scholarly journals VEGF-targeted multispectral optoacoustic tomography and fluorescence molecular imaging in human carotid atherosclerotic plaques

2021 ◽  
Author(s):  
Pieter J. Steinkamp ◽  
Jasper Vonk ◽  
Lydian A. Huisman ◽  
Gert-Jan Meersma ◽  
Gilles F.H. Diercks ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Carotid Artery ◽  
Ex Vivo ◽  
Carotid Plaques ◽  
Symptomatic Carotid ◽  
Optoacoustic Tomography ◽  
Imaging Results ◽  
Human Carotid ◽  
Fluorescence Molecular Imaging

Abstract Background: Vulnerable atherosclerotic carotid plaques are prone to rupture resulting in ischemic strokes. Molecular imaging techniques have the potential to assess plaque vulnerability by visualizing molecular markers. Bevacizumab-800CW is a near-infrared fluorescent contrast agent antibody targeting vascular endothelial growth factor-A (VEGF-A). Here, we study if administration of bevacizumab-800CW is safe and can be visualized using multispectral optoacoustic tomography (MSOT) to evaluate atherosclerotic carotid plaques in vivo by visualizing intra-plaque neovascularization.Methods: Healthy volunteers were imaged with MSOT to determine the technical feasibility of human carotid imaging with MSOT. Patients with symptomatic carotid artery stenosis scheduled for carotid artery endarterectomy were intravenously administered with a bolus injection of 4.5 mg bevacizumab-800CW. Before and two days after tracer administration, in vivo non-invasive MSOT was performed. For validation, ex vivo fluorescence molecular imaging of the surgically removed plaque specimen was performed and correlated with histopathology.Results: Administration of 4.5 mg bevacizumab-800CW was safe in five patients. MSOT achieved accurate visualization of the carotid bifurcation area and assessment of the plaque in all five patients. Bevacizumab-800CW-resolved signal could not be detected with MSOT prior to surgery. However, ex vivo analysis of the carotid plaque showed accumulation of bevacizumab-800CW.Conclusions: These first-in-human MSOT and fluorescence molecular imaging results in carotid artery plaques suggest that bevacizumab is a potential tracer for imaging of vulnerable plaques. However, the microdose used here cannot be detected with MSOT. A subsequent phase I dose-finding study is needed to evaluate bevacizumab-800CW in higher doses as a useful optoacoustic imaging agent. Moreover, the development of dedicated optoacoustic contrast agents for signal attenuation of the targeting moiety is advisable for carotid atherosclerotic plaque assessment using MSOT.

scholarly journals VEGF-Targeted Multispectral Optoacoustic Tomography and Fluorescence Molecular Imaging in Human Carotid Atherosclerotic Plaques

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1227
Author(s):  
Pieter J. Steinkamp ◽  
Jasper Vonk ◽  
Lydian A. Huisman ◽  
Gert-Jan Meersma ◽  
Gilles F. H. Diercks ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Carotid Artery ◽  
Atherosclerotic Plaque ◽  
Near Infrared ◽  
Imaging Techniques ◽  
Carotid Atherosclerotic Plaque ◽  
Carotid Plaques ◽  
Symptomatic Carotid ◽  
Optoacoustic Tomography ◽  
Fluorescence Molecular Imaging

Vulnerable atherosclerotic carotid plaques are prone to rupture, resulting in ischemic strokes. In contrast to radiological imaging techniques, molecular imaging techniques have the potential to assess plaque vulnerability by visualizing diseases-specific biomarkers. A risk factor for rupture is intra-plaque neovascularization, which is characterized by overexpression of vascular endothelial growth factor-A (VEGF-A). Here, we study if administration of bevacizumab-800CW, a near-infrared tracer targeting VEGF-A, is safe and if molecular assessment of atherosclerotic carotid plaques in vivo is possible using multispectral optoacoustic tomography (MSOT). Healthy volunteers and patients with symptomatic carotid artery stenosis scheduled for carotid artery endarterectomy were imaged with MSOT. Secondly, patients were imaged two days after intravenous administration of 4.5 bevacizumab-800CW. Ex vivo fluorescence molecular imaging of the surgically removed plaque specimen was performed and correlated with histopathology. In this first-in-human MSOT and fluorescence molecular imaging study, we show that administration of 4.5 mg bevacizumab-800CW appeared to be safe in five patients and accumulated in the carotid atherosclerotic plaque. Although we could visualize the carotid bifurcation area in all subjects using MSOT, bevacizumab-800CW-resolved signal could not be detected with MSOT in the patients. Future studies should evaluate tracer safety, higher doses of bevacizumab-800CW or develop dedicated contrast agents for carotid atherosclerotic plaque assessment using MSOT.

