 4 mm diameter in the transversal plane, sonication times for sonications 30/50 mm behind the ribs were reduced from 13.9 to 8.38 s/38.2 to 17.4 s, respectively. Energy density levels in the skin for these sonications were decreased from 5.28 to 2.22/9.45 to 3.78 J/mm2 . CONCLUSIONS: VTFS transducers are expected to provide improvement for intercostal HIFU applications compared to currently available clinical transducers, as they reduce both the energy density in the pre-focal zone and the energy exposure of the ribs. These characteristics allow for increasing either the re-sonication rate or the treatment volume per sonication.

Procedural sedation and analgesia for respiratory-gated MR-HIFU in the liver: a feasibility study.

BACKGROUND: Previous studies demonstrated both pre-clinically and clinically the feasibility of magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablations in the liver. To overcome the associated problem of respiratory motion of the ablation area, general anesthesia (GA) and mechanical ventilation was used in conjunction with either respiratory-gated energy delivery or energy delivery during induced apnea. However, clinical procedures requiring GA are generally associated with increased mortality, morbidity, and complication rate compared to procedural sedation and analgesia (PSA). Furthermore, PSA is associated with faster recovery and an increased eligibility for non- and mini-invasive interventions. METHODS: In this study, we investigate both in an animal model and on a small patient group the kinetics of the diaphragm during free-breathing, when a tailored remifentanil/propofol-based PSA protocol inducing partial respiratory depression is used. Subsequently, we demonstrate in an animal study the compatibility of the resulting respiratory pattern of the PSA protocol with a gated HIFU ablation in the liver by direct comparison with gated ablations conducted under GA. Wilcoxon signed-rank tests were performed for statistical analysis of non-perfused and necrosed tissue volumes. Duty cycles (ratio or percentage of the breathing cycle with the diaphragm in its resting position, such that acoustic energy delivery with MR-HIFU was allowed) were statistically compared for both GA and PSA using student's t tests. RESULTS: In both animal and human experiments, the breathing frequency was decreased below 9/min, while maintaining stable vital functions. Furthermore an end-exhalation resting phase was induced by this PSA protocol during which the diaphragm is virtually immobile. Median non-perfused volumes, non-viable volumes based on NADH staining, and duty cycles were larger under PSA than under GA or equal. CONCLUSIONS: We conclude that MR-HIFU ablations of the liver under PSA are feasible and potentially increase the non-invasive nature of this type of intervention.

MRI-Guided HIFU Methods for the Ablation of Liver and Renal Cancers.

MRI-guided High Intensity Focused Ultrasound (MRI-HIFU) is a promising method for the non-invasive ablation of pathological tissue in many organs, including mobile organs such as liver and kidney. The possibility to locally deposit thermal energy in a non-invasive way opens a path towards new therapeutic strategies with improved reliability and reduced associated trauma, leading to improved efficacy, reduced hospitalization and costs. Liver and kidney tumors represent a major health problem because not all patients are suitable for curative treatment with surgery. Currently, radio-frequency is the most used method for percutaneous ablation. The development of a completely non-invasive method based on MR guided high intensity focused ultrasound (HIFU) treatments is of particular interest due to the associated reduced burden for the patient, treatment related patient morbidity and complication rate. The objective of MR-guidance is hereby to control heat deposition with HIFU within the targeted pathological area, despite the physiological motion of these organs, in order to provide an effective treatment with a reduced duration and an increased level of patient safety. Regarding this, several technological challenges have to be addressed: Firstly, the anatomical location of both organs within the thoracic cage requires inter-costal ablation strategies, which preserve the therapeutic efficiency, but prevent undesired tissue damage to the ribs and the intercostal muscle. Secondly, both therapy guidance and energy deposition have to be rendered compatible with the continuous physiological motion of the abdomen.

A framework for the correction of slow physiological drifts during MR-guided HIFU therapies: Proof of concept.

