Quantify tumor CD8 cell infiltration

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Head-to-head comparison of nuclear imaging techniques to quantify tumor CD8+ T cell infiltration (conference abstract)

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quantify tumor CD8+ T-cell infiltration

Head-to-head comparison of nuclear imaging techniques to quantify tumor CD8+ T cell infiltration 

by Gerwin Sandker, René Raavé, Ines Antunes, Peter Wierstra, Iris Hagemans, Milou Boswinkel, Gerben Franssen, Janneke Molkenboer-Kuenen, Johan Bussink, Gosse Adema, Erik Aarntzen, Martijn Verdoes, Sandra Heskamp


EMIM 2022 Conference Abstract

Abstract

Background: 
CD8+ T cells are key effector cells in anti-tumor immune responses. Immunotherapies (re)activating these cells are promising cancer treatments. Prevalent immune-related adverse effects and high costs combined with limited treatment responses necessitate biomarkers predicting response. Previous studies have shown that nuclear imaging techniques with radiolabeled anti-CD8 antibodies, IL2 and ex vivo labeled cells can be used to noninvasively evaluate the whole-body and tumor residing distribution of CD8+ T cells over time. In this study, we perform a head-to-head comparison of these techniques.
Methods: 
C57BL/6 mice bearing B16F10/ova tumors were randomized in 3 groups (n=10) to receive either: 1) 89Zr-labeled DFO-conjugated Fc-silent anti-CD8 antibodies (89Zr-antiCD8lala), 2) from donor mice isolated and ex vivo 89Zr-oxine labeled OT1 T cells (89Zr-OT1), or 3) 18F-labeled RESCA-IL2 (18F-IL2). Mice were injected intravenously with 89Zr-antiCD8lala 72 hours, 89Zr-OT1 48 hours, and 18F-IL2 directly before PET/CT scanning and dissection. Additionally, 89Zr-OT1 mice were PET/CT scanned 24 hours after injection. Following dissection, relevant tissues were collected for ex vivo biodistribution analysis. Next, tumors were halved for subsequent immunohistochemistry and autoradiography evaluation, and flow cytometric analysis to evaluate the number of CD8+ T cells. 
Results/Discussion: 
Preliminary data analysis suggests tumor uptake of 89Zr-antiCD8lala, 89Zr-OT1 and 18F-IL2 above background levels. Furthermore, uptake of 89Zr-antiCD8lala and 89Zr-OT1 was observed in the spleen and lymph nodes. (Figure 1 A and B) 18F-IL2 accumulation was observed in spleen, lung and the excretory organs. (Figure 1 C) The uptake of 89Zr-antiCD8lala and 18F-IL2 in lymphoid organs indicates their target specificity, whereas the uptake of 89Zr-OT1 indicates that the OT1 T cells were viable and retained their migratory ability.
Conclusions: 
Preliminary data analysis suggests quantifiable tumor uptake of each tracer. Further analysis will investigate the correlations between the quantified PET signal and the number of CD8+ T cells in the tumor as determined by flow cytometry. Moreover, immunohistochemistry for CD8 will be performed to investigate the spatial correlation with autoradiographic images.

Quantify tumor CD8+ T-cell infiltration
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IB of lung ventilationfrom XE and OE MRI

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Imaging biomarkers of lung ventilation in interstitial lung disease from 129Xe and oxygen enhanced 1H MRI

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Imaging Biomarker of ventilation in ILD

Imaging biomarkers of lung ventilation in interstitial lung disease from 129Xe and oxygen enhanced 1H MRI

by Marta Tibiletti, James A. Eaden, Josephine H. Naisha, Paul J.C. Hughes, John C. Waterton, Matthew J. Heaton, Nazia Chaudhurie, Sarah Skeoch, Ian N. Bruce, Stephen Bianchi, Jim M. Wild, Geoff J.M. Parker


Magn Reson Imag 2023 (95), p. 39-49. doi: 10.1016/j.mri.2022.10.005

Abstract

Purpose
To compare imaging biomarkers from hyperpolarised 129Xe ventilation MRI and dynamic oxygen-enhanced MRI (OE-MRI) with standard pulmonary function tests (PFT) in interstitial lung disease (ILD) patients. To evaluate if biomarkers can separate ILD subtypes and detect early signs of disease resolution or progression.

Study type
Prospective longitudinal.

Population
Forty-one ILD (fourteen idiopathic pulmonary fibrosis (IPF), eleven hypersensitivity pneumonitis (HP), eleven drug-induced ILD (DI-ILD), five connective tissue disease related-ILD (CTD-ILD)) patients and ten healthy volunteers imaged at visit 1. Thirty-four ILD patients completed visit 2 (eleven IPF, eight HP, ten DIILD, five CTD-ILD) after 6 or 26 weeks.

