Repeatability and correlation of 129Xe- and OE-MRI

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Repeatability and correlation of hyperpolarized xenon-129 and oxygen enhanced MRI parameters in healthy volunteers

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Repeatability and correlation of 129Xe- and OE-MRI

Repeatability and correlation of hyperpolarized xenon-129 and oxygen enhanced MRI parameters in healthy volunteers

Paul J.C. Hughes, Marta Tibiletti, Matthew J. Heaton, Ho-Fung Chan Guilhem J. Collier, Matthew Austin, Laurie J. Smith, Jim Lithgow, Jo Naish, Jim M. Wild, Geoff J.M. Parker


ISMRM Conference 2020

Abstract

Introduction: Hyperpolarized xenon-129 (129Xe) is able to assess both structure and function of the lungs. Oxygen enhanced MRI (OE-MRI) is a low-cost and easier to implement proton MRI acquisition method that may provide alternative functional metrics to 129Xe. We studied the repeatability of 129Xe and OE-MRI parameters in a population of adult healthy volunteers, and evaluated the degree of correlation between the resulting metrics.

Discussion: All 129Xe metrics had bias close to zero, as assessed by Bland-Altman analysis, with the sub-voxel measures of ADC, LmD and RBC:TP being the most repeatable. Furthermore, all 129Xe metrics had narrow limits of agreement suggesting these metrics to be suitable for longitudinal assessment of patients. OE-VVF was the most repeatable OE-MRI metric, with the remaining three having reasonable repeatability, strongly influenced by one subject (HV03) who showed large variability between visits. The existence of a correlation between ΔPO2 and 129Xe ventilation heterogeneity measures in healthy volunteers requires further investigation. 

Conclusions: 129Xe and OE MRI metrics are reproducible and it is feasible to acquire images using both methods in volunteers.
 

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Repeatability and correlation of 129Xe- and OE-MRI
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On gamma variate fitting

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On gamma variate fitting for perfusion quantification in the lung

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Perfusion quantification in the lung

On gamma variate fitting for perfusion quantification in the lung.

Marta Tibiletti, Jo Naish, Matthew J. Heaton, Paul Hughes, Jim Wild, Geoff JM Parker

 

ISMRM Conference 2020

Abstract

Imaging of the first pass of a contrast agent bolus through a tissue allows the measurement of blood flow (BF), blood volume (BV) and mean transit time (MTT). Application of first pass imaging to the lung with MRI has significant advantages over perfusion quantification with SPECT or CT. The majority of works on this topic apply a Singular Value Decomposition (SVD4) with or without a prior fit to a gamma variate (GV) function to the concentration-time curve. In this study we compare lung perfusion quantification with and without GV fitting in a population of patients with interstitial lung disease (ILD). We also compare results from two GV formulations, as described by Madsen and by Li.

The presence and choice of gamma variate fitting has an influence on perfusion parameters, but this is generally very small, except for mean transit time. GV1 is to be preferred to GV2 given the the lower dispersal of results and only minimally higher fitting residuals. Also, the observed correlations between perfusion MR parameters and lung function tests are similar between fitting with GV1 and no fit, suggesting that these approaches are broadly equivalent in practice.
 

PERFUSION QUANTIFICATION IN THE LUNG
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Development of IL2 derived PET tracer

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Development and Evaluation of Interleukin-2–Derived Radiotracers for PET Imaging of T Cells in Mice

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IL2 PET Tracers for imaging mouse T-cells

Development and Evaluation of Interleukin-2–Derived Radiotracers for PET Imaging of T Cells in Mice

Elly L. van der Veen, Frans V. Suurs, Frederik Cleeren, Guy Bormans, Philip H. Elsinga, Geke A.P. Hospers, Marjolijn N. Lub-de Hooge, Elisabeth G.E. de Vries, Erik F.J. de Vries and Inês F. Antunes

Journal of Nuclear Medicine Sept. 2020, 6(9) 1355-1360; DOI:10.2967/jnumed.119.238782

Abstract

Recently, N-(4-18F-fluorobenzoyl)-interleukin-2 (18F-FB-IL2) was introduced as a PET tracer for T cell imaging. However, production is complex and time-consuming. Therefore, we developed 2 radiolabeled IL2 variants, namely aluminum 18F-fluoride-(restrained complexing agent)-IL2 (18F-AlF-RESCA-IL2) and 68Ga-gallium-(1,4,7-triazacyclononane-4,7-diacetic acid-1-glutaric acid)-IL2 (68Ga-Ga-NODAGA-IL2), and compared their in vitro and in vivo characteristics with 18F-FB-IL2. 

