First-in-human Evaluation of a Prostate-specific Membrane Antigen-targeted Near-infrared Fluorescent Small Molecule for Fluorescence-based Identification of Prostate Cancer in Patients with High-risk Prostate Cancer Undergoing Robotic-assisted Prostatectomy.

BACKGROUND: Men with high-risk prostate cancer undergoing surgery likely recur due to failure to completely excise regional and/or local disease. OBJECTIVE: The first-in-human evaluation of safety, pharmacokinetics, and exploratory efficacy of IS-002, a novel near-infrared prostate-specific membrane antigen (PSMA)-targeted fluorescence imaging agent, designed for intraoperative prostate cancer visualization. DESIGN, SETTING, AND PARTICIPANTS: A phase 1, single-center, dose-escalation study was conducted in 24 men with high-risk prostate cancer scheduled for robotic-assisted radical prostatectomy with (extended) pelvic lymph node dissection using the da Vinci surgical system. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adverse events (AEs), vital signs, complete blood count, complete metabolic panel, urinalysis, and electrocardiogram were assessed over a 14-d period and compared with baseline. The pharmacokinetic profile of IS-002 was determined. Diagnostic accuracy was assessed for exploratory efficacy. RESULTS AND LIMITATIONS: AEs predominantly included discoloration of urine (n = 22/24; expected, related, grade 1). There were no grade ≥2 AEs. IS-002 Cmax and area under the curve increased with increasing dose. Plasma concentrations declined rapidly in a biphasic manner, with the median terminal half-lives ranging from 5.0 to 7.6 h, independent of dose and renal function. At 25 µg/kg, the exploratory efficacy readouts for the negative and positive predictive values were, 97% and 45% for lymph nodes, and 100% and 80% for residual/locoregional disease detection, respectively. CONCLUSIONS: IS-002 is safe and well tolerated, and has the potential to enable intraoperative tumor detection that could not be identified using standard imaging. PATIENT SUMMARY: IS-002 is a new imaging agent that specifically targets the prostate-specific membrane antigen receptor. In this study, we tested IS-002 for the first time in men with high-risk prostate cancer undergoing surgery and found that IS-002 is safe, is cleared from the body quickly, and potentially allows identification of prostate cancer in areas that would not be identified by conventional white light imaging.

Nerve Visualization using Phenoxazine-Based Near-Infrared Fluorophores to Guide Prostatectomy.

Fluorescence-guided surgery (FGS) is poised to revolutionize surgical medicine through near-infrared (NIR) fluorophores for tissue- and disease-specific contrast. Clinical open and laparoscopic FGS vision systems operate nearly exclusively at NIR wavelengths. However, tissue-specific NIR contrast agents compatible with clinically available imaging systems are lacking, leaving nerve tissue identification during prostatectomy a persistent challenge. Here, it is shown that combining drug-like molecular design concepts and fluorophore chemistry enabled the production of a library of NIR phenoxazine-based fluorophores for intraoperative nerve-specific imaging. The lead candidate readily delineated prostatic nerves in the canine and iliac plexus in the swine using the clinical da Vinci Surgical System that has been popularized for minimally invasive prostatectomy procedures. These results demonstrate the feasibility of molecular engineering of NIR nerve-binding fluorophores for ready integration into the existing surgical workflow, paving the path for clinical translation to reduce morbidity from nerve injury for prostate cancer patients.

Delphi consensus project on prostate-specific membrane antigen (PSMA)-targeted surgery-outcomes from an international multidisciplinary panel.

