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... Show morePurpose 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 (R). 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. Show less
The introduction of the tethered DROP-IN gamma probe has enabled targeted robot-assisted radioguided prostate cancer (PCa) resection of pelvic sentinel lymph nodes (SLNs) and prostate-specific... Show moreThe introduction of the tethered DROP-IN gamma probe has enabled targeted robot-assisted radioguided prostate cancer (PCa) resection of pelvic sentinel lymph nodes (SLNs) and prostate-specific membrane antigen (PSMA)-positive lesions. While both procedures use Tc-99m-isotopes, the two vary in signal and background intensity. To understand how the different levels of image guidance impact surgical decision-making, computer-vision algorithms are used to extract the DROP-IN probe kinematic form clinical videos. 44 PCa patients undergo SLN (25) and PSMA-targeted (19) resections. PSMA-PET/CT and SPECT/CT create preoperative roadmaps, and intraoperative probe signal intensities are recorded. Using neural network-based software, probe trajectories are extracted from videos to extract multiparametric kinematics and generate decision-making and dexterity scores. PSMA-targeted resections yield significantly lower nodal signal intensities in preoperative SPECT-CT scans (three-fold; p = 0.01), intraoperative probe readouts (eight-fold; p < 0.001), and signal-to-background ratios (SBR; two-fold; p < 0.001). Kinematics assessment reveal that the challenges encounter during PSMA-targeted procedures converted to longer target identification times and increase in probe pick-ups (both five-fold; p < 0.001). This results in a fourfold reduction in the decision-making score (p < 0.001). Reduced signal intensities and intraoperative SBR values negatively affect the impact that image-guided surgery strategies have on the surgical decision-making process. Show less
Background: The occurrence of accidental nerve damage during surgery and the increasing application of image guidance during head-and-neck surgery have highlighted the need for molecular targeted... Show moreBackground: The occurrence of accidental nerve damage during surgery and the increasing application of image guidance during head-and-neck surgery have highlighted the need for molecular targeted nerve-sparing interventions. The implementation of such interventions relies on the availability of nerve-specific tracers. In this paper, we describe the development of a truncated peptide that has an optimized affinity for protein zero (P0), the most abundant protein in myelin. Methods and Materials: Further C- and N-terminal truncation was performed on the lead peptide Cy5-P0(101-125). The resulting nine Cy5-labelled peptides were characterized based on their photophysical properties, P0 affinity, and in vitro staining. These characterizations were combined with evaluation of the crystal structure of P0, which resulted in the selection of the optimized tracer Cy5-P0(112-125). A near-infrared Cy7-functionalized derivative (Cy7-P0(112-125)) was used to perform an initial evaluation of fluorescence-guided surgery in a porcine model. Results: Methodological truncation of the 26-amino-acid lead compound Cy5-P0(101-125) resulted in a size reduction of 53.8% for the optimized peptide Cy5-P0(112-125). The peptide design and the 1.5-fold affinity gain obtained after truncation could be linked to interactions observed in the crystal structure of the extracellular portion of P0. The near-infrared analogue Cy7-P0(112-125) supported nerve illumination during fluorescence-guided surgery in the head-and-neck region in a porcine model. Conclusions: Methodological truncation yielded a second-generation P0-specific peptide. Initial surgical evaluation suggests that the peptide can support molecular targeted nerve imaging. Show less
BackgroundLymph node (LN) metastasis is a relevant predictor for survival in patients with a.o. penile cancer (PeCa), malignant melanoma. The sentinel node (SN) procedure comprises targeted... Show moreBackgroundLymph node (LN) metastasis is a relevant predictor for survival in patients with a.o. penile cancer (PeCa), malignant melanoma. The sentinel node (SN) procedure comprises targeted resection of the first tumour-draining SNs. Here, the hybrid tracer indocyanine green (ICG)-Tc-99m-nanocolloid has been used for several years to combine optical and nuclear detection. Recently, the resource of the nanocolloid precursor stopped production and the precursor was replaced by a different but chemically comparable colloid, nanoscan. Our aim was to study the performance of ICG-Tc-99m-nanoscan compared to ICG-Tc-99m-nanocolloid from a nuclear and surgical perspective.MethodsTwenty-four patients with either PeCa or head-and-neck (H&N) melanoma and scheduled for a SN procedure were included. The initial group (n = 11) received ICG-Tc-99m-nanocolloid until no longer available; the second group (n = 13) received ICG-Tc-99m-nanoscan. Tracer uptake was assessed on lymphoscintigraphy and single-photon emission (SPECT). Intraoperatively, SNs were identified using gamma tracing and fluorescence imaging. Ex vivo (back-table) measurements were conducted to quantify the fluorescence emissions. Chemical analysis was performed to compare the ICG assembly on both precursors.ResultsThe mean tracer uptake in the SNs was similar for ICG-Tc-99m-nanocolloid (2.2 +/- 4.3%ID) and ICG-Tc-99m-nanoscan (1.8 +/- 2.6%ID; p = 0.68). 