NHS-POx-loaded patch versus fibrin sealant patch in a porcine robotic liver bleeding model.

BACKGROUND: The management of bleeding is paramount to any surgical procedure. With the increased use of less invasive laparoscopic and robotic methods, achieving hemostasis can be challenging since the surgeons cannot manually apply hemostatic agents directly onto bleeding tissue. In this study, we assessed the use of a pliable hemostatic sealant patch comprising fibrous gelatin carrier impregnated with poly(2-oxazoline) (NHS-POx) for hemostasis in robotic liver resection in a porcine bleeding model. METHODS: The NHS-POx-loaded patch (GATT-Patch), was first evaluated in a Feasibility Study to treat surgical bleeding in 10 lesions, followed by a Comparative Study in which the NHS-POx patch was compared to a standard-of-care fibrin sealant patch (TachoSil), in 36 lesions (superficial, resection, or deep injuries mimicking metastasectomies). For each lesion type, the NHS-POx and fibrin sealant patches were used in an alternating fashion with 18 lesions treated with NHS-POx and 18 with the fibrin patch. Animal preparation and surgical procedures were consistent across studies. The primary outcome was time to hemostasis (TTH) within 3 min for the Feasibility Study and within 5 min for the Comparative Study. RESULTS: In the Feasibility Study, 8 of the 10 NHS-POx-treated lesions achieved hemostasis at 30 s and 3 min. In the Comparative Study, all 18 NHS-POx patch-treated lesions and 9 of the 18 fibrin sealant patch-treated lesions achieved hemostasis at 5 min. Median TTH with NHS-POx vs fibrin sealant patch was 30 vs 300 s (P < 0.001). CONCLUSIONS: In this animal study, hemostasis during robotic liver surgery was achieved faster and more often with the NHS-POx loaded vs fibrin sealant patch.

First robot-assisted radical prostatectomy in a client-owned Bernese mountain dog with prostatic adenocarcinoma.

OBJECTIVE: To describe robot-assisted radical prostatectomy (RARP) and report the short-term outcome of a dog with prostatic cancer treated with RARP. STUDY DESIGN: Case report ANIMALS: Client-owned 6-year-old male-neutered Bernese mountain dog. METHODS: Robot-assisted radical prostatectomy was performed with a daVinci Si Surgical System through a transperitoneal approach. An interfascial nerve-sparing approach was used to preserve the neurovascular bundles and increase the likelihood of postoperative urinary continence. Urinary continence was assessed by placing white cloth bedding in the kennel during hospitalization and by owners' observation at home. RESULTS: The console time was 120 minutes, and the estimated intraoperative blood loss was 30 mL. No intraoperative complications were observed. The urinary catheter was removed after 7 days, at which point the dog urinated normally. Peritoneal carcinomatosis was diagnosed 43 days after surgery, and the dog was euthanized. CONCLUSION: Robot-assisted radical prostatectomy was successfully completed in a dog with prostatic neoplasia and led to postoperative urinary continence. CLINICAL SIGNIFICANCE: This single-case report provides evidence to justify further evaluation of RARP in dogs with prostatic neoplasms.

hHEPATO-Cy5, a Bimodal Tracer for Image-Guided Hepatobiliary Surgery.

Liver cancer is a leading cause of cancer deaths worldwide. Surgical resection of superficial hepatic lesions is increasingly guided by the disrupted bile excretion of the fluorescent dye indocyanine green (ICG). To extend this approach to deeper lesions, a dedicated bimodal tracer that facilitates both fluorescence guidance and radioguidance was developed. Methods: A tracer comprising a methylated cyanine-5 (Cy5) fluorescent dye and a mercaptoacetyltriserine chelate (hHEPATO-Cy5) was synthesized and characterized. Cellular uptake and excretion were evaluated in hepatocyte cultures (2-dimensional culture and in vitro lesion model), using a fluorescent bile salt, MitoTracker dye, and methylated Cy5 as a control. After radiolabeling, the pharmacokinetics of 99mTc-hHEPATO-Cy5 were assessed in mice over 24 h (percentage injected dose and percentage injected dose per gram of tissue, SPECT/CT imaging and fluorescence imaging). The ability to provide real-time fluorescence guidance during robot-assisted hepatobiliary surgery was evaluated in a porcine model using ICG as a reference. Results: The unique molecular signature of hHEPATO-Cy5 promotes hepatobiliary excretion. In vitro studies on hepatocytes showed that where methylated Cy5 remained internalized, hHEPATO-Cy5 showed fast clearance (10 min) similar to that of fluorescent bile salt. In vivo use of 99mTc-hHEPATO-Cy5 in mice revealed liver accumulation and rapid biliary clearance. The effectiveness of bile clearance was best exemplified by the 2-orders-of-magnitude reduction in count rate for the gallbladder (P = 0.008) over time. During hepatobiliary surgery in a porcine model, hHEPATO-Cy5 enabled fluorescence-based lesion identification comparable to that of ICG. Conclusion: The bimodal 99mTc-hHEPATO-Cy5 provides an effective means to identify liver lesions. Uniquely, it helps overcome the shortcomings of fluorescence-only approaches by allowing for an extension to in-depth radioguidance.

