Development and Evaluation of an Actuated MRI-Compatible Robotic System for MRI-Guided Prostate Intervention.

This paper reports the design, development, and magnetic resonance imaging (MRI) compatibility evaluation of an actuated transrectal prostate robot for MRI-guided needle intervention in the prostate. The robot performs actuated needle MRI-guidance with the goals of providing (i) MRI compatibility, (ii) MRI-guided needle placement with accuracy sufficient for targeting clinically significant prostate cancer foci, (iii) reducing interventional procedure times (thus increasing patient comfort and reducing opportunity for needle targeting error due to patient motion), (iv) enabling real-time MRI monitoring of interventional procedures, and (v) reducing the opportunities for error that arise in manually actuated needle placement. The design of the robot, employing piezo-ceramic-motor actuated needle guide positioning and manual needle insertion, is reported. Results of a MRI compatibility study show no reduction of MRI signal-to-noise-ratio (SNR) with the motors disabled. Enabling the motors reduces the SNR by 80% without RF shielding, but SNR is only reduced by 40% to 60% with RF shielding. The addition of radio-frequency shielding is shown to significantly reduce image SNR degradation caused by the presence of the robotic device. An accuracy study of MRI-guided biopsy needle placements in a prostate phantom is reported. The study shows an average in-plane targeting error of 2.4 mm with a maximum error of 3.7 mm. These data indicate the system's needle targeting accuracy is similar to that obtained with a previously reported manually actuated system, and is sufficient to reliably sample clinically significant prostate cancer foci under MRI-guidance.

High-fidelity detection and sorting of nanoscale vesicles in viral disease and cancer.

Biological nanoparticles, including viruses and extracellular vesicles (EVs), are of interest to many fields of medicine as biomarkers and mediators of or treatments for disease. However, exosomes and small viruses fall below the detection limits of conventional flow cytometers due to the overlap of particle-associated scattered light signals with the detection of background instrument noise from diffusely scattered light. To identify, sort, and study distinct subsets of EVs and other nanoparticles, as individual particles, we developed nanoscale Fluorescence Analysis and Cytometric Sorting (nanoFACS) methods to maximise information and material that can be obtained with high speed, high resolution flow cytometers. This nanoFACS method requires analysis of the instrument background noise (herein defined as the "reference noise"). With these methods, we demonstrate detection of tumour cell-derived EVs with specific tumour antigens using both fluorescence and scattered light parameters. We further validated the performance of nanoFACS by sorting two distinct HIV strains to >95% purity and confirmed the viability (infectivity) and molecular specificity (specific cell tropism) of biological nanomaterials sorted with nanoFACS. This nanoFACS method provides a unique way to analyse and sort functional EV- and viral-subsets with preservation of vesicular structure, surface protein specificity and RNA cargo activity.

Intrarectal amifostine during external beam radiation therapy for prostate cancer produces significant improvements in Quality of Life measured by EPIC score.

PURPOSE: To test whether intrarectal amifostine limits symptoms of radiation proctitis, measured by using the Radiation Therapy Oncology Group (RTOG) gastrointestinal (GI) toxicity score and the Expanded Prostate Cancer Index Composite (EPIC) score. METHODS AND MATERIALS: Patients with localized prostate cancer received amifostine as a rectal suspension 30-45 minutes before daily three-dimensional conformal radiation therapy. The first 18 patients received 1 g of amifostine, and the next 12 patients received 2 g. Toxicity was assessed at baseline, during treatment, and at follow-up visits by using RTOG grading and the EPIC Quality of Life (QoL) 50-item questionnaire. The Bowel Function subset of the bowel domain (EPIC-BF), which targets symptom severity, and the Bowel Bother subset of the bowel domain (EPIC-BB), which assesses QoL, were evaluated and compared with the RTOG GI toxicity score. RESULTS: Median follow-up was 30 months (range, 18-36 months). Overall, EPIC-BF and EPIC-BB scores both tracked closely with the RTOG GI toxicity score. Seven weeks after the start of radiation therapy, the incidence of RTOG Grade 2 toxicity was 33% in the 1-g group (6/18 patients) compared with 0% (0/12 patients) in the 2-g group and tended toward statistical significance (p = 0.06). A significant difference between amifostine groups was observed using the EPIC-BF score at 7 weeks (p = 0.04). A difference in EPIC-BB scores between dose groups was evident at 7 weeks (p = 0.07) and was significant at 12 months (p = 0.04). CONCLUSIONS: Higher doses of amifostine produced significant improvements in acute and late bowel QoL (up to 1 year after therapy), measured using the EPIC score.

