Aims: Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and... Show moreAims: Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and implant retention (DAIR) surgery aimed at cleaning the infected prosthesis often fails, subsequently requiring invasive revision of the complete prosthetic reconstruction. Infection-specific imaging may help to guide DAIR. In this study, we evaluated a bacteria -specific hybrid tracer (99mTc-UBI29-41-Cy5) and its ability to visualize the bacterial load on fem-oral implants using clinical -grade image guidance methods. Methods: 99mTc-UBI29-41- Cy5 specificity for Stapylococcus aureus was assessed in vitro using fluorescence confocal imaging. Topical administration was used to highlight the location of S. aureus cul-tured on femoral prostheses using fluorescence imaging and freehand single photon emis-sion CT (fhSPECT) scans. Gamma counting and fhSPECT were used to quantify the bacterial load and monitor cleaning with chlorhexidine. Microbiological culturing helped to relate the imaging findings with the number of (remaining) bacteria. Results: Bacteria could be effectively stained in vitro and on prostheses, irrespective of the presence of biofilm. Infected prostheses revealed bacterial presence on the transition zone between the head and neck, and in the screw hole. Qualitative 2D fluorescence images could be com-plemented with quantitative 3D fhSPECT scans. Despite thorough chlorhexidine treatments, 28% to 44% of the signal remained present in the locations of the infection that were iden-tified using imaging, which included 500 to 2,000 viable bacteria.Conclusion: The hybrid tracer99mTc-UBI29-41-Cy5 allowed effective bacterial staining. Qualitative real -time fluorescence guidance could be effectively combined with nuclear imaging that enables quantitative monitoring of the effectiveness of cleaning strategies. Show less
Aims Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and... Show moreAims Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and implant retention (DAIR) surgery aimed at cleaning the infected prosthesis often fails, subsequently requiring invasive revision of the complete prosthetic reconstruction. Infection-specific imaging may help to guide DAIR. In this study, we evaluated a bacteria -specific hybrid tracer (99mTc-UBI29-41-Cy5) and its ability to visualize the bacterial load on fem-oral implants using clinical -grade image guidance methods.Methods 99mTc-UBI29-41- Cy5 specificity for Stapylococcus aureus was assessed in vitro using fluorescence confocal imaging. Topical administration was used to highlight the location of S. aureus cul-tured on femoral prostheses using fluorescence imaging and freehand single photon emis-sion CT (fhSPECT) scans. Gamma counting and fhSPECT were used to quantify the bacterial load and monitor cleaning with chlorhexidine. Microbiological culturing helped to relate the imaging findings with the number of (remaining) bacteria.Results Bacteria could be effectively stained in vitro and on prostheses, irrespective of the presence of biofilm. Infected prostheses revealed bacterial presence on the transition zone between the head and neck, and in the screw hole. Qualitative 2D fluorescence images could be com-plemented with quantitative 3D fhSPECT scans. Despite thorough chlorhexidine treatments, 28% to 44% of the signal remained present in the locations of the infection that were iden-tified using imaging, which included 500 to 2,000 viable bacteria.Conclusion The hybrid tracer99mTc-UBI29-41-Cy5 allowed effective bacterial staining. Qualitative real -time fluorescence guidance could be effectively combined with nuclear imaging that enables quantitative monitoring of the effectiveness of cleaning strategies. Show less
Skin-penetrating parasites have something in common; they all need to evade the initial immune response in the skin in order to avoid being evicted by their hostile host and establish an infection.... Show moreSkin-penetrating parasites have something in common; they all need to evade the initial immune response in the skin in order to avoid being evicted by their hostile host and establish an infection. To do so, they are equipped with the necessary cunning stratagems. For example, they can act directly on immune cells to alter their function and they can optimize their migration patterns to their hostile environment. This thesis is aimed at unravelling those mechanisms. We study two devastating parasitic diseases: Malaria and Schistosomiasis. Both deadly and debilitating parasitic diseases, with over 200 million (malaria) and over 240 million (schistosomiasis) cases annually; the need for potent vaccines is evident. Whole weakened parasites can be used to vaccinate individuals against parasitic diseases like malaria. However, delivery of these parasites in the skin, as is commonly done in vaccinations, reduces their protectivity. We hypothesize that this reduction is caused by parasite-mediated immune-regulatory mechanisms that are initiated upon their first encounter with immune cells in the skin. We investigated whether skin penetrating parasites exploit these existing mechanisms in human skin in order to enhance their survival. Show less