3 SNs (interquartile range (IQR) 3-4) were detected on lymphoscintigraphy in PeCa patients receiving ICG-Tc-99m-nanoscan compared to 2 SNs (IQR 2-3) in PeCa patients receiving ICG-Tc-99m-nanocolloid (p = 0.045), no differences were observed in H&N patients. Back-table measurements of resected SNs revealed a lower total fluorescence intensity in the ICG-Tc-99m-nanoscan group (24*10(9) arbitrary units (A.U) IQR 1.6*10(9)-14*10(9) in the ICG-Tc-99m-nanocolloid group versus 4.6*10(9) A.U. IQR 2.4*10(9)-42*10(9) in the ICG-Tc-99m-nanoscan group, p = 0.0054). This was consistent with a larger degree of "stacked" ICG observed in the nanoscan formulation. No tracer-related adverse events were reported.ConclusionsBased on this retrospective analysis, we can conclude that ICG-Tc-99m-nanoscan has similar capacity for SN identification as ICG-Tc-99m-nanocolloid and can safely be implemented in SN procedures. Show less
Aims: Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and... Show moreAims: Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and implant retention (DAIR) surgery aimed at cleaning the infected prosthesis often fails, subsequently requiring invasive revision of the complete prosthetic reconstruction. Infection-specific imaging may help to guide DAIR. In this study, we evaluated a bacteria -specific hybrid tracer (99mTc-UBI29-41-Cy5) and its ability to visualize the bacterial load on fem-oral implants using clinical -grade image guidance methods. Methods: 99mTc-UBI29-41- Cy5 specificity for Stapylococcus aureus was assessed in vitro using fluorescence confocal imaging. Topical administration was used to highlight the location of S. aureus cul-tured on femoral prostheses using fluorescence imaging and freehand single photon emis-sion CT (fhSPECT) scans. Gamma counting and fhSPECT were used to quantify the bacterial load and monitor cleaning with chlorhexidine. Microbiological culturing helped to relate the imaging findings with the number of (remaining) bacteria. Results: Bacteria could be effectively stained in vitro and on prostheses, irrespective of the presence of biofilm. Infected prostheses revealed bacterial presence on the transition zone between the head and neck, and in the screw hole. Qualitative 2D fluorescence images could be com-plemented with quantitative 3D fhSPECT scans. Despite thorough chlorhexidine treatments, 28% to 44% of the signal remained present in the locations of the infection that were iden-tified using imaging, which included 500 to 2,000 viable bacteria.Conclusion: The hybrid tracer99mTc-UBI29-41-Cy5 allowed effective bacterial staining. Qualitative real -time fluorescence guidance could be effectively combined with nuclear imaging that enables quantitative monitoring of the effectiveness of cleaning strategies. Show less
Aims Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and... Show moreAims Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and implant retention (DAIR) surgery aimed at cleaning the infected prosthesis often fails, subsequently requiring invasive revision of the complete prosthetic reconstruction. Infection-specific imaging may help to guide DAIR. In this study, we evaluated a bacteria -specific hybrid tracer (99mTc-UBI29-41-Cy5) and its ability to visualize the bacterial load on fem-oral implants using clinical -grade image guidance methods.Methods 99mTc-UBI29-41- Cy5 specificity for Stapylococcus aureus was assessed in vitro using fluorescence confocal imaging. Topical administration was used to highlight the location of S. aureus cul-tured on femoral prostheses using fluorescence imaging and freehand single photon emis-sion CT (fhSPECT) scans. Gamma counting and fhSPECT were used to quantify the bacterial load and monitor cleaning with chlorhexidine. Microbiological culturing helped to relate the imaging findings with the number of (remaining) bacteria.Results Bacteria could be effectively stained in vitro and on prostheses, irrespective of the presence of biofilm. Infected prostheses revealed bacterial presence on the transition zone between the head and neck, and in the screw hole. Qualitative 2D fluorescence images could be com-plemented with quantitative 3D fhSPECT scans. Despite thorough chlorhexidine treatments, 28% to 44% of the signal remained present in the locations of the infection that were iden-tified using imaging, which included 500 to 2,000 viable bacteria.Conclusion The hybrid tracer99mTc-UBI29-41-Cy5 allowed effective bacterial staining. Qualitative real -time fluorescence guidance could be effectively combined with nuclear imaging that enables quantitative monitoring of the effectiveness of cleaning strategies. Show less
