Publications by authors named "Fijs W B van Leeuwen"

160 Publications

Multicompartment dendrimicelles with binary, ternary and quaternary core composition.

Nanoscale 2021 Sep 23;13(36):15422-15430. Epub 2021 Sep 23.

Laboratory of BioNanoTechnology, Wageningen University & Research, Bornse Weilanden 9, 6708 WG Wageningen, The Netherlands.

Hierarchically built-up multicompartment nanoaggregate systems are of interest for, , novel materials and medicine. Here we present a versatile strategy to generate and unambiguously characterize complex coacervate-core micelles by exploiting four different dendrimeric subcomponents as core-units. The resulting mesoscale structures have a hydrodynamic diameter of 50 nm and a core size of 33 nm, and host about thirty 6th generation polyamidoamine (PAMAM) dendrimers. We have used FRET (efficiency of ∼0.2) between fluorescein and rhodamine moieties immobilized on separate PAMAM dendrimers (G6-F and G6-R, respectively) to prove synchronous encapsulation in the micelle core. Tuning the proximity of the FRET pair molecules either by varying the G6-F : G6-R ratio, or by co-assembling non-functionalized dendrimer (G6-E) in the core, reveals the optimal FRET efficiency to occur at a minimum of 70% loading with G6-F and G6-R. Additional co-encapsulation of 6th generation gold dendrimer-encapsulated nanoparticles (G6-Au) in the micelle core shows a dramatic reduction of the FRET efficiency, which can be restored by chemical etching of the gold nanoparticles from within the micellar core with thiols, leaving the micelle itself intact. This study reveals the controlled co-assembly of up to four different types of subcomponents in one single micellar core and concomitantly shows the wide variety of structures that can be made with a well-defined basic set of subcomponents. It is straightforward to design related strategies, to incorporate inside one micellar core, , even more than 4 different dendrimers, or other classes of (macro)molecules, with different functional groups, other FRET pairs or different encapsulated metal nanoparticles.
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http://dx.doi.org/10.1039/d1nr04556cDOI Listing
September 2021

EANM recommendations based on systematic analysis of small animal radionuclide imaging in inflammatory musculoskeletal diseases.

EJNMMI Res 2021 Sep 6;11(1):85. Epub 2021 Sep 6.

Inflammation and Infection Committee EANM, Vienna, Austria.

Inflammatory musculoskeletal diseases represent a group of chronic and disabling conditions that evolve from a complex interplay between genetic and environmental factors that cause perturbations in innate and adaptive immune responses. Understanding the pathogenesis of inflammatory musculoskeletal diseases is, to a large extent, derived from preclinical and basic research experiments. In vivo molecular imaging enables us to study molecular targets and to measure biochemical processes non-invasively and longitudinally, providing information on disease processes and potential therapeutic strategies, e.g. efficacy of novel therapeutic interventions, which is of complementary value next to ex vivo (post mortem) histopathological analysis and molecular assays. Remarkably, the large body of preclinical imaging studies in inflammatory musculoskeletal disease is in contrast with the limited reports on molecular imaging in clinical practice and clinical guidelines. Therefore, in this EANM-endorsed position paper, we performed a systematic review of the preclinical studies in inflammatory musculoskeletal diseases that involve radionuclide imaging, with a detailed description of the animal models used. From these reflections, we provide recommendations on what future studies in this field should encompass to facilitate a greater impact of radionuclide imaging techniques on the translation to clinical settings.
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http://dx.doi.org/10.1186/s13550-021-00820-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421483PMC
September 2021

Advancing intraoperative magnetic tracing using 3D freehand magnetic particle imaging.

Int J Comput Assist Radiol Surg 2021 Jul 31. Epub 2021 Jul 31.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

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 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 × 10 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.
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http://dx.doi.org/10.1007/s11548-021-02458-2DOI Listing
July 2021

Assessing the value of volume navigation during ultrasound-guided radiofrequency- and microwave-ablations of liver lesions.

Eur J Radiol Open 2021 8;8:100367. Epub 2021 Jul 8.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, the Netherlands.

Purpose: The goal of our study was to determine the influence of ultrasound (US)-coupled volume navigation on the use of computed tomography (CT) during minimally-invasive radiofrequency and microwave ablation procedures of liver lesions.

Method: Twenty-five patients with 40 liver lesions of different histological origin were retrospectively analysed. Lesions were ablated following standard protocol, using 1) conventional US-guidance, 2) manual registered volume navigation (VNav), 3) automatic registered (VNav) or 4) CT-guidance. In case of ultrasonographically inconspicuous lesions, conventional US-guidance was abandoned and VNav was used. If VNav was also unsuccessful, the procedure was either continued with VNav or CT-guidance. The number, size and location of the lesions targeted using the different approaches were documented.

Results: Of the 40 lesions, sixteen (40.0 %) could be targeted with conventional US-guidance only, sixteen (40.0 %) with VNav, three (7.5 %) with VNav and five (12.5 %) only through the use of CT-guidance. Of the three alternatives (VNav, VNav and CT only) the mean size of the lesions targeted using VNav (9.1 ± 4.6 mm) was significantly smaller from those targeted using US-guidance only (20.4 ± 9.4 mm; p < 0.001). The location of the lesions did not influence the selection of the modality used to guide the ablation.

