Pulmonary 18F-FDG uptake helps refine current risk stratification in idiopathic pulmonary fibrosis (IPF).

PURPOSE: There is a lack of prognostic biomarkers in idiopathic pulmonary fibrosis (IPF) patients. The objective of this study is to investigate the potential of 18F-FDG-PET/ CT to predict mortality in IPF. METHODS: A total of 113 IPF patients (93 males, 20 females, mean age ± SD: 70 ± 9 years) were prospectively recruited for 18F-FDG-PET/CT. The overall maximum pulmonary uptake of 18F-FDG (SUVmax), the minimum pulmonary uptake or background lung activity (SUVmin), and target-to-background (SUVmax/ SUVmin) ratio (TBR) were quantified using routine region-of-interest analysis. Kaplan-Meier analysis was used to identify associations of PET measurements with mortality. We also compared PET associations with IPF mortality with the established GAP (gender age and physiology) scoring system. Cox analysis assessed the independence of the significant PET measurement(s) from GAP score. We investigated synergisms between pulmonary 18F-FDG-PET measurements and GAP score for risk stratification in IPF patients. RESULTS: During a mean follow-up of 29 months, there were 54 deaths. The mean TBR ± SD was 5.6 ± 2.7. Mortality was associated with high pulmonary TBR (p = 0.009), low forced vital capacity (FVC; p = 0.001), low transfer factor (TLCO; p  4.9 was 24 months. Combining PET data with GAP data ("PET modified GAP score") refined the ability to predict mortality. CONCLUSIONS: A high pulmonary TBR is independently associated with increased risk of mortality in IPF patients

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor

© 2020 The Author(s). Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF. Methods: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: Baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. Results: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI:-9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. Conclusions: This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. Trial registration: Clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017

Areas of normal pulmonary parenchyma on HRCT exhibit increased FDG PET signal in IPF patients

Purpose: Patients with idiopathic pulmonary fibrosis (IPF) show increased PET signal at sites of morphological abnormality on high-resolution computed tomography (HRCT). The purpose of this investigation was to investigate the PET signal at sites of normal-appearing lung on HRCT in IPF. Methods: Consecutive IPF patients (22 men, 3 women) were prospectively recruited. The patients underwent 18F-FDG PET/HRCT. The pulmonary imaging findings in the IPF patients were compared to the findings in a control population. Pulmonary uptake of 18F-FDG (mean SUV) was quantified at sites of morphologically normal parenchyma on HRCT. SUVs were also corrected for tissue fraction (TF). The mean SUV in IPF patients was compared with that in 25 controls (patients with lymphoma in remission or suspected paraneoplastic syndrome with normal PET/CT appearances). Results: The pulmonary SUV (mean ± SD) uncorrected for TF in the controls was 0.48 ± 0.14 and 0.78 ± 0.24 taken from normal lung regions in IPF patients (p < 0.001). The TF-corrected mean SUV in the controls was 2.24 ± 0.29 and 3.24 ± 0.84 in IPF patients (p < 0.001). Conclusion: IPF patients have increased pulmonary uptake of 18F-FDG on PET in areas of lung with a normal morphological appearance on HRCT. This may have implications for determining disease mechanisms and treatment monitoring. © 2013 The Author(s)

Oxygen isotope transfer rates during the oxidative coupling of methane over a Li/MgO catalyst

The rates of various oxygen isotope transfer processes over Li/MgO catalysts have been investigated in a flow system under conditions relevant to methane coupling. Using ¹⁶O₂/¹⁸O₂ mixtures, mixing to form ¹⁶O₁₈O reached equilibrium at 700 and 750°C when helium was used as the carrier. The extent of equilibration was greatly reduced when the same mixture was used to oxidize methane. The inhibition occurs because mixing requires that the catalytic sites be in oxide form and these sites are converted to carbonate by the carbon dioxide formed from methane concurrently with ethane and ethylene. The same inhibition could be demonstrated directly when using an inert carrier by including C¹⁸O₂ in the feed. When C¹⁸O₂ was added during methane coupling with ¹⁶O₂ as the sole oxidant, there was complete equilibration between added C¹⁸O₂ and C¹⁶O₂ derived from methane. In addition some ¹⁸O was transferred into unreacted ¹⁶O₂. This exchange did not produce ¹⁶O₂, ¹⁶O₁₈O, and ¹⁸O₂ in equilibrium. There was a slight excess of ¹⁸O₂ due to the occurrence of some two-place exchange. Transient experiments in which C¹⁸O₂ alone was carried over Li/MgO showed that only a small fraction of the total oxygen pool of the catalyst participated in exchange. It is probably associated with lithium. When C¹⁸O was included in reacting CH₄/¹⁶O₂ mixtures, approximately one-half of it was oxidized to carbon dioxide. Some exchange of ¹⁸O out of unreacted C¹⁸O took place but the rate of this process was much slower than transfer from carbon dioxide to oxygen. Calculations indicate that the catalyst is able to carry out exchange reactions of oxygen molecules faster than it reacts oxygen with methane. Hence methane coupling is unlikely to be limited by the supply of oxygen to the catalyst surface when the Li/MgO system is used.13 page(s