PURPOSE: Prostate-specific membrane antigen (PSMA) is increasingly considered as a molecular target to achieve precision surgery for prostate cancer. A Delphi consensus was conducted to explore expert views in this emerging field and to identify knowledge and evidence gaps as well as unmet research needs that may help change practice and improve oncological outcomes for patients. METHODS: One hundred and five statements (scored by a 9-point Likert scale) were distributed through SurveyMonkey®. Following evaluation, a consecutive second round was performed to evaluate consensus (16 statements; 89% response rate). Consensus was defined using the disagreement index, assessed by the research and development project/University of California, Los Angeles appropriateness method. RESULTS: Eighty-six panel participants (72.1% clinician, 8.1% industry, 15.1% scientists, and 4.7% other) participated, most with a urological background (57.0%), followed by nuclear medicine (22.1%). Consensus was obtained on the following: (1) The diagnostic PSMA-ligand PET/CT should ideally be taken < 1 month before surgery, 1-3 months is acceptable; (2) a 16-20-h interval between injection of the tracer and surgery seems to be preferred; (3) PSMA targeting is most valuable for identification of nodal metastases; (4) gamma, fluorescence, and hybrid imaging are the preferred guidance technologies; and (5) randomized controlled clinical trials are required to define oncological value. Regarding surgical margin assessment, the view on the value of PSMA-targeted surgery was neutral or inconclusive. A high rate of "cannot answer" responses indicates further study is necessary to address knowledge gaps (e.g., Cerenkov or beta-emissions). CONCLUSIONS: This Delphi consensus provides guidance for clinicians and researchers that implement or develop PSMA-targeted surgery technologies. Ultimately, however, the consensus should be backed by randomized clinical trial data before it may be implemented within the guidelines.

How to objectively evaluate the impact of image-guided surgery technologies.

PURPOSE: This manuscript aims to provide a better understanding of methods and techniques with which one can better quantify the impact of image-guided surgical technologies. METHODS: A literature review was conducted with regard to economic and technical methods of medical device evaluation in various countries. Attention was focused on applications related to image-guided interventions that have enabled procedures to be performed in a minimally invasive manner, produced superior clinical outcomes, or have become standard of care. RESULTS: The review provides examples of successful implementations and adoption of image-guided surgical techniques, mostly in the field of neurosurgery. Failures as well as newly developed technologies still undergoing cost-efficacy analysis are discussed. CONCLUSION: The field of image-guided surgery has evolved from solely using preoperative images to utilizing highly specific tools and software to provide more information to the interventionalist in real time. While deformations in soft tissue often preclude the use of such instruments outside of neurosurgery, recent developments in optical and radioactive guidance have enabled surgeons to better account for organ motion and provide feedback to the surgeon as tissue is cut. These technologies are currently undergoing value assessments in many countries and hold promise to improve outcomes for patients, surgeons, care teams, payors, and society in general.

A narrative review of fluorescence imaging in robotic-assisted surgery.

OBJECTIVE: In this review, we provide examples of applications of fluorescence imaging in urologic, gynecologic, general, and endocrine surgeries. BACKGROUND: While robotic-assisted surgery has helped increase the availability of minimally invasive procedures across surgical specialties, there remains an opportunity to reduce adverse events associated with open, laparoscopic, and robotic-assisted methods. In 2011, fluorescence imaging was introduced as an option to the da Vinci Surgical System, and has been standard equipment since 2014. Without interfering with surgical workflow, this fluorescence technology named Firefly® allows for acquisition and display of near-infrared fluorescent signals that are co-registered with white light endoscopic images. As a result, robotic surgeons of all specialties have been able to explore the clinical utility of fluorescence guided surgery. METHODS: Literature searches were performed using the PubMed and MEDLINE databases using the keywords "robotic-assisted fluorescence surgery", "ICG robotic surgery", and "fluorescence guided surgery" covering the years 2011-2020. CONCLUSIONS: Real-time intraoperative fluorescence guidance has shown great potential in helping guide surgeons in both simple and complex surgical interventions. Indocyanine green is one of the most widely-used imaging agents in fluorescence guided surgery, and other targeted, near-infrared imaging agents are in various stages of development. Fluorescence is becoming a reliable tool that can help surgeons in their decision-making process in some specialties, while explorations continue in others.

Near-infrared nerve-binding fluorophores for buried nerve tissue imaging.

