Expressed on virtually all prostate cancers and their metastases, the transmembrane protein prostate-specific membrane antigen (PSMA) provides a valuable target for the imaging of prostate cancer. ...Not only does PSMA provide a target for noninvasive diagnostic imaging, e.g., PSMA-positron emission tomography (PSMA–PET), it can also be used to guide surgical resections of PSMA-positive lesions. The latter characteristic has led to the development of a plethora of PSMA-targeted tracers, i.e., radiolabeled, fluorescent, or hybrid. With image-guided surgery applications in mind, this review discusses these compounds based on clinical need. Here, the focus is on the chemical aspects (e.g., imaging label, spacer moiety, and targeting vector) and their impact on in vitro and in vivo tracer characteristics (e.g., affinity, tumor uptake, and clearance pattern).
Purpose
Radioguided surgery has been widely used for clinical procedures such as sentinel node resections. In the (robot-assisted) laparoscopic setting radioguidance is realized using laparoscopic ...gamma probes, which have limited maneuverability. To increase the rotational freedom, a tethered DROP-IN gamma probe was designed. Here we present the first in vivo feasibility study of this technology in prostate cancer patients.
Methods
Ten patients scheduled for a sentinel node procedure received four injections into the prostate with (indocyanine green-)
99m
Technetium-nanocolloid and underwent preoperative imaging (lymphoscintigraphy and SPECT/CT). The DROP-IN probe was inserted via the assistant port, still permitting the insertion and usage of additional laparoscopic tools.
Results
The sentinel nodes were resected using the
da Vinci
® Si robot under guidance of DROP-IN gamma tracing and fluorescence imaging. The surgeon was able to independently maneuver the DROP-IN probe using the ProGrasp® forceps of the
da Vinci
® robot and distinguish sentinel nodes from background signal (such as the injection site).
Conclusions
Overall the DROP-IN design proves to be a valuable tool for robot-assisted radioguided surgery approaches.
The objective of this study was to evaluate the safety and feasibility of
Tc-based prostate-specific membrane antigen (PSMA) robot-assisted-radioguided surgery to aid or improve the intraoperative ...detection of lymph node metastases during primary robot-assisted radical prostatectomy (RARP) for prostate cancer (PCa).
Men with primary high-risk PCa (≥ cT3a, International Society of Urological Pathology (ISUP) grade group ≥ 3 or prostate-specific antigen of ≥ 15 ng/mL) with potential lymph node metastasis (Briganti nomogram risk > 10% or on preoperative imaging) were enrolled in the study. Patients underwent staging
Ga-PSMA PET/CT scanning. Preoperatively, a
Tc-labeled PSMA ligand (
Tc PSMA I 500 MBq) was administered followed by SPECT/CT. A RARP including extended pelvic lymph node dissection was performed, with intraoperative tracing of PSMA-avid tissues using a prototype DROP-IN γ-probe. Resected specimens were also measured ex vivo. Histopathologic concordance with probe findings was evaluated. A radiotracer count of ≥ 1.5 times the background reference (in vivo), and ≥ 10 (absolute count) in the ex vivo setting, was considered positive.
Twelve patients were included (median age, 68 y, and prostate-specific antigen, 9.15 ng/mL). Most of the patients harbored ISUP 5 PCa (75%) and had avid lymph nodes on preoperative PSMA PET (64%). The DROP-IN probe aided resection of PSMA-avid (out-of-template) lymph nodes and residual disease at the prostate bed. Eleven metastatic lymph nodes were identified by the probe that were not observed on preoperative
Ga-PSMA PET/CT. Of the 74 extraprostatic tissue specimens that were resected, 22 (29.7%) contained PCa. The sensitivity, specificity, positive predictive value, and negative predictive value of inpatient use of the γ-probe were 76% (95% CI, 53%-92%), 69% (95% CI, 55%-81%), 50%, and 88%, respectively. Ex vivo, the diagnostic accuracy was superior: 76% (95% CI, 53%-92%), 96% (95% CI, 87%-99%), 89%, and 91%, respectively, for sensitivity, specificity, positive predictive value, and negative predictive value. Of the missed lymph nodes in vivo (
= 5) and ex vivo (
= 5), 90% were micrometastasis (≤3 mm). No complications greater than Clavien-Dindo Grade I occurred.
Robot-assisted
Tc-based PSMA-radioguided surgery is feasible and safe in the primary setting, optimizing the detection of nodal metastases at the time of RARP and extended pelvic lymph node dissection. Further improvement of the detector technology may optimize the capabilities of robot-assisted
Tc-based PSMA-radioguided surgery.
