Impact of internal target volume definition for pencil beam scanned proton treatment planning in the presence of respiratory motion variability for lung cancer: A proof of concept.

PURPOSE: Motion management is crucial in scanned proton therapy for mobile tumours. Current motion mitigation approaches rely on single 4DCTs before treatment, ignoring respiratory variability. We investigate the consequences of respiratory variations on internal target volumes (ITV) definition and motion mitigation efficacy, and propose a probabilistic ITV based on 4DMRI. MATERIALS AND METHODS: Four 4DCT(MRI) datasets, each containing 40 variable cycles of synthetic 4DCTs, were generated by warping single-phase CTs of two lung patients with motion fields extracted from two 4DMRI datasets. Two-field proton treatment plans were optimised on ITVs based on different parts of the 4DCT(MRI)s. 4D dose distributions were calculated by considering variable respiratory patterns. Different probabilistic ITVs were created by incorporating the voxels covered by the CTV in at least 25%, 50%, or 75% (ITV25, ITV50, ITV75) of the cycles, and compared with the conservative ITV encompassing all possible CTV positions. RESULTS: Depending on the selected planning 4DCT, ITV volumes vary up to 20%, resulting in significant variation in CTV coverage for 4D treatments. Target coverage and homogeneity improved with the conservative ITV, but was associated with significantly increased lung dose (~1%). ITV25 and ITV50 led to acceptable plan quality in most cases without lung dose increments. ITV75 best minimised lung dose, but was insufficient to ensure coverage under all motion scenarios. CONCLUSION: Irregular respiration significantly affects CTV coverage when ITVs are only defined by single 4DCTs. A probabilistic ITV50 provides an adequate compromise between target coverage and lung dose for most motion and patient scenarios investigated.

Micron-sized PFOB liquid core droplets stabilized with tailored-made perfluorinated surfactants as a new class of endovascular sono-sensitizers for focused ultrasound thermotherapy.

The purpose of this study was to develop micron-sized droplet emulsions able to increase the heat deposition of high intensity focused ultrasound (HIFU), aiming to accelerate the tumour ablation in highly perfused organs with reduced side effects. The investigated droplets consisted of a perfluorooctyl bromide (PFOB) core coated with a biocompatible fluorinated surfactant called F-TAC. The novelty of this work relies on the use, for this application, of a high boiling point perfluorocarbon core (142 °C), combined with an in-house fluorinated surfactant to formulate the emulsion, yielding quasi-reversible strong interactions between the HIFU beam and the droplets. In order to fine-tune the emulsion size, surfactants with different hydrophobic/hydrophilic ratios were screened. Different concentrations of PFOB droplets were homogeneously embedded in two different MRI compatible materials, exhibiting either ultrasound (US) absorbing or non-absorbing properties. For the US absorbing TMM, the speed of sound at each droplet concentration was also assessed. These TMM were sonicated by 1 MHz HIFU with acoustical power of 94 W at two different duty cycles. The temperature elevation was monitored accurately by MRI proton shift resonance frequency in near real-time. The presence of sono-sensitive droplets induced a significant increase of the HIFU thermal effect that persisted under repeated sonication of the same locus. Optimal enhancement was observed at the lowest concentration tested (0.1%) with an additional temperature rise at the focal point of approximately 4 °C per applied kJ of acoustic energy corresponding to one order of magnitude augmentation of the thermal dose. Furthermore, no deformation of the heating pattern pre- or post-focal was observed.

Molecular oxygen loading in candidate theranostic droplets stabilized with biocompatible fluorinated surfactants: Particle size effect and application to in situ19F MRI mapping of oxygen partial pressure.

