Introduction: Radioguided surgery is an ever-evolving part of nuclear medicine. In fact, this nuclear medicine sub-discipline actively bridges non-invasive molecular imaging with surgical care.... Show moreIntroduction: Radioguided surgery is an ever-evolving part of nuclear medicine. In fact, this nuclear medicine sub-discipline actively bridges non-invasive molecular imaging with surgical care. Next to relying on the availability of radio- and bimodal-tracers, the success of radioguided surgery is for a large part dependent on the imaging modalities and imaging concepts available for the surgical setting. With this review, we have aimed to provide a comprehensive update of the most recent advances in the field. Areas covered: We have made an attempt to cover all aspects of radioguided surgery: 1) the use of radioisotopes that emit gamma, beta(+), and/or beta(-) radiation, 2) hardware developments ranging from probes to 2D cameras and even the use of advanced 3D interventional imaging solutions, and 3) multiplexing solutions such as dual-isotope detection or combined radionuclear and optical detection. Expertopinion: Technical refinements in the field of radioguided surgery should continue to focus on supporting its implementation in the increasingly complex minimally invasive surgical setting, e.g. by accommodating robot-assisted laparoscopic surgery. In addition, hybrid concepts that integrate the use of radioisotopes with other image-guided surgery modalities such as fluorescence or ultrasound are likely to expand in the future. Show less
Rietbergen, D.D.D.; Meershoek, P.; Oosterom, M.N. van; Roestenberg, M.; Erkel, A.R. van; Smit, F.; ... ; Leeuwen, F.W.B. van 2019
Purpose: To assess the feasibility of using freehand Single Photon Emission Computed Tomography (free-handSPECT) for the identification of technetium-99m-hydroxydiphosphonate (Tc-99m-HDP) positive... Show morePurpose: To assess the feasibility of using freehand Single Photon Emission Computed Tomography (free-handSPECT) for the identification of technetium-99m-hydroxydiphosphonate (Tc-99m-HDP) positive bone lesions and to evaluate the possibility of using these imaging data-sets for augmented- and virtual-reality based navigation approaches.Material and methods: In 20 consecutive patients referred for scintigraphy with Tc-99m-HDP, 21 three-dimensional freehandSPECT-images were generated using a handheld gamma camera. Concordance of the two different data sets was ranked. Furthermore, feasibility of segmenting the hotspot of tracer accumulation for navigation purposes was assessed.Results: In 86% of the cases freehandSPECT images showed good concordance with the corresponding part of the scintigraphic images. In lesions with a signal to background ratio (SBR) > 1.36, freehandSPECT provided an automatically segmented reference point for navigation purposes. In 14% of the cases (average SBR 1.82, range 1.0-3.4) freehandSPECT images showed intermediate concordance due to difficult anatomical area or negative bone scintigraphy and could not be used as navigation targets.Conclusion: In this pilot study, in 86% of the cases freehandSPECT demonstrated good concordance with traditional scintigraphy. A lesion with a SBR of 1.36 or more was suitable for navigation. These high quality freehandSPECT images supported the future exploration navigation strategies, e.g. guided needle biopsies. (C) 2019 Sociedad Espaiiola de Medicina Nuclear e Imagen Molecular. Published by Elsevier Espatia, S.L.U. All rights reserved. Show less
With the rapid expansion of robot-assisted surgical procedures, the need for robot-compliant image guidance technologies has also increased. Examples hereof are the integrated firefly fluorescence... Show moreWith the rapid expansion of robot-assisted surgical procedures, the need for robot-compliant image guidance technologies has also increased. Examples hereof are the integrated firefly fluorescence camera, the drop-in ultrasound probe, and the recently introduced DROP-IN gamma probe. Combined with Ga-68-prostate-specific membrane antigen-(PSMA)-11 PET/CT (staging) and Tc-99m-PSMA-I&S SPECT/CT (preoperative imaging), the latter DROP-IN gamma probe technology recently allowed us to perform the first clinical cases of robot-assisted PSMA-guided salvage surgery of lymphatic metastases. Show less
BackgroundThe protective efficacy of the most promising malaria whole-parasite based vaccine candidates critically depends on the parasite's potential to migrate in the human host. Key components... Show moreBackgroundThe protective efficacy of the most promising malaria whole-parasite based vaccine candidates critically depends on the parasite's potential to migrate in the human host. Key components of the parasite motility machinery (e.g. adhesive proteins, actin/myosin-based motor, geometrical properties) have been identified, however the regulation of this machinery is an unknown process.MethodsIn vitro microscopic live imaging of parasites in different formulations was performed and analysed, with the quantitative analysis software SMOOTIn vitro, their motility; their adherence capacity, movement pattern and velocity during forward locomotion.ResultsSMOOT(In vitro) enabled the detailed analysis of the regulation of the motility machinery of Plasmodium berghei in response to specific (macro)molecules in the formulation. Albumin acted as an essential supplement to induce parasite attachment and movement. Glucose, salts and other whole serum components further increased the attachment rate and regulated the velocity of the movement.ConclusionsBased on the findings can be concluded that a complex interplay of albumin, glucose and certain salts and amino acids regulates parasite motility. Insights in parasite motility regulation by supplements in solution potentially provide a way to optimize the whole-parasite malaria vaccine formulation. Show less