Nerve-binding fluorophores with near-infrared (NIR; 650 to 900 nm) emission could reduce iatrogenic nerve injury rates by providing surgeons precise, real-time visualization of the peripheral nervous system. Unfortunately, current systemically administered nerve contrast agents predominantly emit at visible wavelengths and show nonspecific uptake in surrounding tissues such as adipose, muscle, and facia, thus limiting detection to surgically exposed surface-level nerves. Here, a focused NIR fluorophore library was synthesized and screened through multi-tiered optical and pharmacological assays to identify nerve-binding fluorophore candidates for clinical translation. NIR nerve probes enabled micrometer-scale nerve visualization at the greatest reported tissue depths (~2 to 3 mm), a feat unachievable with previous visibly emissive contrast agents. Laparoscopic fluorescent surgical navigation delineated deep lumbar and iliac nerves in swine, most of which were invisible in conventional white-light endoscopy. Critically, NIR oxazines generated contrast against all key surgical tissue classes (muscle, adipose, vasculature, and fascia) with nerve signal-to-background ratios ranging from ~2 (2- to 3-mm depth) to 25 (exposed nerve). Clinical translation of NIR nerve-specific agents will substantially reduce comorbidities associated with surgical nerve damage.

Augmented reality for image guidance in transoral robotic surgery.

With the advent of precision surgery, there have been attempts to integrate imaging with robotic systems to guide sound oncologic surgical resections while preserving critical structures. In the confined space of transoral robotic surgery (TORS), this offers great potential given the proximity of structures. In this cadaveric experiment, we describe the use of a 3D virtual model displayed in the surgeon's console with the surgical field in view, to facilitate image-guided surgery at the oropharynx where there is significant soft tissue deformation. We also utilized the 3D model that was registered to the maxillary dentition, allowing for real-time image overlay of the internal carotid artery system. This allowed for real-time visualization of the internal carotid artery system that was qualitatively accurate on cadaveric dissection. Overall, this shows that virtual models and image overlays can be useful in image-guided surgery while approaching different sites in head and neck surgery with TORS.

Intraoperative ureter visualization using a near-infrared imaging agent.

The fluorescent imaging agent IS-001 was determined to be well tolerated in all subjects and has the potential to provide ureter visualization throughout minimally invasive hysterectomy procedures. This study was conducted to evaluate clinical safety and efficacy of a real-time ureter visualization technique for use during hysterectomy surgery. The study drug appears safe, is renally excreted, and allows enhanced ureter visualization when imaged with a clinically approved near-infrared sensitive endoscope. This is a first-in-human study showing preliminary results that the drug is safe and effective during surgery for improved ureter visualization.

Real-time navigation in transoral robotic nasopharyngectomy utilizing on table fluoroscopy and image overlay software: a cadaveric feasibility study.

Inability to integrate surgical navigation systems into current surgical robot is one of the reasons for the lack of development of robotic endoscopic skull base surgery. We describe an experiment to adapt current technologies for real-time navigation during transoral robotic nasopharyngectomy. A cone-beam CT was performed with a robotic C-arm after the injecting contrast into common carotid artery. 3D reconstruction of the skull images with the internal carotid artery (ICA) highlighted red was projected on the console. Robotic nasopharyngectomy was then performed. Fluoroscopy was performed with the C-arm. Fluoroscopic image was then overlaid on the reconstructed skull image. The relationship of the robotic instruments with the bony landmarks and ICA could then been viewed in real-time, acting as a surgical navigation system. Navigation during robotic skull base surgery is feasible with available technologies and can increase the safety of robotic skull base surgery.

Augmented reality and cone beam CT guidance for transoral robotic surgery.

