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
Korne, C.M. de; Schuijlenburg, R. van; Sijtsma, J.C.; Bes, H.M. de; Baalbergen, E.; Azargoshasb, S.; ... ; Roestenberg, M. 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
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
INTRODUCTION: Nuclear medicine has a crucial role in interventional strategies where a combination between the increasing use of targeted radiotracers and intraprocedural detection modalities... Show moreINTRODUCTION: Nuclear medicine has a crucial role in interventional strategies where a combination between the increasing use of targeted radiotracers and intraprocedural detection modalities enable novel, but often complex, targeted procedures in both the fields of interventional radiology and surgery. 3D navigation approaches could assist the interventional radiologist or surgeon in such complex procedures.EVIDENCE ACQUISITION: This review aimed to provide a comprehensive overview of the current application of computer-assisted navigation strategies based on nuclear imaging to assist in interventional radiology and image-guided surgery. This work starts with a brief overview of the typical navigation workflow from a technical perspective, which is followed by the different clinical applications organized based on their anatomical organ of interest.EVIDENCE SYNTHESIS: Although many studies have proven the feasibility of PET- and SPECT-based navigation strategies for various clinical applications in both interventional radiology and surgery, the strategies are spread widely in both navigation workflows and clinical indications, evaluated in small patient groups. Hence, no golden standard has yet been established.CONCLUSIONS: Despite that the clinical outcome is yet to be determined in large patient cohorts, navigation seems to be a promising technology to translate nuclear medicine findings, provided by PET- and SPECT-based molecular imaging, to the intervention and operating room. Interventional Nuclear Medicine (iNM) has an exciting future to come using both PET- and SPECT-based navigation. Show less
Azargoshasb, S.; Houwing, K.H.M.; Roos, P.R.; Leeuwen, S.I. van; Boonekamp, M.; Mazzone, E.; ... ; Oosterom, M.N. van 2021
With translation of the Drop-In gamma-probe, radioguidance has advanced into laparoscopic robot-assisted surgery. Global-positioning-system-like navigation can further enhance the symbiosis between... Show moreWith translation of the Drop-In gamma-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. Show less
Purpose Sentinel lymph node biopsy is a routine procedure for nodal staging in penile cancer. Most commonly, this procedure is guided by radioactive tracers, providing various forms of preoperative... Show morePurpose Sentinel lymph node biopsy is a routine procedure for nodal staging in penile cancer. Most commonly, this procedure is guided by radioactive tracers, providing various forms of preoperative and intraoperative guidance. This is further extended with fluorescence imaging using hybrid radioactive-fluorescence tracers. Alternatively, a magnetic-based approach has become available using superparamagnetic iron-oxide nanoparticles (SPIONs). This study investigates a novel freehand magnetic particle imaging and navigation modality (fhMPI) for intraoperative localization, along with a hybrid approach, combining magnetic and fluorescence guidance. Materials and methods The fhMPI set-up was built with a surgical navigation device, optical tracking system and magnetometer probe. A dedicated reconstruction software based on a look-up-table method was used to reconstruct a superficial 3D volume of the SPION distribution in tissue. For fluorescence guidance, indocyanine green (ICG) was added to the SPIONs. The fhMPI modality was characterized in phantoms, ex vivo human skin and in vivo porcine surgery. Results Phantom and human skin explants illustrated that the current fhMPI modality had a sensitivity of 2.2 x 10(-2) mg/mL SPIONs, a resolving power of at least 7 mm and a depth penetration up to 1.5 cm. Evaluation during porcine surgery showed that fhMPI allowed for an augmented reality image overlay of the tracer distribution in tissue, as well as 3D virtual navigation. Besides, using the hybrid approach, fluorescence imaging provided a visual confirmation of localized nodes. Conclusion fhMPI is feasible in vivo, providing 3D imaging and navigation for magnetic nanoparticles in the operating room, expanding the guidance possibilities during magnetic sentinel lymph node procedures. Furthermore, the integration of ICG provides the ability to visually refine and confirm correct localization. Further clinical evaluation should verify these findings in human patients as well. Show less