Abstract Background Integration of molecular imaging and in particular intraoperative image guidance is expected to improve the surgical accuracy of laparoscopic lymph node (LN) dissection. Objective ...To show the applicability of combining preoperative, intraoperative, and postoperative sentinel node imaging using an integrated diagnostic approach based on an imaging agent that is both radioactive and fluorescent. Design, setting, and participants Before surgery, multimodal indocyanine green (ICG)-99m Tc-NanoColl was injected into the prostate. Subsequent lymphoscintigraphy and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging of pelvic nodes was performed to determine the location of the sentinel lymph nodes (SLNs) preoperatively. During the surgical procedure a fluorescence laparoscope, optimized for detection in the near infrared range, was used to visualize the nodes identified on SPECT/CT. Eleven patients scheduled for robot-assisted laparoscopic prostatectomy (RALP) with an increased risk of nodal metastasis, based on Memorial Sloan-Kettering Cancer Center/Kattan nomogram estimation, participated in a pilot assessment (N09IGF). Surgical procedure Patients underwent RALP with LN dissection for prostate cancer. Measurements Radioactive and fluorescent signals were monitored using different modalities, and the correlation between the two types of signals was studied. The location of preoperatively detected SLNs was documented. Results and limitations Preoperatively, SLNs were identified by SPECT/CT, and the multimodal nature of the imaging agent also enabled intraoperative detection via fluorescence imaging. Fluorescence particularly improved surgical guidance in areas with a high radioactive background signal such as the injection site. Ex vivo analysis revealed a strong correlation between the radioactive and fluorescent content in the excised LNs. Fluorescence detection is limited by the severe tissue attenuation of the signal. Therefore, radio guidance to the areas of interest is still desirable. Conclusions Initial data indicate that multimodal ICG-99m Tc-NanoColloid, in combination with a laparoscopic fluorescence laparoscope, can be used to facilitate and optimize dissection of SLNs during RALP procedures.
This work evaluates the possibility of placement of high-resolution imaging and single-cell analysis via laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) within precision ...medicine by assessing the suitability of LA-ICP-MS as a micro-analytical technique for the localization and quantification of membranous receptors in heterogeneous cell samples that express both the membrane-bound receptors C-X-C chemokine receptor type 4 (CXCR4) and epidermal growth factor receptor (EGFR). Staining of the breast cancer cell lines MDA-MB-231 X4 and MDA-MB-468 was achieved using receptor-specific hybrid tracers, containing both a fluorophore and a DTPA single-lanthanide chelate. Prior to LA-ICP-MS imaging, fluorescence confocal microscopy (FCM) imaging was performed to localize the receptors, hereby enabling direct comparison. Based on the different expression levels of CXCR4 and EGFR, a distinction could be made between the cell lines using both imaging modalities. Furthermore, FCM and LA-ICP-MS demonstrated complementary characteristics, as a more distinct discrimination could be made between both cell lines based on the EGFR-targeting hybrid tracer via LA-ICP-MS, due to the intrinsic CXCR4-related green fluorescent protein (GFP) signal present in the MDA-MB-231 X4 cells. Employing state-of-the-art LA-ICP-MS instrumentation in bidirectional area scanning mode for sub-cellular imaging of MDA-MB-231 X4 cells enabled the specific binding of the CXCR4-targeting hybrid tracer to the cell membrane to be clearly demonstrated. The stretching of cells over the glass substrate led to a considerably higher signal response for pixels at the cell edges, relative to the more central pixels. The determination of the expression levels of CXCR4 and EGFR for the MDA-MB-468 cell line was performed using LA-ICP-MS single-cell analysis (sc-LA-ICP-MS) and external calibration, based on the quantitative ablation of Ho-spiked dried gelatin droplet standards. Additionally, a second calibration approach was applied based on spot ablation of highly homogeneous dried gelatin gels in combination with the determination of the ablated volume using atomic force microscopy (AFM) and yielded results which were in good agreement with the expression levels determined via flow cytometry (FC) and mass cytometry (MC). Hybrid tracers enable a direct comparison between (i) FCM and LA-ICP-MS imaging for the evaluation of the microscopic binding pattern and between (ii) FC, MC and sc-LA-ICP-MS for the quantification of receptor expression levels in single cells.
Display omitted
•LA-ICP-MS imaging revealed the membranous location of receptors in cancer cells.•FCM and LA-ICP-MS imaging demonstrated complementary capabilities.•Expression levels of membranous receptors were quantified via sc-LA-ICP-MS.
Purpose
The aim of the current narrative review was to summarize the available evidence in the literature on artificial intelligence (AI) methods that have been applied during robotic surgery.
...Methods
A narrative review of the literature was performed on MEDLINE/Pubmed and Scopus database on the topics of artificial intelligence, autonomous surgery, machine learning, robotic surgery, and surgical navigation, focusing on articles published between January 2015 and June 2019. All available evidences were analyzed and summarized herein after an interactive peer-review process of the panel.
