Assess Liver Transporter Kinetics and DDI from Imaging Data

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Insights on hepatobiliary transporter kinetics and DDIs from tissue imaging data: Lessons from PBPK modelling of gadoxetate

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Assess Liver Transporter Kinetics and DDI from Imaging Data

Insights on hepatobiliary transporter kinetics and DDIs from tissue imaging data: Lessons from PBPK modelling of gadoxetate

Daniel Scotcher

2021 Drug Metabolism Discussion Group and Swedish Academy of Pharmaceutical Sciences Online Joint Meeting

Abstract

Physiologically-based pharmacokinetic (PBPK) modelling provides a framework for in vitro-in vivo extrapolation (IVIVE) of drug disposition. Quantitative prediction of transporter-mediated processes and tissue permeation remains challenging due to the lack of available in vivo tissue data for model validation. Gadoxetate is a magnetic resonance imaging (MRI) contrast agent and substrate of organic anion transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). Gadoxetate is being explored as a novel imaging biomarker for hepatic transporter function in context of evaluation of drug-drug interactions and drug induced liver injury. The in vitro uptake kinetics of gadoxetate in plated rat hepatocytes were assessed, and transporter kinetic parameters derived using a mechanistic cell model. Subsequently, a novel PBPK model was developed for gadoxetate in rat, where liver uptake and cellular binding were informed by IVIVE. Gadoxetate in vivo blood, spleen and liver data obtained in the presence and absence of a single 10 mg/kg intravenous dose of rifampicin were used for PBPK model refinement. The PBPK model successfully predicted gadoxetate concentrations in systemic blood and spleen and corresponding increase in gadoxetate systemic exposure in the presence of rifampicin, whereas liver concentrations were under-predicted. Refinement of the PBPK model using the dynamic contrast agent enhanced (DCE)-MRI data enabled recovery of the liver profile. The current study demonstrates utility of tissue imaging data in validating and refining PBPK models for prediction of transporter-mediated disposition.
 

Assess Liver Transporter Kinetics and DDI from Imaging Data
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Imaging of DDI risk with liver transporters

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In vivo imaging and evaluation of drug-drug interaction risk arising via hepatobiliary transporters

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Imaging of DDI risk with liver transporters

In vivo imaging and evaluation of drug-drug interaction risk arising via hepatobiliary transporters

J. Gerry Kenna, Claudia Green, Catherine D. G. Hines Iina Laitinen, Aleksandra Galetin, Paul D. Hockings,  Nicola Melillo, Mikael Montelius,  Daniel Scotcher, Steven Sourbron, John C. Watertone, Gunnar Schütz
 

Virtual 2021 Annual Meeting of the US Society of Toxicology and ToxExpo

Abstract

Inhibition of transporters that mediate hepatic drug uptake and/or biliary excretion may cause clinically relevant drug-drug interactions (DDIs) leading to potentiated or reduced efficacy, and/or increased or reduced toxicity to liver or other tissues. These DDIs are difficult to assess, since accurate prediction of changes in tissue exposure in vivo based on in vitro transport interaction data is challenging. Dynamic contract enhanced magnetic resonance imaging (DCE-MRI) enables in vivo visualisation of hepatic transporter mediated uptake and efflux of the contrast agent gadoxetate. When analysed using a compartmental kinetic model of gadoxetate disposition, gadoxetate DCE-MRI studies provide quantitative rate constants for hepatic gadoxetate uptake (khe) and biliary excretion (kbh). These processes are mediated primarily by Organic Anion Transport Polypeptides (OATPs) and Multidrug Resistance Protein Type 2 (MRP2), respectively. To evaluate drug effects on hepatic gadoxetate khe and kbh, DCE-MRI studies were undertaken in adult male Wistar rats (approx. 250g body weight) dosed intravenously (iv) with single doses of 
drugs (rifampicin, asunaprevir, bosentan, cyclosporin, ketoconazole, pioglitazone) that inhibited rat oatp, and human OATP, activities in vitro. Drug doses were selected, via pharmacokinetic modelling and simulation, to achieve rat peripheral blood plasma concentrations following iv administration that were equivalent to steady-state human blood plasma concentrations. Simulations predicted that the selected doses of rifampicin and cyclosporin reduced liver gadoxetate exposure in vivo, whereas the other tested drugs did not. Gadoxetate khe values were determined 20 min after iv administration of dose vehicle and then, in the same animals, after a minimum 48 hr washout interval and following drug administration (n=6 per group). Gadoxetate khe (min-1) was reduced (p < 0.01) following administration of rifampicin at 2 mg/kg (mean +SD, dose: 0.44+0.06; vehicle: 0.92+0.17) or cyclosporin at 5 mg/kg (mean+SD, dose: 0.08+0.02; vehicle: 1.00+0.24); but not after dosing of asunaprevir at 5 mg/kg, bosentan at 2 mg/kg, ketoconazole at 3 mg/kg or pioglitazone at 0.4 mg/kg. These results indicate that gadoxetate DCE-MRI may aid assessment of hepatic transporter-mediated DDI risk.

