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.

In vivo T2 -based MR thermometry in adipose tissue layers for high-intensity focused ultrasound near-field monitoring.

PURPOSE: During MR-guided high-intensity focused ultrasound (HIFU) therapy, ultrasound absorption in the near field represents a safety risk and limits efficient energy deposition at the target. In this study, we investigated the feasibility of using T2 mapping to monitor the temperature change in subcutaneous adipose tissue layers. METHODS: The T2 temperature dependence and reversibility was determined for fresh adipose porcine samples. The accuracy was evaluated by comparing T2 -based temperature measurements with probe readings in an ex vivo HIFU experiment. The in vivo feasibility of T2 -based thermometry was studied during HIFU ablations in the liver in pigs and of uterine fibroids in human patients. RESULTS: T2 changed linearly and reversibly with temperature with an average coefficient of 5.2 ± 0.1 ms/°C. For the ex vivo HIFU experiment, the difference between the T2 -based temperature change and the probe temperature was <0.9°C. All in vivo experiments showed temperature-related T2 changes in the near field directly after sonications. As expected, considerable intersubject variations in the cooling times were measured in the in vivo porcine experiments. CONCLUSIONS: The reversibility and linearity of the T2 -temperature dependence of adipose tissue allows for the monitoring of the temperature in the subcutaneous adipose tissue layers.

Rapid dynamic R1 /R2 */temperature assessment: a method with potential for monitoring drug delivery.

Local drug delivery by hyperthermia-induced drug release from thermosensitive liposomes (TSLs) may reduce the systemic toxicity of chemotherapy, whilst maintaining or increasing its efficacy. Relaxivity contrast agents can be co-encapsulated with the drug to allow the visualization of the presence of liposomes, by means of R2 *, as well as the co-release of the contrast agent and the drug, by means of R1, on heating. Here, the mathematical method used to extract both R2 * and R1 from a fast dynamic multi-echo spoiled gradient echo (ME-SPGR) is presented and analyzed. Finally, this method is used to monitor such release events. R2 * was obtained from a fit to the ME-SPGR data. Absolute R1 was calculated from the signal magnitude changes corrected for the apparent proton density changes and a baseline Look-Locker R1 map. The method was used to monitor nearly homogeneous water bath heating and local focused ultrasound heating of muscle tissue, and to visualize the release of a gadolinium chelate from TSLs in vitro. R2 *, R1 and temperature maps were measured with a 5-s temporal resolution. Both R2 *and R1 measured were found to change with temperature. The dynamic R1 measurements after heating agreed with the Look-Locker R1 values if changes in equilibrium magnetization with temperature were considered. Release of gadolinium from TSLs was detected by an R1 increase near the phase transition temperature, as well as a shallow R2 * increase. Simultaneous temperature, R2 * and R1 mapping is feasible in real time and has the potential for use in image-guided drug delivery studies.

Stochastic ray tracing for simulation of high intensity focal ultrasound therapy.

An algorithm is presented for rapid simulation of high-intensity focused ultrasound (HIFU) fields. Essentially, the method combines ray tracing with Monte Carlo integration to evaluate the Rayleigh-Sommerfeld integral. A large number of computational particles, phonons, are distributed among the elements of a phase-array transducer. The phonons are emitted into random directions and are propagated along trajectories computed with the ray tracing method. As the simulation progresses, an improving stochastic estimate of the acoustic field is obtained. The method can adapt to complicated geometries, and it is well suited to parallelization. The method is verified against reference simulations and pressure measurements from an ex vivo porcine thoracic tissue sample. Results are presented for acceleration with graphics processing units (GPUs). The method is expected to serve in applications, where flexibility and rapid computation time are crucial, in particular clinical HIFU treatment planning.

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.

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.

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.

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.

High intensity focused ultrasound with large aperture transducers: a MRI based focal point correction for tissue heterogeneity.

