How consistently do physicians diagnose and manage drug-induced

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How consistently do physicians diagnose and manage drug-induced interstitial lung disease? Two surveys of European ILD specialist physicians

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Survey: How Consistently do Physicians Diagnose DI-ILD?

How consistently do physicians diagnose and manage drug-induced interstitial lung disease? Two surveys of European ILD specialist physicians

James A. Eaden, Sarah Skeoch, John C. Waterton, Nazia Chaudhuri, Stephen M. Bianchi on behalf of the TRISTAN investigators


ERJ Open Research 2020 6: 00286-2019 doi: 10.1183/23120541.00286-2019.

Abstract

Introduction

Currently there are no general guidelines for diagnosis or management of suspected drug-induced (DI) interstitial lung disease (ILD). The objective was to survey a sample of current European practice in the diagnosis and management of DI-ILD, in the context of the prescribing information approved by regulatory authorities for 28 licenced drugs with a recognised risk of DI-ILD.

Methods

Consultant physicians working in specialist ILD centres across Europe were emailed two surveys via a website link. Initially, opinion was sought regarding various diagnostic and management options based on seven clinical ILD case vignettes and five general questions regarding DI-ILD. The second survey involved 29 statements regarding the diagnosis and management of DI-ILD, derived from the results of the first survey. Consensus agreement was defined as 75% or greater.

Results

When making a diagnosis of DI-ILD, the favoured investigations used (other than computed tomography) included pulmonary function tests, bronchoscopy and blood tests. The preferred method used to decide when to stop treatment was a pulmonary function test. In the second survey, the majority of the statements were accepted by the 33 respondents, with only four of 29 statements not achieving consensus when the responses “agree” and “strongly agree” were combined as one answer.

Conclusion

The two surveys provide guidance for clinicians regarding an approach to the diagnosis and management of DI-ILD in which the current evidence base is severely lacking, as demonstrated by the limited information provided by the manufacturers of the drugs associated with a high risk of DI-ILD that we reviewed.

SURVEY: HOW CONSISTENTLY DO PHYSICIANS DIAGNOSE DI-ILD?
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Oxygen enhanced MRI biomarkers of lung function in interstitial lung disease

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Oxygen enhanced MRI biomarkers of lung function in interstitial lung disease (Conference Abstract)

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Conference Abstract: OE-MRI biomarkers of lung function in ILD

Oxygen enhanced MRI biomarkers of lung function in interstitial lung disease (Conference Abstract)

Tibiletti M, Naish JH, Heaton MJ, Waterton JC, Hughes PJC, Eaden JA, Skeoch S, Chaudhuri N, Bruce I, Stephen SM, Wild JM, Parker GJM


Abstract OA4330 - ERS 30th International Congress held virtually 7–9 September, 2020.

CONFERENCE ABSTRACT: OE-MRI BIOMARKERS OF LUNG FUNCTION IN ILD
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Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T

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Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T

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Gadoxetate Relaxivity in Different Liver Compartments

Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T

Sabina Ziemian, Claudia Green, Steven Sourbron, Gregor Jost, Gunnar Schütz, Catherine D.G. Hines


NMR in Biomedicine, 26 August 2020, e4401; doi:10.1002/nbm.4401

 

Abstract

Quantitative mapping of gadoxetate uptake and excretion rates in liver cells has shown potential to significantly improve the management of chronic liver disease and liver cancer. Unfortunately, technical and clinical validation of the technique is currently hampered by the lack of data on gadoxetate relaxivity. The aim of this study was to fill this gap by measuring gadoxetate relaxivity in liver tissue, which approximates hepatocytes, in blood, urine and bile at magnetic field strengths of 1.41, 1.5, 3, 4.7 and 7 T. Measurements were performed ex vivo in 44 female Mrp2 knockout rats and 30 female wild‐type rats who had received an intravenous bolus of either 10, 25 or 40 μmol/kg gadoxetate. T1 was measured at 37 ± 3°C on NMR instruments (1.41 and 3 T), small‐animal MRI (4.7 and 7 T) and clinical MRI (1.5 and 3 T). Gadolinium concentration was measured with optical emission spectrometry or mass spectrometry. The impact on measurements of gadoxetate rate constants was determined by generalizing pharmacokinetic models to tissues with different relaxivities. Relaxivity values (L mmol−1 s−1) showed the expected dependency on tissue/biofluid type and field strength, ranging from 15.0 ± 0.9 (1.41) to 6.0 ± 0.3 (7) T in liver tissue, from 7.5 ± 0.2 (1.41) to 6.2 ± 0.3 (7) T in blood, from 5.6 ± 0.1 (1.41) to 4.5 ± 0.1 (7) T in urine and from 5.6 ± 0.4 (1.41) to 4.3 ± 0.6 (7) T in bile. Failing to correct for the relaxivity difference between liver tissue and blood overestimates intracellular uptake rates by a factor of 2.0 at 1.41 T, 1.8 at 1.5 T, 1.5 at 3 T and 1.2 at 4.7 T. The relaxivity values derived in this study can be used retrospectively and prospectively to remove a well‐known bias in gadoxetate rate constants. This will promote the clinical translation of MR‐based liver function assessment by enabling direct validation against reference methods and a more effective translation between in vitro findings, animal models and patient studies.