Methods: Radiolabeling of 18F-AlF-RESCA-IL2 and 68Ga-Ga-NODAGA-IL2 was optimized, and stability was evaluated in human serum. Receptor binding was studied with activated human peripheral blood mononuclear cells (hPBMCs). Ex vivo tracer biodistribution in immunocompetent BALB/cOlaHsd (BALB/c) mice was performed at 15, 60, and 90 min after tracer injection. In vivo binding characteristics were studied in severe combined immunodeficient (SCID) mice inoculated with activated hPBMCs in Matrigel. Tracer was injected 15 min after hPBMC inoculation, and a 60-min dynamic PET scan was acquired, followed by ex vivo biodistribution studies. Specific uptake was determined by coinjection of tracer with unlabeled IL2 and by evaluating uptake in a control group inoculated with Matrigel only. 

Results: 68Ga-Ga-NODAGA-IL2 and 18F-AlF-RESCA-IL2 were produced with radiochemical purity of more than 95% and radiochemical yield of 13.1% ± 4.7% and 2.4% ± 1.6% within 60 and 90 min, respectively. Both tracers were stable in serum, with more than 90% being intact tracer after 1 h. In vitro, both tracers displayed preferential binding to activated hPBMCs. Ex vivo biodistribution studies on BALB/c mice showed higher uptake of 18F-AlF-RESCA-IL2 than of 18F-FB-IL2 in liver, kidney, spleen, bone, and bone marrow. 68Ga-Ga-NODAGA-IL2 uptake in liver and kidney was higher than 18F-FB-IL2 uptake. In vivo, all tracers revealed uptake in activated hPBMCs in SCID mice. Low uptake was seen after a blocking dose of IL2 and in the Matrigel control group. In addition, 18F-AlF-RESCA-IL2 yielded the highest-contrast PET images of target lymph nodes. 

Conclusion: Production of 18F-AlF-RESCA-IL2 and 68Ga-Ga-NODAGA-IL2 is simpler and faster than that of 18F-FB-IL2. Both tracers showed good in vitro and in vivo characteristics, with high uptake in lymphoid tissue and hPBMC xenografts.

IL2 PET TRACERS FOR IMAGING MOUSE T-CELLS
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Proton relaxation in liver

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Survey of Water Proton Longitudinal Relaxation in Liver in vivo

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Liver longitudinal relaxation in-vivo

Survey of water proton longitudinal relaxation in liver in vivo

by John Charles Waterton


Magn Reson Mater Phy (2021). doi: 10.1007/s10334-021-00928-x

Abstract

Objective: To determine the variability, and preferred values, for normal liver longitudinal water proton relaxation rate R1 in the published literature.

Methods: Values of mean R1 and between-subject variance were obtained from literature searching. Weighted means were fitted to a heuristic and to a model.

Results: After exclusions, 116 publications (143 studies) remained, representing apparently normal liver in 3392 humans, 99 mice and 249 rats. Seventeen field strengths were included between 0.04 T and 9.4 T. Older studies tended to report higher between-subject coefficients of variation (CoV), but for studies published since 1992, the median between-subject CoV was 7.4%, and in half of those studies, measured R1 deviated from model by 8.0% or less.

Discussion: The within-study between-subject CoV incorporates repeatability error and true between-subject variation. Between-study variation also incorporates between-population variation, together with bias from interactions between methodology and physiology. While quantitative relaxometry ultimately requires validation with phantoms and analysis of propagation of errors, this survey allows investigators to compare their own R1 and variability values with the range of existing literature.

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LIVER LONGITUDINAL RELAXATION IN VIVO
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IB in animal models for DIILD

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Imaging Biomarkers in Animal Models of Drug-Induced Lung Injury: A Systematic Review

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Imaging Biomarkers in DIILD Models

Imaging Biomarkers in Animal Models of Drug-Induced Lung Injury: A Systematic Review

Irma Mahmutovic Persson, Karin von Wachenfeldt, John C Waterton, Lars E Olsson, On Behalf Of The Tristan Consortium


J Clin Med., 30 Dec 2020;10(1):107; doi:10.3390/jcm10010107

 

Abstract

For drug-induced interstitial lung disease (DIILD) translational imaging biomarkers are needed to improve detection and management of lung injury and drug-toxicity. Literature was reviewed on animal models in which in vivo imaging was used to detect and assess lung lesions that resembled pathological changes found in DIILD, such as inflammation and fibrosis. A systematic search was carried out using three databases with key words "Animal models", "Imaging", "Lung disease", and "Drugs". A total of 5749 articles were found, and, based on inclusion criteria, 284 papers were selected for final data extraction, resulting in 182 out of the 284 papers, based on eligibility. Twelve different animal species occurred and nine various imaging modalities were used, with two-thirds of the studies being longitudinal. The inducing agents and exposure (dose and duration) differed from non-physiological to clinically relevant doses. The majority of studies reported other biomarkers and/or histological confirmation of the imaging results. Summary of radiotracers and examples of imaging biomarkers were summarized, and the types of animal models and the most used imaging modalities and applications are discussed in this review. Pathologies resembling DIILD, such as inflammation and fibrosis, were described in many papers, but only a few explicitly addressed drug-induced toxicity experiments.

