A Fully Actuated Robotic Assistant for MRI-Guided Precision Conformal Ablation of Brain Tumors.

This paper reports the development of a fully actuated robotic assistant for magnetic resonance imaging (MRI)-guided precision conformal ablation of brain tumors using an interstitial high intensity needle-based therapeutic ultrasound (NBTU) ablator probe. The robot is designed with an eight degree-of-freedom (DOF) remote center of motion (RCM) manipulator driven by piezoelectric actuators, five for aligning the ultrasound thermal ablator to the target lesions and three for inserting and orienting the ablator and its cannula to generate a desired ablation profile. The 8-DOF fully actuated robot can be operated in the scanner bore during imaging; thus, alleviating the need of moving the patient in or out of the scanner during the procedure, and therefore potentially reducing the procedure time and streamlining the workflow. The free space positioning accuracy of the system is evaluated with the OptiTrack motion capture system, demonstrating the root mean square (RMS) error of the tip position to be 1.11±0.43mm. The system targeting accuracy in MRI is assessed with phantom studies, indicating the RMS errors of the tip position to be 1.45±0.66mm and orientation to be 1.53±0.69°. The feasibility of the system to perform thermal ablation is validated through a preliminary ex-vivo tissue study with position error less than 4.3mm and orientation error less than 4.3°.

Superior Postimplant Dosimetry Achieved Using Dynamic Intraoperative Dosimetry for Permanent Prostate Brachytherapy.

PURPOSE: Low-dose-rate brachytherapy is a highly effective treatment modality for prostate carcinoma, but postimplant dosimetry quality is essential and correlated with likelihood of treatment success. Registered ultrasound and fluoroscopy (iRUF) can facilitate real-time intraoperative monitoring and plan adaptation, with the aim of attaining superior dosimetric outcomes. The purpose of this research was to compare clinical postimplant dosimetric results of iRUF-guided brachytherapy against brachytherapy using standard ultrasound-guided intraoperative dosimetry methods. METHODS AND MATERIALS: We analyzed postimplant dosimetry in 292 patients treated with Pd-103 between January 2007 and December 2018. All patients had postimplant dosimetry measured on day 0 to 1 using fused magnetic resonance/computed tomography assessment. Fifty-two patients were treated in 2 prospective clinical trials using iRUF intraoperative dosimetry, including 6 patients in a pilot study and 46 treated in a phase 2 study. Postimplant dosimetry in iRUF-treated patients was compared with dosimetry from 240 patients treated using standard (real-time ultrasound) intraoperative seed tracking. RESULTS: For every parameter measuring dose coverage to the prostate, iRUF patients had significantly higher values, irrespective of adjustment for year of treatment. In adjusted analyses, parameters of dose to urethra and rectum were not significantly higher among iRUF-treated patients. CONCLUSIONS: Use of iRUF intraoperative dosimetry was associated with improved postimplant dose coverage in prostate, without associated increases in doses to urethra or rectum.

High Contrast Ultrasonic Method With Multi-Spatiotemporal Compounding for Monitoring Catheter-Based Ultrasound Thermal Therapy: Development and Ex Vivo Evaluations.

OBJECTIVE: Changes in ultrasound backscatter energy (CBE) imaging can monitor thermal therapy. Catheter-based ultrasound (CBUS) can treat deep tumors with precise spatial control of energy deposition and ablation zones, of which CBE estimation can be limited by low contrast and robustness due to small or inconsistent changes in ultrasound data. This study develops a multi-spatiotemporal compounding CBE (MST-CBE) imaging approach for monitoring specific to CBUS thermal therapy. METHODS: Ex vivo thermal ablations were performed with stereotactic positioning of a 180° directional CBUS applicator, temperature monitoring probes, endorectal US probe, and subsequent lesion sectioning and measurement. Five frames of raw radiofrequency data were acquired throughout in 15s intervals. Using window-by-window estimation methods, absolute and positive components of MST-CBE images at each point were obtained by the compounding ratio of squared envelope data within an increasing spatial size in each short-time window. RESULTS: Compared with conventional US, Nakagami, and CBE imaging, the detection contrast and robustness quantified by tissue-modification-ratio improved by 37.2 ± 4.7 (p < 0.001), 37.5 ± 5.2 (p < 0.001), and 6.4 ± 4.0 dB (p < 0.05) in the MST-CBE imaging, respectively. Correlation coefficient and bias between cross-sectional dimensions of the ablation zones measured in tissue sections and estimated from MST-CBE were up to 0.91 (p < 0.001) and -0.02 mm2, respectively. CONCLUSION: The MST-CBE approach can monitor the detailed changes within target tissues and effectively characterize the dimensions of the ablation zone during CBUS energy deposition. SIGNIFICANCE: The MST-CBE approach could be practical for improved accuracy and contrast of monitoring and evaluation for CBUS thermal therapy.