OBJECTIVE: Perfluorocarbon nano- and micron-sized emulsions are a new field of investigation in cancer treatment due to their ability to be used as imaging contrast agents, or as delivery vectors for pharmaceuticals. They also demonstrated capability to enhance the efficiency of high intensity focused ultrasound thermo-therapy. In the context of new biomedical applications we investigated perfluorooctyl bromide (PFOB) theranostic droplets using 19F NMR. Each droplet contains biocompatible fluorinated surfactants composed of a polar Tris(hydroxymethyl)aminomethane head unit and hydrophobic perfluorinated tail (abbreviated as F-TAC). The influence of the droplet size on the oxygen loading capacity was determined from longitudinal relaxation (T1) data of 19F NMR signal. MATERIAL AND METHODS: Liquid PFOB and five samples of PFOB droplets of average diameter 0.177, 0.259, 1.43, 3.12 and 4.53 µm were tested with different oxygen levels. A dedicated gas exchange system was validated to maintain steady state oxygen concentrations, including a spatial gradient of oxygen concentration. A prototyped transmit-receive switchable 19F/1H quadrature coil was integrated on a 3 T clinical scanner. The coil is compatible with focused ultrasound sonication for future application. A spectroscopy FID inversion-recovery (IR) sequence was used to measure the T1 value per sample and per value of equilibrium oxygen pressure. Pixel wise, spatial T1 mapping was performed with magnetization prepared 2D gradient echo sequences in tissue mimicking gels doped with theranostic droplets. RESULTS: Experimental data indicated that the longitudinal relaxation rate of 19F signal of the investigated theranostic droplets depended approximately linearly on the oxygen level and its slope decreased with the particle size according to a second order polynomial over the investigated range. This semi-empirical model was derived from general thermodynamics and weak electrostatic forces theory and fitted the experimental data within 0.75% precision. The capacity of oxygen transportation for the described theranostic droplets tended to that of pure PFOB, while micron-sized droplets lost up to 50% of this capacity. In a specific setup producing a steady state gradient of oxygen concentration, we demonstrated spatial mapping of oxygen pressure gradient of 6 kPa/mm with 1 mm in-plane resolution. CONCLUSION: The size-tunable PFOB theranostic droplets stabilized with F-TAC surfactants could be characterized by 19F MRI in a clinical setup readily compatible with interventional in vivo studies under MR guidance. Current precision and spatial resolution of T1 mapping are promising. A potential challenge for further in vivo studies is the reduction of the imaging time.

Ultrasound-driven 4D MRI.

We present an ultrasound-driven 4D magnetic resonance imaging (US-4DMRI) method for respiratory motion imaging in the thorax and abdomen. The proposed US-4DMRI comes along with a high temporal resolution, and allows for organ motion imaging beyond a single respiratory cycle. With the availability of the US surrogate both inside and outside the MR bore, 4D MR images can be reconstructed for 4D treatment planning and online respiratory motion prediction during radiotherapy. US-4DMRI relies on simultaneously acquired 2D liver US images and abdominal 2D MR multi-slice scans under free respiration. MR volumes are retrospectively composed by grouping the MR slices corresponding to the most similar US images. We present two different US similarity metrics: an intensity-based approach, and a similarity measure relying on predefined fiducials which are being tracked over time. The proposed method is demonstrated on MR liver scans of eight volunteers acquired over a duration of 5.5 min each at a temporal resolution of 2.6 Hz with synchronous US imaging at 14 Hz-17 Hz. Visual inspection of the reconstructed MR volumes revealed satisfactory results in terms of continuity in organ boundaries and blood vessels. In quantitative leave-one-out experiments, both US similarity metrics reach the performance level of state-of-the-art navigator-based approaches.

Hybrid ultrasound-MR guided HIFU treatment method with 3D motion compensation.

PURPOSE: Treatments using high-intensity focused ultrasound (HIFU) in the abdominal region remain challenging as a result of respiratory organ motion. A novel method is described here to achieve 3D motion-compensated ultrasound (US) MR-guided HIFU therapy using simultaneous ultrasound and MRI. METHODS: A truly hybrid US-MR-guided HIFU method was used to plan and control the treatment. Two-dimensional ultrasound was used in real time to enable tracking of the motion in the coronal plane, whereas an MR pencil-beam navigator was used to detect anterior-posterior motion. Prospective motion compensation of proton resonance frequency shift (PRFS) thermometry and HIFU electronic beam steering were achieved. RESULTS: The 3D prospective motion-corrected PRFS temperature maps showed reduced intrascan ghosting artifacts, a high signal-to-noise ratio, and low geometric distortion. The k-space data yielded a consistent temperature-dependent PRFS effect, matching the gold standard thermometry within approximately 1°C. The maximum in-plane temperature elevation ex vivo was improved by a factor of 2. Baseline thermometry acquired in volunteers indicated reduction of residual motion, together with an accuracy/precision of near-harmonic referenceless PRFS thermometry on the order of 0.5/1.0°C. CONCLUSIONS: Hybrid US-MR-guided HIFU ablation with 3D motion compensation was demonstrated ex vivo together with a stable referenceless PRFS thermometry baseline in healthy volunteer liver acquisitions. Magn Reson Med 79:2511-2523, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Simultaneous acquisition of image and navigator slices using CAIPIRINHA for 4D MRI.

PURPOSE: Respiratory organ motion is still the major challenge of various image-guided treatments in the abdomen. Dynamic organ motion tracking, necessary for the treatment control, can be performed with volumetric time-resolved MRI that sequentially acquires one image and one navigator slice. Here, a novel imaging method is proposed for truly simultaneous high temporal resolution acquisition. METHODS: A standard balanced steady state free precession sequence was modified to simultaneously acquire two superimposed slices with different phase cycles, namely an image and a navigator slice. Instead of multiband RF pulses, two separate RF pulses were used for the excitation. Images were reconstructed using offline CAIPIRINHA reconstruction. Phantom and in vivo measurements of healthy volunteers were performed and evaluated. RESULTS: Phantom and in vivo measurements showed good image quality with high signal-to-noise ratio (SNR) and no reconstruction issues. CONCLUSION: We present a novel imaging method for truly simultaneous acquisition of image and navigator slices for four-dimensional (4D) MRI of organ motion. In this method, the time lag between the sequential acquisitions is eliminated, leading to an improved accuracy of organ motion models, while CAIPIRINHA reconstruction results in an improved SNR compared with an existing 4D MRI approach.

