Comparative accuracy and cost-effectiveness of dynamic contrast-enhanced CT and positron emission tomography in the characterisation of solitary pulmonary nodules.

INTRODUCTION: Dynamic contrast-enhanced CT (DCE-CT) and positron emission tomography/CT (PET/CT) have a high reported accuracy for the diagnosis of malignancy in solitary pulmonary nodules (SPNs). The aim of this study was to compare the accuracy and cost-effectiveness of these. METHODS: In this prospective multicentre trial, 380 participants with an SPN (8-30 mm) and no recent history of malignancy underwent DCE-CT and PET/CT. All patients underwent either biopsy with histological diagnosis or completed CT follow-up. Primary outcome measures were sensitivity, specificity and overall diagnostic accuracy for PET/CT and DCE-CT. Costs and cost-effectiveness were estimated from a healthcare provider perspective using a decision-model. RESULTS: 312 participants (47% female, 68.1±9.0 years) completed the study, with 61% rate of malignancy at 2 years. The sensitivity, specificity, positive predictive value and negative predictive values for DCE-CT were 95.3% (95% CI 91.3 to 97.5), 29.8% (95% CI 22.3 to 38.4), 68.2% (95% CI 62.4% to 73.5%) and 80.0% (95% CI 66.2 to 89.1), respectively, and for PET/CT were 79.1% (95% CI 72.7 to 84.2), 81.8% (95% CI 74.0 to 87.7), 87.3% (95% CI 81.5 to 91.5) and 71.2% (95% CI 63.2 to 78.1). The area under the receiver operator characteristic curve (AUROC) for DCE-CT and PET/CT was 0.62 (95% CI 0.58 to 0.67) and 0.80 (95% CI 0.76 to 0.85), respectively (p<0.001). Combined results significantly increased diagnostic accuracy over PET/CT alone (AUROC=0.90 (95% CI 0.86 to 0.93), p<0.001). DCE-CT was preferred when the willingness to pay per incremental cost per correctly treated malignancy was below £9000. Above £15 500 a combined approach was preferred. CONCLUSIONS: PET/CT has a superior diagnostic accuracy to DCE-CT for the diagnosis of SPNs. Combining both techniques improves the diagnostic accuracy over either test alone and could be cost-effective. TRIAL REGISTRATION NUMBER: NCT02013063.

Validation of a combined image derived input function and venous sampling approach for the quantification of [18F]GE-179 PET binding in the brain.

Blood-based kinetic analysis of PET data relies on an accurate estimate of the arterial plasma input function (PIF). An alternative to invasive measurements from arterial sampling is an image-derived input function (IDIF). However, an IDIF provides the whole blood radioactivity concentration, rather than the required free tracer radioactivity concentration in plasma. To estimate the tracer PIF, we corrected an IDIF from the carotid artery with estimates of plasma parent fraction (PF) and plasma-to-whole blood (PWB) ratio obtained from five venous samples. We compared the combined IDIF+venous approach to gold standard data from arterial sampling in 10 healthy volunteers undergoing [18F]GE-179 brain PET imaging of the NMDA receptor. Arterial and venous PF and PWB ratio estimates determined from 7 patients with traumatic brain injury (TBI) were also compared to assess the potential effect of medication. There was high agreement between areas under the curves of the estimates of PF (r = 0.99, p<0.001), PWB ratio (r = 0.93, p<0.001), and the PIF (r = 0.92, p<0.001) as well as total distribution volume (VT) in 11 regions across the brain (r = 0.95, p<0.001). IDIF+venous VT had a mean bias of -1.7% and a comparable regional coefficient of variation (arterial: 21.3 ± 2.5%, IDIF+venous: 21.5 ± 2.0%). Simplification of the IDIF+venous method to use only one venous sample provided less accurate VT estimates (mean bias 9.9%; r = 0.71, p<0.001). A version of the method that avoids the need for blood sampling by combining the IDIF with population-based PF and PWB ratio estimates systematically underestimated VT (mean bias -20.9%), and produced VT estimates with a poor correlation to those obtained using arterial data (r = 0.45, p<0.001). Arterial and venous blood data from 7 TBI patients showed high correlations for PF (r = 0.92, p = 0.003) and PWB ratio (r = 0.93, p = 0.003). In conclusion, the IDIF+venous method with five venous samples provides a viable alternative to arterial sampling for quantification of [18F]GE-179 VT.

FDG-PET/CT in colorectal cancer: potential for vascular-metabolic imaging to provide markers of prognosis.