PURPOSE: While respiratory motion compensation for magnetic resonance (MR)-guided high intensity focused ultrasound (HIFU) interventions has been extensively studied, the influence of slow physiological motion due to, for example, peristaltic activity, has so far been largely neglected. During lengthy interventions, the magnitude of the latter can exceed acceptable therapeutic margins. The goal of the present study is to exploit the episodic workflow of these therapies to implement a motion correction strategy for slow varying drifts of the target area and organs at risk over the entire duration of the intervention. METHODS: The therapeutic workflow of a MR-guided HIFU intervention is in practice often episodic: Bursts of energy delivery are interleaved with periods of inactivity, allowing the effects of the beam on healthy tissues to recede and/or during which the plan of the intervention is reoptimized. These periods usually last for at least several minutes. It is at this time scale that organ drifts due to slow physiological motion become significant. In order to capture these drifts, the authors propose the integration of 3D MR scans in the therapy workflow during the inactivity intervals. Displacements were estimated using an optical flow algorithm applied on the 3D acquired images. A preliminary study was conducted on ten healthy volunteers. For each volunteer, 3D MR images of the abdomen were acquired at regular intervals of 10 min over a total duration of 80 min. Motion analysis was restricted to the liver and kidneys. For validating the compatibility of the proposed motion correction strategy with the workflow of a MR-guided HIFU therapy, an in vivo experiment on a porcine liver was conducted. A volumetric HIFU ablation was completed over a time span of 2 h. A 3D image was acquired before the first sonication, as well as after each sonication. RESULTS: Following the volunteer study, drifts larger than 8 mm for the liver and 5 mm for the kidneys prove that slow physiological motion can exceed acceptable therapeutic margins. In the animal experiment, motion tracking revealed an initial shift of up to 4 mm during the first 10 min and a subsequent continuous shift of ∼2 mm/h until the end of the intervention. This leads to a continuously increasing mismatch of the initial shot planning, the thermal dose measurements, and the true underlying anatomy. The estimated displacements allowed correcting the planned sonication cell cluster positions to the true target position, as well as the thermal dose estimates during the entire intervention and to correct the nonperfused volume measurement. A spatial coherence of all three is particularly important to assure a confluent ablation volume and to prevent remaining islets of viable malignant tissue. CONCLUSIONS: This study proposes a motion correction strategy for displacements resulting from slowly varying physiological motion that might occur during a MR-guided HIFU intervention. The authors have shown that such drifts can lead to a misalignment between interventional planning, energy delivery, and therapeutic validation. The presented volunteer study and in vivo experiment demonstrate both the relevance of the problem for HIFU therapies and the compatibility of the proposed motion compensation framework with the workflow of a HIFU intervention under clinical conditions.

Cavitation-enhanced back projection for acoustic rib detection and attenuation mapping.

High-intensity focused ultrasound allows for minimally invasive, highly localized cancer therapies that can complement surgical procedures or chemotherapy. For high-intensity focused ultrasound interventions in the upper abdomen, the thoracic cage obstructs and aberrates the ultrasonic beam, causing undesired heating of healthy tissue. When a phased array therapeutic transducer is used, such complications can be minimized by applying an apodization law based on analysis of beam path obstructions. In this work, a rib detection method based on cavitation-enhanced ultrasonic reflections is introduced and validated on a porcine tissue sample containing ribs. Apodization laws obtained for different transducer positions were approximately 90% similar to those obtained using image analysis. Additionally, the proposed method provides information on attenuation between transducer elements and the focus. This principle was confirmed experimentally on a polymer phantom. The proposed methods could, in principle, be implemented in real time for determination of the optimal shot position in intercostal high-intensity focused ultrasound therapy.

A clinically feasible treatment protocol for magnetic resonance-guided high-intensity focused ultrasound ablation in the liver.