Conclusions: In our cohort, VNav allowed the ablation procedure to become less dependent on the use of CT. VNav supported the ablation of lesions smaller than those that could be ablated with US only and doubled the application of minimally-invasive US-guided ablations.
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http://dx.doi.org/10.1016/j.ejro.2021.100367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273361PMC
July 2021

How molecular imaging will enable robotic precision surgery : The role of artificial intelligence, augmented reality, and navigation.

Eur J Nucl Med Mol Imaging 2021 Jun 29. Epub 2021 Jun 29.

Department of Radiology, Interventional Molecular Imaging Laboratory, Leiden University Medical Center, Leiden, The Netherlands.

Molecular imaging is one of the pillars of precision surgery. Its applications range from early diagnostics to therapy planning, execution, and the accurate assessment of outcomes. In particular, molecular imaging solutions are in high demand in minimally invasive surgical strategies, such as the substantially increasing field of robotic surgery. This review aims at connecting the molecular imaging and nuclear medicine community to the rapidly expanding armory of surgical medical devices. Such devices entail technologies ranging from artificial intelligence and computer-aided visualization technologies (software) to innovative molecular imaging modalities and surgical navigation (hardware). We discuss technologies based on their role at different steps of the surgical workflow, i.e., from surgical decision and planning, over to target localization and excision guidance, all the way to (back table) surgical verification. This provides a glimpse of how innovations from the technology fields can realize an exciting future for the molecular imaging and surgery communities.
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http://dx.doi.org/10.1007/s00259-021-05445-6DOI Listing
June 2021

Translation of c-Met Targeted Image-Guided Surgery Solutions in Oral Cavity Cancer-Initial Proof of Concept Data.

Cancers (Basel) 2021 May 28;13(11). Epub 2021 May 28.

Department of Head and Neck Surgery and Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands.

Intraoperative tumor identification (extension/margins/metastases) via receptor-specific targeting is one of the ultimate promises of fluorescence-guided surgery. The translation of fluorescent tracers that enable tumor visualization forms a critical component in the realization of this approach. Ex vivo assessment of surgical specimens after topical tracer application could help provide an intermediate step between preclinical evaluation and first-in-human trials. Here, the suitability of the c-Met receptor as a potential surgical target in oral cavity cancer was explored via topical ex vivo application of the fluorescent tracer EMI-137. Freshly excised tumor specimens obtained from ten patients with squamous cell carcinoma of the tongue were incubated with EMI-137 and imaged with a clinical-grade Cy5 prototype fluorescence camera. In-house developed image processing software allowed video-rate assessment of the tumor-to-background ratio (TBR). Fluorescence imaging results were related to standard pathological evaluation and c-MET immunohistochemistry. After incubation with EMI-137, 9/10 tumors were fluorescently illuminated. Immunohistochemistry revealed c-Met expression in all ten specimens. Non-visualization could be linked to a more deeply situated lesion. Tumor assessment was improved via video representation of the TBR (median TBR: 2.5 (range 1.8-3.1)). Ex vivo evaluation of tumor specimens suggests that c-Met is a possible candidate for fluorescence-guided surgery in oral cavity cancer.
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http://dx.doi.org/10.3390/cancers13112674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198422PMC
May 2021

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

EJNMMI Res 2021 May 29;11(1):50. Epub 2021 May 29.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.

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-P0 was selected after initial solubility, (photo)physical and in vitro evaluation (including P0-blocking experiments). Cy5-P0 (K = 105 ± 17 nM) allowed in vitro and ex vivo P0-related staining. Furthermore, Cy5-P0  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 [In]In-DTPA-P0 does not enter the central nervous system (CNS).

Conclusion: P0 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.
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http://dx.doi.org/10.1186/s13550-021-00792-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164657PMC
May 2021

The Click-On gamma probe, a second-generation tethered robotic gamma probe that improves dexterity and surgical decision-making.

Eur J Nucl Med Mol Imaging 2021 May 25. Epub 2021 May 25.

Interventional Molecular Imaging-Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.

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. 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-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.
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http://dx.doi.org/10.1007/s00259-021-05387-zDOI Listing
May 2021

c-MET receptor-targeted fluorescence on the road to image-guided surgery in penile squamous cell carcinoma patients.

J Nucl Med 2021 May 14. Epub 2021 May 14.

the Netherlands Cancer Institute, Netherlands.

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 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). EMI-137 tracer performance was initially assessed ex vivo ( = 10) via incubation of freshly excised pSCC in a solution containing EMI-137 (500 nM). The in vivo potential of c-MET targeting and intraoperative tumour visualization was assessed after intravenous administration of EMI-137 in five pSCC patients scheduled for surgical resection using a Cyanine-5 (Cy5) fluorescence camera. Fluorescence imaging results were related to standard pathological tumour evaluation and c-MET immunohistochemistry. Three of the five in vivo patients also underwent a sentinel node resection after local administration of the hybrid tracer indocyanine green (ICG)-Tc-nanocolloid, which could be imaged using a near-infrared fluorescence camera. No tracer-related adverse events were encountered. Both ex vivo and in vivo, EMI-137 enabled c-MET based tumour visualization in all patients. Histopathological analyses showed that all pSCC's expressed c-MET, with expression levels of ≥70% in 14/15 patients. Moreover, the highest c-MET expression levels were seen on the outside rim of the tumours, and a visual correlation was found between c-MET expression and fluorescence signal intensity. No complications were encountered when combining primary tumour targeting with lymphatic mapping. As such, simultaneous use of Cy5 and ICG in the same patient proved to be feasible. Fluorescence imaging of c-MET receptor-expressing pSCC tumours after intravenous injection of EMI-137 was shown to be feasible and can be combined with fluorescence-based lymphatic mapping. This combination is unique and paves the way towards further development of this surgical guidance approach.
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http://dx.doi.org/10.2967/jnumed.120.261864DOI Listing
May 2021

EANM position paper on the role of radiobiology in nuclear medicine.