Click-on fluorescence detectors: using robotic surgical instruments to characterize molecular tissue aspects.

Fluorescence imaging is increasingly being implemented in surgery. One of the drawbacks of its application is the need to switch back-and-forth between fluorescence- and white-light-imaging settings and not being able to dissect safely under fluorescence guidance. The aim of this study was to engineer 'click-on' fluorescence detectors that transform standard robotic instruments into molecular sensing devices that enable the surgeon to detect near-infrared (NIR) fluorescence in a white-light setting. This NIR-fluorescence detector setup was engineered to be press-fitted onto standard forceps instruments of the da Vinci robot. Following system characterization in a phantom setting (i.e., spectral properties, sensitivity and tissue signal attenuation), the performance with regard to different clinical indocyanine green (ICG) indications (e.g., angiography and lymphatic mapping) was determined via robotic surgery in pigs. To evaluate in-human applicability, the setup was also used for ICG-containing lymph node specimens from robotic prostate cancer surgery. The resulting Click-On device allowed for NIR ICG signal identification down to a concentration of 4.77 × 10-6 mg/ml. The fully assembled system could be introduced through the trocar and grasping, and movement abilities of the instrument were preserved. During surgery, the system allowed for the identification of blood vessels and assessment of vascularization (i.e., bowel, bladder and kidney), as well as localization of pelvic lymph nodes. During human specimen evaluation, it was able to distinguish sentinel from non-sentinel lymph nodes. With this introduction of a NIR-fluorescence Click-On sensing detector, a next step is made towards using surgical instruments in the characterization of molecular tissue aspects.

Feasibility of fluorescence imaging at microdosing using a hybrid PSMA tracer during robot-assisted radical prostatectomy in a large animal model.

BACKGROUND: With the rise of prostate-specific membrane antigen (PSMA) radioguided surgery, which is performed using a microdosing regime, demand for visual target confirmation via fluorescence guidance is growing. While proven very effective for radiotracers, microdosing approaches the detection limit for fluorescence imaging. Thus, utility will be highly dependent on the tracer performance, the sensitivity of the fluorescence camera used, and the degree of background signal. Using a porcine model the ability to perform robot-assisted radical prostatectomy under fluorescence guidance using the bimodal or rather hybrid PSMA tracer (99mTc-EuK-(SO3)Cy5-mas3) was studied, while employing the tracer in a microdosing regime. This was followed by ex vivo evaluation in surgical specimens obtained from prostate cancer patients. RESULTS: T50% blood and T50% urine were reached at 85 min and 390 min, in, respectively, blood and urine. Surgical fluorescence imaging allowed visualization of the prostate gland based on the basal PSMA-expression in porcine prostate. Together, in vivo visualization of the prostate and urinary excretion suggests at least an interval of > 7 h between tracer administration and surgery. Confocal microscopy of excised tissues confirmed tracer uptake in kidney and prostate, which was confirmed with PSMA IHC. No fluorescence was detected in other excised tissues. Tumor identification based on ex vivo fluorescence imaging of human prostate cancer specimens correlated with PSMA IHC. CONCLUSION: Intraoperative PSMA-mediated fluorescence imaging with a microdosing approach was shown to be feasible. Furthermore, EuK-(SO3)Cy5-mas3 allowed tumor identification in human prostate samples, underlining the translational potential of this novel tracer. Trial registration Approval for use of biological material for research purposes was provided by the Translational Research Board of the Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital (NKI-AvL) under reference IRBm19-273 (22/10/2019).

Intraoperative visualization of nerves using a myelin protein-zero specific fluorescent tracer.

BACKGROUND: Surgically induced nerve damage is a common but debilitating side effect in oncological surgery. With the aim to use fluorescence guidance to enable nerve-sparing interventions in future surgery, a fluorescent tracer was developed that specifically targets myelin protein zero (P0). RESULTS: Truncated homotypic P0 protein-based peptide sequences were C-terminally functionalized with the far-red cyanine dye Cy5. The lead compound Cy5-P0101-125 was selected after initial solubility, (photo)physical and in vitro evaluation (including P0-blocking experiments). Cy5-P0101-125 (KD = 105 ± 17 nM) allowed in vitro and ex vivo P0-related staining. Furthermore, Cy5-P0101-125  enabled in vivo fluorescence imaging of the Sciatic nerve in mice after local intravenous (i.v.) administration and showed compatibility with a clinical fluorescence laparoscope during evaluation in a porcine model undergoing robot-assisted surgery. Biodistribution data revealed that i.v. administered [111In]In-DTPA-P0101-125 does not enter the central nervous system (CNS). CONCLUSION: P0101-125 has proven to be a potent nerve-specific agent that is able to target P0/myelin under in vitro, ex vivo, and in vivo conditions without posing a threat for CNS-related toxicity.