PURPOSE: This study assesses the potential for vascular-metabolic imaging with FluoroDeoxyGlucose (FDG)-Positron Emission Tomography/Computed Tomography (PET/CT) perfusion to provide markers of prognosis specific to the site and stage of colorectal cancer. METHODS: This prospective observational study comprised of participants with suspected colorectal cancer categorized as either (a) non-metastatic colon cancer (M0colon), (b) non-metastatic rectal cancer (M0rectum), or (c) metastatic colorectal cancer (M+). Combined FDG-PET/CT perfusion imaging was successfully performed in 286 participants (184 males, 102 females, age: 69.60 ± 10 years) deriving vascular and metabolic imaging parameters. Vascular and metabolic imaging parameters alone and in combination were investigated with respect to overall survival. RESULTS: A vascular-metabolic signature that was significantly associated with poorer survival was identified for each patient group: M0colon - high Total Lesion Glycolysis (TLG) with increased Permeability Surface Area Product/Blood Flow (PS/BF), Hazard Ratio (HR) 3.472 (95% CI: 1.441-8.333), p = 0.006; M0rectum - high Metabolic Tumour Volume (MTV) with increased PS/BF, HR 4.567 (95% CI: 1.901-10.970), p = 0.001; M+ participants, high MTV with longer Time To Peak (TTP) enhancement, HR 2.421 (95% CI: 1.162-5.045), p = 0.018. In participants with stage 2 colon cancer as well as those with stage 3 rectal cancer, the vascular-metabolic signature could stratify the prognosis of these participants. CONCLUSION: Vascular and metabolic imaging using FDG-PET/CT can be used to synergise prognostic markers. The hazard ratios suggest that the technique may have clinical utility.

CT texture-based radiomics analysis of carotid arteries identifies vulnerable patients: a preliminary outcome study.

PURPOSE: To assess the potential role of computed tomography (CT) texture analysis (CTTA) in identifying vulnerable patients with carotid artery atherosclerosis. METHODS: In this case-control pilot study, 12 patients with carotid atherosclerosis and a subsequent history of transient ischemic attack or stroke were age and sex matched with 12 control cases with asymptomatic carotid atherosclerosis (follow-up time 103.58 ± 9.2 months). CTTA was performed using a commercially available research software package (TexRAD) by an operator blinded to clinical data. CTTA comprised a filtration-histogram technique to extract features at different scales corresponding to spatial scale filter (fine = 2 mm, medium = 3 mm, coarse = 4 mm), followed by quantification using histogram-based statistical parameters: mean, kurtosis, skewness, entropy, standard deviation, and mean value of positive pixels. A single axial slice was selected to best represent the largest cross-section of the carotid bifurcation or the greatest degree of stenosis, in presence of an atherosclerotic plaque, on each side. RESULTS: CTTA revealed a statistically significant difference in skewness between symptomatic and asymptomatic patients at the medium (0.22 ± 0.35 vs - 0.18 ± 0.39, p < 0.001) and coarse (0.23 ± 0.22 vs 0.03 ± 0.29, p = 0.003) texture scales. At the fine-texture scale, skewness (0.20 ± 0.59 vs - 0.18 ± 0.58, p = 0.009) and standard deviation (366.11 ± 117.19 vs 300.37 ± 82.51, p = 0.03) were significant before correction. CONCLUSION: Our pilot study highlights the potential of CTTA to identify vulnerable patients in stroke and TIA. CT texture may have the potential to act as a novel risk stratification tool in patients with carotid atherosclerosis.

The role of PET in imaging of the tumour microenvironment and response to immunotherapy.

Positron emission tomography (PET) is an exquisitely sensitive molecular imaging technique with broad utility in cancer diagnosis and monitoring. Many ligands labelled with positron-emitting isotopes have been developed that are of interest in the field of cancer imaging. This review intends to provide an overview and outlook of PET in the field of oncology using radiotracers beyond that of the now widespread 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG). A particular focus is the role of PET in understanding and monitoring the tumour microenvironment (TME) in response to chemo-radiotherapy. Furthermore priority will be given to aspects where PET has provided for monitoring of the immune response to cancer including the expanding field of cancer immunotherapy and in the arena of theranostics. The development of new techniques from both preclinical and human studies will be included to give a perspective on future directions, thereby helping to illustrate the importance of PET in cancer patient management.

A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis.

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.

