Corrigendum: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

This corrects the article DOI: 10.1038/nature22364.

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

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.

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.

Novel positron emission tomography/computed tomography of diffuse parenchymal lung disease combining a labeled somatostatin receptor analogue and 2-deoxy-2[18F]fluoro-D-glucose.

We prospectively investigated the potential of positron emission tomography (PET) using the somatostatin receptor (SSTR) analogue 68Ga-DOTATATE and 2-deoxy-2[¹8F]fluoro-D-glucose (¹8F-FDG) in diffuse parenchymal lung disease (DPLD). Twenty-six patients (mean age 68.9 ± 11.0 years) with DPLD were recruited for 68Ga-DOTATATE and ¹8F-FDG combined PET/high-resolution computed tomography (HRCT) studies. Ten patients had idiopathic pulmonary fibrosis (IPF), 12 patients had nonspecific interstitial pneumonia (NSIP), and 4 patients had other forms of DPLD. Using PET, the pulmonary tracer uptake (maximum standardized uptake value [SUV(max)]) was calculated. The distribution of PET tracer was compared to the distribution of lung parenchymal changes on HRCT. All patients demonstrated increased pulmonary PET signal with 68Ga-DOTATATE and ¹8F-FDG. The distribution of parenchymal uptake was similar, with both tracers corresponding to the distribution of HRCT changes. The mean SUV(max) was 2.2 ± 0.7 for 68Ga-DOTATATE and 2.8 ± 1.0 (t-test, p  =  .018) for ¹8F-FDG. The mean 68Ga-DOTATATE SUV(max) in IPF patients was 2.5 ± 0.9, whereas it was 2.0 ± 0.7 (p  =  .235) in NSIP patients. The correlation between 68Ga-DOTATATE SUV(max) and gas transfer (transfer factor of the lung for carbon monoxide [TLCO]) was r  =  -.34 (p  =  .127) and r  =  -.49 (p  =  .028) between ¹8F-FDG SUV(max) and TLCO. We provide noninvasive in vivo evidence in humans showing that SSTRs may be detected in the lungs of patients with DPLD in a similar distribution to sites of increased uptake of ¹8F-FDG on PET.

18F-Fluorodeoxyglucose positron emission tomography pulmonary imaging in idiopathic pulmonary fibrosis is reproducible: implications for future clinical trials.

PURPOSE: Noninvasive markers of disease activity in patients with idiopathic pulmonary fibrosis (IPF) are lacking. We performed this study to investigate the reproducibility of pulmonary (18)F-FDG PET/CT in patients with IPF. METHODS: The study group comprised 13 patients (11 men, 2 women; mean age 71.1 ± 9.9 years) with IPF recruited for two thoracic (18)F-FDG PET/CT studies performed within 2 weeks of each other. All patients were diagnosed with IPF in consensus at multidisciplinary meetings as a result of typical clinical, high-resolution CT and pulmonary function test features. Three methods for evaluating pulmonary (18)F-FDG uptake were used. The maximal (18)F-FDG pulmonary uptake (SUVmax) in the lungs was determined using manual region-of-interest placement. An (18)F-FDG uptake intensity histogram was automatically constructed from segmented lungs to evaluate the distribution of SUVs. Finally, mean SUV was determined for volumes-of-interest in pulmonary regions with interstitial lung changes identified on CT scans. Processing included correction for tissue fraction effects. Bland-Altman analysis was performed and interclass correlation coefficients (ICC) were determined to assess the reproducibility between the first and second PET scans, as well as the level of intraobserver and interobserver agreement. RESULTS: The mean time between the two scans was 6.3 ± 4.3 days. The interscan ICCs for pulmonary SUVmax analysis and mean SUV corrected for tissue fraction effects were 0.90 and 0.91, respectively. Intensity histograms were different in only 1 of the 13 paired studies. Intraobserver agreement was also excellent (0.80 and 0.85, respectively). Some bias was observed between observers, suggesting that serial studies would benefit from analysis by the same observer. CONCLUSION: This study demonstrated that there is excellent short-term reproducibility in pulmonary (18)F-FDG uptake in patients with IPF.

Assessment of the metabolic flow phenotype of primary colorectal cancer: correlations with microvessel density are influenced by the histological scoring method.