In transoral robotic surgery preoperative image data do not reflect large deformations of the operative workspace from perioperative setup. To address this challenge, in this study we explore image guidance with cone beam computed tomographic angiography to guide the dissection of critical vascular landmarks and resection of base-of-tongue neoplasms with adequate margins for transoral robotic surgery. We identify critical vascular landmarks from perioperative c-arm imaging to augment the stereoscopic view of a da Vinci si robot in addition to incorporating visual feedback from relative tool positions. Experiments resecting base-of-tongue mock tumors were conducted on a series of ex vivo and in vivo animal models comparing the proposed workflow for video augmentation to standard non-augmented practice and alternative, fluoroscopy-based image guidance. Accurate identification of registered augmented critical anatomy during controlled arterial dissection and en bloc mock tumor resection was possible with the augmented reality system. The proposed image-guided robotic system also achieved improved resection ratios of mock tumor margins (1.00) when compared to control scenarios (0.0) and alternative methods of image guidance (0.58). The experimental results show the feasibility of the proposed workflow and advantages of cone beam computed tomography image guidance through video augmentation of the primary stereo endoscopy as compared to control and alternative navigation methods.

Intraoperative image-guided transoral robotic surgery: pre-clinical studies.

BACKGROUND: Adequate resection of oropharyngeal neoplasms with transoral robotic surgery (TORS) poses multiple challenges, including difficulty with access, inability to palpate the tumor, loss of landmarks, and intraoperative patient positioning with mouth retractor and tongue extended creating significant tissue distortion from preoperative imaging. METHODS: This study evaluates a workflow integrating intraoperative cone beam computed tomography (CBCT) for image-guided TORS through robotic experimentation locating 8-10 embedded targets in five porcine tongues and a cadaveric head phantom, conducted under various modes of visualization and integration of preoperative/intraoperative imaging. RESULTS: A statistically significant improvement in mean target localization error was achieved for both the porcine tongue ((9.8 ± 4.0) mm vs. (5.3 ± 1.3) mm, P-value = 0.0151) and cadaver ((11.2 ± 5.0) mm vs. (5.8 ± 2.5) mm P-value = 0.0189) in experiments comparing scenarios simulating current standard-of-care practice and the proposed image guidance system. CONCLUSION: Intraoperative image guidance with augmentation of critical surgical structures has the potential to improve target localization for TORS.

2D-3D radiograph to cone-beam computed tomography (CBCT) registration for C-arm image-guided robotic surgery.

PURPOSE: C-arm radiographs are commonly used for intraoperative image guidance in surgical interventions. Fluoroscopy is a cost-effective real-time modality, although image quality can vary greatly depending on the target anatomy. Cone-beam computed tomography (CBCT) scans are sometimes available, so 2D-3D registration is needed for intra-procedural guidance. C-arm radiographs were registered to CBCT scans and used for 3D localization of peritumor fiducials during a minimally invasive thoracic intervention with a da Vinci Si robot. METHODS: Intensity-based 2D-3D registration of intraoperative radiographs to CBCT was performed. The feasible range of X-ray projections achievable by a C-arm positioned around a da Vinci Si surgical robot, configured for robotic wedge resection, was determined using phantom models. Experiments were conducted on synthetic phantoms and animals imaged with an OEC 9600 and a Siemens Artis zeego, representing the spectrum of different C-arm systems currently available for clinical use. RESULTS: The image guidance workflow was feasible using either an optically tracked OEC 9600 or a Siemens Artis zeego C-arm, resulting in an angular difference of Δθ:∼ 30°. The two C-arm systems provided TRE mean ≤ 2.5 mm and TRE mean ≤ 2.0 mm, respectively (i.e., comparable to standard clinical intraoperative navigation systems). CONCLUSIONS: C-arm 3D localization from dual 2D-3D registered radiographs was feasible and applicable for intraoperative image guidance during da Vinci robotic thoracic interventions using the proposed workflow. Tissue deformation and in vivo experiments are required before clinical evaluation of this system.

Toward Intraoperative Image-Guided Transoral Robotic Surgery.