Initial clinical experience with real-time transrectal ultrasonography-magnetic resonance imaging fusion-guided prostate biopsy.

OBJECTIVE: To evaluate the feasibility and utility of registration and fusion of real-time transrectal ultrasonography (TRUS) and previously acquired magnetic resonance imaging (MRI) to guide prostate biopsies. PATIENTS AND METHODS: Two National Cancer Institute trials allowed MRI-guided (with or with no US fusion) prostate biopsies during placement of fiducial markers. Fiducial markers were used to guide patient set-up for daily external beam radiation therapy. The eligible patients had biopsy-confirmed prostate cancer that was visible on MRI. A high-field (3T) MRI was performed with an endorectal coil in place. After moving to an US suite, the patient then underwent TRUS to visualize the prostate. The US transducer was equipped with a commercial needle guide and custom modified with two embedded miniature orthogonal five-degrees of freedom sensors to enable spatial tracking and registration with MR images in six degrees of freedom. The MRI sequence of choice was registered manually to the US using custom software for real-time navigation and feedback. The interface displayed the actual and projected needle pathways superimposed upon the real-time US blended with the prior MR images, with position data updating in real time at 10 frames per second. The registered MRI information blended to the real-time US was available to the physician who performed targeted biopsies of highly suspicious areas. RESULTS: Five patients underwent limited focal biopsy and fiducial marker placement with real-time TRUS-MRI fusion. The Gleason scores at the time of enrollment on study were 8, 7, 9, 9, and 6. Of the 11 targeted biopsies, eight showed prostate cancer. Positive biopsies were found in all patients. The entire TRUS procedure, with fusion, took approximately 10 min. CONCLUSION: The fusion of real-time TRUS and prior MR images of the prostate is feasible and enables MRI-guided interventions (like prostate biopsy) outside of the MRI suite. The technique allows for navigation within dynamic contrast-enhanced maps, or T2-weighted or MR spectroscopy images. This technique is a rapid way to facilitate MRI-guided prostate therapies such as external beam radiation therapy, brachytherapy, cryoablation, high-intensity focused ultrasound ablation, or direct injection of agents, without the cost, throughput, or equipment compatibility issues that might arise with MRI-guided interventions inside the MRI suite.

Patient selection determines the prostate cancer yield of dynamic contrast-enhanced magnetic resonance imaging-guided transrectal biopsies in a closed 3-Tesla scanner.

OBJECTIVE: To evaluate the cancer yield of transrectal prostate biopsies in a 3-T magnetic resonance imaging (MRI) scanner in patients with elevated prostate specific antigen (PSA) levels and recent negative transrectal ultrasonography (TRUS)-guided prostate biopsies. PATIENTS AND METHODS: Between July 2004 and November 2005, patients with at least one previous negative prostate biopsy within the previous 12 months had MRI-guided biopsy of the prostate in a 3-T MRI scanner. Patients with previous positive biopsies for cancer were excluded. Target selection was based on T2-weighted imaging and dynamic contrast-enhanced (DCE) imaging studies. RESULTS: Thirteen patients were eligible; their median (range) age was 61 (47-74) years and PSA value 4.90 (1.3-12.3) ng/mL. Most patients had one previous negative biopsy (range 1-4). Four patients had a family history of prostate cancer. There were 37 distinct targets based on T2-weighted imaging. Fifteen of 16 distinct DCE abnormalities were co-localized with a target based on T2-weighted imaging. Despite this correlation, only one of 13 patients had a directed biopsy positive for cancer. Including systematic biopsies, two of 13 patients had a biopsy positive for prostate cancer. One patient had prostate intraepithelial neoplasia and one had atypical glands in the specimen. CONCLUSION: The prostate-cancer yield of transrectal biopsies in a 3-T MRI scanner, among patients with recent negative TRUS-guided prostate biopsies, is similar to repeat systematic TRUS-guided biopsy. DCE correlates with T2-imaging but does not appear to improve prostate cancer yield in this population.