Azargoshasb, S.; Alphen, S. van; Slof, L.J.; Rosiello, G.; Puliatti, S.; Leeuwen, S.I. van; ... ; Leeuwen, F.W.B. van 2021
Purpose Decision-making and dexterity, features that become increasingly relevant in (robot-assisted) minimally invasive surgery, are considered key components in improving the surgical accuracy.... Show morePurpose Decision-making and dexterity, features that become increasingly relevant in (robot-assisted) minimally invasive surgery, are considered key components in improving the surgical accuracy. Recently, DROP-IN gamma probes were introduced to facilitate radioguided robotic surgery. We now studied if robotic DROP-IN radioguidance can be further improved using tethered Click-On designs that integrate gamma detection onto the robotic instruments themselves. Methods Using computer-assisted drawing software, 3D printing and precision machining, we created a Click-On probe containing two press-fit connections and an additional grasping moiety for a ProGrasp instrument combined with fiducials that could be video tracked using the Firefly laparoscope. Using a dexterity phantom, the duration of the specific tasks and the path traveled could be compared between use of the Click-On or DROP-IN probe. To study the impact on surgical decision-making, we performed a blinded study, in porcine models, wherein surgeons had to identify a hidden Co-57-source using either palpation or Click-On radioguidance. Results When assembled onto a ProGrasp instrument, while preserving grasping function and rotational freedom, the fully functional prototype could be inserted through a 12-mm trocar. In dexterity assessments, the Click-On provided a 40% reduction in movements compared to the DROP-IN, which converted into a reduction in time, path length, and increase in straightness index. Radioguidance also improved decision-making; task-completion rate increased by 60%, procedural time was reduced, and movements became more focused. Conclusion The Click-On gamma probe provides a step toward full integration of radioguidance in minimal invasive surgery. The value of this concept was underlined by its impact on surgical dexterity and decision-making. Show less
Malaria vaccine candidates based on live, attenuated sporozoites have led to high levels of protection. However, their efficacy critically depends on the sporozoites' ability to reach and infect... Show moreMalaria vaccine candidates based on live, attenuated sporozoites have led to high levels of protection. However, their efficacy critically depends on the sporozoites' ability to reach and infect the host liver. Administration via mosquito inoculation is by far the most potent method for inducing immunity but highly impractical. Here, we observed that intradermal syringe-injected Plasmodium berghei sporozoites (syrSPZ) were 3-fold less efficient in migrating to and infecting mouse liver than mosquito-inoculated sporozoites (msqSPZ). This was related to a clustered dermal distribution (2-fold decreased median distance between syrSPZ and msqSPZ) and, more importantly, a 1.4 fold (significantly)-slower and more erratic movement pattern. These erratic movement patterns were likely caused by alteration of dermal tissue morphology (.15 -mm intercellular gaps) due to injection of fluid and may critically decrease sporozoite infectivity. These results suggest that novel microvolume-based administration technologies hold promise for replicating the success of mosquito-inoculated live, attenuated sporozoite vaccines.IMPORTANCE Malaria still causes a major burden on global health and the economy. The efficacy of live, attenuated malaria sporozoites as vaccine candidates critically depends on their ability to migrate to and infect the host liver. This work sheds light on the effect of different administration routes on sporozoite migration. We show that the delivery of sporozoites via mosquito inoculation is more efficient than syringe injection; however, this route of administration is highly impractical for vaccine purposes. Using confocal microscopy and automated imaging software, we demonstrate that syringe-injected sporozoites do cluster, move more slowly, and display more erratic movement due to alterations in tissue morphology. These findings indicate that microneedle-based engineering solutions hold promise for replicating the success of mosquito-inoculated live, attenuated sporozoite vaccines. Show less