scholarly journals Fluorescence grid analysis for the evaluation of piecemeal surgery in sinonasal inverted papilloma: a proof-of-concept study

2021 ◽  
Author(s):  
J Vonk ◽  
FJ Voskuil ◽  
JG de Wit ◽  
WT Heeman ◽  
WB Nagengast ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Ex Vivo ◽  
Inverted Papilloma ◽  
Fluorescence Signal ◽  
Proof Of Concept ◽  
Concept Study ◽  
Grid Analysis ◽  
Sinonasal Inverted Papilloma ◽  
Fluorescence Molecular Imaging

Abstract Purpose Local recurrence occurs in ~ 19% of sinonasal inverted papilloma (SNIP) surgeries and is strongly associated with incomplete resection. During surgery, it is technically challenging to visualize and resect all SNIP tissue in this anatomically complex area. Proteins that are overexpressed in SNIP, such as vascular endothelial growth factor (VEGF), may serve as a target for fluorescence molecular imaging to guide surgical removal of SNIP. A proof-of-concept study was performed to investigate if the VEGF-targeted near-infrared fluorescent tracer bevacizumab-800CW specifically localizes in SNIP and whether it could be used as a clinical tool to guide SNIP surgery. Methods In five patients diagnosed with SNIP, 10 mg of bevacizumab-800CW was intravenously administered 3 days prior to surgery. Fluorescence molecular imaging was performed in vivo during surgery and ex vivo during the processing of the surgical specimen. Fluorescence signals were correlated with final histopathology and VEGF-A immunohistochemistry. We introduced a fluorescence grid analysis to assess the fluorescence signal in individual tissue fragments, due to the nature of the surgical procedure (i.e., piecemeal resection) allowing the detection of small SNIP residues and location of the tracer ex vivo. Results In all patients, fluorescence signal was detected in vivo during endoscopic SNIP surgery. Using ex vivo fluorescence grid analysis, we were able to correlate bevacizumab-800CW fluorescence of individual tissue fragments with final histopathology. Fluorescence grid analysis showed substantial variability in mean fluorescence intensity (FImean), with SNIP tissue showing a median FImean of 77.54 (IQR 50.47–112.30) compared to 35.99 (IQR 21.48–57.81) in uninvolved tissue (p < 0.0001), although the diagnostic ability was limited with an area under the curve of 0.78. Conclusions A fluorescence grid analysis could serve as a valid method to evaluate fluorescence molecular imaging in piecemeal surgeries. As such, although substantial differences were observed in fluorescence intensities, VEGF-A may not be the ideal target for SNIP surgery. Trial registration NCT03925285.

scholarly journals Preclinical Evaluation of [18F]FACH in Healthy Mice and Piglets: An 18F-Labeled Ligand for Imaging of Monocarboxylate Transporters with PET

2021 ◽  
Vol 22 (4) ◽  
pp. 1645
Author(s):  
Daniel Gündel ◽  
Masoud Sadeghzadeh ◽  
Winnie Deuther-Conrad ◽  
Barbara Wenzel ◽  
Paul Cumming ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Ex Vivo ◽  
Specific Binding ◽  
Monocarboxylate Transporters ◽  
Binding Potential ◽  
Kidney Cortex ◽  
Binding Studies ◽  
Imaging Tool ◽  
Pre Treatment