Berrens, A.C.; Oosterom, M.N. van; Slof, L.J.; Leeuwen, F.W.B. van; Poel, H.G. van der; Buckle, T. 2022
Antibodies can prevent malaria by neutralizing the infectious Plasmodium falciparum sporozoites (SPZ) before they establish an infection in the liver. Circumsporozoite protein (CSP), the most... Show moreAntibodies can prevent malaria by neutralizing the infectious Plasmodium falciparum sporozoites (SPZ) before they establish an infection in the liver. Circumsporozoite protein (CSP), the most abundant surface protein of SPZ is the leading candidate for passive (and subunit) immunization approaches against malaria. Comprehensive assessment of the parasite-inhibitory capacity of anti-CSP monoclonal antibodies (mAbs) is an important step in advancing CSP-based immunization strategies. In this study, we employed a quantitative imaging-based motility assay to quantify the effect of anti-CSP mAbs on SPZ motility, both in vitro and in human skin. Our assay provided a quantitative measure of mAb parasite-inhibitory capacity through measurement of the half-maximal motility inhibitory concentration (IC50M) value for anti-CSP mAbs (IC50M 2A10: 24 nM, IC50M 3SP2: 71 nM). We found a sevenfold discrepancy between the IC50M and the binding saturation concentration measured by ELISA, possibly related to the observed shedding of CSP-mAb complexes during SPZ movement. In a subset of SPZ (5%), in vitro motility was unaffected by the presence of 2A10 while 3SP2 was able to completely block movement. In our ex vivo skin explant model, SPZ proved less susceptible to anti-CSP mAbs compared to SPZ in an in vitro environment. By quantitatively assessing motility, we created a valuable tool that can be used for comprehensive assessment of anti-CSP mAb potency. Insight that will help deepen our understanding of anti-CSP mAb potency and guide selection of the most promising anti-CSP mAbs for downstream clinical development. Show less
Background: Extended pelvic nodal dissection (ePLND) represents the gold standard for nodal staging in prostate cancer (PCa). Prostate-specific membrane antigen (PSMA) radioguided surgery (RGS)... Show moreBackground: Extended pelvic nodal dissection (ePLND) represents the gold standard for nodal staging in prostate cancer (PCa). Prostate-specific membrane antigen (PSMA) radioguided surgery (RGS) could identify lymph node invasion (LNI) during robotassisted radical prostatectomy (RARP).Objective: To report the planned interim analyses of a phase 2 prospective study (NCT04832958) aimed at describing PSMA-RGS during RARP.Design, setting, and participants: A phase 2 trial aimed at enrolling 100 patients with intermediate- or high-risk cN0cM0 PCa at conventional imaging with a risk of LNI of >5% was conducted. Overall, 18 patients were enrolled between June 2021 and March 2022. Among them, 12 patients underwent PSMA-RGS and represented the study cohort.Surgical procedure: All patients received Ga-68-PSMA positron emission tomography (PET)/magnetic resonance imaging; Tc-99m-PSMA-I&S was synthesised and administered intravenously the day before surgery, followed by single-photon emission computed tomography/computed tomography. A Drop-In gamma probe was used for in vivo measurements. All positive lesions (count rate >= 2 compared with background) were excised and ePLND was performed.Measurements: Side effects, perioperative outcomes, and performance characteristics of robot-assisted PSMA-RGS for LNI were measured.Results and limitations: Overall, four (33%), six (50%), and two (17%) patients had intermediate-risk, high-risk, and locally advanced PCa. Overall, two (17%) patients had pathologic nodal uptake at PSMA PET. The median operative time, blood loss, and length of stay were 230 min, 100 ml, and 5 d, respectively. No adverse events and intraoperative complications were recorded. One patient experienced a 30-d complication (ClavienDindo 2; 8.3%). Overall, three (25%) patients had LNI at ePLND. At per-region analyses on 96 nodal areas, sensitivity, specificity, positive predictive value, and negative predictive value of PSMA-RGS were 63%, 99%, 83%, and 96%, respectively. On a per-patient level, sensitivity, specificity, positive predictive value, and negative predictive values of PSMA-RGS were 67%, 100%, 100%, and 90%, respectively.Conclusions: Robot-assisted PSMA-RGS in primary staging is a safe and feasible procedure characterised by acceptable specificity but suboptimal sensitivity, missing micrometastatic nodal disease.Patient summary: Prostate-specific membrane antigen radioguided robot-assisted surgery is a safe and feasible procedure for the intraoperative identification of nodal metastases in cN0cM0 prostate cancer patients undergoing robot-assisted radical prostatectomy with extended pelvic lymph node dissection. However, this approach might still miss micrometastatic nodal dissemination. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. Show less