Field strength/sequence
MRI was performed at 1.5 T, including inversion recovery T1 mapping, dynamic MRI acquisition with varying oxygen levels, and hyperpolarised 129Xe ventilation MRI. Subjects underwent standard spirometry and gas transfer testing.

Assessment
Five 1H MRI and two 129Xe MRI ventilation metrics were compared with spirometry and gas transfer measurements.

Statistical test
To evaluate differences at visit 1 among subgroups: ANOVA or Kruskal-Wallis rank tests with correction for multiple comparisons. To assess the relationships between imaging biomarkers, PFT, age and gender, at visit 1 and for the change between visit 1 and 2: Pearson correlations and multilinear regression models.

Results
The global PFT tests could not distinguish ILD subtypes. Percentage ventilated volumes were lower in ILD patients than in HVs when measured with 129Xe MRI (HV 97.4 ± 2.6, CTD-ILD: 91.0 ± 4.8 p = 0.017, DI-ILD 90.1 ± 7.4 p = 0.003, HP 92.6 ± 4.0 p = 0.013, IPF 88.1 ± 6.5 p < 0.001), but not with OE-MRI. 129Xe reported more heterogeneous ventilation in DI-ILD and IPF than in HV, and OE-MRI reported more heterogeneous ventilation in DI-ILD and IPF than in HP or CTD-ILD. The longitudinal changes reported by the imaging biomarkers did not correlate with the PFT changes between visits.

Data conclusion
Neither 129Xe ventilation nor OE-MRI biomarkers investigated in this study were able to differentiate between ILD subtypes, suggesting that ventilation-only biomarkers are not indicated for this task. Limited but progressive loss of ventilated volume as measured by 129Xe-MRI may be present as the biomarker of focal disease progresses. OE-MRI biomarkers are feasible in ILD patients and do not correlate strongly with PFT. Both OE-MRI and 129Xe MRI revealed more spatially heterogeneous ventilation in DI-ILD and IPF.

Imaging Biomarker for Ventilation in ILD
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In vivo PET of 89Zr-PLGA-NH2 labelled Monocytes

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In Vivo PET Imaging of Monocytes Labeled with [89Zr]Zr-PLGA-NH2 Nanoparticles in Tumor and Staphylococcus aureus Infection Models

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PET  of Monocytes IN tUMOR AND INFECTION MODEL

In Vivo PET Imaging of Monocytes Labeled with [89Zr]Zr-PLGA-NH2 Nanoparticles in Tumor and Staphylococcus aureus Infection Models

by Massis Krekorian, Kimberley R. G. Cortenbach ,Milou Boswinkel, Annemarie Kip, Gerben M. Franssen, Andor Veltien, Tom W. J. Scheenen, René Raavé, Nicolaas Koen van Riessen, Mangala Srinivas, Ingrid Jolanda M. de Vries, Carl G. Figdor, Erik H. J. G. Aarntzen and Sandra Heskamp


Cancers 2021, 13(20), 5069. doi: 10.3390/cancers13205069

Abstract

Non-invasive imaging biomarkers (IBs) are warranted to enable improved diagnostics and follow-up monitoring of interstitial lung disease (ILD) including drug-induced ILD (DIILD). Of special interest are IB, which can characterize and differentiate acute inflammation from fibrosis. The aim of the present study was to evaluate a PET-tracer specific for Collagen-I, combined with multi-echo MRI, in a rat model of DIILD. Rats were challenged intratracheally with bleomycin, and subsequently followed by MRI and PET/CT for four weeks. PET imaging demonstrated a significantly increased uptake of the collagen tracer in the lungs of challenged rats compared to controls. This was confirmed by MRI characterization of the lesions as edema or fibrotic tissue. The uptake of tracer did not show complete spatial overlap with the lesions identified by MRI. Instead, the tracer signal appeared at the borderline between lesion and healthy tissue. Histological tissue staining, fibrosis scoring, lysyl oxidase activity measurements, and gene expression markers all confirmed establishing fibrosis over time. In conclusion, the novel PET tracer for Collagen-I combined with multi-echo MRI, were successfully able to monitor fibrotic changes in bleomycin-induced lung injury. The translational approach of using non-invasive imaging techniques show potential also from a clinical perspective.