Isotopic evidence for direct methyl coupling and ethane to ethylene conversion during partial oxidation of methane over Li/MgO

The products of the reaction of a CH₄/CD₄/O₂ mixture over a Li-promoted MgO (Li/MgO) catalyst at 750°C have been determined by mass spectrometry and high-resolution Fourier transform infrared spectroscopy. Under these conditions there was no significant hydrogen exchange between CH₄ and CD₄. C₂H₆, CD₃CH₃, and C₂D₆ were the only ethanes detected, and C₂H₄, CD₂CH₂, and C₂D₄ were the only ethylenes. The relative concentrations of the hydrocarbon products could be predicted on the basis of the relative concentrations of CH₃ and CD₃ determined by the kinetic isotope effect. The results suggest that the reaction proceeds almost exclusively by gas-phase methyl coupling and that ethylene is produced by gas-phase conversion of ethane.4 page(s

Measurements of kinetic isotope effects and hydrogen/deuterium distributions over methane oxidative coupling catalysts

The kinetic isotope effect for CH₄ compared to that for CD₄ has been measured for the oxidative coupling reaction of methane over LiMgO, SrCO₃, and Sm₂O₃ catalysts in a flow reactor. Each catalyst gave results consistent with C?H bond breaking being the slow step. For temperatures between 680-780°C over LiMgO, kHKD decreased slightly with temperature. The isotope effect for ethane production was more sensitive to the level of conversion and declined from 1.8 at low conversion to near unity under conditions where the ethylene to ethane ratio was high (~1). Selectivities to hydrocarbons were lower with CD₄ and did not change with decreased flow rates, implying that either COₓ and C₂ products arise by totally separate slow steps or, if a common step with CH3 radicals is involved, then COₓ formation occurs on the catalyst. Experiments with CH₄CD₄ mixtures showed that CH₃CD₃ and CH₂CD₂ were the dominant mixed products. The distribution of the ethanes always reflected the relative concentrations of CH3 and CD₃ determined by the kinetic isotope effect. At low ethylene to total C₂ ratios (~0.2) this was also true for ethylene; but at higher ratios substantial exchange to produce ethylenes other than C₂H₄, CH₂CD₂, and C₂D₄ occurred. The concentration of the exchanged methanes correlated with total methane conversion but was dependent on the surface. Exchange in the ethylenes also correlated with exchange in the methanes and purely gas phase processes appear at least partially responsible. H₂: HD: D₂ ratios are always at equilibrium and exchange also occurs between CD₄ and H₂.15 page(s

Making biodiversity offsets work in South Africa - A governance perspective

South Africa is increasingly putting itself into an undesirable state of ecological deficit. Regulatory and other interventions are needed to stop and reverse ecosystem degradation. Biodiversity offsets are seen as one possible method of mitigating the current trends in biodiversity and ecosystem services loss in the country. However, for offsetting to succeed in practice, a number of barriers will have to be overcome. This paper discusses concerns raised by South African stakeholders as part of a policy development process implemented by the Department of Environmental Affairs and proposes how the identified barriers may be overcome in the South African setting

The rate controlling step In the oxidative coupling of methane over a lithium-promoted magnesium-oxide catalyst

The rate of conversion of CH₄ in the oxidative coupling reaction over a Li/MgO catalyst at 750°C is 1.5 times greater than that of CD₄ demonstrating that C–H bond breaking is the rate determining step in this reaction.3 page(s