Hyperpolarised 129xenon MR spectroscopy and diffusion-weighted

Private
Public

Hyperpolarised 129xenon MR spectroscopy and diffusion-weighted MRI at baseline in patients with interstitial lung disease (Conference Abstract)

  • 135

Publications
Take a look

Conference Abstract: Hyperpolarised 129xenon MRS in ILD

Hyperpolarised 129xenon MR spectroscopy and diffusion-weighted MRI at baseline in patients with interstitial lung disease (Conference Abstract)

James Eaden, Paul Hughes, Ho-Fung Chan, Guilhem Collier, Oliver Rodgers, Graham Norquay, Matthew Austin, Laurie Smith, Steve Renshaw, Colm Leonard, Sarah Skeoch, Nazia Chaudhuri, Geoff Parker, Stephen Bianchi, and Jim Wild


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

CONFERENCE ABSTRACT: HYPERPOLARISED 129XENON MRS IN ILD
Article categories

Evaluation of automatic methods for arterial input function extraction

Private
Public

Evaluation of automatic methods for arterial input function extraction for perfusion quantification in the lung (Conference Abstract)

  • 134

Publications
Take a look

Conference Abstract: Automated AIF extraction

Evaluation of automatic methods for arterial input function extraction for perfusion quantification in the lung (Conference Abstract)

Marta Tibiletti, Josephine H Naish, Paul J.C. Hughes, Helen Marshall, Colm Leonard, Sarah Skeoch, Nazia Chaudhuri, Ian Bruce, James Eaden, Stephen Bianchi, Jim M Wild, Geoff JM Parker


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

 

CONFERENCE ABSTRACT: AUTOMATED AIF EXTRACTION
Article categories

Comparison of algorithm to determine Ventilated Volume Fraction

Private
Public

Comparison of algorithm to determine Ventilated Volume Fraction from Oxygen-Enhanced MRI in Cystic Fibrosis (Conference Abstract)

  • 133

Publications
Take a look

Conference Abstract: Determine ventilated volume fraction

Comparison of algorithm to determine Ventilated Volume Fraction from Oxygen-Enhanced MRI in Cystic Fibrosis (Conference Abstract)

Marta Tibiletti, Josephine H Naish, Katharina Martini, Thomas Frauenfelder, Geoff JM Parker


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

 

CONFERENCE ABSTRACT: DETERMINE VENTILATED VOLUME FRACTION
Article categories

Repeatability and reproducibility of longitudinal relaxation rate

Private
Public

Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems

  • 132

Publications
Take a look

R1 repeatability and reproducibility for animal MRI

Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems

Waterton JC, Hines CDG, Hockings PD, Laitinen I, Ziemian S, Campbell S, Gottschalk M, Green C, Haase M, Hoffmann K, Juretschke H-P, Koehler S, Lloyd W, Y Luo Y, Mahmutovic Persson I, O’Connor JPB, Olsson LE, Parker GJM, Pindoria K, Schneider JE, Steinmann D, Strobel K, Teh I, Veltien A, Zhang X, Schütz G


Magnetic Resonance Imaging, Volume 59, June 2019, Pages 121-129 doi:10.1016/j.mri.2019.03.008

 

Abstract

Background: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R1, but evidence for between-site reproducibility of R1 in small-animal MRI is lacking.

Objective: To assess R1 repeatability and multi-site reproducibility in phantoms for preclinical MRI.

Methods: R1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days. R1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured.

Results: CoV for day-to-day repeatability (N=180 regions of interest) was 2.34% and for between-centre reproducibility (N=9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R1-based MR biomarkers were found to be quite sensitive even to such small errors in R1, notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni2+ in 2% agarose varied between 0.66 s-1mM-1 at 3T and 0.94 s-1mM-1 at 11.7T.

Interpretation: While several factors affect the reproducibility of R1-based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases special care in R1-accuracy is warranted.

R1 REPEATABILITY AND REPRODUCIBILITY FOR ANIMAL MRI
Article categories

Experimental and quantitative imaging techniques

Private
Public

Experimental and quantitative imaging techniques in interstitial lung disease

  • 131

Publications
Take a look

Imaging Techniques in ILD

Experimental and quantitative imaging techniques in interstitial lung disease

Nicholas D Weatherley, James A Eaden, Neil J Stewart, Brian J Bartholmai, Andrew J Swift, Stephen Mark Bianchi, Jim M Wild


Thorax 2019;74:611-619. doi:10.1136/thoraxjnl-2018-211779.