Eur J Nucl Med Mol Imaging 2021 10 29;48(11):3365-3377. Epub 2021 Apr 29.

Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.

With an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine.
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http://dx.doi.org/10.1007/s00259-021-05345-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440244PMC
October 2021

The Design and Preclinical Evaluation of a Single-Label Bimodal Nanobody Tracer for Image-Guided Surgery.

Biomolecules 2021 02 26;11(3). Epub 2021 Feb 26.

Laboratory for In Vivo Cellular and Molecular Imaging, ICMI-BEFY, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.

Intraoperative guidance using targeted fluorescent tracers can potentially provide surgeons with real-time feedback on the presence of tumor tissue in resection margins. To overcome the limited depth penetration of fluorescent light, combining fluorescence with SPECT/CT imaging and/or gamma-ray tracing has been proposed. Here, we describe the design and preclinical validation of a novel bimodal nanobody-tracer, labeled using a "multifunctional single attachment point" (MSAP) label, integrating a Cy5 fluorophore and a diethylenetriaminepentaacetic acid (DTPA) chelator into a single structure. After conjugation of the bimodal MSAP to primary amines of the anti-HER2 nanobody 2Rs15d and In-labeling of DTPA, the tracer's characteristics were evaluated in vitro. Subsequently, its biodistribution and tumor targeting were assessed by SPECT/CT and fluorescence imaging over 24 h. Finally, the tracer's ability to identify small, disseminated tumor lesions was investigated in mice bearing HER2-overexpressing SKOV3.IP1 peritoneal lesions. [In]In-MSAP.2Rs15d retained its affinity following conjugation and remained stable for 24 h. In vivo SPECT/CT and fluorescence images showed specific uptake in HER2-overexpressing tumors with low background. High tumor-to-muscle ratios were obtained at 1h p.i. and remained 19-fold on SPECT/CT and 3-fold on fluorescence images over 24 h. In the intraperitoneally disseminated model, the tracer allowed detection of larger lesions via nuclear imaging, while fluorescence enabled accurate removal of submillimeter lesions. Bimodal nuclear/fluorescent nanobody-tracers can thus be conveniently designed by conjugation of a single-molecule MSAP-reagent carrying a fluorophore and chelator for radioactive labeling. Such tracers hold promise for clinical applications.
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http://dx.doi.org/10.3390/biom11030360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996797PMC
February 2021

Technologic (R)Evolution Leads to Detection of More Sentinel Nodes in Patients with Melanoma in the Head and Neck Region.

J Nucl Med 2021 Oct 26;62(10):1357-1362. Epub 2021 Feb 26.

Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.

Sentinel lymph node (SN) biopsy (SNB) has proven to be a valuable tool for staging melanoma patients. Since its introduction in the early 1990s, this procedure has undergone several technologic refinements, including the introduction of SPECT/CT, as well as radioguidance and fluorescence guidance. The purpose of the current study was to evaluate the effect of this technologic evolution on SNB in the head and neck region. The primary endpoint was the false-negative (FN) rate. Secondary endpoints were number of harvested SNs, overall operation time, operation time per harvested SN, and postoperative complications. A retrospective database was queried for cutaneous head and neck melanoma patients who underwent SNB at The Netherlands Cancer Institute between 1993 and 2016. The implementation of new detection techniques was divided into 4 groups: 1993-2005, with preoperative lymphoscintigraphy and intraoperative use of both a γ-ray detection probe and patent blue ( = 30); 2006-2007, with addition of preoperative road maps based on SPECT/CT ( = 15); 2008-2009, with intraoperative use of a portable γ-camera ( = 40); and 2010-2016, with addition of near-infrared fluorescence guidance ( = 192). In total, 277 patients were included. At least 1 SN was identified in all patients. A tumor-positive SN was found in 59 patients (21.3%): 10 in group 1 (33.3%), 3 in group 2 (20.0%), 6 in group 3 (15.0%), and 40 in group 4 (20.8%). Regional recurrences in patients with tumor-negative SNs resulted in an overall FN rate of 11.9% (group 1, 16.7%; group 2, 0%; group 3, 14.3%; group 4, 11.1%). The number of harvested nodes increased with advancing technologies ( = 0.003), whereas Breslow thickness and operation time per harvested SN decreased ( = 0.003 and = 0.017, respectively). There was no significant difference in percentage of tumor-positive SNs, overall operation time, and complication rate between the different groups. The use of advanced detection technologies led to a higher number of identified SNs without an increase in overall operation time, possibly indicating an improved surgical efficiency. Operation time per harvested SN decreased; the average FN rate remained 11.9% and was unchanged over 23 y. There was no significant change in postoperative complication rate.
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http://dx.doi.org/10.2967/jnumed.120.246819DOI Listing
October 2021

Cyclodextrin/Adamantane-Mediated Targeting of Inoculated Bacteria in Mice.