PURPOSE: The risk of undesired tissue damage to thoracic cage, heart, and lung during MR guided HIFU ablations of breast cancer can be greatly reduced if a phased array transducer design with a lateral beam direction is used in combination with a large aperture. The disadvantage is an increased sensitivity to focus aberrations due to tissue heterogeneity. Here, the authors propose to restore the focal coherence by using a matched aperture phase correction, which is based on a noninvasively obtained tissue model. METHODS: The method combines high resolution MRI with ultrasound wave measurements of different tissue types to determine a phase correction, which compensates focal point aberrations caused by tissue heterogeneity. 3D segmentation of tissue is used to quantify the relative proportion of each tissue type along a line running from the center of each element of the phased array to the target focal point. RESULTS: For tissue types with a celerity difference of 3%, the proposed method allows to quantify the phase aberration with an accuracy of 6° ± 20° and a correlation factor R(2) = 0.95. Using the refocusing method for a complex heterogeneous phantom resulted in 95% of the maximal pressure, whereas only 70% of the maximal pressure is obtained in absence of any phase correction. CONCLUSIONS: Since the proposed refocusing algorithm is compatible with a standard interventional preplanning and requires only a minimal amount of processing, it presents a promising approach to compensate for aberration in heterogeneous tissues such as the human breast.

Spectrally selective pencil-beam navigator for motion compensation of MR-guided high-intensity focused ultrasound therapy of abdominal organs.

MR-guided high-intensity focused ultrasound (MR-HIFU) is a noninvasive technique for depositing thermal energy in a controlled manner deep within the body. However, the MR-HIFU treatment of mobile abdominal organs is problematic as motion-related thermometry artifacts need to be corrected and the focal point position must be updated in order to follow the moving organ to avoid damaging healthy tissue. In this article, a fat-selective pencil-beam navigator is proposed for real-time monitoring and compensation of through-plane motion. As opposed to the conventional spectrally nonselective navigator, the fat-selective navigator does not perturb the water-proton magnetization used for proton resonance frequency shift thermometry. This allows the proposed navigator to be placed directly on the target organ for improved motion estimation accuracy. The spectral and spatial selectivity of the proposed navigator pulse is evaluated through simulations and experiments, and the improved slice tracking performance is demonstrated in vivo by tracking experiments on a human kidney and on a human liver. The direct motion estimation provided by the fat-selective navigator is also shown to enable accurate motion compensated MR-HIFU therapy of in vivo porcine kidney, including motion compensation of thermometry and beam steering based on the observed three-dimensional kidney motion.

Real-time volumetric MRI thermometry of focused ultrasound ablation in vivo: a feasibility study in pig liver and kidney.

MR thermometry offers the possibility to precisely guide high-intensity focused ultrasound (HIFU) for the noninvasive treatment of kidney and liver tumours. The objectives of this study were to demonstrate therapy guidance by motion-compensated, rapid and volumetric MR temperature monitoring and to evaluate the feasibility of MR-guided HIFU ablation in these organs. Fourteen HIFU sonications were performed in the kidney and liver of five pigs under general anaesthesia using an MR-compatible Philips HIFU platform prototype. HIFU sonication power and duration were varied. Volumetric MR thermometry was performed continuously at 1.5 T using the proton resonance frequency shift method employing a multi-slice, single-shot, echo-planar imaging sequence with an update frequency of 2.5 Hz. Motion-related suceptibility artefacts were compensated for using multi-baseline reference images acquired prior to sonication. At the end of the experiment, the animals were sacrificed for macroscopic and microscopic examinations of the kidney, liver and skin. The standard deviation of the temperature measured prior to heating in the sonicated area was approximately 1 °C in kidney and liver, and 2.5 °C near the skin. The maximum temperature rise was 30 °C for a sonication of 1.2 MHz in the liver over 15 s at 300 W. The thermal dose reached the lethal threshold (240 CEM(43) ) in two of six cases in the kidney and four of eight cases in the liver, but remained below this value in skin regions in the beam path. These findings were in agreement with histological analysis. Volumetric thermometry allows real-time monitoring of the temperature at the target location in liver and kidney, as well as in surrounding tissues. Thermal ablation was more difficult to achieve in renal than in hepatic tissue even using higher acoustic energy, probably because of a more efficient heat evacuation in the kidney by perfusion.