Literature review
The preliminary results of the implementation of AI in clinical setting are encouraging. By providing a readout of the full telemetry and a sophisticated viewing console, robot-assisted surgery can be used to study and refine the application of AI in surgical practice. Machine learning approaches strengthen the feedback regarding surgical skills acquisition, efficiency of the surgical process, surgical guidance and prediction of postoperative outcomes. Tension-sensors on the robotic arms and the integration of augmented reality methods can help enhance the surgical experience and monitor organ movements.
Conclusions
The use of AI in robotic surgery is expected to have a significant impact on future surgical training as well as enhance the surgical experience during a procedure. Both aim to realize precision surgery and thus to increase the quality of the surgical care. Implementation of AI in master–slave robotic surgery may allow for the careful, step-by-step consideration of autonomous robotic surgery.
Abstract Background Sentinel node (SN) biopsy in penile cancer is typically performed using a combination of radiocolloid and blue dye. Recently, the hybrid radioactive and fluorescent tracer ...indocyanine green (ICG)-99m Tc-nanocolloid was developed to combine the beneficial properties of both radio-guidance and fluorescence imaging. Objective To explore the added value of SN biopsy using ICG-99m Tc-nanocolloid in patients with penile carcinoma. Design, setting, and participants Sixty-five patients with penile squamous cell carcinoma were prospectively included (January 2011 to December 2012). Preoperative SN mapping was performed using lymphoscintigraphy and single-proton emission computed tomography supplemented with computed tomography (SPECT/CT) after peritumoural injection of ICG-99m Tc-nanocolloid. During surgery, SNs were initially approached using a gamma probe, followed by patent blue dye and/or fluorescence imaging. A portable gamma camera was used to confirm excision of all SNs. Surgical procedure Patients underwent SN biopsy of the cN0 groin and treatment of the primary tumour. Outcome measurements and statistical analysis The number and location of preoperatively identified SNs were documented. Intraoperative SN identification rates using radio- and/or fluorescence guidance were assessed and compared with blue dye. Statistical evaluation was performed using a two-sample test for equality of proportions with continuity correction. Results and limitations Preoperative imaging after injection of ICG-99m Tc-nanocolloid enabled SN identification in all patients (a total of 183 SNs dispersed over 119 groins). Intraoperatively, all SNs identified by preoperative SN mapping were localised using combined radio-, fluorescence-, and blue dye guidance. Fluorescence imaging enabled visualisation of 96.8% of SNs, while only 55.7% was stained by blue dye ( p < 0.0001). The tissue penetration of the fluorescent signal, and the rapid flow of blue dye limited the detection sensitivity. A tumour-positive SN was found in seven patients. Conclusions ICG-99m Tc-nanocolloid allows for both preoperative SN mapping and combined radio- and fluorescence-guided SN biopsy in penile carcinoma patients and significantly improves optical SN detection compared with blue dye.
Surgically induced nerve damage is a common but debilitating side effect. By developing tracers that specifically target the most abundant protein in peripheral myelin, namely myelin protein zero ...(P0), we intend to support fluorescence-guided nerve-sparing surgery. To that end, we aimed to develop a dimeric tracer that shows a superior affinity for P0.
Following truncation of homotypic P0 protein-based peptide sequences and fluorescence labeling, the lead compound Cy5-P0
was selected. Using a bifunctional fluorescent dye, the dimeric Cy5-(P0
)
was created. Assessment of the performance of the mono- and bi-labeled compounds was based on (photo)physical evaluation. This was followed by in vitro assessment in P0 expressing Schwannoma cell cultures by means of fluorescence confocal imaging (specificity, location of binding) and flow cytometry (binding affinity; K
).
Dimerization resulted in a 1.5-fold increase in affinity compared to the mono-labeled counterpart (70.3 +/- 10.0 nM vs. 104.9 +/- 16.7 nM;
= 0.003) which resulted in a 4-fold increase in staining efficiency in P0 expressing Schwannoma cells. Presence of two targeting vectors also improves a pharmacokinetics of labeled compounds by lowering serum binding and optical stability by preventing dye stacking.
Dimerization of the nerve-targeting peptide P0
proves a valid strategy to improve P0 targeting.
Colon cancer prevention currently relies on colonoscopy using white light to detect and remove polyps, but small and flat polyps are difficult to detect and frequently missed when using this ...technique. Fluorescence colonoscopy combined with a fluorescent probe specific for a polyp biomarker may improve polyp detection. Here we describe GE-137, a water-soluble probe consisting of a 26-amino acid cyclic peptide that binds the human tyrosine kinase c-Met conjugated to a fluorescent cyanine dye. Intravenous administration of GE-137 leads to its accumulation specifically in c-Met-expressing tumors in mice, and it is safe and well tolerated in humans. Fluorescence colonoscopy in patients receiving intravenous GE-137 enabled visualization of all neoplastic polyps that were visible with white light (38), as well as an additional nine polyps that were not visible with white light. This first-in-human pilot study shows that molecular imaging using an intravenous fluorescent agent specific for c-Met is feasible and safe, and that it may enable the detection of polyps missed by other techniques.
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