Bioconjug Chem 2021 03 23;32(3):607-614. Epub 2021 Feb 23.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands.

Cyclodextrin (CD)-based host-guest interactions with adamantane (Ad) have demonstrated use for functionalizing living cells . The next step in this supramolecular functionalization approach is to explore the concept to deliver chemical cargo to living cells , e.g., inoculated bacteria, in order to study their dissemination. We validated this concept in two rodent models. Bacteria (1 × 10 viable ) were inoculated by (1) intramuscular injection or (2) intrasplenic injection followed by dissemination throughout the liver. The bacteria were prefunctionalized with Tc-UBI-Ad (primary vector), which allowed us to both determine the bacterial load and create an target for the secondary host-vector (24 h post-inoculation). The secondary vector, i.e., chemical cargo delivery system, made use of a In-Cy5CDPIBMA polymer that was administered intravenously. Bacteria-specific cargo delivery as a result of vector complexation was evaluated by dual-isotope SPECT imaging and biodistribution studies (In), and by fluorescence (Cy5); these evaluations were performed 4 h post-injection of the secondary vector. Mice inoculated with nonfunctionalized and mice without an infection served as controls. Dual-isotope SPECT imaging demonstrated that In-Cy5CDPIBMA colocalized with Tc-UBI-Ad-labeled bacteria in both muscle and liver. In inoculated muscle, a 2-fold higher uptake level (3.2 ± 1.0%ID/g) was noted compared to inoculation with nonfunctionalized bacteria (1.9 ± 0.4%ID/g), and a 16-fold higher uptake level compared to noninfected muscle (0.2 ± 0.1%ID/g). The hepatic accumulation of the host-vector was nearly 10-fold higher (27.1 ± 11.1%ID/g) compared to the noninfected control (2.7 ± 0.3%ID/g; < 0.05). Fluorescence imaging of the secondary vector corroborated SPECT-imaging and biodistribution findings. We have demonstrated that supramolecular host-guest complexation can be harnessed to achieve an cargo delivery strategy, using two different bacterial models in soft tissue and liver. This proof-of-principle study paves a path toward developing innovative drug delivery concepts via cell functionalization techniques.
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http://dx.doi.org/10.1021/acs.bioconjchem.1c00061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028042PMC
March 2021

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

J Nucl Med 2021 Sep 8;62(9):1314-1317. Epub 2021 Jan 8.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands;

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. 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 ( = 3), we pursued robotic navigation on SPECT/CT, whereas intraoperative feasibility was validated during porcine surgery ( = 4). 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. Optical navigation of the Drop-In probe provides a next step toward connecting nuclear medicine with robotic surgery.
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http://dx.doi.org/10.2967/jnumed.120.259796DOI Listing
September 2021

Salvage Surgery in Patients with Local Recurrence After Radical Prostatectomy.

Eur Urol 2021 04 11;79(4):537-544. Epub 2020 Dec 11.

Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background: Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, isolated local recurrence after radical prostatectomy (RP) can be delineated accurately.

Objective: To describe and evaluate surgical technique, biochemical response, and therapy-free survival (TFS) after salvage surgery in patients with local recurrence in the seminal vesicle bed.

Design, Setting, And Participants: We retrospectively assessed 40 patients treated with open salvage surgery in two centres (11/2014-02/2020). All patients presented with biochemical recurrence (BCR) after RP with a singular local recurrence at PSMA PET imaging. Thirty-three (82.5%) patients received previous salvage radiation therapy.

Surgical Procedure: Open salvage surgery with PSMA radioguidance.

Measurements: Prostate-specific antigen (PSA) nadir and percentage of patients with complete biochemical response (cBR) without further treatment (PSA < 0.2 ng/ml) after 6-16 wk were assessed. BCR-free survival and TFS were calculated using Kaplan-Meier estimates. Clavien-Dindo complications were evaluated.

Results And Limitations: Prior to salvage surgery, median PSA was 0.9 ng/ml (interquartile range [IQR]: 0.5-1.7 ng/ml). Postoperatively, median PSA nadir was 0.1 ng/ml (IQR: 0-0.4 ng/ml). In 31 (77.5%) patients, cBR was observed. During the median follow-up of 24.4 months, 22 (55.0%) patients experienced BCR and 12 (30.0%) received further therapy. At 1 yr of follow-up, BCR-free survival rate was 62.2% and TFS rate was 88.3%. Three (7.5%) Clavien-Dindo grade III complications were observed. The main limitations are the retrospective design, short follow-up, and lack of a control group.

Conclusions: Salvage surgery of local recurrence within the seminal vesicle bed is feasible. It may present an opportunity in selected, locally recurrent patients to prolong BCR-free survival and increase TFS. Further studies are needed to confirm our findings.

Patient Summary: We looked at the outcomes from prostate cancer patients with locally recurrent disease after radical prostatectomy and radiotherapy. We found that surgery in well-selected patients may be an opportunity to prolong treatment-free survival.
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http://dx.doi.org/10.1016/j.eururo.2020.11.012DOI Listing
April 2021

A DROP-IN Gamma Probe for Robot-assisted Radioguided Surgery of Lymph Nodes During Radical Prostatectomy.