Modeling of Interstitial Ultrasound Ablation for Continuous Applicator Rotation With MR Validation.

The primary objective of cancer intervention is the selective removal of malignant cells while conserving surrounding healthy tissues. However, the accessibility, size and shape of the cancer can make achieving appropriate margins a challenge. One minimally invasive treatment option for these clinical cases is interstitial needle based therapeutic ultrasound (NBTU). In this work, we develop a finite element model (FEM) capable of simulating continuous rotation of a directional NBTU applicator. The developed model was used to simulate the thermal deposition for different rotation trajectories. The actual thermal deposition patterns for the simulated trajectories were then evaluated using magnetic resonance thermal imaging (MRTI) in a porcine skin gelatin phantom. An MRI-compatible robot was used to control the rotation motion profile of the physical NBTU applicator to match the simulated trajectory. The model showed agreement when compared to experimental measurements with Pearson correlation coefficients greater than 0.839 when comparing temperature fields within an area of 12.6 mm radius from the ultrasound applicator. The average temperature error along a 6.3 mm radius profile from the applicator was 1.27 °C. The model was able to compute 1 s of thermal deposition by the applicator in 0.2 s on average with a 0.1 mm spatial resolution and 0.5 s time steps. The developed simulation demonstrates performance suitable for real-time control which may enable robotically-actuated closed-loop conformal tumor ablation.

An Integrated Robotic System for MRI-Guided Neuroablation: Preclinical Evaluation.

OBJECTIVE: Treatment of brain tumors requires high precision in order to ensure sufficient treatment while minimizing damage to surrounding healthy tissue. Ablation of such tumors using needle-based therapeutic ultrasound (NBTU) under real-time magnetic resonance imaging (MRI) can fulfill this need. However, the constrained space and strong magnetic field in the MRI bore restricts patient access limiting precise placement of the NBTU ablation tool. A surgical robot compatible with use inside the bore of an MRI scanner can alleviate these challenges. METHODS: We present preclinical trials of a robotic system for NBTU ablation of brain tumors under real-time MRI guidance. The system comprises of an updated robotic manipulator and corresponding control electronics, the NBTU ablation system and applications for planning, navigation and monitoring of the system. RESULTS: The robotic system had a mean translational and rotational accuracy of 1.39  ± 0.64 mm and 1.27 [Formula: see text] in gelatin phantoms and 3.13  ± 1.41 mm and 5.58 [Formula: see text] in 10 porcine trials while causing a maximum reduction in signal to noise ratio (SNR) of 10.3%. CONCLUSION: The integrated robotic system can place NBTU ablator at a desired target location in porcine brain and monitor the ablation in realtime via magnetic resonance thermal imaging (MRTI). SIGNIFICANCE: Further optimization of this system could result in a clinically viable system for use in human trials for various diagnostic or therapeutic neurosurgical interventions.

High-resolution intravascular MRI-guided perivascular ultrasound ablation.