OBJECTIVES: Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) allows for noninvasive thermal ablation under real-time temperature imaging guidance. The purpose of this study was to assess the feasibility and safety of MR-HIFU ablation of liver tissue in a clinically acceptable setting. The experimental protocol was designed with a clinical ablation procedure of a small malignant tumor in mind; the procedures were performed within a clinically feasible time frame and care was taken to avoid adverse events. The main outcome was the size and quality of the ablated liver tissue volume on imaging and histology. Secondary outcomes were safety and treatment time. MATERIALS AND METHODS: Healthy pigs (n = 10) under general anesthesia were positioned on a clinical MR-HIFU system, which consisted of an HIFU tabletop with a skin cooling system integrated into a 1.5-T MR scanner. A liver tissue volume was ablated with multiple sonication cells (4 × 4 × 10 mm, 450 W). Both MR thermometry and sonication were respiratory-gated using a pencil beam navigator on the diaphragm. Contrast-enhanced T1-weighted (CE-T1w) imaging was performed for treatment evaluation. Targeted total treatment time was 3 hours. The abdominal wall, liver, and adjacent organs were inspected postmortem for thermal damage. Ablated tissue volumes were processed for cell viability staining. The ablated volumes were analyzed using MR imaging, MR thermometry, and cell viability histology. RESULTS: Eleven volume ablations were performed in 10 animals, resulting in a median nonperfused volume (NPV) on CE-T1w imaging of 1.6 mL (interquartile range [IQR], 0.8-2.3; range, 0.7-3.0). Cell viability histology showed a damaged volume of 1.5 mL (IQR, 1.1-1.8; range, 0.7-2.3). The NPV was confluent in 10 of the 11 cases. The ablated tissue volume on cell viability histology was confluent in all 9 available cases. In all cases, there was a good correspondence between the aspects of the NPV on CE-T1w and the ablated volume on cell viability histology. Two treatment-related adverse events occurred: 1 animal had a 7-mm skin burn and 1 animal showed evidence of thermal damage on the surface of the spleen. Median ablation time was 108 minutes (IQR, 101-120; range, 96-181 minutes) and median total treatment time was 180 minutes (IQR, 165-224; 130-250 minutes). CONCLUSIONS: Our results demonstrate the feasibility and safety of MR-HIFU ablation of liver tissue volumes. The imaging data and cell viability histology show, for the first time, that confluent ablation volumes can be achieved with motion-gated ablation and MR guidance. These results were obtained using a readily available MR-HIFU system with only minor modifications, within a clinically acceptable time frame, and with only minor adverse events. This shows that this technique is sufficiently reliable and safe to initiate a clinical trial.

Non-invasive magnetic resonance-guided high intensity focused ultrasound ablation of a vascular malformation in the lower extremity: a case report.

INTRODUCTION: Therapy of choice for symptomatic vascular malformations consists of surgery, sclerotherapy, or embolization. However, these techniques are invasive with possible complications and require hospitalization. We present a novel non-invasive technique, i.e., magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablation, for the treatment of a vascular malformation in a patient. This technique applies high-intensity sound waves transcutaneously to the body and is fully non-invasive. MRI guidance is the novel aspect of HIFU treatments and is used for exquisite delineation and localization of the lesion and accurate real-time temperature monitoring during tissue ablation. MR-HIFU is a well-established treatment option for uterine fibroids and is currently being investigated for, e.g., bone tumors, breast cancer, prostate cancer, and liver cancer. MR-HIFU of vascular malformations has not been a topic of research yet. CASE DESCRIPTION: Volumetric MR-HIFU ablation of a vascular malformation in the lower extremity of an 18-year-old male patient was performed. Temperatures of 62-80 °C were reached in the target lesion with sonications of 4 × 4 × 8 mm using powers of 200 W for <20 s. At 1-month follow-up, the patient reported qualitatively sustained reduction of pain and normal motor function. Three-month follow-up imaging indicated successful nidus destruction, which resulted in reduction of >30 % of the tumor volume. After 13 months, pain score was reduced to <2 after extreme exertion for several hours and to 0 for daily activities. DISCUSSION AND EVALUATION: Radiofrequency ablation and cryoablation are minimally invasive techniques that have been tried on low-flow vascular malformations with inconsistent results. Furthermore, both techniques require probe insertion, which is associated with risks of wound infection and hospitalization. Since MR-HIFU is truly non-invasive, these risks are negligible. CONCLUSIONS: In conclusion, we reported a successful non-invasive treatment of a vascular malformation with MR-HIFU in a clinical patient including long-term follow-up data for the first time. The patient reported qualitatively sustained pain reduction up to 13 months post treatment.