Pet of Monocytes in tumor and infection model
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Dual-Labeled Immunoconjugates for PET/NIRF

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Site-Specific, Platform-Based Conjugation Strategy for the Synthesis of Dual-Labeled Immunoconjugates for Bimodal PET/NIRF Imaging of HER2-Positive Tumors

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dual-labelled Immunoconjugates for PET/NIRF

Site-Specific, Platform-Based Conjugation Strategy for the Synthesis of Dual-Labeled Immunoconjugates for Bimodal PET/NIRF Imaging of HER2-Positive Tumors

by Pierre Adumeau, René Raavé, Milou Boswinkel, Sandra Heskamp, Hans J. C. T. Wessels, Alain J. van Gool, Mathieu Moreau, Claire Bernhard, Laurène Da Costa, Victor Goncalves, and Franck Denat


Bioconjugate Chem. 2022, 33, 3, 530–540. doi: 10.1021/acs.bioconjchem.2c00049

Abstract

Because positron emission tomography (PET) and optical imaging are very complementary, the combination of these two imaging modalities is very enticing in the oncology field. Such bimodal imaging generally relies on imaging agents bearing two different imaging reporters. In the bioconjugation field, this is mainly performed by successive random conjugations of the two reporters on the protein vector, but these random conjugations can alter the vector properties. In this study, we aimed at abrogating the heterogeneity of the bimodal imaging immunoconjugate and mitigating the impact of multiple random conjugations. A trivalent platform bearing a DFO chelator for 89Zr labeling, a NIR fluorophore, IRDye800CW, and a bioconjugation handle was synthesized. This bimodal probe was site-specifically grafted to trastuzumab via glycan engineering. This new bimodal immunoconjugate was then investigated in terms of radiochemistry, in vitro and in vivo, and compared to the clinically relevant random equivalent. In vitro and in vivo, our strategy provides several improvements over the current clinical standard. The combination of site-specific conjugation with the monomolecular platform reduced the heterogeneity of the final immunoconjugate, improved the resistance of the fluorophore toward radiobleaching, and reduced the nonspecific uptake in the spleen and liver compared to the standard random immunoconjugate. To conclude, the strategy developed is very promising for the synthesis of better defined dual-labeled immunoconjugates, although there is still room for improvement. Importantly, this conjugation strategy is highly modular and could be used for the synthesis of a wide range of dual-labeled immunoconjugates.

Dual-Labeled Immunoconjugates for PET/NIRF
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AI based segmentation for dosimetry

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Manual versus artificial intelligence-based segmentations as a pre-processing step in whole-body dosimetry calculations (conference abstract)

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Manual vs AI based segmentation for dosimetry

Manual versus artificial intelligence-based segmentations as a pre-processing step in whole-body dosimetry calculations

by Joyce van Sluis, Walter Noordzij, Lars Edenbrandt, Elisabeth G. E. de Vries, Adrienne H. Brouwers, and Ronald Boellaard


Poster presentation at the EANM 2021 conference

Abstract

Aim/Introduction

Over the last decades, labelling of monoclonal antibodies (MAbs) with zirconium-89 (89Zr) allowed whole body assessment of MAb distribution and tumour targeting over time with molecular imaging. The main advantage of 89Zr is the long half-life of 78.4 h matching the pharmacokinetic behaviour of antibodies, making it suitable for labelling of MAbs.     
The long physical half-life of 89Zr and the long biological half-life of MAbs may cause high radiation burden and/or limits the amount of activity that can be administered, which in turn limits image quality. It is therefore important to obtain reliable radiation dose estimates to optimize the amount of activity that can be administered while keeping radiation burden within acceptable limits.
Organ segmentation is required for whole-body dosimetry but is a very time-consuming task. Therefore, we explored the possibility of using an AI based automated segmentation tool as a pre-processing step for calculating the organ and whole-body effective doses. 

Materials and Methods

Retrospective PET/CT data of six patients undergoing treatment with 89Zr-labelled pembrolizumab were included in this study. Manual organ segmentations were performed using in-house developed software and biodistribution information was obtained. Using the activity biodistribution information, residence times were calculated. The obtained residence times served as input for OLINDA XLM version 1.0 (Vanderbilt University, 2003) to calculate the effective dose per organ as well as the whole-body effective dose (mSv/MBq) according to ICRP60 and ICRP103 guidelines.     
Subsequently, organ segmentations were also performed using Recomia, a cloud-based AI platform for nuclear medicine and radiology research. The workflow for calculating residence times and whole-body effective doses, as described above, was repeated. 