PURPOSE: To develop and test in animal studies ex vivo and in vivo, an intravascular (IV) MRI-guided high-intensity focused ultrasound (HIFU) ablation method for targeting perivascular pathology with minimal injury to the vessel wall. METHODS: IV-MRI antennas were combined with 2- to 4-mm diameter water-cooled IV-ultrasound ablation catheters for IV-MRI on a 3T clinical MRI scanner. A software interface was developed for monitoring thermal dose with real-time MRI thermometry, and an MRI-guided ablation protocol developed by repeat testing on muscle and liver tissue ex vivo. MRI thermal dose was measured as cumulative equivalent minutes at 43°C (CEM43 ). The IV-MRI IV-HIFU protocol was then tested by targeting perivascular ablations from the inferior vena cava of 2 pigs in vivo. Thermal dose and lesions were compared by gross and histological examination. RESULTS: Ex vivo experiments yielded a 6-min ablation protocol with the IV-ultrasound catheter coolant at 3-4°C, a 30 mL/min flow rate, and 7 W ablation power. In 8 experiments, 5- to 10-mm thick thermal lesions of area 0.5-2 cm2 were produced that spared 1- to 2-mm margins of tissue abutting the catheters. The radial depths, areas, and preserved margins of ablation lesions measured from gross histology were highly correlated (r ≥ 0.79) with those measured from the CEM43 = 340 necrosis threshold determined by MRI thermometry. The psoas muscle was successfully targeted in the 2 live pigs, with the resulting ablations controlled under IV-MRI guidance. CONCLUSION: IV-MRI-guided, IV-HIFU has potential as a precision treatment option that could preserve critical blood vessel wall during ablation of nonresectable perivascular tumors or other pathologies.

System Integration and Preliminary Clinical Evaluation of a Robotic System for MRI-Guided Transperineal Prostate Biopsy.

This paper presents the development, preclinical evaluation, and preliminary clinical study of a robotic system for targeted transperineal prostate biopsy under direct interventional magnetic resonance imaging (MRI) guidance. The clinically integrated robotic system is developed based on a modular design approach, comprised of surgical navigation application, robot control software, MRI robot controller hardware, and robotic needle placement manipulator. The system provides enabling technologies for MRI-guided procedures. It can be easily transported and setup for supporting the clinical workflow of interventional procedures, and the system is readily extensible and reconfigurable to other clinical applications. Preclinical evaluation of the system is performed with phantom studies in a 3 Tesla MRI scanner, rehearsing the proposed clinical workflow, and demonstrating an in-plane targeting error of 1.5mm. The robotic system has been approved by the institutional review board (IRB) for clinical trials. A preliminary clinical study is conducted with the patient consent, demonstrating the targeting errors at two biopsy target sites to be 4.0mm and 3.7mm, which is sufficient to target a clinically significant tumor foci. First-in-human trials to evaluate the system's effectiveness and accuracy for MR image-guide prostate biopsy are underway.

Evaluation of robot-assisted MRI-guided prostate biopsy: needle path analysis during clinical trials.

While the interaction between a needle and the surrounding tissue is known to cause a significant targeting error in prostate biopsy leading to false-negative results, few studies have demonstrated how it impacts in the actual procedure. We performed a pilot study on robot-assisted MRI-guided prostate biopsy with an emphasis on the in-depth analysis of the needle-tissue interaction in vivo. The data were acquired during in-bore transperineal prostate biopsies in patients using a 4 degrees-of-freedom (DoF) MRI-compatible robot. The anatomical structures in the pelvic area and the needle path were reconstructed from MR images, and quantitatively analyzed. We analyzed each structure individually and also proposed a mathematical model to investigate the influence of those structures in the targeting error using the mixed-model regression. The median targeting error in 188 insertions (27 patients) was 6.3 mm. Both the individual anatomical structure analysis and the mixed-model analysis showed that the deviation resulted from the contact between the needle and the skin as the main source of error. On contrary, needle bending inside the tissue (expressed as needle curvature) did not vary among insertions with targeting errors above and below the average. The analysis indicated that insertions crossing the bulbospongiosus presented a targeting error lower than the average. The mixed-model analysis demonstrated that the distance between the needle guide and the patient skin, the deviation at the entry point, and the path length inside the pelvic diaphragm had a statistically significant contribution to the targeting error (p < 0.05). Our results indicate that the errors associated with the elastic contact between the needle and the skin were more prominent than the needle bending along the insertion. Our findings will help to improve the preoperative planning of transperineal prostate biopsies.

Needle release mechanism enabling multiple insertions with an ultrasound-guided prostate brachytherapy robot.