OBJECTIVES: To investigate how the histological scoring of microvessel density affects correlations between integrated (18)F-FDG-PET/perfusion CT parameters and CD105 microvessel density. METHODS: A total of 53 patients were enrolled from 2007 to 2010. Integrated (18)F-FDG-PET/perfusion CT was successful in 45 patients, 35 of whom underwent surgery without intervening treatment. Tumour SUV(max), SUV(mean) and regional blood flow (BF) were derived. Immunohistochemical staining for CD105 expression and analysis were performed for two hot spots, four hot spots and the Chalkley method. Correlations between metabolic flow parameters and CD105 expression were assessed using Spearman's rank correlation. RESULTS: Mean (SD) for tumour size was 38.5 (20.5) mm, for SUV(max), SUV(mean) and BF it was 19.1 (4.5), 11.6 (2.5) and 85.4 (40.3) mL/min/100 g tissue, and for CD105 microvessel density it was 71.4 (23.6), 66.8 (22.9) and 6.18 (2.07) for two hot spots, four hot spots and the Chalkley method, respectively. Positive correlation between BF and CD105 expression was modest but higher for Chalkley than for four hot spots analysis (r = 0.38, P = 0.03; r = 0.33, P = 0.05, respectively). There were no significant correlations between metabolic parameters (SUV(max) or SUV(mean)) and CD105 expression (r = 0.08-0.22, P = 0.21-0.63). CONCLUSIONS: The histological analysis method affects correlations between tumour CD105 expression and BF but not SUV(max) or SUV(mean). KEY POINTS: • FDG-PET/perfusion CT offers new surrogate biomarkers of angiogenesis. • Microvessel density scoring influences histopathological correlations with CT blood flow. • Highest correlations were found with the Chalkley analysis method. • Correlations between SUV and CD105 are not affected by the scoring method.

Integrated (18)F-FDG PET/CT and perfusion CT of primary colorectal cancer: effect of inter- and intraobserver agreement on metabolic-vascular parameters.

OBJECTIVE: The purpose of this article is to assess the effect of observers on combined metabolic-vascular parameters in colorectal cancer. SUBJECTS AND METHODS: Twenty-five prospective patients (12 men and 13 women; mean age, 66.9 years) with proven primary colorectal adenocarcinoma underwent integrated (18)F-FDG PET/perfusion CT to assess tumor metabolism (mean and maximum standardized uptake value [SUV(mean) and SUV(max), respectively]) and vascularization (blood flow [BF], blood volume [BV], permeability surface-area product, and standardized perfusion value). Intra- and interobserver agreement for PET, perfusion CT, and combined metabolic-flow parameters were determined by Bland-Altman statistics and intraclass correlation coefficients (ICCs). RESULTS: The mean tumor size was 3.8 ± 1.6 cm; there were five stage IA/B, six stage IIA/B, eight stage IIIA/B, and six stage IV tumors. Intra- and interobserver agreement for individual parameters was fair to good, with mean differences between observers of -0.74 for SUV(max), -0.16 for SUV(mean), 9.72 for BF, 0.15 for BV, -0.76 for permeability surface-area product, and 0.09 for standardized perfusion value. ICCs were 0.44-0.99 and 0.38-0.89 for intra- and interobserver agreement, respectively. Interobserver agreement was variable for combined metabolic-flow parameters but better for metabolic-flow difference than for metabolic-flow ratio: ICCs were 0.69-0.88 for the metabolic-flow difference and 0.44-0.94 for the metabolic-flow ratio. CONCLUSION: Combined parameters to assess the metabolic-flow relationship are influenced by observer variation. Intra- and interobserver agreement are better for the metabolic-flow differences than for the ratios, suggesting that metabolic-flow differences may be a more robust parameter for clinical practice.

The importance of correction for tissue fraction effects in lung PET: preliminary findings.

PURPOSE: It has recently been recognized that PET/CT may play a role in diffuse parenchymal lung disease. However, interpretation can be confounded due to the variability in lung density both within and between individuals. To address this issue a novel correction method is proposed. METHODS: A CT scan acquired during shallow breathing is registered to a PET study and smoothed so as to match the PET resolution. This is used to derive voxel-based tissue fraction correction factors for the individual. The method was evaluated in a lung phantom study in which the lung was simulated by a Styrofoam/water mixture. The method was further evaluated using (18)F-FDG in 12 subjects free from pulmonary disease where ranges before and after correction were considered. RESULTS: Correction resulted in similar activity concentrations for the lung and background regions, consistent with the experimental phantom set-up. Correction resulted in reduced inter- and intrasubject variability in the estimated SUV. The possible application of the method was further demonstrated in five subjects with interstitial lung changes where increased SUV was demonstrated. Single study pre- and post-treatment studies were also analysed to further illustrate the utility of the method. CONCLUSION: The proposed tissue fraction correction method is a promising technique to account for variability of density in interpreting lung PET studies.

What is the relationship between ¹8F-FDG aortic aneurysm uptake on PET/CT and future growth rate?