Results

Patient data were obtained at three different time-points, day 2, 4, and 7 postinjecton, resulting in 18 PET/CT scans. Overall analysis time was approximately half a workday for manual segmentations compared to ≤30 min using Recomia. Whole-body effective doses differed minimally for the six patients with a median difference in received mSv/MBq of 0.49% (range 0.12 – 1.58%) according to ICRP60 and 0.52% (range 0.15 – 1.95%) according to ICRP103.

Conclusion

These first results suggest that whole-body dosimetry calculations can benefit from fast automated AI based whole-organ segmentations using Recomia. As newly developed MAbs are quickly emerging in anti-cancer therapy, whole-body effective doses for these different therapeutic agents can be assessed quickly and efficiently.

Manual vs AI based segmentation for dosimetry
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Zr-Pembro to assess PD-1 block in patients

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89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer

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89Zr-Pembrolizumab to assess clinical PD-1 Block

89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer

by II.C.Kok, J.S.Hooiveld, P.P.van de Donk, D.Giesen, E.L.van der Veen, M.N.Lub-de Hooge, A.H.Brouwers, T.J.N.Hiltermann, A.J.van der Wekken, L.B.M.Hijmering-Kappelle, W.Timens, S.G.Elias, G.A.P.Hospers, H.J.M.Groen, W.Uyterlinde, B.van der Hiel, J.B.Haanen, D.J.A.de Groot, M.Jalving, E.G.E.de Vries


Annals of Oncology. 2022, 33(1), 80. doi: 10.1016/j.annonc.2021.10.213

Abstract

Background
Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment.

Patients and methods
Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUVmax) and expressed as geometric mean. Normal organ uptake was calculated as SUVmean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1.

Results
Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUVmax did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUVmean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation.

Conclusion
89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.

89Zr-Pembrolizumab to clinically assess PD-1 blockade
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PBPK Modelling of PV in Rats

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Physiologically Based Pharmacokinetic Modeling of Transporter-Mediated Hepatic Disposition of Imaging Biomarker Gadoxetate in Rats

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PBPK Modelling of gadoxetate in rat liver

Physiologically Based Pharmacokinetic Modeling of Transporter-Mediated Hepatic Disposition of Imaging Biomarker Gadoxetate in Rats

Daniel Scotcher, Nicola Melillo, Sirisha Tadimalla, Adam S. Darwich, Sabina Ziemian, Kayode Ogungbenro, Gunnar Schütz, Steven Sourbron, and Aleksandra Galetin


ACS Mol. Pharmaceutics 2021, 18, 8, 2997-3009; doi:10.1021/acs.molpharmaceut.1c00206

Abstract

Physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development to simulate changes in both systemic and tissue exposures that arise as a result of changes in enzyme and/or transporter activity. Verification of these model-based simulations of tissue exposure is challenging in the case of transporter-mediated drug–drug interactions (tDDI), in particular as these may lead to differential effects on substrate exposure in plasma and tissues/organs of interest. Gadoxetate, a promising magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). In this study, we developed a gadoxetate PBPK model and explored the use of liver-imaging data to achieve and refine in vitro–in vivo extrapolation (IVIVE) of gadoxetate hepatic transporter kinetic data. In addition, PBPK modeling was used to investigate gadoxetate hepatic tDDI with rifampicin i.v. 10 mg/kg. In vivo dynamic contrast-enhanced (DCE) MRI data of gadoxetate in rat blood, spleen, and liver were used in this analysis. Gadoxetate in vitro uptake kinetic data were generated in plated rat hepatocytes. Mean (%CV) in vitro hepatocyte uptake unbound Michaelis–Menten constant (Km,u) of gadoxetate was 106 μM (17%) (n = 4 rats), and active saturable uptake accounted for 94% of total uptake into hepatocytes. PBPK–IVIVE of these data (bottom-up approach) captured reasonably systemic exposure, but underestimated the in vivo gadoxetate DCE–MRI profiles and elimination from the liver. Therefore, in vivo rat DCE–MRI liver data were subsequently used to refine gadoxetate transporter kinetic parameters in the PBPK model (top-down approach). Active uptake into the hepatocytes refined by the liver-imaging data was one order of magnitude higher than the one predicted by the IVIVE approach. Finally, the PBPK model was fitted to the gadoxetate DCE–MRI data (blood, spleen, and liver) obtained with and without coadministered rifampicin. Rifampicin was estimated to inhibit active uptake transport of gadoxetate into the liver by 96%. The current analysis highlighted the importance of gadoxetate liver data for PBPK model refinement, which was not feasible when using the blood data alone, as is common in PBPK modeling applications. The results of our study demonstrate the utility of organ-imaging data in evaluating and refining PBPK transporter IVIVE to support the subsequent model use for quantitative evaluation of hepatic tDDI.