Eur Urol 2021 01 14;79(1):124-132. Epub 2020 Nov 14.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address:

Background: The DROP-IN gamma probe was introduced to overcome the restricted manoeuvrability of traditional laparoscopic gamma probes. Through enhanced manoeuvrability and surgical autonomy, the DROP-IN promotes the implementation of radioguided surgery in the robotic setting.

Objective: To confirm the utility and safety profile of the DROP-IN gamma probe and to perform a comparison with the traditional laparoscopic gamma probe and fluorescence guidance.

Design, Setting, And Participants: Twenty-five prostate cancer patients were scheduled for a robot-assisted sentinel lymph node (SN) procedure, extended pelvic lymph node dissection, and prostatectomy at a single European centre.

Surgical Procedure: After intraprostatic injection of indocyanine green (ICG)-Tc-nanocolloid (n = 12) or Tc-nanocolloid + ICG (n = 13), SN locations were defined using preoperative imaging. Surgical excision of SNs was performed under image guidance using the DROP-IN gamma probe, the traditional laparoscopic gamma probe, and fluorescence imaging.

Measurements: Intraoperative SN detection was assessed for the different modalities and related to anatomical locations. Patient follow-up was included (a median of 18 mo).

Results And Limitations: Overall, 47 SNs were pursued in vivo by the DROP-IN gamma probe, of which 100% were identified. No adverse events related to its use were observed. In vivo fluorescence imaging identified 91% of these SNs. The laparoscopic gamma probe identified only 76% of these SNs, where the detection inaccuracies appeared to be related to specific anatomical regions.

Conclusions: Owing to improved manoeuvrability, the DROP-IN probe yielded improved SN detection rates compared with the traditional gamma probe and fluorescence imaging. These findings underline that the DROP-IN technology provides a valuable tool for radioguided surgery in the robotic setting.

Patient Summary: Radioguided robot-assisted surgery with the novel DROP-IN gamma probe is feasible and safe. It enables more efficient intraoperative identification of sentinel lymph nodes than can be achieved with a traditional laparoscopic gamma probe. The use of the DROP-IN probe in combination with fluorescence imaging allows for a complementary optical confirmation of node localisations.
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http://dx.doi.org/10.1016/j.eururo.2020.10.031DOI Listing
January 2021

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

J Robot Surg 2021 Oct 11;15(5):751-760. Epub 2020 Nov 11.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

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.
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http://dx.doi.org/10.1007/s11701-020-01170-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423683PMC
October 2021

Multi-Wavelength Fluorescence in Image-Guided Surgery, Clinical Feasibility and Future Perspectives.

Mol Imaging 2020 Jan-Dec;19:1536012120962333

Interventional Molecular Imaging Laboratory, Department of Radiology, 4501Leiden University Medical Center, Leiden, The Netherlands.

With the rise of fluorescence-guided surgery, it has become evident that different types of fluorescence signals can provide value in the surgical setting. Hereby a different range of targets have been pursued in a great variety of surgical indications. One of the future challenges lies in combining complementary fluorescent readouts during one and the same surgical procedure, so-called multi-wavelength fluorescence guidance. In this review we summarize the current clinical state-of-the-art in multi-wavelength fluorescence guidance, basic technical concepts, possible future extensions of existing clinical indications and impact that the technology can bring to clinical care.
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http://dx.doi.org/10.1177/1536012120962333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607779PMC
October 2020

Near-infrared fluorescence imaging compared to standard sentinel lymph node detection with blue dye in patients with vulvar cancer - a randomized controlled trial.

Gynecol Oncol 2020 12 8;159(3):672-680. Epub 2020 Oct 8.

Department of Gynecology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Objective: The aim of this study was to assess the superiority of ICG-Tc-nanocolloid for the intraoperative visual detection of sentinel lymph nodes (SLNs) in vulvar squamous cell carcinoma (VSCC) patients compared to standard SLN detection using Tc-nanocolloid with blue dye.

Methods: In this multicenter, randomized controlled trial, VSCC patients underwent either the standard SLN procedure or with the hybrid tracer ICG-Tc-nanocolloid. The primary endpoint was the percentage of fluorescent SLNs compared to blue SLNs. Secondary endpoints were successful SLN procedures, surgical outcomes and postoperative complications.

Results: Forty-eight patients were randomized to the standard (n = 24) or fluorescence imaging group (n = 24) using ICG-Tc-nanocolloid. The percentage of blue SLNs was 65.3% compared to 92.5% fluorescent SLNs (p < 0.001). A successful SLN procedure was obtained in 92.1% of the groins in the standard group and 97.2% of the groins in the fluorescence imaging group (p = 0.33). Groups did not differ in surgical outcome, although more short-term postoperative complications were documented in the standard group (p = 0.041).

Conclusions: Intraoperative visual detection of SLNs in patients with VSCC using ICG-Tc-nanocolloid was superior compared to Tc-nanocolloid and blue dye. The rate of successful SLN procedures between both groups was not significantly different. Fluorescence imaging has potential to be used routinely in the SLN procedure in VSCC patients to facilitate the search by direct visualization.