Imaging of DDI risk with liver transporters
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129Xe-MRI to Differentiate Fibrosis and Inflammation

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Hyperpolarised 129-xenon MRI in differentiating between fibrotic and inflammatory interstitial lung disease and assessing longitudinal change

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129Xe-MRI to Differentiate Fibrosis and Inflammation

Hyperpolarised 129-xenon MRI in differentiating between fibrotic and inflammatory interstitial lung disease and assessing longitudinal change

by Irma Mahmutovic Persson, Nina Fransén Pettersson, Jian Liu, Hanna Falk Håkansson, Anders Örbom, René JA Eaden, GJ Collier, G Norquay, H-F Chan, PJC Hughes, ND Weatherley, S Rajaram, A Swift, CT Leonard, S Skeoch, N Chaudhuri, GJM Parker, SM Bianchi, JM Wild


Thorax 2021;76:A46-A47. doi: 10.1136/thorax-2020-BTSabstracts.80

Abstract

Introduction and Objectives: Apparent diffusion coefficient (ADC) and mean diffusive length scale (LmD) are diffusion-weighted (DW) MRI measurements of alveolar gas diffusion, providing novel lung microstructure information. Hyperpolarised 129-xenon (129Xe) MR spectroscopy is a quantitative marker of gas exchange, using the ratio of uptake of 129Xe in red blood cells to tissue/plasma (RBC:TP).

The objective was to evaluate hyperpolarised 129Xe MRI in differentiating between fibrotic and inflammatory ILD and assessing longitudinal change.

Methods: A prospective, multicentre study of ILD patients including connective tissue disease ILD (CTD-ILD), drug induced ILD (DI-ILD), hypersensitivity pneumonitis (HP), idiopathic non-specific interstitial pneumonia (iNSIP) and idiopathic pulmonary fibrosis (IPF). Hyperpolarised 129Xe MRI was performed on a 1.5T scanner. Baseline HRCT scan was performed within a year prior to the MRI scan. Semi-quantitative visual CT analysis was performed by two consultant chest radiologists. In the non-IPF subtypes, a ground glass opacity score <2 and ≥2 was used to define fibrotic and inflammatory ILD respectively. All IPF subjects were classified as fibrotic.

Results: To date, 34 patients (5 CTD-ILD, 9 DI-ILD, 7 HP, 2 iNSIP, 11 IPF) have complete MRI scan data for two separate visits (6 weeks apart for DI-ILD/HP/iNSIP and 6 months apart for CTD-ILD/IPF). There were 18 patients in the fibrotic group and 16 in the inflammatory group. At baseline visit there was no significant difference in mean RBC:TP between the fibrotic and inflammatory groups (0.17 vs 0.14; p=0.083), but a significant difference between the fibrotic and inflammatory groups in mean ADC (0.048 vs 0.043; p=0.030) (figure 1a) and mean LmD(261.3 vs 243.4; p=0.017) (figure 1b). In longitudinal change, there was a significant difference in mean RBC:TP between the fibrotic and inflammatory groups (-0.026 vs 0.0016; p=0.023), but no significant difference between the fibrotic and inflammatory groups in mean ADC (0.00089 vs -0.00025; p=0.25) and mean LmD (2.1 vs -0.19; p=0.39).