Synergistic application of pulmonary 18F-FDG PET/HRCT and computer-based CT analysis with conventional severity measures to refine current risk stratification in idiopathic pulmonary fibrosis (IPF).

INTRODUCTION: To investigate the combined performance of quantitative CT (qCT) following a computer algorithm analysis (IMBIO) and 18F-FDG PET/CT to assess survival in patients with idiopathic pulmonary fibrosis (IPF). METHODS: A total of 113 IPF patients (age 70 ± 9 years) prospectively and consecutively underwent 18F-FDG PET/CT and high-resolution CT (HRCT) at our institution. During a mean follow-up of 29.6 ± 26 months, 44 (48%) patients died. As part of the qCT analysis, pattern evaluation of HRCT (using IMBIO software) included the total extent (percentage) of the following features: normal-appearing lung, hyperlucent lung, parenchymal damage (comprising ground-glass opacification, reticular pattern and honeycombing), and the pulmonary vessels. The maximum (SUVmax) and minimum (SUVmin) standardized uptake value (SUV) for 18F-FDG uptake in the lungs, and the target-to-background (SUVmax/SUVmin) ratio (TBR) were quantified using routine region-of-interest (ROI) analysis. Pulmonary functional tests (PFTs) were acquired within 14 days of the PET/CT/HRCT scan. Kaplan-Meier (KM) survival analysis was used to identify associations with mortality. RESULTS: Data from 91 patients were available for comparative analysis. The average ± SD GAP [gender, age, physiology] score was 4.2 ± 1.7 (range 0-8). The average ± SD SUVmax, SUVmin, and TBR were 3.4 ± 1.4, 0.7 ± 0.2, and 5.6 ± 2.8, respectively. In all patients, qCT analysis demonstrated a predominantly reticular lung pattern (14.9 ± 12.4%). KM analysis showed that TBR (p = 0.018) and parenchymal damage assessed by qCT (p = 0.0002) were the best predictors of survival. Adding TBR and qCT to the GAP score significantly increased the ability to differentiate between high and low risk (p < 0.0001). CONCLUSION: 18F-FDG PET and qCT are independent and synergistic in predicting mortality in patients with IPF.

Magnetic Resonance Texture Analysis in Identifying Complete Pathological Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer.

BACKGROUND: A certain proportion of patients with locally advanced rectal cancer experience complete response after undergoing neoadjuvant chemoradiotherapy. These patients might be suitable for a conservative "watch and wait" approach, avoiding high-morbidity surgery. Texture analysis is a new modality that can assess heterogeneity in medical images by statistically analyzing gray-level intensities on a pixel-by-pixel basis. This study hypothesizes that texture analysis of magnetic resonance images can identify patients with a complete response. OBJECTIVE: This study aims to determine whether texture analysis of magnetic resonance images as a quantitative imaging biomarker can accurately identify patients with complete response. DESIGN: This is a retrospective diagnostic accuracy study. SETTINGS: This study was conducted at Colchester General Hospital, January 2003 to 2014. PATIENTS: All patients diagnosed with locally advanced rectal cancer who underwent long-course chemoradiotherapy had a posttreatment magnetic resonance scan and underwent surgery are included. INTERVENTION: Texture analysis was extracted from T2-weighted magnetic resonance images of the rectal cancer. MAIN OUTCOME MEASURES: Textural features that are able to identify complete responders were identified by a Mann-Whitney U test. Their diagnostic accuracy in identifying complete responders was determined by the area under the receiver operator characteristics curve. Cutoff values were determined by the Youden index. Pathology was the standard of reference. RESULTS: One hundred fourteen patients with first posttreatment MRI scans (6.2 weeks after completion of neoadjuvant treatment) were included. Sixty-eight patients had a second posttreatment scan (10.4 weeks). With no filtration, mean (p = 0.033), SD (p = 0.048), entropy (p = 0.007), and skewness (p = 0.000) from first posttreatment scans, and SD (p = 0.042), entropy (p = 0.014), mean of positive pixels (p = 0.032), and skewness (p = 0.000) from second posttreatment scans were all able to identify complete response. Area under the curve ranged from 0.750 to 0.88. LIMITATIONS: Texture analysis of MRI is a new modality; therefore, further studies are necessary to standardize the methodology of extraction of texture features, timing of scans, and acquisition parameters. CONCLUSIONS: Texture analysis of MRI is a potentially significant imaging biomarker that can accurately identify patients who have experienced complete response and might be suitable for a nonsurgical approach. (Cinicaltrials.gov:NCT02439086). See Video Abstract at http://links.lww.com/DCR/A760.