Clinical Trial Registration: Netherlands Trial Register (Trial ID NL7443).
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http://dx.doi.org/10.1016/j.ygyno.2020.09.044DOI Listing
December 2020

Hybrid Indocyanine Green-Tc-nanocolloid for Single-photon Emission Computed Tomography and Combined Radio- and Fluorescence-guided Sentinel Node Biopsy in Penile Cancer: Results of 740 Inguinal Basins Assessed at a Single Institution.

Eur Urol 2020 12 17;78(6):865-872. Epub 2020 Sep 17.

Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:

Background: Sentinel node (SN) biopsy in penile cancer (PeCa) is typically performed using Tc-nanocolloid and blue dye. Recent reports suggested that the hybrid (radioactive and fluorescent) tracer indocyanine green (ICG)-Tc-nanocolloid may improve intraoperative optical SN identification.

Objective: The current study aimed to confirm the reliability of ICG-Tc-nanocolloid and to assess whether blue dye is still of added value.

Design, Setting, And Participants: A total of 400 ≥T1G2N0 PeCa patients were staged with SN biopsy at a single European centre. SNs were preoperatively identified with lymphoscintigraphy and single-photon emission computed tomography. Intraoperatively, SNs were detected via gamma tracing, blue staining, and fluorescence imaging.

Outcome Measurements And Statistical Analysis: All patients (n=400, 740 groins) received ICG-Tc-nanocolloid. Intraoperative SN identification rates were retrospectively evaluated. In those patients who received ICG-Tc-nanocolloid and blue dye (n=266, 492 groins), SN visualisation rates were compared using the McNemar test.

Results And Limitations: In total, 740 groins were assessed. No tracer-related (allergic) reactions were reported. All preoperatively defined SNs (n=1163) were localised intraoperatively. Of all excised SNs, 98% were detectable with gamma probe and 96% were visible with fluorescence imaging. In the analysis of the patients who received ICG-Tc-nanocolloid and blue dye, fluorescence imaging yielded a 39% higher SN detection rate than blue dye (95% confidence interval 36-43%, p<0.001). Of the SNs that were tumour positive, 100% were intraoperatively visualised by fluorescence imaging, whereas merely 84% of the positive nodes stained blue.

Conclusions: This study confirms that ICG-Tc-nanocolloid is a reliable SN tracer for PeCa that significantly improves optical SN detection over blue dye.

Patient Summary: Hybrid indocyanine green (ICG)-Tc-nanocolloid is a safe and reliable sentinel node (SN) tracer, as established in this large series of 400 penile cancer patients (740 groins). It enables accurate pre- and intraoperative SN identification and significantly improves SN detection rate compared with blue dye, without staining the surgical field or the need for an additional injection.
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http://dx.doi.org/10.1016/j.eururo.2020.09.007DOI Listing
December 2020

Head-to-head comparison of the hybrid tracer indocyanine green-99mTc-nanocolloid with 99mTc-Senti-Scint using sentinel node lymphoscintigraphy and single-photon emission computed tomography combined with computer tomography in melanoma.

Nucl Med Commun 2020 Oct;41(10):1010-1017

Surgical Oncology, Netherlands Cancer Institute, Amsterdam.

Objective: The hybrid tracer indocyanine green (ICG)-Tc-nanocolloid has been introduced for sentinel node imaging. However, until now, a comparison of this tracer with other radiocolloids with a larger particle size has not been effectuated. Based on a head-to-head evaluation in patients with melanoma, we have compared ICG-Tc-nanocolloid (particle size 5-80 nm) with Tc-Senti-Scint (particle size 100-600 nm) to establish differences in drainage pattern and sentinel node localization using lymphoscintigraphy and single-photon emission computed tomography combined with computer tomography (SPECT-CT) in melanoma patients scheduled for sentinel node biopsy.

Methods: Twenty-five patients (mean age: 56.9 years, range: 25-79 years) with a melanoma scheduled for SLN biopsy prior to (re)excision of the primary lesion (scar) were prospectively included following a two-day procedure. The first day, after Tc-Senti-Scint injection in four intradermal depots around the primary lesion or scar, early/delayed lymphoscintigraphy and SPECT-CT images were acquired. The injection sites were marked. The second day, after assessing lymph node radioactivity using planar scintigraphy, ICG-Tc-nanocolloid was injected at the previously marked skin points and imaging was performed. The paired planar and SPECT-CT images of both tracers were evaluated with respect to drainage patterns, SLN visualization and non-SLN appearing.

Results: Twenty-four out of 25 patients were evaluable. SLN visualization on a patient basis was 100% for ICG-Tc-nanocolloid and 96% for Tc-Senti-Scint, whereas uptake in non-SLNs was found in, respectively, 71% (17/24) and 61% (14/23). Concordance in drainage to 45 lymph node basins was 91%. Discordant drainage was found for two melanomas in the head-and-neck and one in the clavicular area. Unique lymph node basins were seen in 44/45 (98%) for ICG-Tc-nanocolloid and 42/45 (93%) for Tc-Senti-Scint. Concerning identified SLNs, the number was similar for both tracers (n = 58); however, more non-SLNs (65 vs 50) were visualized with ICG-Tc-nanocolloid than with Tc-Senti-Scint.