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... Show moreInflammatory 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. Show less
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,... Show moreMolecular 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. Show less
Within interventional nuclear medicine (iNM) a prominent role is allocated for the sub-discipline of radioguided surgery. Unique for this discipline is the fact that an increasing number of... Show moreWithin interventional nuclear medicine (iNM) a prominent role is allocated for the sub-discipline of radioguided surgery. Unique for this discipline is the fact that an increasing number of clinical indications (e.g. lymphatic mapping, local tumor demarcation and/or tumor receptor targeted applications) have been adopted into routine care. The clinical integration is further strengthened by technical innovations in chemistry and engineering that enhance the translational potential of radioguided procedures in iNM. Together, these features not only ensure ongoing expansion of iNM but also warrant a lasting clinical impact for the sub-discipline of radioguided surgery. Show less
Debie, P.; Lafont, C.; Defrise, M.; Hansen, I.; Willigen, D.M. van; Leeuwen, F.W.B. van; ... ; Hernot, S. 2020
A compound's intratumoural distribution is an important determinant for the effectiveness of molecular therapy or imaging. Antibodies (Abs), though often used in the design of targeted compounds,... Show moreA compound's intratumoural distribution is an important determinant for the effectiveness of molecular therapy or imaging. Antibodies (Abs), though often used in the design of targeted compounds, struggle to achieve a homogenous distribution due to their large size and bivalent binding mechanism. In contrast, smaller compounds like nanobodies (Nbs) are expected to distribute more homogenously, though this has yet to be demonstrated in vivo at the microscopic level. We propose an intravital approach to evaluate the intratumoural distribution of different fluorescently labeled monomeric and dimeric Nb tracers and compare this with a monoclonal antibody (mAb).Monomeric and dimeric formats of the anti-HER2 (2Rb17c and 2Rb17c-2Rb17c) and control (R3B23 and R3B23-R3B23) Nb, as well as the dimeric monovalent Nb 2Rbl7c-R3B23 were generated and fluorescently labeled with a Cy5 fluorophore. The mAb trastuzumab-Cy5 was also prepared. Whole-body biodistribution of all constructs was investigated in mice bearing subcutaneous xenografts (HER2 + SKOV3) using in vivo epi-fluorescence imaging. Next, for intravital experiments, GFP-expressing SKOV3 cells were grown under dorsal window chambers on athymic nude mice (n = 3/group), and imaged under a fluorescence stereo microscope immediately after intravenous injection of the tracers. Consecutive fluorescence images within the tumour were acquired over the initial 20 min after injection and later, single images were taken at 1, 3 and 24 h post-injection. Additionally, two-photon microscopy was used to investigate the colocalization of GFP (tumour cells) and Cy5 fluorescence (tracers) at higher resolution.Whole-body images showed rapid renal clearance of all Nbs, and fast tumour targeting for the specific Nbs. Specific tumour uptake of the mAb could only be clearly distinguished from background after several hours. Intravital imaging revealed that monomeric Nb tracers accumulated rapidly and distributed homogenously in the tumour mere minutes after intravenous injection. The dimeric compounds initially achieved lower fluorescence intensities than the monomeric. Furthermore, whereas the HER2-specific dimeric bivalent compound remained closely associated to the blood vessels over 24 h, the HER2-specific dimeric monovalent tracer achieved a more homogenous tumour distribution from 1 h post-injection onwards. Non-specific tracers were not retained in the tumour. Trastuzumab had the most heterogenous intratumoural distribution of all evaluated compounds, while -due to the long blood retention- achieving the highest overall tumour uptake at 24 h post-injection.In conclusion, monomeric Nbs very quickly and homogenously distribute through tumour tissue, at a rate significantly greater than dimeric Nbs and mAbs. This underlines the potential of monomeric Nb tracers and therapeutics in molecular imaging and targeted therapies. Show less
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