The expression of monocarboxylate transporters (MCTs) is linked to pathophysiological changes in diseases, including cancer, such that MCTs could potentially serve as diagnostic markers or therapeutic targets. We recently developed [18F]FACH as a radiotracer for non-invasive molecular imaging of MCTs by positron emission tomography (PET). The aim of this study was to evaluate further the specificity, metabolic stability, and pharmacokinetics of [18F]FACH in healthy mice and piglets. We measured the [18F]FACH plasma protein binding fractions in mice and piglets and the specific binding in cryosections of murine kidney and lung. The biodistribution of [18F]FACH was evaluated by tissue sampling ex vivo and by dynamic PET/MRI in vivo, with and without pre-treatment by the MCT inhibitor α-CCA-Na or the reference compound, FACH-Na. Additionally, we performed compartmental modelling of the PET signal in kidney cortex and liver. Saturation binding studies in kidney cortex cryosections indicated a KD of 118 ± 12 nM and Bmax of 6.0 pmol/mg wet weight. The specificity of [18F]FACH uptake in the kidney cortex was confirmed in vivo by reductions in AUC0–60min after pre-treatment with α-CCA-Na in mice (−47%) and in piglets (−66%). [18F]FACH was metabolically stable in mouse, but polar radio-metabolites were present in plasma and tissues of piglets. The [18F]FACH binding potential (BPND) in the kidney cortex was approximately 1.3 in mice. The MCT1 specificity of [18F]FACH uptake was confirmed by displacement studies in 4T1 cells. [18F]FACH has suitable properties for the detection of the MCTs in kidney, and thus has potential as a molecular imaging tool for MCT-related pathologies, which should next be assessed in relevant disease models.

scholarly journals Discovery of novel mechanosensitive genes in vivo using mouse carotid artery endothelium exposed to disturbed flow

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. e66-e73 ◽  
Author(s):  
Chih-Wen Ni ◽  
Haiwei Qiu ◽  
Amir Rezvan ◽  
Kihwan Kwon ◽  
Douglas Nam ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Ex Vivo ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Gene Expression Profiles ◽  
Disturbed Flow ◽  
A Genome ◽  
Pattern Comparison

Abstract Recently, we showed that disturbed flow caused by a partial ligation of mouse carotid artery rapidly induces atherosclerosis. Here, we identified mechanosensitive genes in vivo through a genome-wide microarray study using mouse endothelial RNAs isolated from the flow-disturbed left and the undisturbed right common carotid artery. We found 62 and 523 genes that changed significantly by 12 hours and 48 hours after ligation, respectively. The results were validated by quantitative polymerase chain reaction for 44 of 46 tested genes. This array study discovered numerous novel mechanosensitive genes, including Lmo4, klk10, and dhh, while confirming well-known ones, such as Klf2, eNOS, and BMP4. Four genes were further validated for protein, including LMO4, which showed higher expression in mouse aortic arch and in human coronary endothelium in an asymmetric pattern. Comparison of in vivo, ex vivo, and in vitro endothelial gene expression profiles indicates that numerous in vivo mechanosensitive genes appear to be lost or dysregulated during culture. Gene ontology analyses show that disturbed flow regulates genes involved in cell proliferation and morphology by 12 hours, followed by inflammatory and immune responses by 48 hours. Determining the functional importance of these novel mechanosensitive genes may provide important insights into understanding vascular biology and atherosclerosis.

scholarly journals Proof of concept of a multimodal intravital molecular imaging system for tumour transpathology investigation

2021 ◽  
Author(s):  
Zhen Liu ◽  
Tao Cheng ◽  
Stephan Düwel ◽  
Ziying Jian ◽  
Geoffrey J. Topping ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Imaging System ◽  
Ex Vivo ◽  
Fiducial Markers ◽  
Proof Of Concept ◽  
Registration Accuracy ◽  
Microscopic Imaging ◽  
Window Chamber

Abstract Background Transpathology highlights the interpretation of the underlying physiology behind molecular imaging. However, it remains challenging due to the discrepancies between in vivo and in vitro measurements and difficulties of precise co-registration between trans-scaled images. This study aims to develop a multimodal intravital molecular imaging (MIMI) system as a tool for in vivo tumour transpathology investigation. Methods The proposed MIMI system integrates high-resolution positron imaging, magnetic resonance imaging (MRI) and microscopic imaging on a dorsal skin window chamber on an athymic nude rat. The window chamber frame was designed to be compatible with multimodal imaging and its fiducial markers were customized for precise physical alignment among modalities. The co-registration accuracy was evaluated based on phantoms with thin catheters. For proof of concept, tumour models of the human colorectal adenocarcinoma cell line HT-29 were imaged. The tissue within the window chamber was sectioned, fixed and haematoxylin–eosin (HE) stained for comparison with multimodal in vivo imaging. Results The final MIMI system had a maximum field of view (FOV) of 18 mm × 18 mm. Using the fiducial markers and the tubing phantom, the co-registration errors are 0.18 ± 0.27 mm between MRI and positron imaging, 0.19 ± 0.22 mm between positron imaging and microscopic imaging and 0.15 ± 0.27 mm between MRI and microscopic imaging. A pilot test demonstrated that the MIMI system provides an integrative visualization of the tumour anatomy, vasculatures and metabolism of the in vivo tumour microenvironment, which was consistent with ex vivo pathology. Conclusions The established multimodal intravital imaging system provided a co-registered in vivo platform for trans-scale and transparent investigation of the underlying pathology behind imaging, which has the potential to enhance the translation of molecular imaging.