Conclusion: A slightly higher SLN visualization accompanied by a tendency to depict more non-SLNs was found for ICG-Tc-nanocolloid. Excepting the head and neck area, an overall high concordance in drainage was found for both radiotracers. With an additional value for the hybrid tracer due to the combination of preoperative imaging and the additional visual signal in the operation room, added by the fluorescent component of the hybrid tracer, there was a preference for ICG-Tc-nanocolloid.
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http://dx.doi.org/10.1097/MNM.0000000000001256DOI Listing
October 2020

Fluorescence background quenching as a means to increase Signal to Background ratio - a proof of concept during Nerve Imaging.

Theranostics 2020 6;10(21):9890-9898. Epub 2020 Aug 6.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Adequate signal to background ratios are critical for the implementation of fluorescence-guided surgery technologies. While local tracer administrations help to reduce the chance of systemic side effects, reduced spatial migration and non-specific tracer diffusion can impair the discrimination between the tissue of interest and the background. To combat background signals associated with local tracer administration, we explored a pretargeting concept aimed at quenching non-specific fluorescence signals. The efficacy of this concept was evaluated in an neuronal tracing set-up. Neuronal tracing was achieved using a wheat germ agglutinin (WGA) lectin functionalized with an azide-containing Cy5 dye (). A Cy7 quencher dye () was subsequently used to yield , a compound wherein the Cy5 emission is quenched by Förster resonance energy transfer to Cy7. The photophysical properties of and were evaluated together with deactivation kinetics (Schwannoma cell culture) (muscle tissue from mice; used for dose optimization), and ( in THY-1 YFP mice) , conjugation of to resulted in >90% reduction of the Cy5 fluorescence signal intensity at 30 minutes after addition of the quencher. In cells, pretargeting with the lectin yielded membranous staining, which could efficiently be deactivated by over the course of 30 minutes (91% Cy5 signal decrease). In muscle tissue, administration of at the site where was injected induced 80-90% quenching of the Cy5-related signal after 10-20 minutes, while the Cy7-related signal remained stable over time. effectively quenched the non-specific background signal up to 73% within 5 minutes, resulting in a 50% increase in the signal-to-background ratio between the nerve and injection site. The presented pretargeted fluorescence-quenching technology allowed fast and effective reduction of the background signal at the injection site, while preserving nerve visualization. While this proof-of-principle study was focused on imaging of nerves using a fluorescent WGA-lectin, the same concept could in the future also apply to applications such as sentinel node imaging.
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http://dx.doi.org/10.7150/thno.46806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449926PMC
May 2021

A DROP-IN beta probe for robot-assisted Ga-PSMA radioguided surgery: first ex vivo technology evaluation using prostate cancer specimens.

EJNMMI Res 2020 Aug 6;10(1):92. Epub 2020 Aug 6.

Istituto Nazionale di Fisica Nucleare, Sezione di Roma, Piazzale Aldo Moro 2, 00185, Rome, Italy.

Background: Recently, a flexible DROP-IN gamma-probe was introduced for robot-assisted radioguided surgery, using traditional low-energy SPECT-isotopes. In parallel, a novel approach to achieve sensitive radioguidance using beta-emitting PET isotopes has been proposed. Integration of these two concepts would allow to exploit the use of PET tracers during robot-assisted tumor-receptor-targeted. In this study, we have engineered and validated the performance of a novel DROP-IN beta particle (DROP-IN) detector.

Methods: Seven prostate cancer patients with PSMA-PET positive tumors received an additional intraoperative injection of ~ 70 MBq Ga-PSMA-11, followed by robot-assisted prostatectomy and extended pelvic lymph node dissection. The surgical specimens from these procedures were used to validate the performance of our DROP-IN probe prototype, which merged a scintillating detector with a housing optimized for a 12-mm trocar and prograsp instruments.

Results: After optimization of the detector and probe housing via Monte Carlo simulations, the resulting DROP-IN probe prototype was tested in a robotic setting. In the ex vivo setting, the probe-positioned by the robot-was able to identify Ga-PSMA-11 containing hot-spots in the surgical specimens: signal-to-background (S/B) was > 5 when pathology confirmed that the tumor was located < 1 mm below the specimen surface. Ga-PSMA-11 containing (and PET positive) lymph nodes, as found in two patients, were also confirmed with the DROP-IN probe (S/B > 3). The rotational freedom of the DROP-IN design and the ability to manipulate the probe with the prograsp tool allowed the surgeon to perform autonomous beta-tracing.

Conclusions: This study demonstrates the feasibility of beta-radioguided surgery in a robotic context by means of a DROP-IN detector. When translated to an in vivo setting in the future, this technique could provide a valuable tool in detecting tumor remnants on the prostate surface and in confirmation of PSMA-PET positive lymph nodes.
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http://dx.doi.org/10.1186/s13550-020-00682-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410888PMC
August 2020

Sentinel Node Imaging and Radioguided Surgery in the Era of SPECT/CT and PET/CT: Toward New Interventional Nuclear Medicine Strategies.

Clin Nucl Med 2020 Oct;45(10):771-777

From the Interventional Molecular Imaging Laboratory.