Boekestijn, I.; Oosterom, M.N. van; Dell'Oglio, P.; Velden, F.H.P. van; Pool, M.; Maurer, T.; ... ; Leeuwen, F.W.B. van 2022
Molecular imaging technologies are increasingly used to diagnose, monitor, and guide treatment of i.e., cancer. In this review, the current status and future prospects of the use of molecular... Show moreMolecular imaging technologies are increasingly used to diagnose, monitor, and guide treatment of i.e., cancer. In this review, the current status and future prospects of the use of molecular imaging as an instrument to help realize precision surgery is addressed with focus on the main components that form the conceptual basis of intraoperative molecular imaging. Paramount for successful interventions is the relevance and accessibility of surgical targets. In addition, selection of the correct combination of imaging agents and modalities is critical to visualize both microscopic and bulk disease sites with high affinity and specificity. In this context developments within engineering/imaging physics continue to drive the growth of image-guided surgery. Particularly important herein is enhancement of sensitivity through improved contrast and spatial resolution, features that are critical if sites of cancer involvement are not to be overlooked during surgery. By facilitating the connection between surgical planning and surgical execution, digital surgery technologies such as computer-aided visualization nicely complement these technologies. The complexity of image guidance, combined with the plurality of technologies that are becoming available, also drives the need for evaluation mechanisms that can objectively score the impact that technologies exert on the performance of healthcare professionals and outcome improvement for patients. Show less
Purpose Navigational strategies create a scenario whereby percutaneous needle-based interventions of the liver can be guided using both pre-interventional 3D imaging datasets and dynamic... Show morePurpose Navigational strategies create a scenario whereby percutaneous needle-based interventions of the liver can be guided using both pre-interventional 3D imaging datasets and dynamic interventional ultrasound (US). To score how such technologies impact the needle placement process, we performed kinematic analysis on different user groups. Methods Using a custom biopsy phantom, three consecutive exercises were performed by both novices and experts (n = 26). The exercise came in three options: (1) US-guidance, (2) US-guidance with pre-interventional image-registration (US + Reg) and (3) US-guidance with pre-interventional image-registration and needle-navigation (US + Reg + Nav). The traveled paths of the needle were digitized in 3D. Using custom software algorithms, kinematic metrics were extracted and related to dexterity, decision making indices to obtain overall performance scores (PS). Results Kinematic analysis helped quantifying the visual assessment of the needle trajectories. Compared to US-guidance, novices yielded most improvements using Reg (PSavg(US) = 0.43 vs. PSavg(US+Reg) = 0.57 vs. PSavg(US+Reg+Nav) = 0.51). Interestingly, the expert group yielded a reversed trend (PSavg(US) = 0.71 vs PSavg(US+Reg) = 0.58 vs PSavg(US+Reg+Nav) = 0.59). Conclusion Digitizing the movement trajectory allowed us to objectively assess the impact of needle-navigation strategies on percutaneous procedures. In particular, our findings suggest that these advanced technologies have a positive impact on the kinematics derived performance of novices. Show less
Purpose Navigational strategies create a scenario whereby percutaneous needle-based interventions of the liver can be guided using both pre-interventional 3D imaging datasets and dynamic... Show morePurpose Navigational strategies create a scenario whereby percutaneous needle-based interventions of the liver can be guided using both pre-interventional 3D imaging datasets and dynamic interventional ultrasound (US). To score how such technologies impact the needle placement process, we performed kinematic analysis on different user groups. Methods Using a custom biopsy phantom, three consecutive exercises were performed by both novices and experts (n = 26). The exercise came in three options: (1) US-guidance, (2) US-guidance with pre-interventional image-registration (US + Reg) and (3) US-guidance with pre-interventional image-registration and needle-navigation (US + Reg + Nav). The traveled paths of the needle were digitized in 3D. Using custom software algorithms, kinematic metrics were extracted and related to dexterity, decision making indices to obtain overall performance scores (PS). Results Kinematic analysis helped quantifying the visual assessment of the needle trajectories. Compared to US-guidance, novices yielded most improvements using Reg (PSavg(US) = 0.43 vs. PSavg(US+Reg) = 0.57 vs. PSavg(US+Reg+Nav) = 0.51). Interestingly, the expert group yielded a reversed trend (PSavg(US) = 0.71 vs PSavg(US+Reg) = 0.58 vs PSavg(US+Reg+Nav) = 0.59). Conclusion Digitizing the movement trajectory allowed us to objectively assess the impact of needle-navigation strategies on percutaneous procedures. In particular, our findings suggest that these advanced technologies have a positive impact on the kinematics derived performance of novices. Show less