Accuracy of 3D volumetric image registration based on CT, MR and PET/CT phantom experiments.

Registration is critical for image-based treatment planning and image-guided treatment delivery. Although automatic registration is available, manual, visual-based image fusion using three orthogonal planar views (3P) is always employed clinically to verify and adjust an automatic registration result. However, the 3P fusion can be time consuming, observer dependent, as well as prone to errors, owing to the incomplete 3-dimensional (3D) volumetric image representations. It is also limited to single-pixel precision (the screen resolution). The 3D volumetric image registration (3DVIR) technique was developed to overcome these shortcomings. This technique introduces a 4th dimension in the registration criteria beyond the image volume, offering both visual and quantitative correlation of corresponding anatomic landmarks within the two registration images, facilitating a volumetric image alignment, and minimizing potential registration errors. The 3DVIR combines image classification in real-time to select and visualize a reliable anatomic landmark, rather than using all voxels for alignment. To determine the detection limit of the visual and quantitative 3DVIR criteria, slightly misaligned images were simulated and presented to eight clinical personnel for interpretation. Both of the criteria produce a detection limit of 0.1 mm and 0.1 degree. To determine the accuracy of the 3DVIR method, three imaging modalities (CT, MR and PET/CT) were used to acquire multiple phantom images with known spatial shifts. Lateral shifts were applied to these phantoms with displacement intervals of 5.0+/-0.1 mm. The accuracy of the 3DVIR technique was determined by comparing the image shifts determined through registration to the physical shifts made experimentally. The registration accuracy, together with precision, was found to be: 0.02+/-0.09 mm for CT/CT images, 0.03+/-0.07 mm for MR/MR images, and 0.03+/-0.35 mm for PET/CT images. This accuracy is consistent with the detection limit, suggesting an absence of detectable systematic error. This 3DVIR technique provides a superior alternative to the 3P fusion method for clinical applications.

Pretransplant pulmonary function tests predict risk of mortality following fractionated total body irradiation and allogeneic peripheral blood stem cell transplant.

PURPOSE: To determine the value of pulmonary function tests (PFTs) done before peripheral blood stem cell transplant (PBSCT) in predicting mortality after total body irradiation (TBI) performed with or without dose reduction to the lung. METHODS AND MATERIALS: From 1997 to 2004, 146 consecutive patients with hematologic malignancies received fractionated TBI before PBSCT. With regimen A (n=85), patients were treated without lung dose reduction to 13.6 gray (Gy). In regimen B (n=35), total body dose was decreased to 12 Gy (1.5 Gy twice per day for 4 days) and lung dose was limited to 9 Gy by use of lung shielding. In regimen C (n=26), lung dose was reduced to 6 Gy. All patients received PFTs before treatment, 90 days after treatment, and annually. RESULTS: Median follow-up was 44 months (range, 12-90 months). Sixty-one patients had combined ventilation/diffusion capacity deficits defined as both a forced expiratory volume in the first second (FEV1) and a diffusion capacity of carbon dioxide (DLCO)<100% predicted. In this group, there was a 20% improvement in one-year overall survival with lung dose reduction (70 vs. 50%, log-rank test p=0.042). CONCLUSION: Among those with combined ventilation/diffusion capacity deficits, lung dose reduction during TBI significantly improved survival.

Intrarectal amifostine suspension may protect against acute proctitis during radiation therapy for prostate cancer: a pilot study.

PURPOSE: Our goal was to test the ability of intrarectal amifostine to limit symptoms of radiation proctitis. METHODS AND MATERIALS: The first 18 patients received 1 g of intrarectal amifostine suspension placed 30-45 min before each radiation treatment. The following 12 patients received 2 g of amifostine. Total dose prescribed ranged from 66 to 76 Gy. All patients were treated with three-dimensional conformal radiation therapy. The suspension remained intrarectal during treatment and was expelled after treatment. For gastrointestinal symptoms, during treatment and follow-up, all patients had a Radiation Therapy Oncology Group (RTOG) grade recorded. RESULTS: Median follow-up was 18 months (range, 6-24 months). With 2 g vs. 1 g amifostine, there was a nearly significant decrease in RTOG Grade 2 acute rectal toxicity. Seven weeks after the start of radiation therapy, the incidence of Grade 2 toxicity was 33% in the 1-g group (6/18) compared with 0% (0/12) in the 2-g group (p=0.06). No Grade 3 toxicity or greater occurred in this study. CONCLUSION: This trial suggests greater rectal radioprotection from acute effects with 2 g vs. 1 g amifostine suspension. Further studies should be conducted in populations at higher risk for developing symptomatic acute and late proctitis.