IMAGING BIOMARKERS FOR DIILD MODELS
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New TRISTAN Project Leverages Potential of Imaging Techniques

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New TRISTAN Project Leverages Potential of Imaging Techniques in Drug Safety Assessment

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Press Release

New TRISTAN Project Leverages Potential of Imaging Techniques in Drug Safety Assessment

Brussels, April 12 2017 – The Innovative Medicines Initiative (IMI) has approved the 5-year project TRISTAN focusing on validation of translational imaging methods as potential imaging biomarkers.

TRISTAN (Translational Imaging in Drug Safety Assessment) is a public-private partnership supported by the Innovative Medicines Initiative (IMI) and involving 21 organisations including academics centres, research organisations, small and medium-size enterprises (SMEs), imaging and pharmaceutical companies. The objective of the project is to validate or qualify translational imaging methods as potential imaging biomarkers. The imaging biomarker qualification will be specifically addressed in three areas with a high unmet medical need: the assessment of liver toxicity, lung toxicity and the bio-distribution of biologics. The in-kind contributions to the project of around EUR 12 million by the industrial partners are complemented by IMI-funding in a total budget of EUR 24 million. TRISTAN is led by Bayer and coordinated by the European Organisation for Research and Treatment of Cancer (EORTC), who also leads one imaging biomarker qualification study for cancer drug induced interstitial lung disease.

Imaging techniques are firm components of today’s medical practices, just as the use of biomarkers has become commonplace in pre-clinical and clinical research. However, imaging biomarkers are not widely used in the drug discovery process although they could advance drug safety evaluation, both for pre-clinical and clinical development. Imaging biomarkers have the potential to improve translatability of pre-clinical (animal) data to healthy volunteers and patients and thus could help avoid late stage attrition of development programmes. In addition, functional diagnostic imaging methods used as biomarkers would offer the possibility to confirm drug toxicity mechanisms in humans, including the potential to determine drug-drug interactions.

Data relevant for validation of methods addressed in the project and aggregated data will be made publicly available in compliance with data privacy laws. Significant interactions with existing imaging biomarker initiatives as well as with regulatory authorities will have a strong impact on the future value of imaging biomarker procedures. To sustainably offer access to the validated imaging biomarkers, the three project SME partners are planning to offer respective biomarker imaging services commercially.

About Imaging Biomarkers

An imaging biomarker is a functional radiographic imaging procedure utilising imaging modalities like Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET). In research and development, imaging biomarkers are used as characteristics to objectively measure biological processes, pathological changes, or pharmaceutical responses to a therapeutic intervention. They have the advantage of remaining non-invasive and being spatially and temporally resolved. Imaging biomarkers have the potential to improve translatability of animal data to healthy volunteers and patients, thereby helping to improve our understanding of drug mechanisms, interactions and metabolic processes.

About the Innovative Medicines Initiative (IMI)

The Innovative Medicines Initiative (IMI) is working to improve health by speeding up the development of, and patient access to, innovative medicines, particularly in areas where there is an unmet medical or social need. It does this by facilitating collaboration between the key players involved in healthcare research, including universities, the pharmaceutical and other industries, small and medium-sized enterprises (SMEs), patient organisations, and medicines regulators. IMI is a partnership between the European Union and the European pharmaceutical industries, represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA). Through the IMI 2 programme, IMI has a budget of EUR 3.3 billion for the period 2014-2024. Half of this comes from the EU’s research and innovation programme, Horizon 2020. The other half comes from large companies, mostly from the pharmaceutical sector; these do not receive any EU funding, but contribute to the projects ‘in kind’, for example by donating their researchers’ time or providing access to research facilities or resources.

The research leading to these results received funding from the Innovative Medicines Initiatives 2 Joint Undertaking under grant agreement No 116106. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

 

 

 

Partners in TRISTAN

The project is coordinated and led by:

European Organisation for Research and Treatment of Cancer, EORTC (Coordinator)
Bayer (Lead)
Bioxydyn (Co-coordinator)
GlaxoSmithKline (Co-lead)

Other partners
AbbVie
Antaros Medical
Bruker
Chalmers University of Technology
Université de Bourgogne Dijon
GE Healthcare
University Medical Center Groningen
University of Leeds
Lund University
University of Manchester
MSD
Radboud University Nijmegen
Novo Nordisk
Pfizer
Sanofi
University of Sheffield
Truly Labs

More info on IMI: www.imi.europa.eu

PRESS RELEASE
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89Zr-Immuno-Positron Emission Tomography in Oncology

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89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry.