PBPK Modelling of Gadoxetate in Rat Liver
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Liver T1 Mapping with vFA

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Bias, repeatability and reproducibility of liver T1 mapping with variable flip angles

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Liver T1 Mapping with vFA

Bias, repeatability and reproducibility of liver T1 mapping with variable flip angles

Sirisha Tadimalla, Daniel Wilson, David Shelley, Gavin Bainbridge, Margaret Saysell, Iosif A Mendichovszky, Martin Graves, Geoff JM Parker, Steven Sourbron


ISMRM Conference 2021

Abstract

A multi-centre, multi-vendor study in 8 travelling healthy volunteers was conducted for technical validation of variable flip angle (VFA) T1 mapping in the liver across 6 scanners (3 vendors and 2 field strengths). The 95% CI was 28 ± 8% for the bias in liver T1, 10 ± 3% for the intra-scanner repeatability CV and 28 ± 6% for the inter-scanner reproducibility CV. These values are comparable to literature values for B1+-corrected VFA T1 in prostate, brain, breast, and phantoms. Any proposed refinement of the VFA method in the liver should demonstrate a significant improvement on those benchmarks before it can be recommended as a future standard.

Liver T1 Mapping with vFA
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Population AIF for lung perfusion

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Population Arterial Input Function for Lung Perfusion Imaging

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Population AIF for lung perfusion

Population Arterial Input Function for Lung Perfusion Imaging

Marta Tibiletti, Jo Naish, John C Waterton, Paul JC Hughes, James A Eaden, James M Wild, Geoff JM Parker


ISMRM Conference 2021

Abstract

Introduction: T1-weighted contrast agent (CA)-based perfusion imaging can be used to characterize the first pass of a CA bolus through the lung, allowing for the measurement of blood flow, relative blood volume and mean transit time. 
One of the method’s challenges is the accurate extraction of the Arterial Input Function (AIF), the concentration of CA in a feeding artery. Some of the issues that may arise are: curve sampling at too low temporal resolution for the rapidly changing curve; errors in the peak height due to signal saturation at high CA concentrations; incomplete spoiling; partial volume and inflow effects; and motion. 
Previous investigators have used  consensus or population-based arterial input functions (AIFs) in the analysis of extended dynamic contrast-enhanced MR data. However it is not known whether population-based AIFs are also useful in perfusion imaging based on first-pass DCEMRI.
In this work, we explore the possibility of extracting a population AIF for lung perfusion imaging, detailing the first pass of the CA bolus at high temporal resolution in the pulmonary arteries (PA). The results of the analysis using a measured AIF and the population AIF are compared.
Comments:
A population AIF was obtained from the PA. While there is significant variation among the GV fitting from which the population AIF was obtained, the variation is not related to dose but the AUC is linearly related to dose. When comparing the results of the perfusion analysis within our patient population, the only significant difference was observed in in BV, which is lower when using a population AIF. This is probably due to some of the measured AIF presenting too low AUC.

Conclusion:
In this work, we have derived a population AIF for perfusion quantification in the lung. This AIF may be of use in settings where measured AIF quality is insufficient to allow reliable quantification.
 

Population AIF for lung perfusion
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Gadoxetate MRI to assess rifampicin effect

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Acute and chronic rifampicin effect on gadoxetate uptake in rats using gadoxetate DCE-MRI

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Gadoxetate MRI to assess rifampicin effect

Acute and chronic rifampicin effect on gadoxetate uptake in rats using gadoxetate DCE-MRI

Mikael Montelius, Steven Sourbron, Nicola Melillo, Daniel Scotcher, Aleksandra Galetin, Gunnar Schuetz, Claudia Green, Edvin Johansson, John Waterton, Paul D. Hockings


ISMRM Conference 2021

Abstract

Non-invasive biomarkers for Drug Induced Liver Injury, which cause liver failure and impede drug development, and Drug-Drug Interactions affecting pharmacokinetics of drugs when combined are needed. We used gadoxetate DCE-MRI to measure clinical and high dose rifampicin effects on hepatocellular uptake in acute and chronic settings in rats. At high dose, uptake was significantly reduced after acute dosing, and returned to baseline after chronic dosing. Similar but non-significant effects was seen at clinical dose levels. We thus demonstrated the potential of gadoxetate DCE-MRI to non-invasively assess drug-induced inhibition of hepatocellular transport and DDIs. 
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Gadoxetate MRI to assess rifampicin effect
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