PURPOSE: In this study we investigate the relationship between (18)F-fluorodeoxyglucose (FDG) metabolism and future aneurysm expansion measured by serial duplex ultrasound. Current screening programmes are increasing the identification of patients with abdominal aortic aneurysm (AAA). The management of these patients remains challenging and methods of risk stratification are sought. METHODS: Thirty-four consecutive patients [31 men, 3 women, median age 75 years, interquartile range (IQR) 71-78] with aortic aneurysms under routine surveillance with serial ultrasound were prospectively recruited for (18)F-FDG positron emission tomography (PET)/CT. A whole vessel type analysis was performed measuring the highest aortic wall (18)F-FDG uptake (standardized uptake value or SUV(max)), and target to background ratio (TBR) for each axial image and median SUV(max) and TBR value were calculated. Institutional Review Board permission and informed patient consent were obtained. RESULTS: Nine patients failed to undergo 12-month follow-up study (deceased n = 2, withdrew n = 1, failed to attend ultrasound scan n = 5, emergency aneurysm repair n = 1) leaving 25 patients for analysis. The median whole vessel SUV(max) was 1.70 (IQR 1.45-2.08). The median whole vessel TBR was 1.15 (IQR 1.00-1.40). The median aneurysm expansion at 12 months was 2.0 mm (IQR 0.5-5.0). The correlation (r) between (18)F-FDG SUV(max) and ultrasound expansion at 1 year was -0.501 (p = 0.011). CONCLUSION: The preliminary findings from this observational longitudinal pilot study suggest that there is an inverse trend between (18)F-FDG uptake on PET and future AAA expansion. Aortic aneurysms with lower metabolic activity may therefore be more likely to expand.

¹8F-FDG PET and biomarkers for tumour angiogenesis in early breast cancer.

PURPOSE: Tumour angiogenesis is an independent and strong prognostic factor in early breast carcinoma. We performed this study to investigate the ability of (18)F-FDG to detect angiogenesis in early breast carcinoma using PET/CT. METHODS: Twenty consecutive patients with early (T1-T2) breast carcinoma were recruited prospectively for 18F-FDG PET/CT. The PET/CT data were used to calculate whole tumour maximum standardized uptake value (SUV(max)) and mean standardized uptake value (SUV(mean)). All patients underwent subsequent surgery without prior chemotherapy or radiotherapy. The excised tumour underwent immunohistochemistry for vascular endothelial growth factor (VEGF), CD105 and glucose transporter protein 1 (GLUT1). RESULTS: The SUV(max) showed the following correlation with tumour histology: CD105: r = 0.60, p = 0.005; GLUT1: r = 0.21, p = 0.373; VEGF: r = -0.16, p = 0.496. The SUV(mean) showed the following correlation with tumour histology: CD105: r = 0.65, p = 0.002; GLUT1: r = 0.34, p = 0.144; VEGF: r = -0.18, p = 0.443 CONCLUSION: (18)F-FDG uptake is highly significantly associated with angiogenesis as measured by the immunohistochemistry with CD105 for new vessel formation. Given that tumour angiogenesis is an important prognostic indicator and a predictor of treatment response, (18)F-FDG PET may have a role in the management of primary breast cancer patients even in early-stage disease.

Commercial software upgrades may significantly alter Perfusion CT parameter values in colorectal cancer.

OBJECTIVE: To determine how commercial software platform upgrades impact on derived parameters for colorectal cancer. MATERIALS AND METHODS: Following ethical approval, 30 patients with suspected colorectal cancer underwent Perfusion CT using integrated 64 detector PET/CT before surgery. Analysis was performed using software based on modified distributed parameter analysis (Perfusion software version 4; Perfusion 4.0), then repeated using the previous version (Perfusion software version 3; Perfusion 3.0). Tumour blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface area product (PS) were determined for identical regions-of-interest. Slice-by-slice and 'whole tumour' variance was assessed by Bland-Altman analysis. RESULTS: Mean BF, BV and PS was 20.4%, 59.5%, and 106% higher, and MTT 14.3% shorter for Perfusion 4.0 than Perfusion 3.0. The mean difference (95% limits of agreement) were +13.5 (-44.9 to 72.0), +2.61 (-0.06 to 5.28), -1.23 (-6.83 to 4.36), and +14.2 (-4.43 to 32.8) for BF, BV, MTT and PS respectively. Within subject coefficient of variation was 36.6%, 38.0%, 27.4% and 60.6% for BF, BV, MTT and PS respectively indicating moderate to poor agreement. CONCLUSION: Software version upgrades of the same software platform may result in significantly different parameter values, requiring adjustments for cross-version comparison.

Vascular inflammation imaging with 18F-FDG PET/CT: when to image?