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 < 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. CONCLUSIONS: A high pulmonary TBR is independently associated with increased risk of mortality in IPF patients.

Streamlining staging of lung and colorectal cancer with whole body MRI; study protocols for two multicentre, non-randomised, single-arm, prospective diagnostic accuracy studies (Streamline C and Streamline L).

BACKGROUND AND AIMS: Rapid and accurate cancer staging following diagnosis underpins patient management, in particular the identification of distant metastatic disease. Current staging guidelines recommend sequential deployment of various imaging platforms such as computerised tomography (CT) and positron emission tomography (PET) which can be time and resource intensive and onerous for patients. Recent studies demonstrate that whole body magnetic resonance Imaging (WB-MRI) may stage cancer efficiently in a single visit, with potentially greater accuracy than current staging investigations. The Streamline trials aim to evaluate whether WB-MRI increases per patient detection of metastases in non-small cell lung and colorectal cancer compared to standard staging pathways. METHODS: The Streamline trials are multicentre, non-randomised, single-arm, prospective diagnostic accuracy studies with a novel design to capture patient management decisions during staging pathways. The two trials recruit adult patients with proven or highly suspected new diagnosis of primary colorectal (Streamline C) or non-small cell lung cancer (Streamline L) referred for staging. Patients undergo WB-MRI in addition to standard staging investigations. Strict blinding protocols are enforced for those interpreting the imaging. A first major treatment decision is made by the multi-disciplinary team prior to WB-MRI revelation based on standard staging investigations only, then based on the WB-MRI and any additional tests precipitated by WB-MRI, and finally based on all available test results. The reference standard is derived by a multidisciplinary consensus panel who assess 12 months of follow-up data to adjudicate on the TNM stage at diagnosis. Health psychology assessment of patients' experiences of the cancer staging pathway will be undertaken via interviews and questionnaires. A cost (effectiveness) analysis of WB-MRI compared to standard staging pathways will be performed. DISCUSSION: We describe a novel approach to radiologist and clinician blinding to ascertain the 'true' diagnostic accuracy of differing imaging pathways and discuss our approach to assessing the impact of WB-MRI on clinical decision making in real-time. The Streamline trials will compare WB-MRI and standard imaging pathways in the same patients, thereby informing the most accurate and efficient approach to staging. TRIAL REGISTRATION: Streamline C ISRCTN43958015 (registered 25/7/2012). Streamline L ISRCTN50436483 (registered 31/7/2012).

"Textural analysis of multiparametric MRI detects transition zone prostate cancer".

OBJECTIVES: To evaluate multiparametric-MRI (mpMRI) derived histogram textural-analysis parameters for detection of transition zone (TZ) prostatic tumour. METHODS: Sixty-seven consecutive men with suspected prostate cancer underwent 1.5T mpMRI prior to template-mapping-biopsy (TPM). Twenty-six men had 'significant' TZ tumour. Two radiologists in consensus matched TPM to the single axial slice best depicting tumour, or largest TZ diameter for those with benign histology, to define single-slice whole TZ-regions-of-interest (ROIs). Textural-parameter differences between single-slice whole TZ-ROI containing significant tumour versus benign/insignificant tumour were analysed using Mann Whitney U test. Diagnostic accuracy was assessed by receiver operating characteristic area under curve (ROC-AUC) analysis cross-validated with leave-one-out (LOO) analysis. RESULTS: ADC kurtosis was significantly lower (p < 0.001) in TZ containing significant tumour with ROC-AUC 0.80 (LOO-AUC 0.78); the difference became non-significant following exclusion of significant tumour from single-slice whole TZ-ROI (p = 0.23). T1-entropy was significantly lower (p = 0.004) in TZ containing significant tumour with ROC-AUC 0.70 (LOO-AUC 0.66) and was unaffected by excluding significant tumour from TZ-ROI (p = 0.004). Combining these parameters yielded ROC-AUC 0.86 (LOO-AUC 0.83). CONCLUSION: Textural features of the whole prostate TZ can discriminate significant prostatic cancer through reduced kurtosis of the ADC-histogram where significant tumour is included in TZ-ROI and reduced T1 entropy independent of tumour inclusion. KEY POINTS: • MR textural features of prostate transition zone may discriminate significant prostatic cancer. • Transition zone (TZ) containing significant tumour demonstrates a less peaked ADC histogram. • TZ containing significant tumour reveals higher post-contrast T1-weighted homogeneity. • The utility of MR texture analysis in prostate cancer merits further investigation.