 

Abstract

Interstitial lung diseases (ILDs) are a heterogeneous group of conditions, with a wide and complex variety of imaging features. Difficulty in monitoring, treating and exploring novel therapies for these conditions is in part due to the lack of robust, readily available biomarkers. Radiological studies are vital in the assessment and follow-up of ILD, but currently CT analysis in clinical practice is qualitative and therefore somewhat subjective. In this article, we report on the role of novel and quantitative imaging techniques across a range of imaging modalities in ILD and consider how they may be applied in the assessment and understanding of ILD. We critically appraised evidence found from searches of Ovid online, PubMed and the TRIP database for novel and quantitative imaging studies in ILD. Recent studies have explored the capability of texture-based lung parenchymal analysis in accurately quantifying several ILD features. Newer techniques are helping to overcome the challenges inherent to such approaches, in particular distinguishing peripheral reticulation of lung parenchyma from pleura and accurately identifying the complex density patterns that accompany honeycombing. Robust and validated texture-based analysis may remove the subjectivity that is inherent to qualitative reporting and allow greater objective measurements of change over time. In addition to lung parenchymal feature quantification, pulmonary vessel volume analysis on CT has demonstrated prognostic value in two retrospective analyses and may be a sign of vascular changes in ILD which, to date, have been difficult to quantify in the absence of overt pulmonary hypertension. Novel applications of existing imaging techniques, such as hyperpolarised gas MRI and positron emission tomography (PET), show promise in combining structural and functional information. Although structural imaging of lung tissue is inherently challenging in terms of conventional proton MRI techniques, inroads are being made with ultrashort echo time, and dynamic contrast-enhanced MRI may be used for lung perfusion assessment. In addition, inhaled hyperpolarised 129Xenon gas MRI may provide multifunctional imaging metrics, including assessment of ventilation, intra-acinar gas diffusion and alveolar-capillary diffusion. PET has demonstrated high standard uptake values (SUVs) of 18F-fluorodeoxyglucose in fibrosed lung tissue, challenging the assumption that these are ‘burned out’ and metabolically inactive regions. Regions that appear structurally normal also appear to have higher SUV, warranting further exploration with future longitudinal studies to assess if this precedes future regions of macroscopic structural change. Given the subtleties involved in diagnosing, assessing and predicting future deterioration in many forms of ILD, multimodal quantitative lung structure-function imaging may provide the means of identifying novel, sensitive and clinically applicable imaging markers of disease. Such imaging metrics may provide mechanistic and phenotypic information that can help direct appropriate personalised therapy, can be used to predict outcomes and could potentially be more sensitive and specific than global pulmonary function testing. Quantitative assessment may objectively assess subtle change in character or extent of disease that can assist in efficacy of antifibrotic therapy or detecting early changes of potentially pneumotoxic drugs involved in early intervention studies.

IMAGING TECHNIQUES IN ILD
Article categories

Development of a CD8 tracer for in vivo evaluation of CD8

Private
Public

Development of a CD8 tracer for in vivo evaluation of CD8 T cell tumor infiltration during immunotherapy (Conference Abstract)

  • 130

Publications
Take a look

Conference Abstract: Tracer for CD8 T-cell tumor infiltration

Development of a CD8 tracer for in vivo evaluation of CD8 T cell tumor infiltration during immunotherapy (Conference Abstract)

René Raavé, Milou Boswinkel, Gerwin Sandker, Peter Wierstra, Erik H. J. G. Aarntzen, Sandra Heskamp


EMIM 2019, Glasgow: #858. EMIM 2019 Abstracts.

Abstract

Introduction

Immunotherapy is considered a hallmark in cancer treatment by its profound and durable clinical responses in patients with various types of cancer. However, only a subgroup of patients responds to immunotherapy and methods for accurate early response monitoring are lacking. Noninvasive quantitative imaging of CD8+ cytotoxic T cells can provide dynamic and spatial information of anti-tumor response. In the present study we characterized an 111In-labeled anti-mouse CD8 antibody for imaging of tumor infiltrating CD8+ cytotoxic T cells in vitro and in vivo in mice bearing murine CT26 colon tumors.

