tissue distribution of GLP1 by PET vs Autoradiography

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Comparison of the Tissue Distribution of a Long-Circulating Glucagon-like Peptide-1 Agonist Determined by Positron Emission Tomography and Quantitative Whole-Body Autoradiography

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tissue distribution of GLP1 by PET vs Autoradiography

Comparison of the Tissue Distribution of a Long-Circulating Glucagon-like Peptide-1 Agonist Determined by Positron Emission Tomography and Quantitative Whole-Body Autoradiography

by Eduardo Felipe Alves Fernandes, Jonas Wilbs, Rene Raavé, Christian Borch Jacobsen, Hanne Toftelund, Hans Helleberg, Milou Boswinkel, Sandra Heskamp, Magnus Bernt Frederik Gustafsson, and Inga Bjørnsdottir


ACS Pharmacol. Transl. Sci. 2022, 5, 8, 616–624. doi: 10.1021/acsptsci.2c00075

Abstract

Positron emission tomography (PET) is a molecular imaging modality that enables non-invasive visualization of tracer distribution and pharmacology. Recently, peptides with long half-lives allowed once-a-week dosing of glucagon-like peptide-1 receptor (GLP-1R) agonists with therapeutic applications in diabetes and obesity. PET imaging for such long-lived peptides is hindered by the typically used short-lived radionuclides. Zirconium-89 (89Zr) emerged as a promising PET radionuclide with a sufficiently long half-life to be applied for biodistribution studies of long-circulating biomolecules. A comparison between the biodistribution profiles obtained via 89Zr-PET and the current standard, quantitative whole-body autoradiography (QWBA), will be valuable for the development of novel peptide drugs. We determined the PET biodistribution of a 89Zr-labeled acylated peptide agonist of GLP-1R and compared it to the profile obtained by QWBA using analogous tritiated tracers for up to 1 week after administration. The plasma metabolic profile was obtained and identification was done for the tritiated tracers. We found that, at early time points, the biodistribution profiles agreed between PET and QWBA. At the latertime points, the 89Zr tracer remained primarily trapped in the kidneys. The introduction of desferrioxamine (DFO) chelator reduced the peptide stability, and UPLC-MS analysis identified a circulating metabolite arising from DFO hydrolysis. Kidney accumulation of radiolabeled peptides and DFO metabolic instability may compromise biodistribution studies using 89Zr-PET to support the development of new biopharmaceuticals. PET and QWBA biodistribution data correlated well during the absorption phase, but new and more stable 89Zr chelators are needed for a more accurate description of the elimination phase.

Tissue distribution of GLP1 by PET vs Autoradiography
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MTT and pulmonary blood flow

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Meta-analysis of mean transit time and pulmonary blood flow in the lung (conference abstract)
 

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MEta-analysis of MTT and pulomary blood flow

Meta-analysis of mean transit time and pulmonary blood flow in the lung

by M Tibiletti, L Edwards, J Naish, G J M Parker, J C Waterton


European Respiratory Journal 2022 60: 2147. doi: 10.1183/13993003.congress-2022.2147

Abstract

Introduction: CT and MRI can assess mean transit time (MTT) and pulmonary blood flow (PBF) in the lung. We aimed to determine whether MTT and PBF in the healthy lung are consistent across studies and differentiated from results in disease.

Method: A systematic literature search was conducted in PubMed to identify studies that quantified MTT and/or PBF in the lung. Inclusion criteria were limited to MRI or CT, English language, human subjects, injection of intravenous contrast agent, and quantitative values determined by indicator dilution theory. The weighted mean and standard deviation (SD) of MTT and PBF were estimated from the healthy volunteers’ (HV) values reported, weighted by number of subjects.

Results: We identified 34 studies for meta-analysis after exclusions, summarised in figure 1. In HV, weighted MTT was 5.91±1.84s (10 studies) and the weighted PBF 246±93 ml/100ml/min (14 studies).

Conclusion: MTT was consistent across studies in healthy volunteers and similarly in diseased subjects, with few values outside of the normal range. In comparison, PBF values were consistently markedly reduced in multiple diseases.

MTT and pulmonary blood flow
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Manual vs AI based segmentation for dosimetry

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Manual Versus Artificial Intelligence-Based Segmentations as a Pre-processing Step in Whole-body PET Dosimetry Calculations
 

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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 PET Dosimetry Calculations

by Joyce van Sluis, Walter Noordzij, Elisabeth G. E. de Vries, Iris C. Kok, Derk Jan A. de Groot, Mathilde Jalving, Marjolijn N. Lub-de Hooge, Adrienne H. Brouwers & Ronald Boellaard 


Mol Imaging Biol (2022). doi: 10.1007/s11307-022-01775-5

Abstract

Purpose
As novel tracers are continuously under development, it is 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 quantification of specific uptake in organs of interest and whole-body dosimetry but is a time-consuming task which induces high interobserver variability. Therefore, we explored using manual segmentations versus an artificial intelligence (AI)-based automated segmentation tool as a pre-processing step for calculating whole-body effective doses to determine the influence of variability in volumetric whole-organ segmentations on dosimetry.