This paper presents the development and evaluation of video augmentation on the stereoscopic da Vinci S system with intraoperative image guidance for base of tongue tumor resection in transoral robotic surgery (TORS). Proposed workflow for image-guided TORS begins by identifying and segmenting critical oropharyngeal structures (e.g., the tumor and adjacent arteries and nerves) from preoperative computed tomography (CT) and/or magnetic resonance (MR) imaging. These preoperative planned data can be deformably registered to the intraoperative endoscopic view using mobile C-arm cone-beam computed tomography (CBCT) [1, 2]. Augmentation of TORS endoscopic video defining surgical targets and critical structures has the potential to improve navigation, spatial orientation, and confidence in tumor resection. Experiments in animal specimens achieved statistically significant improvement in target localization error when comparing the proposed image guidance system to simulated current practice.

Robotic skull base surgery via supraorbital keyhole approach: a cadaveric study.

BACKGROUND: The supraorbital keyhole approach has been used in anterior skull base tumor and aneurysm surgery. However, there are debates regarding the safety and limitations of this kind of approach. OBJECTIVE: To determine the feasibility and potential benefits of surgical robotic technology in minimally invasive neurosurgery. METHODS: Two fresh cadaver heads were studied with the da Vinci Surgical System with 0° and 30° stereoscopic endoscopes to visualize neuroanatomy. The ability of the system to suture and place clips under the keyhole approach was tested. RESULTS: The da Vinci Surgical System was used throughout the supraorbital transeyebrow keyhole approach. With the use of standard microdissection techniques, the optic nerve, optic chiasm, carotid artery, and third cranial nerve were visualized. The sylvian fissure was then exposed from the proximal sylvian membrane to the distal M1 segment. With the EndoWrist microforceps, suturing can be achieved smoothly to close a defect created on the M2 artery. Although the benefits in adjusting clips during aneurysm surgery could be provided by an articulating applier, a proper robotic applier is not currently available. CONCLUSION: The minimally invasive supraorbital keyhole surgery can be achieved with the da Vinci Surgical System in cadaver models. This system provides neurosurgeons with broader vision and articulable instruments, which standard microsurgical systems do not provide. Further studies are necessary to evaluate the safety and benefits of using the da Vinci Surgical System in minimally invasive neurosurgery.

Radiation dosimetry and biodistribution of the hypoxia tracer (18)F-EF5 in oncologic patients.

UNLABELLED: The primary goals of this study were to determine the biodistribution and excretion of (18)F-EF5 in oncologic patients, to estimate the radiation-absorbed dose and to determine the safety of this drug. METHODS: Sixteen patients with histologically confirmed malignancy received a mean intravenous infusion of 217 MBq (range 107-364 MBq) of (18)F-EF5. Over a 4-6-hour period, four to five serial positron emission tomography (PET) or PET/computed tomography (CT) scans were obtained. To calculate the radiation dosimetry estimates, volumes of interest were drawn over the source organs for each PET scan or on the CT for each PET/CT scan. Serial blood samples were obtained to measure (18)F-EF5 blood clearance. Bladder-wall dose was calculated based on urine activity measurements. RESULTS: The urinary bladder received the largest radiation-absorbed dose, 0.12 ± 0.034 mSv/MBq (mean ± SD). The average effective dose equivalent and the effective dose of (18)F-EF5 were 0.021 ± 0.003 mSv/MBq and 0.018 ± 0.002 mSv/MBq, respectively. (18)F-EF5 was well tolerated in all subjects. CONCLUSIONS: (18)F-EF5 was demonstrated to be safe for patients, and the radiation exposure is clinically acceptable. As with any radiotracer with primary excretion in the urine, the bladder-wall dose can be minimized by active hydration and frequent voiding.

Nerve mapping for prostatectomies: novel technologies under development.