Methods

An anti-mouse CD8 antibody (clone: YTS 169.4) was randomly conjugated with a 30 times molar excess of NCS-DTPA and radiolabeled with 111In. Using CD8+ TK1 mice lymphoma cells, the immunoreactivity, IC50, internalization and affinity characteristics were determined. CT26 tumor bearing BALB/c mice (10-12 weeks old) were intravenously injected with 8.5 µg (8.5 MBq) [111In]In-DTPA-anti-CD8. One group received an excess of non-radiolabeled CD8 antibody (250 µg). SPECT/CT imaging was performed and organs were collected to quantify tracer uptake at 4h, 24h, 48h and 72h after injection. Autoradiography and immunohistochemistry were performed on paraffin embedded tissue sections of tumor, spleen, lymph nodes and duodenum.

Results/Discussion

In vitro assays demonstrated that the immunoreactive fraction was 44%, IC50 was 1.77 nM, Kd was 3.83 nM, and 6.5% internalization of the total membrane bound activity after 4.5 h of incubation. CD8+ T cell containing organs (lymph nodes, spleen and duodenum) were clearly visible on SPECT scans of mice injected with [111In]In-DTPA-CD8-antibody at all time points. Mice that received an excess of non-radiolabeled CD8-antibody showed most uptake in the spleen. Low to moderate tumor uptake was visible in all groups. Ex vivo biodistribution data confirmed results from SPECT imaging. In the lymph nodes, spleen, duodenum and tumor, an uptake of 38.6 ± 12.3% ID/g (±SD), 87.1 ± 18.0% ID/g, 31.7 ± 16.9% ID/g, and 12.9 ±2.9% ID/g at 24h after injection, respectively. The tumor-to-blood ratio increased from 0.48 at 4h after injection to 2.23 at 72h after injection. Autoradiography and immunohistochemistry confirmed these findings.

Conclusions

The CD8 antibody showed specific uptake in CD8+ T cell containing tissues in vivo, but uptake in the tumor was limited because of presence low number of CD8+ T cells. In the future, this tracer has potential for in vivo evaluation of CD8+ T cell infiltration in tumors and lymphoid tissues before and during immunotherapy.

CONFERENCE ABSTRACT: TRACER FOR CD8 T-CELL TUMOR INFILTRATION
Article categories

Evaluation of novel 89Zr chelators and corresponding

Private
Public

Evaluation of novel 89Zr chelators and corresponding 89Zr-labeled immunoconjugates (Conference Abstract)

  • 129

Publications
Take a look

Conference Abstract: Novel 89Zr chelators and immunoconjugates

Evaluation of novel 89Zr chelators and corresponding 89Zr-labeled immunoconjugates (Conference Abstract)

Pierre Adumeau, René Raavé, Christian B. Jacobsen, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Adrien Dubois, Laurène Da Costa, Victor Goncalves, Franck Denat


EMIM 2019, Glasgow, #654. EMIM 2019 Abstracts.

Abstract

Introduction

For immunoPET with 89Zr, the current gold standard to label antibodies is desferrioxamine (DFO).1 However, preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, leading to 89Zr release and subsequent accumulation in mineral bone. This bone uptake may impede 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 more stable 89Zr chelators.

Methods

We have synthesized new octacoordinating 89Zr-bifunctional chelating agents derivated from the DFO* chelator.2 These new chelators were synthesized by coupling different hydroxamic acid-bearing arms to DFO, followed by the introduction of an isothiocyanate moiety. The model antibody trastuzumab was conjugated to the NCS-derivated chelators and DFO-pPhe-NCS as a reference, and radiolabeled with 89Zr. The stability of the radiolabeled chelators and radiolabeled conjugates were evaluated in human plasma, and in PBS in presence of EDTA or DFO. The in vitro behavior of the most promising compounds was investigated more thoroughly using HER2-experessing SK-OV3 cells, and in vivo distribution was studied in mice with subcutaneous SK-OV3 xenografts by PET/CCT imaging and ex vivo tissue analysis.