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Erik H. J. G. Aarntzen ◽  
Edel Noriega-Álvarez ◽  
Vera Artiko ◽  
André H. Dias ◽  
Olivier Gheysens ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Radionuclide Imaging ◽  
Musculoskeletal Diseases ◽  
Ex Vivo ◽  
Imaging Techniques ◽  
Large Body ◽  
Therapeutic Interventions ◽  
Histopathological Analysis ◽  
Complementary Value

AbstractInflammatory 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.

Abstract 2509: Standardized Reports Are Needed To Describe Carotid Artery Stenosis

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Eric Cheng ◽  
Salomeh Keyhani ◽  
Susan Ofner ◽  
Linda Williams ◽  
Dawn Bravata
Keyword(s):  
Decision Making ◽  
Clinical Trials ◽  
Carotid Artery ◽  
Carotid Artery Stenosis ◽  
Diagnostic Tests ◽  
Artery Stenosis ◽  
Fiscal Year ◽  
Symptomatic Carotid ◽  
Imaging Results ◽  
Exact Degree

Background: Landmark clinical trials have shown that carotid procedures can greatly reduce the risk of stroke in persons with symptomatic carotid artery stenosis between 70 and 99% and can somewhat reduce the risk of stroke in persons with symptomatic carotid stenosis between 50 and 69%. Guidelines have recommended that results from carotid artery imaging tests be presented in these ranges to facilitate decision-making. We sought to determine how carotid imaging results were reported across Veterans Administration (VA) facilities. Methods: Carotid artery imaging results were obtained as part of a comprehensive chart review of veterans hospitalized with ischemic stroke at 127 VA hospitals in fiscal year 2007. Abstractors recorded the results of carotid ultrasound, MR angiography, CT angiography, or catheter angiography performed in the twelve months prior to admission to six months after admission. We excluded carotid artery imaging reports with results of “no stenosis”, “mild stenosis”, exact degree of stenosis <50%, or any range of stenosis <50% to focus on those reports that would likely inform decisions about carotid procedures. The unit of analysis was the carotid artery. We described how often the results were presented as an exact degree (such as 60%), as a range (such as 50 to 69%), or as a descriptive category (“moderate” or “severe” stenosis). For results described as a range, we examined how often it matched those used in landmark trials. Results: Of 6527 results of carotid artery imaging, there were 1315 results of greater than 50% or at least “moderate stenosis” (see Table ). Only 234 of the reports used a range to describe the stenosis; among this set, only 55 of the reports used a 50-69% or 70-99% range to describe the stenosis. Conclusions: In this national healthcare system, significant carotid artery stenosis was rarely reported in a way that exactly mapped onto recommendations from landmark clinical trials and guidelines. Clinicians who order these diagnostic tests as well as clinicians who interpret these diagnostic tests should collaborate to produce standardized reports that facilitate decision-making.

scholarly journals Construction of an in vivo carotid siphon model for testing endovascular devices for neuro-interventions

2017 ◽  
Vol 23 (3) ◽  
pp. 325-329
Author(s):  
Bu-Lang Gao ◽  
Yong-Li Wang ◽  
Xue-Jing Zhang ◽  
Qiong-Ying Fan ◽  
Wei-Li Hao ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Glass Tube ◽  
Covered Stent ◽  
Covered Stents ◽  
Carotid Siphon ◽  
Endovascular Interventions ◽  
Pass Through ◽  
Endovascular Devices ◽  
Human Carotid

Objective The aim of this study was to construct an in vivo carotid siphon model for testing neurovascular devices for endovascular interventions. Methods A model of a human carotid siphon was pre-shaped using a glass tube from a human cadaver and used to confine a segment of one side of the common carotid artery (CCA) in canines. This segment of CCA with the glass carotid siphon on was interposed end-to-end onto the contralateral CCA so as to simulate a human carotid artery siphon in vivo. Two weeks later, the siphon model was evaluated using computed tomography angiography and digital subtraction angiography, and the covered stent specially designed for intracranial vasculature was navigated through the siphon model for a longitudinal flexibility test. Results All dogs tolerated the procedures well, and the artificial siphon model in vivo provided realistic conditions for device testing. Two weeks later, the in vivo carotid siphon model remained patent with no thrombosis. Five covered stents were navigated to pass through five siphon models successfully, with vasospasm occurring in two siphons. Conclusion Construction of an in vivo siphon model in dogs with a glass tube is feasible and useful for the test of endovascular devices for treating neurovascular diseases.