Azargoshasb, S.; Boekestijn, I.; Roestenberg, M.; KleinJan, G.H.; Hage, J.A. van der; Poel, H.G. van der; ... ; Leeuwen, F.W.B. van 2022
Purpose Surgical fluorescence guidance has gained popularity in various settings, e.g., minimally invasive robot-assisted laparoscopic surgery. In pursuit of novel receptor-targeted tracers, the... Show morePurpose Surgical fluorescence guidance has gained popularity in various settings, e.g., minimally invasive robot-assisted laparoscopic surgery. In pursuit of novel receptor-targeted tracers, the field of fluorescence-guided surgery is currently moving toward increasingly lower signal intensities. This highlights the importance of understanding the impact of low fluorescence intensities on clinical decision making. This study uses kinematics to investigate the impact of signal-to-background ratios (SBR) on surgical performance.Methods Using a custom grid exercise containing hidden fluorescent targets, a da Vinci Xi robot with Firefly fluorescence endoscope and ProGrasp and Maryland forceps instruments, we studied how the participants' (N=16) actions were influenced by the fluorescent SBR. To monitor the surgeon's actions, the surgical instrument tip was tracked using a custom video-based tracking framework. The digitized instrument tracks were then subjected to multi-parametric kinematic analysis, allowing for the isolation of various metrics (e.g., velocity, jerkiness, tortuosity). These were incorporated in scores for dexterity (Dx), decision making (DM), overall performance (PS) and proficiency. All were related to the SBR values.Results Multi-parametric analysis showed that task completion time, time spent in fluorescence-imaging mode and total pathlength are metrics that are directly related to the SBR. Below SBR 1.5, these values substantially increased, and handling errors became more frequent. The difference in Dx and DM between the targets that gave SBR <1.50 and SBR> 1.50, indicates that the latter group generally yields a 2.5-fold higher Dx value and a threefold higher DM value. As these values provide the basis for the PS score, proficiency could only be achieved at SBR> 1.55.Conclusion By tracking the surgical instruments we were able to, for the first time, quantitatively and objectively assess how the instrument positioning is impacted by fluorescent SBR. Our findings suggest that in ideal situations a minimum SBR of 1.5 is required to discriminate fluorescent lesions, a substantially lower value than the SBR 2 often reported in literature. Show less
Background: It has been proven that intraoperative prostate-specific membrane antigen (PSMA)-targeted radioguidance is valuable for the detection of prostate cancer (PCa) lesions during open... Show moreBackground: It has been proven that intraoperative prostate-specific membrane antigen (PSMA)-targeted radioguidance is valuable for the detection of prostate cancer (PCa) lesions during open surgery. Rapid extension of robot-assisted, minimally invasive surgery has increased the need to make PSMA-radioguided surgery (RGS) robot-compliant.Objective: To evaluate whether the miniaturized DROP-IN gamma probe facilitates translation of PSMA-RGS to robotic surgery in men with recurrent PCa.Design, setting, and participants: This prospective feasibility study included 20 patients with up to three pelvic PCa recurrences (nodal or local) on staging PSMA positron emission tomography (PET) after previous curative-intent therapy.Surgical procedure: Robot-assisted PSMA-RGS using the DROP-IN gamma probe was carried out 19-23 h after intravenous injection of (99m)technetium PSMA-Investigation & Surgery (Tc-99m-PSMA-I&S).Measurements: The primary endpoint was the feasibility of robot-assisted PSMA-RGS. Secondary endpoints were a comparison of the radioactive status (positive or negative) of resected specimens and final histopathology results, prostate-specific antigen (PSA) response following PSMA-RGS, and complications according to the Clavien-Dindo classification.Results and limitations: Using the DROP-IN probe, 19/21 (90%) PSMA-avid lesions could be resected robotically. On a per-lesion basis, the sensitivity and specificity of robot-assisted PSMA-RGS was 86% and 100%, respectively. A prostate-specific antigen (PSA) reduction of >50% and a complete biochemical response (PSA <0.2 ng/ml) were seen in 12/18 (67%) and 4/18 (22%) patients, respectively. During follow-up of up to 15 mo,* Corresponding author. Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands. Tel. +31 205126988. E-mail address: h.d.barros@nki.nl (H.A. de Barros) Show less