Conclusions: 129Xe DW-MRI could have a role in differentiating changes in the airway microstructure between fibrotic and inflammatory ILD. 129Xe RBC:TP has sensitivity to longitudinal change with a decline in gas exchange observed in the fibrotic group but not in the inflammatory group.
 

129Xe-MRI to Differentiate Fibrosis and Inflammation
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Profiling of DIILD in a Bleomycin Rat Model

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Gene expression and cellular profiling in a rat bleomycin model of drug-induced interstitial lung disease (DIILD)

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Profiling of DIILD in a Bleomycin Rat Model

Gene expression and cellular profiling in a rat bleomycin model of drug-induced interstitial lung disease (DIILD)

Irma Mahmutovic Persson, Nina Fransén Pettersson, Jian Liu, Hanna Falk-Håkansson, Lars E. Olsson and Karin von Wachenfeldt - on behalf of the TRISTAN Consortium


ESR Conference 2020

Abstract

A large number of frequently prescribed drugs have the potential to cause DIILD. We have characterized a rat model of bleomycin-triggered DIILD, by gene profiling combined with flow cytometric characterization of immune cell populations in lungs over 28 days.


Methods & Results: Sprague-Dawley rats received a single dose of intratracheal bleomycin. Longitudinal imaging was performed (MRI and 18F-FDG-PET/CT) and BAL fluid, blood, lungs and spleen collected. Lung homogenates were used for analysis of gene expression (RT-qPCR), assessment of hydroxyproline content and for flow cytometric analysis of immune cell populations in lung. Early time points were dominated by pro-inflammatory gene expression. Interestingly, fibrosis related genes, such as Gremlin1, CTGF and TGFβs, were also up-regulated (p<0.001) during the inflammatory phase (d3-7). In addition, at later time points during the fibrosis phase (d14-28) inflammatory related genes such as CCL3 (p<0.01) and TNFα stayed up-regulated. Some genes, such as IL-4 and IL-5, revealed dual peaks at d7 and at d28. Animals identified by MRI to have more severe disease demonstrated a different gene profile compared to those with less disease.  Analysis of immune cell populations during the different stages of the disease showed increased numbers of eosinophils, neutrophils and NK cells at the early stages. Neutrophils and macrophages also showed up in a second cell-peak at d28.


Conclusion: Linking the pathological changes observed by imaging to gene expression patterns and immune cell profiles in the lung, has provided an increasing understanding of how biomarkers can be implemented to develop improved DIILD- and lung injury models.

Profiling of DIILD in a Bleomycin Rat Model
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Uptake of Pembrolizumab in lymphoid organs

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89Zr-pembrolizumab biodistribution is influenced by PD-1-mediated uptake in lymphoid organs

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Uptake of Pembrolizumab in lymphoid organs 

89Zr-pembrolizumab biodistribution is influenced by PD-1-mediated uptake in lymphoid organs

Elly L van der Veen, Danique Giesen, Linda Pot-de Jong, Annelies Jorritsma-Smit, Elisabeth G E De Vries, and Marjolijn N Lub-de Hooge

 

J Immunother Cancer. 2020; 8(2): e000938. doi: 10.1136/jitc-2020-000938

Abstract

Background
To better predict response to immune checkpoint therapy and toxicity in healthy tissues, insight in the in vivo behavior of immune checkpoint targeting monoclonal antibodies is essential. Therefore, we aimed to study in vivo pharmacokinetics and whole-body distribution of zirconium-89 (89Zr) labeled programmed cell death protein-1 (PD-1) targeting pembrolizumab with positron-emission tomography (PET) in humanized mice.