Optical Navigation of the Drop-In γ-Probe as a Means to Strengthen the Connection Between Robot-Assisted and Radioguided Surgery.

With translation of the Drop-In γ-probe, radioguidance has advanced into laparoscopic robot-assisted surgery. Global-positioning-system-like navigation can further enhance the symbiosis between nuclear medicine and surgery. Therefore, we developed a fluorescence-video-based tracking method that integrates the Drop-In with navigated robotic surgery. Methods: Fluorescent markers, integrated into the Drop-In, were automatically detected using a daVinci Firefly laparoscope. Subsequently, a declipseSPECT-navigation platform calculated the Drop-In location within the surgical field. Using a phantom (n = 3), we pursued robotic navigation on SPECT/CT, whereas intraoperative feasibility was validated during porcine surgery (n = 4). Results: Video-based tracking allowed for navigation of the Drop-In toward all lesions detected on SPECT/CT (external iliac and common iliac artery regions). Augmented-reality visualization in the surgical console indicated the distance to these lesions in real time, confirmed by the Drop-In readout. Porcine surgery underlined the feasibility of the concept. Conclusion: Optical navigation of the Drop-In probe provides a next step toward connecting nuclear medicine with robotic surgery.

Multi-wavelength fluorescence imaging with a da Vinci Firefly-a technical look behind the scenes.

The field of fluorescence-guided surgery builds on colored fluorescent tracers that have become available for different clinical applications. Combined use of complementary fluorescent emissions can allow visualization of different anatomical structures (e.g. tumor, lymphatics and nerves) in the same patient. With the aim to assess the requirements for multi-color fluorescence guidance under in vivo conditions, we thoroughly characterized two FDA-approved laparoscopic Firefly camera systems available on the da Vinci Si or da Vinci Xi surgical robot. In this process, we studied the cameras' performance with respect to the photophysical properties of the FDA-approved dyes Fluorescein and ICG. Our findings indicate that multi-wavelength fluorescence imaging of Fluorescein and ICG is possible using clinical-grade fluorescence laparoscopes, but critical factors for success include the photophysical dye properties, imaging system performance and the amount of accumulated dye. When comparing the camera performance, the Xi system provided more effective excitation (adaptions in the light source) and higher detection sensitivity (chip-on-a-tip and/or enhanced image processing) for both Fluorescein and ICG. Both systems can readily be used for multi-wavelength fluorescence imaging of Fluorescein and ICG under clinically relevant conditions. With that, another step has been made towards the routine implementation of multi-wavelength image-guided surgery concepts.

A novel hybrid 3D endoscope zooming and repositioning system: Design and feasibility study.

BACKGROUND: Manipulation of the endoscope during minimally invasive surgery is a major source of inconvenience and discomfort. This report elucidates the architecture of a novel one-hand controlled endoscope positioning device and presents a practicability evaluation. METHODS AND MATERIALS: Setup time and total surgery time, number and duration of the manipulations, side effects of three-dimensional (3D) imaging, and ergonomic complaints were assessed by three surgeons during cadaveric and in vivo porcine trials. RESULTS: Setup was accomplished in an average (SD) of 230 (120) seconds. The manipulation time was 3.87 (1.77) seconds for angular movements and 0.83 (0.24) seconds for zooming, with an average (SD) of 30.5 (16.3) manipulations per procedure. No side effects of 3D imaging or ergonomic complaints were reported. CONCLUSIONS: The integration of an active zoom into a passive endoscope holder delivers a convenient synergy between a human and a machine-controlled holding device. It is shown to be safe, simple, and intuitive to use and allows unrestrained autonomic control of the endoscope by the surgeon.

Multispectral-Fluorescence Imaging as a Tool to Separate Healthy from Disease-Related Lymphatic Anatomy During Robot-Assisted Laparoscopy.

To reduce the invasive nature of extended pelvic lymph node (LN) dissections in prostate cancer, we have developed a multispectral-fluorescence guidance approach that enables discrimination between prostate-draining LNs and lower-limb-draining LNs. Methods: In 5 pigs, multispectral-fluorescence guidance was used on da Vinci Si and da Vinci Xi robots. The animals received fluorescein into the lower limb and indocyanine green-nanocolloid into the prostate. Results: Fluorescein was detected in 29 LNs (average of 3.6 LNs/template), and indocyanine green-nanocolloid was detected in 12 LNs (average of 1.2 LNs/template). Signal intensities appeared equal for both dyes, and no visual overlap in lymphatic drainage patterns was observed. Furthermore, fluorescein supported both the identification of leakage from damaged lymphatic structures and the identification of ureters. Conclusion: We demonstrated that the differences in lymphatic flow pattern between the prostate and lower limbs could be intraoperatively distinguished using multispectral-fluorescence imaging.