Motion correction in MR thermometry of abdominal organs: a comparison of the referenceless vs. the multibaseline approach.

Reliable temperature and thermal-dose measurements using proton resonance frequency shift-based magnetic resonance (MR) thermometry for MR-guided ablation of abdominal organs require a robust correction of artefacts induced by the target displacement through an inhomogeneous and time-variant magnetic field. Two correction approaches emerged recently as promising candidates to allow continuous real-time MR-thermometry under free-breathing conditions: The multibaseline correction method, which relies on a pre-recorded correction table allowing to correct for periodic phase changes, and the referenceless method, which depends on a background phase estimation in the target area based on the assumption of a smooth spatial variation of the phase across the organ. This study combines both methods with real-time in-plane motion correction to permit both temperature and thermal-dose calculations on the fly. Subsequently, the practical aspects of both methods are compared in two application scenarios, a radio frequency-ablation and a high-intensity focused ultrasound ablation. A hybrid approach is presented that exploits the strong points of both methods, allowing accurate and precise proton resonance frequency-thermometry measurements during periodical displacement, even in the presence of spontaneous motion and strong susceptibility variations in the target area.

Real-time 3D target tracking in MRI guided focused ultrasound ablations in moving tissues.

Magnetic resonance imaging-guided high intensity focused ultrasound is a promising method for the noninvasive ablation of pathological tissue in abdominal organs such as liver and kidney. Due to the high perfusion rates of these organs, sustained sonications are required to achieve a sufficiently high temperature elevation to induce necrosis. However, the constant displacement of the target due to the respiratory cycle render continuous ablations challenging, since dynamic repositioning of the focal point is required. This study demonstrates subsecond 3D high intensity focused ultrasound-beam steering under magnetic resonance-guidance for the real-time compensation of respiratory motion. The target is observed in 3D space by coupling rapid 2D magnetic resonance-imaging with prospective slice tracking based on pencil-beam navigator echoes. The magnetic resonance-data is processed in real-time by a computationally efficient reconstruction pipeline, which provides the position, the temperature and the thermal dose on-the-fly, and which feeds corrections into the high intensity focused ultrasound-ablator. The effect of the residual update latency is reduced by using a 3D Kalman-predictor for trajectory anticipation. The suggested method is characterized with phantom experiments and verified in vivo on porcine kidney. The results show that for update frequencies of more than 10 Hz and latencies of less then 114 msec, temperature elevations can be achieved, which are comparable to static experiments.

Real-time MR-thermometry and dosimetry for interventional guidance on abdominal organs.

The use of proton resonance frequency shift-based magnetic resonance (MR) thermometry for interventional guidance on abdominal organs is hampered by the constant displacement of the target due to the respiratory cycle and the associated thermometry artifacts. Ideally, a suitable MR thermometry method should for this role achieve a subsecond temporal resolution while maintaining a precision comparable to those achieved on static organs while not introducing significant processing latencies. Here, a computationally effective processing pipeline for two-dimensional image registration coupled with a multibaseline phase correction is proposed in conjunction with high-frame-rate MRI as a possible solution. The proposed MR thermometry method was evaluated for 5 min at a frame rate of 10 images/sec in the liver and the kidney of 11 healthy volunteers and achieved a precision of less than 2 degrees C in 70% of the pixels while delivering temperature and thermal dose maps on the fly. The ability to perform MR thermometry and dosimetry in vivo during a real intervention was demonstrated on a porcine kidney during a high-intensity focused ultrasound heating experiment.

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.

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.

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.

Real-time geometric distortion correction for interventional imaging with echo-planar imaging (EPI).

Many MR-guided interventional procedures rely on fast imaging sequences for providing images in real-time with a precise relation between the target position in the image and its true position. Echo-planar imaging (EPI) methods are very fast but prone to geometric distortions. Here, we propose a correction method designed for real-time conditions, adapting existing approaches based on dual EPI acquisition with varying echo times. The method is demonstrated with MR-thermometry for guiding thermal therapies. The proposed approach imposes a small penalty in acquisition speed but adds negligible latency to data processing, an important element for interventions of mobile organs.