Methods
Humanized (huNOG) and non-humanized NOG mice were xenografted with human A375M melanoma cells. PET imaging was performed on day 7 post 89Zr-pembrolizumab (10 µg, 2.5 MBq) administration, followed by ex vivo biodistribution studies. Other huNOG mice bearing A375M tumors received a co-injection of excess (90 µg) unlabeled pembrolizumab or 89Zr-IgG4 control (10 µg, 2.5 MBq). Tumor and spleen tissue were studied with autoradiography and immunohistochemically including PD-1.

Results
PET imaging and biodistribution studies showed high 89Zr-pembrolizumab uptake in tissues containing human immune cells, including spleen, lymph nodes and bone marrow. Tumor uptake of 89Zr-pembrolizumab was lower than uptake in lymphoid tissues, but higher than uptake in other organs. High uptake in lymphoid tissues could be reduced by excess unlabeled pembrolizumab. Tracer activity in blood pool was increased by addition of unlabeled pembrolizumab, but tumor uptake was not affected. Autoradiography supported PET findings and immunohistochemical staining on spleen and lymph node tissue showed PD-1 positive cells, whereas tumor tissue was PD-1 negative.

Conclusion
89Zr-pembrolizumab whole-body biodistribution showed high PD-1-mediated uptake in lymphoid tissues, such as spleen, lymph nodes and bone marrow, and modest tumor uptake. Our data may enable evaluation of 89Zr-pembrolizumab whole-body distribution in patients.
 

Uptake of Pembrolizumab in lymphoid organs
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Bimodal PET/NIRF imaging of HER-2 tumors

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Site-specific, platform-based dual-labeled immunoconjugate for bimodal PET/NIRF imaging of HER2-positive tumors

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Biomodal PET/NIRF Imaging of her-2 tumors

Site-specific, platform-based dual-labeled immunoconjugate for bimodal PET/NIRF imaging of HER2-positive tumors

Pierre Adumeau, René Raavé, Milou Boswinkel, Sandra Heskamp, Mathieu Moreau, Claire Bernhard, Laurène Da Costa, Victor Goncalves, Franck Denat


EMIM Conference 2020

Abstract

Introduction 
Immuno-PET/NIRF imaging is very promising for cancer therapy, as it allows non-invasive localization of the tumor and its image-guided resection. The mostly used strategy to synthesize such dual-labeled conjugates relies on a double, sequential random conjugation of the fluorophore and the radionuclide/chelator with the antibody. However, the random conjugation leads to high heterogeneity and potential loss of bioactivity and these phenomena are exponentially amplified by sequential modifications. Therefore, there is a need for a better dual-labeling strategy for PET/NIRF imaging.

Results/Discussion 
The trivalent platform BCN-DFO-IR800 was obtained in a five steps synthetic route with a global yield of 5%. Trastuzumab-N3, obtained through chemoenzymatic glycoengineering, was efficiently conjugated with the trivalent platform, leading to trastss-DFO/IR800 with a degree of labeling (DOL) of 2.0 (theoretical maximum). Trastrd-DFO/IR800 was synthesized with comparable DOL for the sake of comparison.
Radiolabeling of the conjugates with 89Zr yielded the radioconjugates with high yield, purity and specific activity (RCY >95%, RCP >99%, SA >50 MBq/mg).
The site-specific conjugate displayed lesser aggregation over time than its random cousin (after 7 days in PBS: 5.0±0.1 % vs 12.7±5.2 % for trastss-DFO/IR800 and trastrd-DFO/IR800, respectively). Fluorescence intensity of the site-specific conjugate also showed an improved stability compared to the random conjugate, the first displaying 90±1 % of the initial fluorescence intensity after 7 days in PBS, with only 25±3 % for trastrd-DFO/IR800.

Conclusion 
This is the first example of a platform-based, site-specific PET/NIRF conjugate. This strategy gives complete control over the dual-labeling of antibody. The preliminary results have demonstrated the in vitro superiority of our conjugate over the classical random bimodal conjugate. We expect these results to translate into a superior in vivo behavior of the site-specific conjugate. In vivo experiment results will be presented at the conference.
 

Bimodal PET/NIRF Imaging of HER-2 Tumors
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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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