Anatomical and functional imaging of tumors in animal models: focus on pheochromocytoma.

This review focuses on anatomical (computed tomography, magnetic resonance imaging) and functional (positron emission tomography) imaging methods for tumor localization and identification of experimentally induced tumors in animal models, especially pheochromocytoma. Although anatomical imaging can precisely locate primary and metastatic tumors, functional imaging has high specificity for some tumors, especially those of endocrine origin. This is due to the fact that endocrine tumor cells take up hormone precursors, express hormone receptors and transporters, and synthesize, store, and release hormones. These characteristic properties of endocrine tumors enable investigators to create highly specific radiopharmaceuticals, particularly for positron emission tomography. For example, localization of pheochromocytoma involves [18F]-6F-dopamine. It is a highly specific radiopharmaceutical since it uses the norepinephrine transporter system expressed in most pheochromocytoma cells. Here we review both anatomical and functional imaging methods that are used conjointly in order to localize and identify specific characteristics of tumors.

Inverse treatment planning based on MRI for HDR prostate brachytherapy.

PURPOSE: To develop and optimize a technique for inverse treatment planning based solely on magnetic resonance imaging (MRI) during high-dose-rate brachytherapy for prostate cancer. METHODS AND MATERIALS: Phantom studies were performed to verify the spatial integrity of treatment planning based on MRI. Data were evaluated from 10 patients with clinically localized prostate cancer who had undergone two high-dose-rate prostate brachytherapy boosts under MRI guidance before and after pelvic radiotherapy. Treatment planning MRI scans were systematically evaluated to derive a class solution for inverse planning constraints that would reproducibly result in acceptable target and normal tissue dosimetry. RESULTS: We verified the spatial integrity of MRI for treatment planning. MRI anatomic evaluation revealed no significant displacement of the prostate in the left lateral decubitus position, a mean distance of 14.47 mm from the prostatic apex to the penile bulb, and clear demarcation of the neurovascular bundles on postcontrast imaging. Derivation of a class solution for inverse planning constraints resulted in a mean target volume receiving 100% of the prescribed dose of 95.69%, while maintaining a rectal volume receiving 75% of the prescribed dose of <5% (mean 1.36%) and urethral volume receiving 125% of the prescribed dose of <2% (mean 0.54%). CONCLUSION: Systematic evaluation of image spatial integrity, delineation uncertainty, and inverse planning constraints in our procedure reduced uncertainty in planning and treatment.

Accuracy analysis in MRI-guided robotic prostate biopsy.

PURPOSE: To assess retrospectively the clinical accuracy of an magnetic resonance imaging-guided robotic prostate biopsy system that has been used in the US National Cancer Institute for over 6 years. METHODS: Series of 2D transverse volumetric MR image slices of the prostate both pre (high-resolution T2-weighted)- and post (low-resolution)- needle insertions were used to evaluate biopsy accuracy. A three-stage registration algorithm consisting of an initial two-step rigid registration followed by a B-spline deformable alignment was developed to capture prostate motion during biopsy. The target displacement (distance between planned and actual biopsy target), needle placement error (distance from planned biopsy target to needle trajectory), and biopsy error (distance from actual biopsy target to needle trajectory) were calculated as accuracy assessment. RESULTS: A total of 90 biopsies from 24 patients were studied. The registrations were validated by checking prostate contour alignment using image overlay, and the results were accurate to within 2 mm. The mean target displacement, needle placement error, and clinical biopsy error were 5.2, 2.5, and 4.3 mm, respectively. CONCLUSION: The biopsy error reported suggests that quantitative imaging techniques for prostate registration and motion compensation may improve prostate biopsy targeting accuracy.

Biopsy needle artifact localization in MRI-guided robotic transrectal prostate intervention.

