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Recent EACVI recommendations described the importance of limiting cardiovascular imaging during the COVID-19 pandemic in order to reduce virus transmission, protect healthcare professionals from contamination, and reduce consumption of personal protective equipment. However, an elevated troponin remains a frequent request for cardiac imaging in COVID-19 patients, partly because it signifies cardiac injury due to a variety of causes and partly because it is known to convey a worse prognosis. The present paper aims to provide guidance to clinicians regarding the appropriateness of cardiac imaging in the context of troponin elevation and myocardial injury, how best to decipher the mechanism of myocardial injury, and how to guide patient management.

Brain metastases form a challenge in breast cancer patients, especially in HER2+ patients whose peripheral metastases can often be controlled using standard-of-care HER2 regimens, but with relapse or progression in the brain. This determines survival for such patients. Penetration in brain lesions as well as the therapeutic outcome can be hampered due to the particular tumour microenvironment. The here used anti-HER2 agent is a single- domain antibody or nanobody that targets HER2 with nanomolar affinity but with a size that is ten-fold smaller than conventional antibodies. This could be an important factor in diagnostic and even therapeutic efficacy for nanobody radiopharmaceuticals. The 68Ga- anti-HER2 VHH1 has been successfully tested in phase I trial in 20 breast cancer patients, confirming safety and tolerability, low irradiation burden for PET/CT procedures and high uptake in HER2-positive lesions. The aim of the current study is to test its application potential for PET/CT imaging of breast cancer brain metastases. If favourable, this would support the development therapeutic analogues for targeted radionuclide therapy. Trial design This is an open label non-randomized monocenter phase II trial in breast cancer patients with brain metastasis, investigating the uptake of the radiopharmaceutical 68Ga-anti-HER2 VHH1 in brain metastasis using PET/CT imaging. To evaluate the specificity of uptake, both HER2-positive and HER2-negative patients are eligible. The tumor targeting potential in brain metastases and other known lesions will be visually scored and quantified by an experienced nuclear medicine physician, unaware of the HER2-status. HER2 amplification will be reassessed on blood-derived cell-free DNA. A total of 30 patients (10 HER2-neg, 20 HER2-pos) will be included. The most important inclusion criteria are (i) presence of at least 1 brain metastasis of at least 8 mm, measured either on CT or MRI; (ii) minimal age 18 years old; (iii) informed consent given. Trial is in progress, with 3 HER2-postive and 1 HER2-negative patients enrolled so far. Clinical trial identification EudraCT 2015-002328-24, NCT03331601

Gelsolin amyloidosis is a dominantly inherited, incurable type of amyloidosis. A single point mutation in the gelsolin gene (G654A is most common) results in the loss of a Ca2+ binding site in the second gelsolin domain. Consequently, this domain partly unfolds and exposes an otherwise buried furin cleavage site at the surface. During secretion of mutant plasma gelsolin consecutive cleavage by furin and MT1-MMP results in the production of 8 and 5 kDa amyloidogenic peptides. Nanobodies that are able to (partly) inhibit furin or MT1-MMP proteolysis have previously been reported. In this study, the nanobodies have been combined into a single bispecific format able to simultaneously shield mutant plasma gelsolin from intracellular furin and extracellular MT1-MMP activity. We report the successful in vivo expression of this bispecific nanobody following adeno-associated virus serotype 9 gene therapy in gelsolin amyloidosis mice. Using SPECT/CT and immunohistochemistry, a reduction in gelsolin amyloid burden was detected which translated into improved muscle contractile properties. We conclude that a nanobody-based gene therapy using adeno-associated viruses shows great potential as a novel strategy in gelsolin amyloidosis and potentially other amyloid diseases.