Model-guided respiratory organ motion prediction of the liver from 2D ultrasound.

With the availability of new and more accurate tumour treatment modalities such as high-intensity focused ultrasound or proton therapy, accurate target location prediction has become a key issue. Various approaches for diverse application scenarios have been proposed over the last decade. Whereas external surrogate markers such as a breathing belt work to some extent, knowledge about the internal motion of the organs inherently provides more accurate results. In this paper, we combine a population-based statistical motion model and information from 2d ultrasound sequences in order to predict the respiratory motion of the right liver lobe. For this, the motion model is fitted to a 3d exhalation breath-hold scan of the liver acquired before prediction. Anatomical landmarks tracked in the ultrasound images together with the model are then used to reconstruct the complete organ position over time. The prediction is both spatial and temporal, can be computed in real-time and is evaluated on ground truth over long time scales (5.5 min). The method is quantitatively validated on eight volunteers where the ultrasound images are synchronously acquired with 4D-MRI, which provides ground-truth motion. With an average spatial prediction accuracy of 2.4 mm, we can predict tumour locations within clinically acceptable margins.

Real-time method for motion-compensated MR thermometry and MRgHIFU treatment in abdominal organs.

PURPOSE: Magnetic resonance-guided high-intensity focused ultrasound is considered to be a promising treatment for localized cancer in abdominal organs such as liver, pancreas, or kidney. Abdominal motion, anatomical arrangement, and required sustained sonication are the main challenges. METHODS: MR acquisition consisted of thermometry performed with segmented gradient-recalled echo echo-planar imaging, and a segment-based one-dimensional MR navigator parallel to the main axis of motion to track the organ motion. This tracking information was used in real-time for: (i) prospective motion correction of MR thermometry and (ii) HIFU focal point position lock-on target. Ex vivo experiments were performed on a sheep liver and a turkey pectoral muscle using a motion demonstrator, while in vivo experiments were conducted on two sheep liver. RESULTS: Prospective motion correction of MR thermometry yielded good signal-to-noise ratio (range, 25 to 35) and low geometric distortion due to the use of segmented EPI. HIFU focal point lock-on target yielded isotropic in-plane thermal build-up. The feasibility of in vivo intercostal liver treatment was demonstrated in sheep. CONCLUSION: The presented method demonstrated in moving phantoms and breathing sheep accurate motion-compensated MR thermometry and precise HIFU focal point lock-on target using only real-time pencil-beam navigator tracking information, making it applicable without any pretreatment data acquisition or organ motion modeling.

Hybrid ultrasound/magnetic resonance simultaneous acquisition and image fusion for motion monitoring in the upper abdomen.

OBJECTIVES: The combination of ultrasound (US) and magnetic resonance imaging (MRI) may provide a complementary description of the investigated anatomy, together with improved guidance and assessment of image-guided therapies. The aim of the present study was to integrate a clinical setup for simultaneous US and magnetic resonance (MR) acquisition to obtain synchronized monitoring of liver motion. The feasibility of this hybrid imaging and the precision of image fusion were evaluated. MATERIALS AND METHODS: Ultrasound imaging was achieved using a clinical US scanner modified to be MR compatible, whereas MRI was achieved on 1.5- and 3-T clinical scanners. Multimodal registration was performed between a high-resolution T1 3-dimensional (3D) gradient echo (volume interpolated gradient echo) during breath-hold and a simultaneously acquired 2D US image, or equivalent, retrospective registration of US imaging probe in the coordinate frame of MRI. A preliminary phantom study was followed by 4 healthy volunteer acquisitions, performing simultaneous 4D MRI and 2D US harmonic imaging (Fo = 2.2 MHz) under free breathing. RESULTS: No characterized radiofrequency mutual interferences were detected under the tested conditions with commonly used MR sequences in clinical routine, during simultaneous US/MRI acquisition. Accurate spatial matching between the 2D US and the corresponding MRI plane was obtained during breath-hold. In situ fused images were delivered. Our 4D MRI sequence permitted the dynamic reconstruction of the intra-abdominal motion and the calculation of high temporal resolution motion field vectors. CONCLUSIONS: This study demonstrates that, truly, simultaneous US/MR dynamic acquisition in the abdomen is achievable using clinical instruments. A potential application is the US/MR hybrid guidance of high-intensity focused US therapy in the liver.