Recently a number of robotic intervention systems for magnetic resonance image (MRI)-guided needle placement in the prostate have been reported. In MRI-guided needle interventions, after a needle is inserted, the needle position is often confirmed with a volumetric MRI scan. Commonly used titanium needles are not directly visible in an MRI, but they generate a susceptibility artifact in the immediate neighborhood of the needle. This paper reports the results of a quantitative study of the relationship between the true position of titanium biopsy needle and the corresponding needle artifact position in MRI, thereby providing a better understanding of the influence of needle artifact on targeting errors. The titanium needle tip artifact extended 9 mm beyond the actual needle tip location with tendency to bend toward the scanner's B (0) magnetic field direction, and axially displaced 0.38 and 0.32 mm (mean) in scanner's frequency and phase encoding direction, respectively.

Early Experiences of Image Guided Prostate and Pelvic Nodal Irradiation With Intensity Modulated Radiation Treatment in Localized Prostate Cancer.

BACKGROUND: To present the early findings of a phase I clinical trial studying the use of intensity modulated radiation treatment (IMRT) to treat at risk pelvic and lower para-aortic lymph nodes in patients with high risk prostate cancer while escalating dose. Dose escalation was performed with a technique particularly aiming to limit the dose to surrounding critical structures. METHODS: A total of 12 patients were treated with an IMRT plan that delivered 45 Gy to the pelvic lymph nodes, prostate and proximal seminal vesicles. This was followed by an image guided IMRT plan that delivered 9 Gy to the prostate and seminal vesicles and then an additional 21.6 Gy delivered to the prostate for a total dose of 75.6 Gy to the prostate. Gastrointestinal (GI) and genitourinary (GU) toxicity were recorded weekly throughout treatment and in follow up (range: 20 - 49 months). RESULTS: At diagnosis, median age was 64, median PSA 15.5 (range: 5 - 103) and Gleason score ranged 7 - 9. The median dose to the bladder was 52 Gy, the median dose to the rectum was 53 Gy and the median dose to the small bowel was 26 Gy. During treatment, Grade 2 GU toxicity was noted in 3/12 (25%) patients and Grade 2 GI toxicity was noted in 2/12 patients (16%). At a median follow-up of 28 months, Grade 2 late GI toxicity was seen in 1/12 (8%) and late GU in 3/12 (25%) of patients. There were no acute or late grade 3 and 4 GU or GI toxicities. CONCLUSIONS: Our study shows the feasibility of using IMRT for pelvic and lower para-aortic nodal irradiation as the toxicities are low for the total dose that was delivered. This shows promise for reducing normal tissue doses, improving target control, and potentially allowing for additional dose escalation to the pelvic/lower para-aortic lymph nodes in our successive cohorts.

Target motion tracking in MRI-guided transrectal robotic prostate biopsy.

PURPOSE: MRI-guided prostate needle biopsy requires compensation for organ motion between target planning and needle placement. Two questions are studied and answered in this paper: 1) is rigid registration sufficient in tracking the targets with an error smaller than the clinically significant size of prostate cancer and 2) what is the effect of the number of intraoperative slices on registration accuracy and speed? METHODS: we propose multislice-to-volume registration algorithms for tracking the biopsy targets within the prostate. Three orthogonal plus additional transverse intraoperative slices are acquired in the approximate center of the prostate and registered with a high-resolution target planning volume. Both rigid and deformable scenarios were implemented. Both simulated and clinical MRI-guided robotic prostate biopsy data were used to assess tracking accuracy. RESULTS: average registration errors in clinical patient data were 2.6 mm for the rigid algorithm and 2.1 mm for the deformable algorithm. CONCLUSION: rigid tracking appears to be promising. Three tracking slices yield significantly high registration speed with an affordable error.

A Study of Needle Image Artifact Localization in Confirmation Imaging of MRI-guided Robotic Prostate Biopsy.

Recently several systems for magnetic resonance image (MRI) guided needle placement in the prostate have been reported. In comparison to conventional ultrasound-guided needle placement in the prostate, these MRI-guided systems promise improved targeting accuracy for prostate intervention procedures including biopsy, fiducial marker insertion, injection and focal therapy. In MRI-guided needle interventions, after a needle is inserted, the needle position is often confirmed with a volumetric MRI scan. Commonly used titanium needles are not directly visible in an MR image, but they generate a susceptibility artifact in the immediate neighborhood of the needle. This paper reports the results of a quantitative study of the relation between the true position of titanium biopsy needle and the corresponding needle artifact position in MR images. The titanium needle artifact was found to be displaced 0.38 mm and 0.32 mm shift in scanner's frequency and phase encoding direction, respectively. The artifact at the tip of the titanium needle was observed to bend toward the scanner's B(0) magnetic field direction.