We present a robotic system for transrectal ultrasound-guided prostate brachytherapy that employs a quick release mechanism to enable multiple needles to be inserted into the prostate prior to plan optimization. The mechanism consists of two actuated fingers that act as needle guides, thereby allowing insertion of both parallel and angled needles. Path planning, including reordering of needles within a batch, is required to avoid collisions with previously inserted needles. We perform two phantom experiments using clinical implant plans. The extra time required for the robotic motions, including finger actuation, is less than three minutes for the entire procedure. Mean position error is measured to be less than 0.5 mm, presumably due to the design of the needle guides, which have a toroidal shape to enable needle angulation.

A Combined Intravascular MRI Endoscope and Intravascular Ultrasound (IVUS) Transducer for High-Resolution Image-Guided Ablation.

An intravascular MRI (IMRI) loopless antenna is combined for the first time with an intravascular water-cooled ultrasound ablation transducer as a possible tool for providing high-resolution MRI-guided ablations of pathological tissue via intravascular access. High resolution anatomical MRI, and real-time MRI thermometry were used to monitor ablation delivery in phantoms and tissue specimens. Results show that IMRI can guide IVUS-mediated directional ablation with minimal image artifacts. This permits the monitoring of thermal dose and therapy titration while minimizing potential thermal damage to the vessel wall.

Robotic system with multiplex power transmission for MRI-guided percutaneous interventions.

In minimally invasive prostate percutaneous interventions, Magnetic Resonance Imaging (MRI) compatible robotic assistive systems developed over the years tend to have multiple degrees of freedom (DOF) to accomplish complex surgical tasks. This paper presents a novel design of an MRI-compatible transmission that allows one driving motor to control a multiplexed DOF robot system. The transmission could reduce the number of motors in the system, while maintaining the functionality of the system, by controlling each motion sequentially rather than simultaneously. A series of preliminary experiments as well as a targeting accuracy test are conducted to evaluate the accuracy of the system.

Review of the Dielectric Properties of Animal and Human Tumors Determined from In Vivo Measurements.

In this article, we combine a review of the wide range of tissue dielectric studies and applications (e.g., safety, imaging, therapy) being pursued by the bioelectromagnetics community with a description of one specific application of dielectric measurements (in vivo tumor classification). The tumor measurements were acquired over a frequency range of 0.01-4.0 GHz using a technique based on the impedance change recorded by a short antenna when placed near or in a lossy dielectric. Substantial differences (up to 300%) were found between the dielectric properties of tumors (mammary adenocarcinoma, melanoma, lung carcinoma, glioblastoma and ependymoblastoma) and normal host tissues. Such differences reflect the known heterogeneity of abnormal cell growth in cancer. In addition, in vivo human measurements of breast carcinoma, normal skin and breast tissue indicate that a maximum differential power absorption (30% higher in tumor) occurs between 1.0 and 2.0 GHz. This information, when combined with tumor size, geometry, and anatomical location, enable the design and development of effective systems for the detection of tumors and for electromagnetically induced differential hyperthermia treatment. Finally, we also discuss these results in the context of other impedance and dielectric approaches used to characterize normal and neoplastic cells and tissues.

Trimodal Therapy: Combining Hyperthermia with Repurposed Bexarotene and Ultrasound for Treating Liver Cancer.

Repurposing of existing cancer drugs to overcome their physical limitations, such as insolubility, represents an attractive strategy to achieve enhanced therapeutic efficacy and broaden the range of clinical applications. Such an approach also promises to offer substantial cost savings in drug development efforts. Here we repurposed FDA-approved topical agent bexarotene (Targretin), currently in limited use for cutaneous manifestations of T-cell lymphomas, and re-engineer it for use in solid tumor applications by forming self-assembling nanobubbles. Physico-chemical characterization studies of the novel prodrug nanobubbles demonstrated their stability, enhanced target cell internalization capability, and highly controlled release profile in response to application of focused ultrasound energy. Using an in vitro model of hepatocellular carcinoma and an in vivo large animal model of liver ablation, we demonstrate the effectiveness of bexarotene prodrug nanobubbles when used in conjunction with catheter-based ultrasound, thereby highlighting the therapeutic promise of this trimodal approach.

Characterization of ultrasound elevation beamwidth artifacts for prostate brachytherapy needle insertion.