Prostatic neuroanatomy is difficult to visualize intraoperatively and can be extremely variable. Damage to these nerves during prostatectomies may lead to postoperative complications such as erectile dysfunction and incontinence. This review aims to discuss the prostatic neuroanatomy, sites of potential nerve damage during a prostatectomy, and nerve-mapping technologies being developed to prevent neural injury. These technologies include stimulation, dyes, and direct visualization. Nerve stimulation works by testing an area and observing a physiologic response but is limited by the long half-life for an erectile response; examples include CaverMap, ProPep, and optical nerve stimulation. Few nerve dyes have been approved by the Food and Drug Administration (FDA) because of the extensive testing required; examples of nerve dyes include compounds from Avelas and General Electric, fluorescent cholera toxin subunit B, indocyanine green, fluorescent inactivated herpes simplex 2, and Fluoro-Gold. Direct visualization techniques have a simpler FDA approval process; examples include optical coherence tomography, multiphoton microscopy, ultrasound, coherent anti-Stokes Raman scattering. Many researchers are developing several novel technologies that can be categorized as stimulation based, dye-based, or direct visualization. As of yet, none has shown clear evidence to improve surgical outcomes and consequently lack wide adoption. Further development of these technologies may lead to improved complication rates after prostatectomies. Clinically, some technologies have demonstrated utility in predicting the development of complications. By using that information, more aggressive rehabilitation programs may lead to improved long-term function. These technologies can also be applied for research to improve our knowledge of the neuroanatomy and physiology of erection and incontinence.

Torsion of the left ventricle during pacing with MRI tagging.

The effects of different pacing protocols on left ventricular (LV) torsion were evaluated over the full cardiac cycle. A systolic and diastolic series of magnetic resonance imaging (MRI) scans were combined and used to calculate the torsion of the LV in a canine model. The asynchronous activation resulting from ventricular pacing interferes with the temporal evolution of LV torsion. The torsion of the left ventricle was investigated under three different protocols: 1) right atrial pacing, 2) right ventricular pacing, and 3) simultaneous pacing from the right ventricular apex and LV base. The temporal evolution of torsion was determined from tagged MRI and evaluated over the cardiac cycle. The peak rotation for the atrially paced hearts was 11.1 degrees (+/- 3.5 degrees) compared to 6.1 degrees (+/- 1.7 degrees) and 6.1 degrees (+/- 0.7 degree) for those hearts paced from the right ventricle and from both ventricles, respectively. While biventricular pacing increases the synchrony of contraction, it significantly alters the pattern of LV torsion. From these experiments we have shown that measuring torsion is an extremely sensitive indicator of the existence of ectopic excitation.

Catheter-based endomyocardial injection with real-time magnetic resonance imaging.

BACKGROUND: We tested the feasibility of targeted left ventricular (LV) mural injection using real-time MRI (rtMRI). METHODS AND RESULTS: A 1.5T MRI scanner was customized with a fast reconstruction engine, transfemoral guiding catheter-receiver coil (GCC), MRI-compatible needle, and tableside consoles. Commercial real-time imaging software was customized to facilitate catheter navigation and visualization of injections at 4 completely refreshed frames per second. The aorta was traversed and the left ventricular cavity was entered under direct rtMRI guidance. Pigs underwent multiple injections with dilute gadolinium-DTPA. All myocardial segments were readily accessed. The active GCC and the passive Stiletto needle injector were readily visualized. More than 50 endomyocardial injections were performed with the aid of rtMRI; 81% were successful with this first-generation prototype. CONCLUSION: Percutaneous endomyocardial drug delivery is feasible with the aid of rtMRI, which permits precise 3-dimensional localization of injection within the LV wall.

Real-time volume rendered MRI for interventional guidance.

Volume renderings from magnetic resonance imaging data can be created and displayed in real-time with user interactivity. This can provide continuous 3D feedback to assist in guiding an interventional procedure. A system is presented which can produce real-time volume renderings from 2D multi-slice or 3D MR pulse sequences. Imaging frame rates up to 30 per second have been demonstrated with a latency of approximately one-third of a second, depending on the image matrix size. Several interactive capabilities have been implemented to enhance visualization such as cut planes, individual channel scaling and color highlighting, view sharing, saturation preparation, complex subtraction, gating control, and choice of alpha blending or MIP rendering. The system is described and some interventional application examples are shown. To view movies of some of the examples, enter the following address into a web browser: http://nhlbi.nih.gov/labs/papers/lce/guttman/rtvolmri/index/htm.