Procedures
PET/CT data of six patients undergoing imaging with 89Zr-labelled pembrolizumab were included. Manual organ segmentations were performed, using in-house developed software, and biodistribution information was obtained. Based on the activity biodistribution information, residence times were calculated. The residence times served as input for OLINDA/EXM version 1.0 (Vanderbilt University, 2003) to calculate the whole-body effective dose (mSv/MBq).

Subsequently, organ segmentations were 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
Data were acquired on days 2, 4, and 7 post-injection, resulting in 18 scans. Overall analysis time per scan was approximately 4 h for manual segmentations compared to ≤ 30 min using AI-based segmentations. Median Jaccard similarity coefficients between manual and AI-based segmentations varied from 0.05 (range 0.00–0.14) for the pancreas to 0.78 (range 0.74–0.82) for the lungs. Whole-body effective doses differed minimally for the six patients with a median difference in received mSv/MBq of 0.52% (range 0.15–1.95%).

Conclusion
This pilot study suggests that whole-body dosimetry calculations can benefit from fast, automated AI-based whole organ segmentations.

Manual vs AI based segmentation for dosimetry
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longitudinal lung UTE-MRI vs CT for ILD

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Longitudinal comparison of quantitative UTE lung MRI and CT biomarkers in interstitial lung disease (conference abstract)

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Longitudinal comparison of lung UTE-MRI and CT

Longitudinal comparison of quantitative UTE lung MRI and CT biomarkers in interstitial lung disease

by Ho-Fung Chan, Timothy J Baldwin, Harry Barker, Neil J Stewart, James A Eaden, Paul J.C Hughes, Nicholas D Weatherley, Joshua Astley, Bilal A Tahir, Kevin M Johnson, Ronald A Karwoski, Brian J Bartholmai, Marta Tibiletti, Colm T Leonard, Sarah Skeoch, Nazia Chaudhuri, Ian N Bruce, Geoff J.M Parker, Stephen M Bianchi, and Jim M Wild


ISMRM 2022 conference abstract

Synopsis
UTE lung MRI approaches the diagnostic quality of CT, opening up the possibility for longitudinal follow-up of interstitial lung disease (ILD) progression. Two quantitative biomarkers of UTE lung signal were developed for monitoring longitudinal change in ILD and benchmarked against quantitative CT CALIPER measurements. Normalized UTE lung signal and UTE high percentage (based on 95% cutoff of healthy UTE lung values) was significantly different between nine healthy volunteers and sixteen ILD patients. Longitudinal change in UTE biomarkers correlated with change in CT CALIPER ILD% in the ILD patients, and most-strongly correlated to CT ground-glass changes in the lung parenchyma.

Longitudinal comparison of lung UTE-MRI and CT for ILD
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Bias, Repeatability and Reproducibility of Liver T1 Mapping

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Bias, Repeatability and Reproducibility of Liver T1 Mapping With Variable Flip Angles

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REpeatability and Reproducibility of Liver T1 Mapping

Bias, Repeatability and Reproducibility of Liver T1 Mapping With Variable Flip Angles

by Sirisha Tadimalla PhD, Daniel J. Wilson PhD, David Shelley BSc, Gavin Bainbridge BSc, Margaret Saysell BSc, Iosif A. Mendichovszky MD, Martin J. Graves PhD, J. Ashley Guthrie MB, John C. Waterton PhD, Geoffrey J.M. Parker PhD, Steven P. Sourbron PhD


JMRI 2022, 56(4), 1042-1052. doi: 10.1002/jmri.28127

Abstract

Background
Three-dimensional variable flip angle (VFA) methods are commonly used for T1 mapping of the liver, but there is no data on the accuracy, repeatability, and reproducibility of this technique in this organ in a multivendor setting.

Purpose
To measure bias, repeatability, and reproducibility of VFA T1 mapping in the liver.

Study Type
Prospective observational.

Population
Eight healthy volunteers, four women, with no known liver disease.

Field Strength/Sequence
1.5-T and 3.0-T; three-dimensional steady-state spoiled gradient echo with VFAs; Look-Locker.

Assessment
Traveling volunteers were scanned twice each (30 minutes to 3 months apart) on six MRI scanners from three vendors (GE Healthcare, Philips Medical Systems, and Siemens Healthineers) at two field strengths. The maximum period between the first and last scans among all volunteers was 9 months. Volunteers were instructed to abstain from alcohol intake for at least 72 hours prior to each scan and avoid high cholesterol foods on the day of the scan.

Statistical Tests
Repeated measures ANOVA, Student t-test, Levene's test of variances, and 95% significance level. The percent error relative to literature liver T1 in healthy volunteers was used to assess bias. The relative error (RE) due to intrascanner and interscanner variation in T1 measurements was used to assess repeatability and reproducibility.

Results
The 95% confidence interval (CI) on the mean bias and mean repeatability RE of VFA T1 in the healthy liver was 34 ± 6% and 10 ± 3%, respectively. The 95% CI on the mean reproducibility RE at 1.5 T and 3.0 T was 29 ± 7% and 25 ± 4%, respectively.

Data Conclusion
Bias, repeatability, and reproducibility of VFA T1 mapping in the liver in a multivendor setting are similar to those reported for breast, prostate, and brain.

Repeatability and reproducibility of liver T1 mapping
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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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