We review recent technological advances and new clinical indications for sentinel node (SN) and radioguided surgery in order to delineate future tendencies of interventional nuclear medicine in this field. A literature research was performed in PubMed to select relevant articles to be used as key references for analysis of the current approaches and tendencies in SN and radioguided surgery, as well as the evolving contribution of nuclear medicine intervention techniques to the various clinical applications. For classic indications such as melanoma and breast cancer, the incorporation of the SN approach based on the combined use of existing and new preoperative and intraoperative technologies in high-risk patient categories is becoming an emerging area of clinical indication. For SN biopsy staging in other malignancies with more complex lymphatic drainage, the incorporation of sophisticated tools is most helpful. The consecutive use of PET/CT and the SN procedure is increasing as a potential combined approach for the management of specific areas such as the axilla and the pelvis in patients at high risk of regional dissemination. Also, for the management of locoregional metastasis and oligometastatic disease, interventional nuclear medicine techniques are becoming valuable alternatives. The extended experience with SN biopsy is leading to technological advances facilitating the incorporation of this procedure to stage other malignancies with complex lymphatic drainage. New nuclear medicine-based approaches, incorporating SPECT/CT and PET/CT to guide resection of SNs and occult metastases, have recently been gaining ground.
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http://dx.doi.org/10.1097/RLU.0000000000003206DOI Listing
October 2020

A Supramolecular Platform Technology for Bacterial Cell Surface Modification.

ACS Infect Dis 2020 07 15;6(7):1734-1744. Epub 2020 May 15.

Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands.

In an era of antimicrobial resistance, a better understanding of the interaction between bacteria and the sentinel immune system is needed to discover new therapeutic targets for combating bacterial infectious disease. Sentinel immune cells such as macrophages phagocytose intact bacteria and thereby initiate ensuing immune responses. The bacterial surface composition is a key element that determines the macrophage signaling. To study the role of the bacterial cell surface composition in immune recognition, we developed a platform technology for altering bacterial surfaces in a controlled manner with versatile chemical scaffolds. We show that these scaffolds are efficiently loaded onto both Gram-positive and -negative bacteria and that their presence does not impair the capacity of monocyte-derived macrophages to phagocytose bacteria and subsequently signal to other components of the immune system. We believe this technology thus presents a useful tool to study the role of bacterial cell surface composition in disease etiology and potentially in novel interventions utilizing intact bacteria for vaccination.
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http://dx.doi.org/10.1021/acsinfecdis.9b00523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359023PMC
July 2020

A controlled human Schistosoma mansoni infection model to advance novel drugs, vaccines and diagnostics.

Nat Med 2020 03 17;26(3):326-332. Epub 2020 Feb 17.

Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands.

Schistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas. Novel medicines and vaccines are urgently needed. An experimental human model for schistosomiasis could accelerate the development of these products. We performed a dose-escalating clinical safety trial in 17 volunteers with male Schistosoma mansoni cercariae, which do not produce eggs (clinicaltrials.gov NCT02755324), at the Leiden University Medical Center, the Netherlands. The primary endpoints were adverse events and infectivity. We found a dose-related increase in adverse events related to acute schistosomiasis syndrome, which occurred in 9 of 17 volunteers. Overall, 5 volunteers (all 3 of the high dose group and 2 of 11 of the medium dose group) reported severe adverse events. Worm-derived circulating anodic antigen, the biomarker of the primary infection endpoint, peaked in 82% of volunteers at 3-10 weeks following exposure. All volunteers showed IgM and IgG1 seroconversion and worm-specific cytokine production by CD4 T cells. All volunteers were cured with praziquantel provided at 12 weeks after exposure. Infection with 20 Schistosoma mansoni cercariae led to severe adverse events in 18% of volunteers and high infection rates. This infection model paves the way for fast-track product development for treatment and prevention of schistosomiasis.
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http://dx.doi.org/10.1038/s41591-020-0759-xDOI Listing
March 2020

COvalent monolayer patterns in Microfluidics by PLasma etching Open Technology - COMPLOT.

Analyst 2020 Mar;145(5):1629-1635

Laboratory of BioNanoTechnology, Wageningen University and Research, Bornse Weilanden 9, 6708 WG Wageningen, the Netherlands.

Plasma microcontact patterning (PμCP) and replica molding were combined to make PDMS/glass microfluidic devices with β-cyclodextrin (β-CD) patterns attached covalently on the glass surface inside microchannels. The supramolecular reactivity, reusability and association constant of β-CD with Cy5-Ad2 was tested by analyzing signal-to-noise ratios of patterns vs. spacing with fluorescence microscopy.
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http://dx.doi.org/10.1039/c9an02407gDOI Listing
March 2020

Image-Guided Surgery: Are We Getting the Most Out of Small-Molecule Prostate-Specific-Membrane-Antigen-Targeted Tracers?

Bioconjug Chem 2020 02 6;31(2):375-395. Epub 2020 Jan 6.

Interventional Molecular Imaging Laboratory, Department of Radiology , Leiden University Medical Center , 2333 ZA Leiden , The Netherlands.

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).
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033908PMC
February 2020

Artificial intelligence and robotics: a combination that is changing the operating room.

World J Urol 2020 Oct 27;38(10):2359-2366. Epub 2019 Nov 27.

ORSI Academy, Melle, Belgium.

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.
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http://dx.doi.org/10.1007/s00345-019-03037-6DOI Listing
October 2020
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