Background Bacterial infections are still a major global healthcare problem. To combat the increasing antimicrobial resistance, early diagnosis of bacterial infection-including the identification... Show moreBackground Bacterial infections are still a major global healthcare problem. To combat the increasing antimicrobial resistance, early diagnosis of bacterial infection-including the identification of bacterial specie-is needed to improve antibiotic stewardship and to help reduce the use of broad-spectrum antibiotics. To aid successful targeted antibiotic treatment, specific detection and localisation of infectious organisms is warranted. Nuclear medicine imaging approaches have been successfully used to diagnose bacterial infections and to differentiate between pathogen induced infections and sterile inflammatory processes.Aim In this comprehensive review we present an overview of recent developments in radiolabelled bacterial imaging tracers.Methods The PubMed/MEDLINE and Embase (OvidSP) literature databases were systematically searched for publications on SPECT and PET on specific imaging of bacterial using specific guidelines with MeSH-terms, truncations, and completion using cross-references. Tracers in literature that was extensively reviewed before 2016 were not included in this update. Where possible, the chemical structure of the radiolabelled compounds and clinical images were shown.Results In 219 original articles pre-clinical and clinical imaging of bacterial infection with new tracers were included. In our view, the highest translational potential lies with tracers that are specific to target the pathogens: e.g., Tc-99m- and Ga-68-labelled UBI29-41, Tc-99m-vancomycin, m-[F-18]-fluoro-PABA, [methyl-C-11]-D-methionine, [F-18]-FDS, [F-18]-maltohexaose and [F-18]-maltotriose. An encouraging note is that some of these tracers have already been successfully evaluated in clinical settings.Conclusion This review summarises updates in tracer development for specific (pre-clinical and clinical) imaging of bacterial infections. We propsed some promising tracers that are likely to become innovative standards in the clinical setting in the near feature. Show less
PurposeNear-infrared spectroscopy (NIRS) has recently been proposed as an indirect technique to assess brown adipose tissue (BAT) in young men. NIRS arises as a novel technique to avoid the... Show morePurposeNear-infrared spectroscopy (NIRS) has recently been proposed as an indirect technique to assess brown adipose tissue (BAT) in young men. NIRS arises as a novel technique to avoid the limitations of the gold-standard 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]DG) positron emission tomography combined with X-ray computed tomography (PET/CT). The aim of this study was to examine the association between near-infrared spatially resolved spectroscopy (NIRSRS) parameters and BAT volume and activity estimated by [F-18]DG-PET/CT in 18 young healthy women.ProceduresNIR(SRS) parameters [tissue saturation index and concentrations of total haemoglobin, oxy-haemoglobin, and deoxy-haemoglobin] were continuously measured in the supraclavicular and forearm regions, in both warm and cold (2h of personalised cold exposure) conditions. Then, the NIRSRS data were analysed as an average of 5min in 4 different periods: (i) warm period as the baseline record, (ii) cold period I, (iii) cold period II, and (iv) cold period III. The data were then correlated with BAT volume and activity (SUVmean and SUVpeak) estimated by [F-18]DG-PET/CT.ResultsThere was no association between the NIRSRS parameters in the supraclavicular region in warm conditions (no previous cold exposure) and BAT volume and activity (P>0.05). Similarly, the cold-induced changes of the NIRSRS parameters in the supraclavicular region were not associated with BAT volume and activity (P>0.05).ConclusionsNIR(SRS) does not seem to be a valid technique to indirectly assess BAT in young healthy women. Further research is needed to validate this technique against other methods such as PET/CT using different radiotracers or magnetic resonance imaging. Show less
Molecular imaging plays a vital role in current medical diagnostics. There is a constant need for new and improved molecular imaging agents in terms of resolution, specificity, stability, safety... Show moreMolecular imaging plays a vital role in current medical diagnostics. There is a constant need for new and improved molecular imaging agents in terms of resolution, specificity, stability, safety and cost. The research described in this thesis deals with the development of activatable luminescence lifetime imaging agents as well as with the use of supramolecular chemistry to introduce cell surface modifications to living cells. Show less
Spa, S.J.; Hensbergen, A.W.; Wal, S. van der; Kuil, J.; Leeuwen, F.W.B. van 2018