Results/Discussion

The bifunctional chelators were conjugated efficiently to trastuzumab. Radiolabeling of the conjugates with 89Zr yielded the radioconjugates with high yield, purity and specific activity (RCY >95%, RCP >99%, SA >100 MBq/mg). When challenged with EDTA or DFO, the 89Zr-chelates and the corresponding radioconjugates displayed an improved stability compared to 89Zr-DFO and 89Zr-DFO-trastuzumab, with the best results obtained for the chelator dubbed cycloDFO*. The immunoreactive fraction and IC50 were similar for 89Zr-DFO-trastuzumab and 89Zr-cycloDFO*-trastuzumab. Internalisation after 2h was significantly higher for 89Zr-cycloDFO*-trastuzumab compared to 89Zr-DFO-trastuzumab. Accumulation of 89Zr in bone was significantly lower for 89Zr-DFO-cyclo*-trastuzumab compared to 89Zr-DFO-trastuzumab in knee (3.6 ± 0.4% vs 5.9 ±0.6%), femur (2.2 ± 0.2% vs 3.4 ± 0.3%), and sternum (3.5± 0.4% vs 4.5 ±0.4%) at 72 h after injection. Uptake in the SK-OV3 tumor was similar for both antibody conjugates.

Conclusions

The new 89Zr-chelators and the associated radioconjugates show improved in vitro stability compared to DFO and 89Zr-DFO-trastuzumab. The radioconjugate derivated from the more promising chelator, 89Zr-cycloDFO*-trastuzumab, demonstrated a better in vivo stability compared to 89Zr-DFO-trastuzumab. Therefore, less radiation exposure to bone marrow and improved bone metastasis detection could be achieved using cycloDFO*.

References

1 S. Heskamp, R. Raavé, O. Boerman, M. Rijpkema, V. Goncalves, F. Denat, Bioconjugate Chem., 2017, 28, 2211-2223.

2 D. Vugts, C. Klaver, C. Sewing, A. Poot, K. Adamzek; S. Huegli, C. Mari, G. Visser, I. Valverde, G. Gasser, T. Mindt, G. van Dongen, Eur. J. Nucl. Med. Mol. Imaging, 2017, 44, 286-295

CONFERENCE ABSTRACT: NOVEL 89ZR CHELATORS AND IMMUNOCONJUGATES
Article categories

Direct comparison of the in vitro and in vivo stability

Private
Public

Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89Zr-immunoPET.

  • 128

Publications
Take a look

89Zr-DFO Derivative Stability

Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89Zr-immunoPET.

René Raavé, Gerwin Sandker, Pierre Adumeau, Christian Borch Jacobsen, Floriane Mangin, Michel Meyer, Mathieu Moreau, Claire Bernhard, Laurène Da Costa, Adrien Dubois, Victor Goncalves, Magnus Gustafsson, Mark Rijpkema, Otto Boerman, Jean-Claude Chambron, Sandra Heskamp, Franck Denat


European Journal of Nuclear Medicine and Molecular Imaging August 2019, Volume 46, Issue 9, pp 1966–1977 doi:10.1007/s00259-019-04343-2.

 

Abstract

 

Currently, the most commonly used chelator for labelling antibodies with 89Zr for immunoPET is desferrioxamine B (DFO). However, preclinical studies have shown that the limited in vivo stability of the 89Zr-DFO complex results in release of 89Zr, which accumulates in mineral bone. Here we report a novel chelator DFOcyclo*, a preorganized extended DFO derivative that enables octacoordination of the 89Zr radiometal. The aim was to compare the in vitro and in vivo stability of [89Zr]Zr-DFOcyclo*, [89Zr]Zr-DFO* and [89Zr]Zr-DFO.

Methods

The stability of 89Zr-labelled chelators alone and after conjugation to trastuzumab was evaluated in human plasma and PBS, and in the presence of excess EDTA or DFO. The immunoreactive fraction, IC50, and internalization rate of the conjugates were evaluated using HER2-expressing SKOV-3 cells. The in vivo distribution was investigated in mice with subcutaneous HER2+ SKOV-3 or HER2 MDA-MB-231 xenografts by PET/CT imaging and quantitative ex vivo tissue analyses 7 days after injection.