Introduction: The skin stage of malaria is a vital and vulnerable migratory life stage of the parasite. It has been characterised in rodent models, but remains wholly uninvestigated for human... Show moreIntroduction: The skin stage of malaria is a vital and vulnerable migratory life stage of the parasite. It has been characterised in rodent models, but remains wholly uninvestigated for human malaria parasites. To enable in depth analysis of not genetically modified (non-GMO) Plasmodium falciparum (Pf) sporozoite behaviour in human skin, we devised a labelling technology (Cy5M(2), targeting the sporozoite mitochondrion) that supports tracking of individual non-GMO sporozoites in human skin.Methods: Sporozoite labelling with Cy5M(2) was performed in vitro as well as via the feed of infected Anopheles mosquitos. Labelling was validated using confocal microscopy and flow cytometry and the fitness of labelled sporozoites was determined by analysis of infectivity to human hepatocytes in vitro, and in vivo in a rodent infection model. Using confocal video microscopy and custom software, single-sporozoite tracking studies in human skin-explants were performed.Results: Both in vitro and in mosquito labelling strategies yielded brightly fluorescent sporozoites of three different Plasmodium species. Cy5M(2) uptake colocalized with MitoTracker (R) green and could be blocked using the known Translocator protein (TSPO)-inhibitor PK11195. This method supported the visualization and subsequent quantitative analysis of the migration patterns of individual non-GMO Pf sporozoites in human skin and did not affect the fitness of sporozoites.Conclusions: The ability to label and image non-GMO Plasmodium sporozoites provides the basis for detailed studies on the human skin stage of malaria with potential for in vivo translation. As such, it is an important tool for development of vaccines based on attenuated sporozoites and their route of administration. Show less
Schottelius, M.; Wurzer, A.; Wissmiller, K.; Beck, R.; Koch, M.; Gorpas, D.; ... ; Wester, H.J. 2019
The prostate-specific membrane antigen (PSMA)-targeted radiotracers Ga-68/Lu-177-PSMA-I&T and Tc-99m-PSMA-I&S (for imaging and surgery) are currently successfully used for clinical PET... Show moreThe prostate-specific membrane antigen (PSMA)-targeted radiotracers Ga-68/Lu-177-PSMA-I&T and Tc-99m-PSMA-I&S (for imaging and surgery) are currently successfully used for clinical PET imaging, radionuclide therapy, and radioguided surgery of metastatic prostate cancer. To additionally exploit the high sensitivity and spatial resolution of fluorescence imaging for improved surgical guidance, a PSMA-I&T-based hybrid tracer, PSMA-I&F (DOTAGA-k(Sulfo-Cy5)-y-nal-k-Sub-KuE), has been developed and evaluated. Methods: The in vitro PSMA-targeting efficiency of PSMA-I&F, the reference PSMA-I&T, and their corresponding Ga-nat-/Ga-68- and Lu-nat/Lu-177 counterparts was determined in LNCaP cells via competitive binding assays (IC50) and dual-tracer radioligand and fluorescence internalization studies. Biodistribution and small-animal PET imaging studies were performed in CB17 SCID and LNCaP xenograft-bearing SHO mice, respectively, and complemented by intraoperative far-red fluorescence imaging using a clinical laparoscope. Additionally, fully automated serial cryosectioning and fluorescence imaging of 1 tumor-bearing animal as well as PSMA immunohistochemistry and fluorescence microscopy of organ cryosections (tumor, kidney, spleen) were also performed. Results: Compared with the parent PSMA-I&T analogs, the PSMA affinities of PSMA-I&F and its Ga-nat-/Lu-nat-complexes remained high and unaffected by dye conjugation (7.9 < IC50 < 10.5 nM for all ligands). The same was observed for the internalization of Ga-68- and Lu-177-PSMA-I&F. In vivo, blood clearance of Ga-68- and Lu-177-PSMA-I&F was only slightly delayed by high plasma protein binding (94%-95%), and very low accumulation in nontarget organs was observed already at 1 h after injection. Dynamic PET imaging confirmed PSMA-specific (as demonstrated by coinjection of 2-PMPA) uptake into the LNCaP xenograft (4.5% +/- 1.8 percentage injected dose per gram) and the kidneys (106% +/- 23 percentage injected dose per gram). Tumor-to-background ratios of 2.1, 5.2, 9.6, and 9.6 for blood, liver, intestines, and muscle, respectively, at 1 h after injection led to excellent imaging contrast in Ga-68-PSMA-I&F PET and in intraoperative fluorescence imaging. Furthermore, fluorescence imaging of tissue cryosections allowed high-resolution visualization of intraorgan PSMA-I&F distribution in vivo and its correlation with PSMA expression as determined by immunohistochemistry. Conclusion: Thus, with its high PSMA-targeting efficiency and favorable pharmacokinetic profile, Ga-68/Lu-177-PSMA-I&F serves as an excellent proof-of-concept compound for the general feasibility of PSMA-I&T-based hybrid imaging. The PSMA-I&T scaffold represents a versatile PSMA-targeted lead structure, allowing relatively straightforward adaptation to the different structural requirements of dedicated nuclear or hybrid imaging agents. Show less
Schottelius, M.; Wurzer, A.; Wissmiller, K.; Beck, R.; Koch, M.; Gorpas, D.; ... ; Wester, H.J. 2019