An MRI-compatible robotic system with hybrid tracking for MRI-guided prostate intervention.

This paper reports the development, evaluation, and first clinical trials of the access to the prostate tissue (APT) II system-a scanner independent system for magnetic resonance imaging (MRI)-guided transrectal prostate interventions. The system utilizes novel manipulator mechanics employing a steerable needle channel and a novel six degree-of-freedom hybrid tracking method, comprising passive fiducial tracking for initial registration and subsequent incremental motion measurements. Targeting accuracy of the system in prostate phantom experiments and two clinical human-subject procedures is shown to compare favorably with existing systems using passive and active tracking methods. The portable design of the APT II system, using only standard MRI image sequences and minimal custom scanner interfacing, allows the system to be easily used on different MRI scanners.

Target motion compensation in MRI-guided prostate biopsy with static images.

PURPOSE: MRI-guided prostate needle biopsy requires compensation for organ motion between target planning and needle placement. METHODS: We propose slice-to-volume registration algorithms for tracking the prostate motion. Three orthogonal intra-operative slices are acquired in the approximate center of the prostate and registered with a high-resolution target planning volume. Both rigid and deformable scenarios were implemented. MRI-guided robotic prostate biopsy cases were analyzed retrospectively. RESULTS: Average registration errors were 2.55mm for the rigid algorithm and 2.05mm for the deformable algorithm. CONCLUSION: Slice-based tracking appears to be promising. Deformable registration does not seem warranted.

MRI-guided robotic prostate biopsy: a clinical accuracy validation.

UNLABELLED: Prostate cancer is a major health threat for men. For over five years, the U.S. National Cancer Institute has performed prostate biopsies with a magnetic resonance imaging (MRI)-guided robotic system. PURPOSE: A retrospective evaluation methodology and analysis of the clinical accuracy of this system is reported. METHODS: Using the pre and post-needle insertion image volumes, a registration algorithm that contains a two-step rigid registration followed by a deformable refinement was developed to capture prostate dislocation during the procedure. The method was validated by using three-dimensional contour overlays of the segmented prostates and the registrations were accurate up to 2 mm. RESULTS: It was found that tissue deformation was less of a factor than organ displacement. Out of the 82 biopsies from 21 patients, the mean target displacement, needle placement error, and clinical biopsy error was 5.9 mm, 2.3 mm, and 4 mm, respectively. CONCLUSION: The results suggest that motion compensation for organ displacement should be used to improve targeting accuracy.

Accuracy validation for MRI-guided robotic prostate biopsy.

We report a quantitative evaluation of the clinical accuracy of a MRI-guided robotic prostate biopsy system that has been in use for over five years at the U.S. National Cancer Institute. A two-step rigid volume registration using mutual information between the pre and post needle insertion images was performed. Contour overlays of the prostate before and after registration were used to validate the registration. A total of 20 biopsies from 5 patients were evaluated. The maximum registration error was 2 mm. The mean biopsy target displacement, needle placement error, and biopsy error was 5.4 mm, 2.2 mm, and 5.1 mm respectively. The results show that the pre-planned biopsy target did dislocate during the procedure and therefore causing biopsy errors.

Design and preliminary accuracy studies of an MRI-guided transrectal prostate intervention system.

This paper reports a novel system for magnetic resonance imaging (MRI) guided transrectal prostate interventions, such as needle biopsy, fiducial marker placement, and therapy delivery. The system utilizes a hybrid tracking method, comprised of passive fiducial tracking for initial registration and subsequent incremental motion measurement along the degrees of freedom using fiber-optical encoders and mechanical scales. Targeting accuracy of the system is evaluated in prostate phantom experiments. Achieved targeting accuracy and procedure times were found to compare favorably with existing systems using passive and active tracking methods. Moreover, the portable design of the system using only standard MRI image sequences and minimal custom scanner interfacing allows the system to be easily used on different MRI scanners.