AIMS: Positron emission tomography-computed tomography (PET-CT) is a highly sensitive clinical molecular imaging modality to study atherosclerotic plaque biology. Therefore, we sought to develop a new PET tracer, targeting vascular cell adhesion molecule (VCAM)-1 and validate it in a murine atherosclerotic model as a potential agent to detect atherosclerotic plaque inflammation. METHODS AND RESULTS: The anti-VCAM-1 nanobody (Nb) (cAbVCAM-1-5) was radiolabelled with Fluorine-18 ((18)F), with a radiochemical purity of >98%. In vitro cell-binding studies showed specific binding of the tracer to VCAM-1 expressing cells. In vivo PET/CT imaging of ApoE(-/-) mice fed a Western diet or control mice was performed at 2h30 post-injection of [(18)F]-FB-cAbVCAM-1-5 or (18)F-control Nb. Additionally, plaque uptake in different aorta segments was evaluated ex vivo based on extent of atherosclerosis. Atherosclerotic lesions in the aortic arch of ApoE(-/-) mice, injected with [(18)F]-FB-anti-VCAM-1 Nb, were successfully identified using PET/CT imaging, while background signal was observed in the control groups. These results were confirmed by ex vivo analyses where uptake of [(18)F]-FB-cAbVCAM-1-5 in atherosclerotic lesions was significantly higher compared with control groups. Moreover, uptake increased with the increasing extent of atherosclerosis (Score 0: 0.68 ± 0.10, Score 1: 1.18 ± 0.36, Score 2: 1.49 ± 0.37, Score 3: 1.48 ± 0.38%ID/g, Spearman's r(2) = 0.675, P < 0.0001). High lesion-to-heart, lesion-to-blood, and lesion-to-control vessel ratios were obtained (12.4 ± 0.4, 3.3 ± 0.4, and 3.1 ± 0.6, respectively). CONCLUSION: The [(18)F]-FB-anti-VCAM-1 Nb, cross-reactive for both mouse and human VCAM-1, allows non-invasive PET/CT imaging of VCAM-1 expression in atherosclerotic plaques in a murine model and may represent an attractive tool for imaging vulnerable atherosclerotic plaques in patients.

Camelid-derived single-domain antibody-fragments (similar to 15 kDa), called nanobodies, are a new class of molecular tracers that are routinely identified with nanomolar affinity for their target and that are easily tailored for molecular imaging and drug delivery applications. We hypothesized that they are well-suited for the design of targeted microbubbles (mu Bs) and aimed to develop and characterize eGFP- and VCAM-1-targeted mu Bs. Anti-eGFP (cAbGFP4) and anti-VCAM-1 (cAbVCAM1-5) nanobodies were site-specifically biotinylated in bacteria. This metabolic biotinylation method yielded functional nanobodies with one biotin located at a distant site of the antigen-binding region of the molecule. The biotinylated nanobodies were coupled to biotinylated lipid mu Bs via streptavidin-biotin bridging. The ability of mu B-cAbGFP4 to recognize eGFP was tested as proof-of-principle by fluorescent microscopy and confirmed the specific binding of eGFP to mu B-cAbGFP4. Dynamic flow chamber studies demonstrated the ability of mu B-cAbVCAM1-5 to bind VCAM-1 in fast flow (up to 5 dynes/cm(2)). In vivo targeting studies were performed in MC38 tumor-bearing mice (n=4). mu B-cAbVCAM1-5 or control mu B-cAbGFP4 were injected intravenously and imaged using a contrast-specific ultrasound imaging mode. The echo intensity in the tumor was measured 10 min post-injection. mu B-cAbVCAM1-5 showed an enhanced signal compared to control mu Bs (p

The rapid proliferation of micro-computed tomography (micro-CT) scanners in preclinical small animal studies has created a need for a method on scanner performance evaluation and scan parameter optimisation. The purpose of this study was to investigate the performance of the scanner with a dedicated micro-CT phantom. The phantom was developed with different independent sections that allow for measurement of major scanner characteristics such as uniformity, linearity, contrast response, dosimetry and resolution. The results of a thorough investigation are discussed.