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... Show moreFluorescence 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 x 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. Show less
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... Show moreBackground: 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 (Tc-99m-EuK-(SO3)Cy5-mas(3)) 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: T-50% blood and T-50% 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-mas(3) 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). Show less
The objective of this study was to evaluate the safety and feasibility of 99mTc-based prostate-specific membrane antigen (PSMA) robot-assisted–radioguided surgery to aid or improve the... Show moreThe objective of this study was to evaluate the safety and feasibility of 99mTc-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). Methods: 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 68Ga-PSMA PET/CT scanning. Preoperatively, a 99mTc-labeled PSMA ligand (99mTc PSMA I&S; 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. Results: 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 68Ga-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 (n = 5) and ex vivo (n = 5), 90% were micrometastasis (≤3 mm). No complications greater than Clavien–Dindo Grade I occurred. Conclusion: Robot-assisted 99mTc-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 99mTc-based PSMA-radioguided surgery. Show less
In penile squamous cell carcinoma (pSCC), primary surgery aims to obtain oncologically safe margins while minimizing mutilation. Surgical guidance provided by receptor-specific tracers could... Show moreIn penile squamous cell carcinoma (pSCC), primary surgery aims to obtain oncologically safe margins while minimizing mutilation. Surgical guidance provided by receptor-specific tracers could potentially improve margin detection and reduce unnecessary excision of healthy tissue. Here, we present the first results of a prospective feasibility study for real-time intraoperative visualization of pSCC using a fluorescent mesenchymal-epithelial transition factor (c-MET) receptor targeting tracer (EMI-137). Methods: EMI137 tracer performance was initially assessed ex vivo (n = 10) via incubation of freshly excised pSCC in a solution containing EMI137 (500 nM). The in vivo potential of c-MET targeting and intraoperative tumor visualization was assessed after intravenous administration of EMI-137 to 5 pSCC patients scheduled for surgical resection using a cyanine-5 fluorescence camera. Fluorescence imaging results were related to standard pathologic tumor evaluation and c-MET immunohistochemistry. Three of the 5 in vivo patients also underwent a sentinel node resection after local administration of the hybrid tracer indocyanine green- 99mTc-nanocolloid, which could be imaged using a near-infrared fluorescence camera. Results: No tracer-related adverse events were encountered. Both ex vivo and in vivo, EMI-137 enabled c-MET-based tumor visualization in all patients. Histopathologic analyses showed that all pSCCs expressed c-MET, with expression levels of at least 70% in 14 of 15 patients. Moreover, the highest c-MET expression levels were seen on the outside rim of the tumors, and a visual correlation was found between c-MET expression and fluorescence signal intensity. No complications were encountered when combining primary tumor targeting with lymphatic mapping. As such, simultaneous use of cyanine-5 and indocyanine green in the same patient proved to be approach. Show less
Developments within the field of image-guided surgery are ever expanding, driven by collective involvement of clinicians, researchers, and industry. While the general conception of the potential of... Show moreDevelopments within the field of image-guided surgery are ever expanding, driven by collective involvement of clinicians, researchers, and industry. While the general conception of the potential of image-guided surgery is to improve surgical outcome, the specific motives and goals that drive can differ between the different expert groups. To establish the current and future role of intra-operative image guidance within the field of image-guided surgery a Delphi consensus survey was conducted during the 2'd European Congress on Image-guided surgery. This multidisciplinary survey included questions on the conceptual potential and clinical value of image-guided surgery and was aimed at defining specific areas of research and development in the field in order to stimulate further advances towards precision surgery. Obtained results based on questionnaires filled in by 56 panel experts (clinicians: N=30, researchers: N=20 and industry: N=6) were discussed during a dedicated expert discussion session during the conference. The outcome of this Delphi consensus is indicative of the potential improvements offered by image-guided surgery and of the need for further research in this emerging-field, that can be enriched by the identification of reliable molecular targets. Show less