PURPOSE: Ultrasound elevation beamwidth leads to image artifacts and uncertainties in localizing objects (such as a surgical needle) in ultrasound images. The authors examined the clinical significance of errors caused by elevation beamwidth artifacts and imaging parameters in needle insertion procedures. METHODS: Beveled prostate brachytherapy needles were inserted through all holes of a grid template under real-time transrectal ultrasound (TRUS) guidance. The needle tip position as indicated by the TRUS image was compared to their observed physical location. A new device was developed to measure the ultrasound elevation beamwidth. RESULTS: Imaging parameters of the TRUS scanner have direct impact on the localization error ranging from 0.5 up to 4 mm. The smallest localization error was observed laterally close to the center of the grid template and axially within the beam's focal zone. Largest localization error occurs laterally around both sides of the grid template and axially within the beam's far field. The authors also found that the localization errors vary with both lateral and elevation offsets. CONCLUSIONS: The authors found properly adjusting the TRUS imaging settings to lower the ultrasound gain and power effectively minimized the appearance of elevation beamwidth artifacts and in turn reduced the localization errors of the needle tip.

Automatic segmentation of radiographic fiducial and seeds from X-ray images in prostate brachytherapy.

Prostate brachytherapy guided by transrectal ultrasound is a common treatment option for early stage prostate cancer. Prostate cancer accounts for 28% of cancer cases and 11% of cancer deaths in men with 217,730 estimated new cases and 32,050 estimated deaths in 2010 in the United States alone. The major current limitation is the inability to reliably localize implanted radiation seeds spatially in relation to the prostate. Multimodality approaches that incorporate X-ray for seed localization have been proposed, but they require both accurate tracking of the imaging device and segmentation of the seeds. Some use image-based radiographic fiducials to track the X-ray device, but manual intervention is needed to select proper regions of interest for segmenting both the tracking fiducial and the seeds, to evaluate the segmentation results, and to correct the segmentations in the case of segmentation failure, thus requiring a significant amount of extra time in the operating room. In this paper, we present an automatic segmentation algorithm that simultaneously segments the tracking fiducial and brachytherapy seeds, thereby minimizing the need for manual intervention. In addition, through the innovative use of image processing techniques such as mathematical morphology, Hough transforms, and RANSAC, our method can detect and separate overlapping seeds that are common in brachytherapy implant images. Our algorithm was validated on 55 phantom and 206 patient images, successfully segmenting both the fiducial and seeds with a mean seed segmentation rate of 96% and sub-millimeter accuracy.

Intraoperative 3D reconstruction of prostate brachytherapy implants with automatic pose correction.

The success of prostate brachytherapy critically depends on delivering adequate dose to the prostate gland, and the capability of intraoperatively localizing implanted seeds provides potential for dose evaluation and optimization during therapy. REDMAPS is a recently reported algorithm that carries out seed localization by detecting, matching and reconstructing seeds in only a few seconds from three acquired x-ray images (Lee et al 2011 IEEE Trans. Med. Imaging 29 38-51). In this paper, we present an automatic pose correction (APC) process that is combined with REDMAPS to allow for both more accurate seed reconstruction and the use of images with relatively large pose errors. APC uses a set of reconstructed seeds as a fiducial and corrects the image pose by minimizing the overall projection error. The seed matching and APC are iteratively computed until a stopping condition is met. Simulations and clinical studies show that APC significantly improves the reconstructions with an overall average matching rate of ⩾99.4%, reconstruction error of ⩽0.5 mm, and the matching solution optimality of ⩾99.8%.

Robotic needle guide for prostate brachytherapy: clinical testing of feasibility and performance.

PURPOSE: Optimization of prostate brachytherapy is constrained by tissue deflection of needles and fixed spacing of template holes. We developed and clinically tested a robotic guide toward the goal of allowing greater freedom of needle placement. METHODS AND MATERIALS: The robot consists of a small tubular needle guide attached to a robotically controlled arm. The apparatus is mounted and calibrated to operate in the same coordinate frame as a standard template. Translation in x and y directions over the perineum ±40 mm are possible. Needle insertion is performed manually. RESULTS: Five patients were treated in an institutional review board-approved study. Confirmatory measurements of robotic movements for initial 3 patients using infrared tracking showed mean error of 0.489 mm (standard deviation, 0.328 mm). Fine adjustments in needle positioning were possible when tissue deflection was encountered; adjustments were performed in 54 (30.2%) of 179 needles placed, with 36 (20.1%) of 179 adjustments of >2mm. Twenty-seven insertions were intentionally altered to positions between the standard template grid to improve the dosimetric plan or avoid structures such as pubic bone and blood vessels. CONCLUSIONS: Robotic needle positioning provided a means of compensating for needle deflections and the ability to intentionally place needles into areas between the standard template holes. To our knowledge, these results represent the first clinical testing of such a system. Future work will be incorporation of direct control of the robot by the physician, adding software algorithms to help avoid robot collisions with the ultrasound, and testing the angulation capability in the clinical setting.