Non-small-cell lung cancer resectability: diagnostic value of PET/MR.

PURPOSE: To assess the diagnostic performance of PET/MR in patients with non-small-cell lung cancer. METHODS: Fifty consecutive consenting patients who underwent routine (18)F-FDG PET/CT for potentially radically treatable lung cancer following a staging CT scan were recruited for PET/MR imaging on the same day. Two experienced readers, unaware of the results with the other modalities, interpreted the PET/MR images independently. Discordances were resolved in consensus. PET/MR TNM staging was compared to surgical staging from thoracotomy as the reference standard in 33 patients. In the remaining 17 nonsurgical patients, TNM was determined based on histology from biopsy, imaging results (CT and PET/CT) and follow-up. ROC curve analysis was used to assess accuracy, sensitivity and specificity of the PET/MR in assessing the surgical resectability of primary tumour. The kappa statistic was used to assess interobserver agreement in the PET/MR TNM staging. Two different readers, without knowledge of the PET/MR findings, subsequently separately reviewed the PET/CT images for TNM staging. The generalized kappa statistic was used to determine intermodality agreement between PET/CT and PET/MR for TNM staging. RESULTS: ROC curve analysis showed that PET/MR had a specificity of 92.3 % and a sensitivity of 97.3 % in the determination of resectability with an AUC of 0.95. Interobserver agreement in PET/MR reading ranged from substantial to perfect between the two readers (Cohen's kappa 0.646 - 1) for T stage, N stage and M stage. Intermodality agreement between PET/CT and PET/MR ranged from substantial to almost perfect for T stage, N stage and M stage (Cohen's kappa 0.627 - 0.823). CONCLUSION: In lung cancer patients PET/MR appears to be a robust technique for preoperative staging.

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 (18)F-FDG PET/HRCT. The pulmonary imaging findings in the IPF patients were compared to the findings in a control population. Pulmonary uptake of (18)F-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 (18)F-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.

[18F]FDG PET/CT Signal Correlates with Neoangiogenesis Markers in Patients with Fibrotic Interstitial Lung Disease Who Underwent Lung Biopsy: Implication for the Use of PET/CT in Diffuse Lung Diseases.

The use of [18F]FDG PET/CT as a biomarker in diffuse lung diseases is increasingly recognized. We investigated the correlation between [18F]FDG uptake with histologic markers on lung biopsy of patients with fibrotic interstitial lung disease (fILD). Methods: We recruited 18 patients with fILD awaiting lung biopsy for [18F]FDG PET/CT. We derived a target-to-background ratio (TBR) of maximum pulmonary uptake of [18F]FDG (SUVmax) divided by the lung background (SUVmin). Consecutive paraffin-embedded lung biopsy sections were immunostained for alveolar and interstitial macrophages (CD68), microvessel density (MVD) (CD31 and CD105/endoglin), and glucose transporter 1. MVD was expressed as vessel area percentage per high-power field (Va%/hpf). Differences in imaging and angiogenesis markers between histologic usual interstitial pneumonia (UIP) and non-UIP were assessed using a nonparametric Mann-Whitney test. Correlation of imaging with angiogenesis markers was assessed using the nonparametric Spearman rank correlation. Univariate Kaplan-Meier survival analysis assessed the difference in the survival curves for each of the angiogenesis markers (separated by their respective optimal cutoff) using the log-rank test. Statistical analysis was performed using SPSS. Results: In total, 18 patients were followed for an average of 41.36 mo (range, 5.69-132.46 mo; median, 30.07 mo). Only CD105 MVD showed a significantly positive correlation with [18F]FDG TBR (Spearman rank correlation, 0.556; P < 0.05, n = 13). There was no correlation between [18F]FDG uptake and macrophage expression of glucose transporter 1. CD105 and CD31 were higher for UIP than for non-UIP, with CD105 reaching statistical significance (P = 0.011). In all patients, MVD assessed with either CD105 or CD31 quantification on biopsy predicted overall survival. Patients with CD105 MVD of less than 12 Va%/hpf or CD31 MVD of less than 35 Va%/hpf had a significantly better prognosis (no deaths during follow-up in the case of CD105) than did patients with higher scores of CD105 MVD (median survival, 35 mo; P = 0.041, n = 13) or CD31 MVD (median survival, 28 mo; P = 0.014, n = 13). Conclusion: Previous work has used [18F]FDG uptake in PET/CT as a biomarker in fILD. Here, we highlight a correlation between angiogenesis and [18F]FDG TBR. We show that MVD is higher for UIP than for non-UIP and is associated with mortality in patients with fILD. These data set the scene to investigate the potential role of vasculature and angiogenesis in fibrosis.