GADOXETATE RELAXIVITY IN DIFFERENT LIVER COMPARTMENTS
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PET of 89Zr-Pembrolizumab in Cynomolgus

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PET/CT Imaging of 89Zr-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys

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PET of 89Zr-Pembrolizumab in Cynomolgus

PET/CT Imaging of 89Zr-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys

Wenping Li, Yuchuan Wang, Daniel Rubins, Idriss Bennacef, Marie Holahan, Hyking Haley, Mona Purcell, Liza Gantert, SuChun Hseih, Michael Judo, Wolfgang Seghezzi, Shuli Zhang, Elly L. van der Veen, Marjolijn N. Lub-de Hooge, Elisabeth G.E. de Vries, Jeffrey L. Evelhoch, Michael Klimas, Eric D. Hostetler


Molecular Imaging and Biology 2020 Oct 26. doi: 10.1007/s11307-020-01558-w

Abstract

Purpose:

Programmed cell death-1 receptor (PD-1) and its ligand (PD-L1) are the targets for immunotherapy in many cancer types. Although PD-1 blockade has therapeutic effects, the efficacy differs between patients. Factors contributing to this variability are PD-L1 expression levels and immune cells present in tumors. However, it is not well understood how PD-1 expression in the tumor microenvironment impacts immunotherapy response. Thus, imaging of PD-1-expressing immune cells is of interest. This study aims to evaluate the biodistribution of Zirconium-89 (89Zr)-labeled pembrolizumab, a humanized IgG4 kappa monoclonal antibody targeting PD-1, in healthy cynomolgus monkeys as a translational model of tracking PD-1- positive immune cells.

Procedures:

Pembrolizumab was conjugated with the tetrafluorophenol-N-succinyl desferal- Fe(III) ester (TFP-N-sucDf) and subsequently radiolabeled with 89Zr. Four cynomolgus monkeys with no previous exposure to humanized monoclonal antibodies received tracer only or tracer co-injected with pembrolizumab intravenously over 5 min. Thereafter, a static whole-body positron emission tomography (PET) scan was acquired with 10 min per bed position on days 0, 2, 5, and 7. Image-derived standardized uptake values (SUVmean) were quantified by region of interest (ROI) analysis.

Results:

89Zr-N-sucDf-pembrolizumab was synthesized with high radiochemical purity (>99 %) and acceptable molar activity (>7 MBq/nmol). In animals dosed with tracer only, 89Zr-N-sucDf-pembrolizumab distribution in lymphoid tissues such as mesenteric lymph nodes, spleen, and tonsils increased over time. Except for the liver, low radiotracer distribution was observed in all non-lymphoid tissue including the lung, muscle, brain, heart, and kidney. When a large excess of pembrolizumab was co-administered with a radiotracer, accumulation in the lymph nodes, spleen, and tonsils was reduced, suggestive of target-mediated accumulation.

Conclusions:

89Zr-N-sucDf-pembrolizumab shows preferential uptake in the lymphoid tissues including the lymph nodes, spleen, and tonsils. 89Zr-N-sucDf-pembrolizumab may be useful in tracking the distribution of a subset of immune cells in non-human primates and humans.

Trial registration:

ClinicalTrials.gov; Identifier: NCT02760225

PET of 89Zr-Pembrolizumab in Cynomolgus
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Collagen I-PET and MRI in a Rat Lung Injury Model

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Longitudinal Imaging Using PET/CT with Collagen-I PET-Tracer and MRI for Assessment of Fibrotic and Inflammatory Lesions in a Rat Lung Injury Model

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Collagen I-PET and MRI in a Rat Lung Injury Model

Longitudinal Imaging Using PET/CT with Collagen-I PET-Tracer and MRI for Assessment of Fibrotic and Inflammatory Lesions in a Rat Lung Injury Model

by Irma Mahmutovic Persson, Nina Fransén Pettersson, Jian Liu, Hanna Falk Håkansson, Anders Örbom, René In ’t Zandt, Ritha Gidlöf, Marie Sydoff, Karin von Wachenfeldt and Lars E. Olsson on behalf of the TRISTAN Consortium


J. Clin. Med. 2020, 9(11), 3706. doi: 10.3390/jcm9113706

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.

Collagen I-PET and MRI in a Rat Lung Injury Model
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