REDMAPS: reduced-dimensionality matching for prostate brachytherapy seed reconstruction.

The success of prostate brachytherapy critically depends on delivering adequate dose to the prostate gland. Intraoperative localization of the implanted seeds provides potential for dose evaluation and optimization during therapy. A reduced-dimensionality matching algorithm for prostate brachytherapy seed reconstruction (REDMAPS) that uses multiple X-ray fluoroscopy images obtained from different poses is proposed. The seed reconstruction problem is formulated as a combinatorial optimization problem, and REDMAPS finds a solution in a clinically acceptable amount of time using dimensionality reduction to create a smaller space of possible solutions. Dimensionality reduction is possible since the optimal solution has approximately zero cost when the poses of the acquired images are known to be within a small error. REDMAPS is also formulated to address the "hidden seed problem" in which seeds overlap on one or more observed images. REDMAPS uses a pruning algorithm to avoid unnecessary computation of cost metrics and the reduced problem is solved using linear programming. REDMAPS was first evaluated and its parameters tuned using simulations. It was then validated using five phantom and 21 patient datasets. REDMAPS was successful in reconstructing the seeds with an overall seed matching rate above 99% and a reconstruction error below 1 mm in less than 5 s.

C-arm Pose Estimation Using a Set of Coplanar Ellipses in Correspondence.

C-arms are increasingly being used to assist in a large number of surgical procedures. Fairly accurate and fast pose estimates are needed for non-encoded c-arms that are commonly available in most operating rooms in order to attain quantitative feedback from the x-ray images. We propose the use of an image-based fiducial composed of a set of coplanar ellipses to track the c-arm. We adopt an existing method for planar homography and propose a variation consisting of three modifications: including a weighting scheme for the linear system used, orthonormalizing the vectors pertaining to the rotation component of the transformation, and fine tuning the estimates using a constrained optimization step. We show that these variations make the approach more robust to noise that typically arises in fluoroscopy imaging and guarantee the orthonormality of the estimated rotation. The performance of the modified algorithm is demonstrated using realistic x-ray simulations. We also run sensitivity analysis for segmentation and calibration errors that are likely to occur in a practical setting. Preliminary results show mean tracking accuracy within 0.5 degrees and 0.9 mm for segmentation error variance up to 2 pixels squared. The algorithm also proves to be robust to calibration errors up to 1 cm.

Prostate brachytherapy seed reconstruction with Gaussian blurring and optimal coverage cost.

Intraoperative dosimetry in prostate brachytherapy requires localization of the implanted radioactive seeds. A tomosynthesis-based seed reconstruction method is proposed. A three-dimensional volume is reconstructed from Gaussian-blurred projection images and candidate seed locations are computed from the reconstructed volume. A false positive seed removal process, formulated as an optimal coverage problem, iteratively removes "ghost" seeds that are created by tomosynthesis reconstruction. In an effort to minimize pose errors that are common in conventional C-arms, initial pose parameter estimates are iteratively corrected by using the detected candidate seeds as fiducials, which automatically "focuses" the collected images and improves successive reconstructed volumes. Simulation results imply that the implanted seed locations can be estimated with a detection rate of > or = 97.9% and > or = 99.3% from three and four images, respectively, when the C-arm is calibrated and the pose of the C-arm is known. The algorithm was also validated on phantom data sets successfully localizing the implanted seeds from four or five images. In a Phase-1 clinical trial, we were able to localize the implanted seeds from five intraoperative fluoroscopy images with 98.8% (STD=1.6) overall detection rate.