scholarly journals In Vivo Tracking of Murine Adipose Tissue-Derived Multipotent Adult Stem Cells and Ex Vivo Cross-Validation

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Chiara Garrovo ◽  
Natascha Bergamin ◽  
Dave Bates ◽  
Daniela Cesselli ◽  
Antonio Paolo Beltrami ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Optical Imaging ◽  
Adult Stem Cells ◽  
Near Infrared ◽  
Cross Validation ◽  
Ex Vivo ◽  
Imaging Data ◽  
Imaging Results

Stem cells are characterized by the ability to renew themselves and to differentiate into specialized cell types, while stem cell therapy is believed to treat a number of different human diseases through either cell regeneration or paracrine effects. Herein, an in vivo and ex vivo near infrared time domain (NIR TD) optical imaging study was undertaken to evaluate the migratory ability of murine adipose tissue-derived multipotent adult stem cells [mAT-MASC] after intramuscular injection in mice. In vivo NIR TD optical imaging data analysis showed a migration of DiD-labelled mAT-MASC in the leg opposite the injection site, which was confirmed by a fibered confocal microendoscopy system. Ex vivo NIR TD optical imaging results showed a systemic distribution of labelled cells. Considering a potential microenvironmental contamination, a cross-validation study by multimodality approaches was followed: mAT-MASC were isolated from male mice expressing constitutively eGFP, which was detectable using techniques of immunofluorescence and qPCR. Y-chromosome positive cells, injected into wild-type female recipients, were detected by FISH. Cross-validation confirmed the data obtained by in vivo/ex vivo TD optical imaging analysis. In summary, our data demonstrates the usefulness of NIR TD optical imaging in tracking delivered cells, giving insights into the migratory properties of the injected cells.

Visualization of pulmonary inflammation using noninvasive fluorescence molecular imaging

2008 ◽  
Vol 104 (3) ◽  
pp. 795-802 ◽  
Author(s):  
Jodi Haller ◽  
Damon Hyde ◽  
Nikolaos Deliolanis ◽  
Ruben de Kleine ◽  
Mark Niedre ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Quantitative Imaging ◽  
Pulmonary Inflammation ◽  
Small Animal ◽  
Mouse Lung ◽  
Chronic Obstructive ◽  
Therapy Assessment ◽  
Fluorescence Molecular Imaging

The ability to visualize molecular processes and cellular regulators of complex pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), or adult respiratory distress syndrome (ARDS), would aid in the diagnosis, differentiation, therapy assessment and in small animal-based drug-discovery processes. Herein we report the application of normalized transillumination and fluorescence molecular tomography (FMT) for the noninvasive quantitative imaging of the mouse lung in vivo. We demonstrate the ability to visualize and quantitate pulmonary response in a murine model of LPS-induced airway inflammation. Twenty-four hours prior to imaging, BALB/c female mice were injected via tail vein with 2 nmol of a cathepsin-sensitive activatable fluorescent probe (excitation: 750 nm; emission: 780 nm) and 2 nmol of accompanying intravascular agent (excitation: 674 nm; emission: 694 nm). Six hours later, the mice were anesthetized with isoflurane and administered intranasal LPS in sterile 0.9% saline in 25 μl aliquots (one per nostril). Fluorescence molecular imaging revealed the in vivo profile of cysteine protease activation and vascular distribution within the lung typifying the inflammatory response to LPS insult. Results were correlated with standard in vitro laboratory tests (Western blot, bronchoalveolar lavage or BAL analysis, immunohistochemistry) and revealed good correlation with the underlying activity. We demonstrated the capacity of fluorescence tomography to noninvasively and longitudinally characterize physiological, cellular, and subcellular processes associated with inflammatory disease burden in the lung. The data presented herein serve to further evince fluorescence molecular imaging as a technology highly appropriate for the biomedical laboratory.

Sign in / Sign up

Export Citation Format

Share Document