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89Zr Radiochemistry Review

89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry.

Heskamp S, Raavé R, Boerman O, Rijpkema M, Goncalves V, Denat F.


Bioconjug Chem. 2017 Aug 24. doi: 10.1021/acs.bioconjchem.7b00325.

Abstract

Immuno-positron emission tomography (immunoPET) with 89Zr-labeled antibodies has shown great potential in cancer imaging. It can provide important information about the pharmacokinetics and tumor-targeting properties of monoclonal antibodies and may help in anticipating on toxicity. Furthermore, it allows accurate dose planning for individualized radioimmunotherapy and may aid in patient selection and early-response monitoring for targeted therapies. The most commonly used chelator for 89Zr is desferrioxamine (DFO). Preclinical studies have shown that DFO is not an ideal chelator because the 89Zr–DFO complex is partly unstable in vivo, which results in the release of 89Zr from the chelator and the subsequent accumulation of 89Zr in bone. This bone accumulation interferes with accurate interpretation and quantification of bone uptake on PET images. Therefore, there is a need for novel chelators that allow more stable complexation of 89Zr. In this Review, we will describe the most recent developments in 89Zr radiochemistry, including novel chelators and site-specific conjugation methods.

89ZR RADIOCHEMISTRY REVIEW
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In vivo models of Drug Induced ILD; tools to study

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In vivo models of Drug Induced ILD; tools to study and improve drug safety (Conference Abstract)

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Conference Abstract: DIILD in vivo models

In vivo models of Drug Induced ILD; tools to study and improve drug safety (Conference Abstract)

Irma Mahmutovic Persson, Hanna Falk Håkansson, Per-Ola Önnervik, Janne Persson, Karin von Wachenfeldt, Lars E. Olsson - on behalf of the TRISTAN Consortium


ERS Lung Science Conference (LSC), 8-11 March 2018, Estoril, Portugal

 

Background

Drug safety is extremely important, yet many drugs on the market have the possibility to induce interstitial lung injury, also known as drug induced interstitial lung disease (DIILD), although they are not administered locally into the lung. Once DIILD starts to develop, patients are normally taken off the drug, and in more severe cases treated with glucocorticoids. As a result, the induced lung injury resolve in many patients while others continue to develop progressive disease. In order to improve drug development in the future, and also to understand how to better treat patients with progressive DIILD, additional studies are required to investigate the underlying mechanisms of e.g. cell and matrix interactions. Well characterized models are needed for evaluation and development of biomarkers in order to better understand and accordingly prevent the progression of DIILD. The work presented here is part of a larger effort supported by IMI aiming at developing and validating pre-clinical imaging biomarkers for DIILD (TRISTAN). As a first step, a robust Bleomycin model is developed by testing various doses of Bleomycin from different manufacturers, along with imaging-monitoring of disease progression correlating this to cell- and histology analyses.

CONFERENCE ABSTRACT: DIILD IN VIVO MODELS
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Noninvasive Preclinical and Clinical Imaging of Liver

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Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

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DILI Book Chapter

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

J. Gerry Kenna, John C. Waterton, Andreas Baudy, Aleksandra Galetin, Catherine D. G. Hines, Paul Hockings, Manishkumar Patel, Daniel Scotcher, Steven Sourbron, Sabina Ziemian and Gunnar Schuetz


In: Chen M., Will Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. Humana Press, New York, NY doi: 10.1007/978-1-4939-7677-5_30.

 

Abstract

Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and drug-induced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug−drug interactions mediated via hepatobiliary transporter perturbation.

DILI BOOK CHAPTER
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In vitro and in vivo comparison of the novel

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In vitro and in vivo comparison of the novel 89Zr chelator DFO-cyclo* with DFO (Conference Abstract)

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Conference Abstract: DFO-cyclo versus DFO

In vitro and in vivo comparison of the novel 89Zr chelator DFO-cyclo* with DFO (Conference Abstract)

Rene Raave, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Victor Goncalves, Franck Denat


ESRR 18, 19th European Symposium on Radiopharmacy and Radiopharmaceuticals, 05-08 April 2018, Groningen, Netherlands

Abstract

The current “gold standard” chelator to label antibodies with 89Zr for immunoPET is desferrioxamine (DFO). Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in release of 89Zr and subsequent accumulation of 89Zr in mineral bone tissue. This bone uptake may prevent the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for a more stable 89Zr chelator. Here we report DFO-cyclo*, a preorganized extended DFO derivative introducing an octacoordination, and investigate the stability of its 89Zr complex over the unsaturated hexacoordinated 89Zr-DFO complex in vitro and in vivo.

CONFERENCE ABSTRACT: DFO-CYCLO VERSUS DFO
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