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer.

INTRODUCTION: Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS: More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS: The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS: With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.

Dynamic contrast-enhanced MRI improves accuracy for detecting focal splenic involvement in children and adolescents with Hodgkin disease.

BACKGROUND: Accurate assessment of splenic disease is important for staging Hodgkin lymphoma. OBJECTIVE: The purpose of this study was to assess T2-weighted imaging with and without dynamic contrast-enhanced (DCE) MRI for evaluation of splenic Hodgkin disease. MATERIALS AND METHODS: Thirty-one children with Hodgkin lymphoma underwent whole-body T2-weighted MRI with supplementary DCE splenic imaging, and whole-body PET-CT before and following chemotherapy. Two experienced nuclear medicine physicians derived a PET-CT reference standard for splenic disease, augmented by follow-up imaging. Unaware of the PET-CT, two experienced radiologists independently evaluated MRI exercising a locked sequential read paradigm (T2-weighted then DCE review) and recorded the presence/absence of splenic disease at each stage. Performance of each radiologist was determined prior to and following review of DCE-MRI. Incorrect MRI findings were ascribed to reader (lesion present on MRI but missed by reader) or technical (lesion not present on MRI) error. RESULTS: Seven children had splenic disease. Sensitivity/specificity of both radiologists for the detection of splenic involvement using T2-weighted images alone was 57%/100% and increased to 100%/100% with DCE-MRI. There were three instances of technical error on T2-weighted imaging; all lesions were visible on DCE-MRI. CONCLUSIONS: T2-weighted imaging when complemented by DCE-MRI imaging may improve evaluation of Hodgkin disease splenic involvement.

Optimisation of the air fraction correction for lung PET/CT: addressing resolution mismatch.

BACKGROUND: Increased pulmonary [Formula: see text]F-FDG metabolism in patients with idiopathic pulmonary fibrosis, and other forms of diffuse parenchymal lung disease, can predict measurements of health and lung physiology. To improve PET quantification, voxel-wise air fractions (AF) determined from CT can be used to correct for variable air content in lung PET/CT. However, resolution mismatches between PET and CT can cause artefacts in the AF-corrected image. METHODS: Three methodologies for determining the optimal kernel to smooth the CT are compared with noiseless simulations and non-TOF MLEM reconstructions of a patient-realistic digital phantom: (i) the point source insertion-and-subtraction method, [Formula: see text]; (ii) AF-correcting with varyingly smoothed CT to achieve the lowest RMSE with respect to the ground truth (GT) AF-corrected volume of interest (VOI), [Formula: see text]; iii) smoothing the GT image to match the reconstruction within the VOI, [Formula: see text]. The methods were evaluated both using VOI-specific kernels, and a single global kernel optimised for the six VOIs combined. Furthermore, [Formula: see text] was implemented on thorax phantom data measured on two clinical PET/CT scanners with various reconstruction protocols. RESULTS: The simulations demonstrated that at [Formula: see text] iterations (200 i), the kernel width was dependent on iteration number and VOI position in the lung. The [Formula: see text] method estimated a lower, more uniform, kernel width in all parts of the lung investigated. However, all three methods resulted in approximately equivalent AF-corrected VOI RMSEs (<10%) at [Formula: see text]200i. The insensitivity of AF-corrected quantification to kernel width suggests that a single global kernel could be used. For all three methodologies, the computed global kernel resulted in an AF-corrected lung RMSE <10%  at [Formula: see text]200i, while larger lung RMSEs were observed for the VOI-specific kernels. The global kernel approach was then employed with the [Formula: see text] method on measured data. The optimally smoothed GT emission matched the reconstructed image well, both within the VOI and the lung background. VOI RMSE was <10%, pre-AFC, for all reconstructions investigated. CONCLUSIONS: Simulations for non-TOF PET indicated that around 200i were needed to approach image resolution stability in the lung. In addition, at this iteration number, a single global kernel, determined from several VOIs, for AFC, performed well over the whole lung. The [Formula: see text] method has the potential to be used to determine the kernel for AFC from scans of phantoms on clinical scanners.