Results

89Zr-labelled DFO, DFO* and DFOcyclo* were stable in human plasma for up to 7 days. In competition with EDTA, DFO* and DFOcyclo* showed higher stability than DFO. In competition with excess DFO, DFOcyclo*-trastuzumab was significantly more stable than the corresponding DFO and DFO* conjugates (p < 0.001). Cell binding and internalization were similar for the three conjugates. In in vivo studies, HER2+ SKOV-3 tumour-bearing mice showed significantly lower bone uptake (p < 0.001) 168 h after injection with [89Zr]Zr-DFOcyclo*-trastuzumab (femur 1.5 ± 0.3%ID/g, knee 2.1 ± 0.4%ID/g) or [89Zr]Zr-DFO*-trastuzumab (femur 2.0 ± 0.3%ID/g, knee 2.68 ± 0.4%ID/g) than after injection with [89Zr]Zr-DFO-trastuzumab (femur 4.5 ± 0.6%ID/g, knee 7.8 ± 0.6%ID/g). Blood levels, tumour uptake and uptake in other organs were not significantly different at 168 h after injection. HER2 MDA-MB-231 tumour-bearing mice showed significantly lower tumour uptake (p < 0.001) after injection with [89Zr]Zr-DFOcyclo*-trastuzumab (16.2 ± 10.1%ID/g) and [89Zr]Zr-DFO-trastuzumab (19.6 ± 3.2%ID/g) than HER2+ SKOV-3 tumour-bearing mice (72.1 ± 14.6%ID/g and 93.1 ± 20.9%ID/g, respectively), while bone uptake was similar.

Conclusion

89Zr-labelled DFOcyclo* and DFOcyclo*-trastuzumab showed higher in vitro and in vivo stability than the current commonly used 89Zr-DFO-trastuzumab. DFOcyclo* is a promising candidate to become the new clinically used standard chelator for 89Zr immunoPET.

89ZR-DFO DERIVATIVE STABILITY
Article categories

Clinical-grade N-(4-[18F]fluorobenzoyl)-interleukin-2 for PET

Private
Public

Clinical-grade N-(4-[18F]fluorobenzoyl)-interleukin-2 for PET imaging of activated T-cells in humans

  • 127

Publications
Take a look

18F-IL2 for clinical PET

Clinical-grade N-(4-[18F]fluorobenzoyl)-interleukin-2 for PET imaging of activated T-cells in humans

Elly L. van der Veen, Inês F. Antunes, Petra Maarsingh, Janet Hessels-Scheper, Rolf Zijlma, Hendrikus H. Boersma, Annelies Jorritsma-Smit, Geke A. P. Hospers, Elisabeth G. E. de Vries, Marjolijn N. Lub-de Hooge, Erik F. J. de Vries


EJNMMI Radiopharmacy and Chemistry, Dec 2019, 4,15. doi: 10.1186/s41181-019-0062-7.

Abstract

Background

Molecular imaging of immune cells might be a potential tool for response prediction, treatment evaluation and patient selection in inflammatory diseases as well as oncology. Targeting interleukin-2 (IL2) receptors on activated T-cells using positron emission tomography (PET) with N-(4-[18F]fluorobenzoyl)-interleukin-2 ([18F]FB-IL2) could be such a strategy. This paper describes the challenging translation of the partly manual labeling of [18F]FB-IL2 for preclinical studies into an automated procedure following Good Manufacturing Practices (GMP), resulting in a radiopharmaceutical suitable for clinical use.

Methods

The preclinical synthesis of [18F]FB-IL2 was the starting point for translation to a clinical production method. To overcome several challenges, major adaptations in the production process were executed. The final analytical methods and production method were validated and documented. All data with regards to the quality and safety of the final drug product were documented in an investigational medicinal product dossier.

Results

Restrictions in the [18F]FB-IL2 production were imposed by hardware configuration of the automated synthesis equipment and by use of disposable cassettes. Critical steps in the [18F]FB-IL2 production comprised the purification method, stability of recombinant human IL2 and the final formulation. With the GMP compliant production method, [18F]FB-IL2 could reliably be produced with consistent quality complying to all specifications.

Conclusions

To enable the use of [18F]FB-IL2 in clinical studies, a fully automated GMP compliant production process was developed. [18F]FB-IL2 is now produced consistently for use in clinical studies.

18F-IL2 FOR CLINICAL PET
Article categories

Tracer kinetic modelling of dynamic Gadoxetate-enhanced MRI

Private
Public

Tracer kinetic modelling of dynamic Gadoxetate-enhanced MRI (Conference Abstract)

  • 126

Publications
Take a look

Conference Abstract: Kinetic modelling of Gadoxetate MRI

Tracer kinetic modelling of dynamic Gadoxetate-enhanced MRI (Conference Abstract)

Steven Sourbron


Hepatocyte Transporter Network Meeting, September 2019. HTNM 2019 Presentation.

CONFERENCE ABSTRACT: KINETIC MODELLING OF GADOXETATE MRI
Article categories
Subscribe to Publications