Planar 2D x-ray mammography is generally accepted as the preferred screening technique used for breast cancer detection. Recently, digital breast tomosynthesis (DBT) has been introduced to overcome some of the inherent limitations of conventional planar imaging, and future technological enhancements are expected to result in the introduction of further innovative modalities. However, it is crucial to understand the impact of any new imaging technology or methodology on cancer detection rates and patient recall. Any such assessment conventionally requires large scale clinical trials demanding significant investment in time and resources. The concept of virtual clinical trials and virtual performance assessment may offer a viable alternative to this approach. However, virtual approaches require a collection of specialized modelling tools which can be used to emulate the image acquisition process and simulate images of a quality indistinguishable from their real clinical counterparts. In this paper, we present two image simulation chains constructed using modelling tools that can be used for the evaluation of 2D-mammography and DBT systems. We validate both approaches by comparing simulated images with real images acquired using the system being simulated. A comparison of the contrast-to-noise ratios and image blurring for real and simulated images of test objects shows good agreement ( < 9% error). This suggests that our simulation approach is a promising alternative to conventional physical performance assessment followed by large scale clinical trials.

Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics and pharmacodynamics. Omipalisib was dosed at 0.25 mg, 1 mg and 2 mg twice daily for 8 days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2 mg twice daily).17 subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose-related increases in insulin and glucose were observed. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs. 18F-2-fluoro-2-deoxy-d-glucose(FDG)-positron emission tomography/computed tomography scans revealed an exposure-dependent reduction in 18F-FDG uptake in fibrotic areas of the lung, as measured by target-to-background, ratio thus confirming pharmacodynamic activity.This experimental medicine study demonstrates acceptable tolerability of omipalisib in subjects with IPF at exposures for which target engagement was confirmed both systemically and in the lungs.

PurposeThere 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.MethodsA 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.ResultsDuring 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 < 0.001), high GAP index (p = 0.003), and high GAP stage (p = 0.003). Stepwise forward-Wald–Cox analysis revealed that the pulmonary TBR was independent of GAP classification (p = 0.010). The median survival in IPF patients with a TBR < 4.9 was 71 months, whilst in those with TBR > 4.9 was 24 months. Combining PET data with GAP data (“PET modified GAP score”) refined the ability to predict mortality.ConclusionsA high pulmonary TBR is independently associated with increased risk of mortality in IPF patients.Electronic supplementary materialThe online version of this article (10.1007/s00259-017-3917-8) contains supplementary material, which is available to authorized users.

Abstract. A new method of generating realistic three dimensional simulated breastrealistic masses with more variability in shape compared to the RW method. DLA 24 generated lesions can overcome the lack of complexity in structure and shape in many 25 current methods of mass simulation.

Digital breast tomosynthesis (DBT) is suggested to have superior performance compared to 2D mammography in terms of cancer visibility, especially in the case of dense breasts. However, the overall performance of tomosynthesis for screening applications, and the manner in which tomosynthesis should be optimally used for screening remains unclear. This motivates the development of software tools that can insert user-defined synthetic pathology of realistic appearance into clinical tomosynthesis images for subsequent use in virtual clinical trials. We present a method for inserting lesions grown using Diffusion Limited Aggregation, previously validated in 2D mammograms, into clinical DBT images. A preliminary pilot study was used to validate the realism of the masses, wherein three readers each viewed 19 cases and rated the realism of the inserted masses. Each case included a simulated mass inserted in the tomosynthesis projections and the counterpart digital 2D mammogram. These results show that masses can be successfully embedded in the tomosynthesis projections and can produce visually authentic DBT images containing synthetic pathology. These results will be used to further optimize the appearance of these masses in DBT for an upcoming validation.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease, with an incidence of ∼1 per 10 000 per year, and a poor prognosis with limited treatments [1]. The role of hypoxia in disease progression is unclear.Although it is plausible that the IPF lung is hypoxic, much of the evidence is indirect. To our knowledge this is the first study to explore the potential role of the hypoxia tracer fluoromisonidazole (F-MISO) in understanding pathomechanisms in IPF. We present data from 10 IPF patients.The hypoxia response is regulated by the hypoxia inducible transcription factors (HIF) which regulate gene expression. There is upregulation of hypoxia-related markers in the IPF lung [2]; in some reports CA-IX, a cellular signal of hypoxia, alongside HIF-1α and -2α has been found in the epithelium overlying fibroblastic foci in IPF. Levels of lactic acid are high in the IPF lung, supporting the concept of a hypoxic microenvironment [3].Nitroimidazoles are "electron-affinic" molecules that accumulate in hypoxic cells in culture and in vivo. These compounds, including F-MISO, are metabolised by intracellular nitroreductases, and at low oxygen levels serve as competing electron acceptors. They are reduced and form covalent bonds to macromolecules, thus becoming biochemically trapped within these hypoxic yet metabolically active cells [4]. A quantitative, although non-linear, inverse relationship between nitroimidazole binding and oxygen concentration has been described [5]. Positron emission tomography (PET) imaging of tissue hypoxia (oxygen tension ⩽3 mmHg) using 18 F-labelled fluoromisonidazole ( 18 F-MISO) is the most frequent use of a nitroimidazole imaging agent [6].A better understanding of the degree and extent of hypoxia in individual patients with IPF may offer novel approaches for treatment, allow stratification of patients for clinic trials, and detect treatment response. Using the hypoxic reporter F-MISO, we have a tool to detect hypoxia in IPF with molecular imaging. 10 patients with IPF consented and underwent 18 F-MISO PET/computed tomography (CT) following ethical approval (REC reference number 06/Q0505/22). Each patient had been discussed in an interstitial lung disease multidisciplinary meeting that had reached a consensus diagnosis of IPF, based on clinical, radiological and pathological (when available) findings. In indeterminate cases, patients were referred for biopsy. Patients were included in this study if the biopsy showed histological usual interstitial pneumonia. Lung cancer patients that had undergone 18 F-MISO PET/CT were included as controls.PET/CT data were acquired on the same PET/CT (VCT PET/64-detector CT instrument, GE Healthcare Technology, WI, USA). "Combined CTs" [7], were used for attenuation and air fraction correction [7,8].1 cm 3 spherical volumes of interest were placed on fibrotic (F) and normal appearing control (C) regions distant from fibrosis, in each IPF patient; and at sites of tumour or radiological/ non-emphysematous lung in patients with lung cancer. Average pulm...

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The aim of the present work was to develop a method for simulating breast lesions in digital mammographic images. Based on the visual appearance of real masses, three dimensional masses were created using a 3D random walk method where the choice of parameters (number of walks and number of steps) enables one to control the appearance of the simulated structure. This work is the first occasion that the random walk results have been combined with a model of digital mammographic imaging systems. This model takes into account appropriate physical image acquisition processes representing a particular digital X-ray mammography system. The X-ray spectrum, local glandularity above the insertion site and scatter were all taken account during the insertion procedure. A preliminary observer study was used to validate the realism of the masses. Seven expert readers each viewed 60 full field mammograms and rated the realism of the masses they contained. Half of the images contained real, histologically-confirmed masses, and half contained simulated lesions. The ROC analysis of the study (average AUC of 0.58±0.06) suggests that, on the average, there is evidence that the radiologists could distinguish, somewhat, between real and simulated masses.