UNLABELLED: We prospectively investigated the ideal imaging time to measure vascular uptake after injection of (18)F-FDG. METHODS: A total of 17 patients with atherosclerotic abdominal aortic aneurysm underwent dynamic abdominal PET/CT using 2-min frames between 45 and 53, 57 and 65, 115 and 123, and 175 and 183 min after injection of (18)F-FDG. For each period of dynamic imaging, vessel wall and lumen uptake were measured using the maximum standardized uptake value (SUV(max)) and target-to-background ratio (TBR). RESULTS: No significant difference in TBR across all time points (repeated measures ANOVA, P = 0.206) was observed, despite a significant difference in aortic wall and lumen uptake with time (repeated measures ANOVA, P = 0.02 and P < 0.001, respectively). There was no significant difference between aortic wall uptake at 60 min (SUV(max), 2.15 +/- 0.11 SE) and 180 min (SUV(max), 1.99 +/- 0.18 SE) (paired t test, P = 0.367). There was a significant difference in lumen uptake at 60 min (SUV(max), 2.4 +/- 0.11 SE) and 180 min (SUV(max), 1.7 +/- 0.1 SE) (paired t test, P = 0.001). There was no significant difference in TBR between 60 min (0.91 +/- 0.03) and 180 min (1.01 +/- 0.06 SE) (paired t test, P = 0.131). With increasing delayed imaging, there was increasing variability (SE) in the SUV(max) for the aortic wall and TBRs. CONCLUSION: There was no significant advantage in imaging at 3 h over 1 h after (18)F-FDG injection.

Idiopathic pulmonary fibrosis and diffuse parenchymal lung disease: implications from initial experience with 18F-FDG PET/CT.

UNLABELLED: The purpose of this study was to evaluate integrated (18)F-FDG PET/CT in patients with idiopathic pulmonary fibrosis (IPF) and diffuse parenchymal lung disease (DPLD). METHODS: Thirty-six consecutive patients (31 men and 5 women; mean age +/- SD, 68.7 +/- 9.4 y) with IPF (n = 18) or other forms of DPLD (n = 18) were recruited for PET/CT and high-resolution CT (HRCT), acquired on the same instrument. The maximal pulmonary (18)F-FDG metabolism was measured as a standardized uptake value (SUV(max)). At this site, the predominant lung parenchyma HRCT pattern was defined for each patient: ground-glass or reticulation/honeycombing. Patients underwent a global health assessment and pulmonary function tests. RESULTS: Raised pulmonary (18)F-FDG metabolism in 36 of 36 patients was observed. The parenchymal pattern on HRCT at the site of maximal (18)F-FDG metabolism was predominantly ground-glass (7/36), reticulation/honeycombing (26/36), and mixed (3/36). The mean SUV(max) in patients with ground-glass and mixed patterns was 2.0 +/- 0.4, and in reticulation/honeycombing it was 3.0 +/- 1.0 (Mann-Whitney U test, P = 0.007). The mean SUV(max) in patients with IPF was 2.9 +/- 1.1, and in other DPLD it was 2.7 +/- 0.9 (Mann-Whitney U test, P = 0.862). The mean mediastinal lymph node SUV(max) (2.7 +/- 1.3) correlated with pulmonary SUV(max) (r = 0.63, P < 0.001). Pulmonary (18)F-FDG uptake correlated with the global health score (r = 0.50, P = 0.004), forced vital capacity (r = 0.41, P = 0.014), and transfer factor (r = 0.37, P = 0.042). CONCLUSION: Increased pulmonary (18)F-FDG metabolism in all patients with IPF and other forms of DPLD was observed. Pulmonary (18)F-FDG uptake predicts measurements of health and lung physiology in these patients. (18)F-FDG metabolism was higher when the site of maximal uptake corresponded to areas of reticulation/honeycomb on HRCT than to those with ground-glass patterns.

First experience of combined cardiac PET/64-detector CT angiography with invasive angiographic validation.

PURPOSE: Despite modern CT systems and expert evaluators, the diagnostic performance of coronary CT angiography is limited by overestimation of vessel stenosis which reduces the positive predictive value (PPV) of the test. The aim of this study was to evaluate the performance of combined cardiac PET/64-detector CT angiography. METHODS: Included in this retrospective study were 33 consecutive patients (5 women, 28 men; mean age 61.6 years, range 47-87 years, mean BMI 27.3+/-5.2 kg/m(2)) with clinically suspected flow-limiting coronary artery disease who underwent combined cardiac PET/64-detector CT angiography and invasive angiography. Combined PET/CT images were reported by an experienced dual-accredited radiologist/nuclear physician. An experienced cardiac CT radiologist re-read the CT images without PET. Stenotic disease was defined as >50% vessel narrowing. Invasive coronary angiography was used as a reference standard. Local ethics committee approval and patient consent were obtained. RESULTS: CT angiography (without PET data) was concordant with invasive angiography in 31/33 patients and at a patient level, the sensitivity in detecting significant coronary artery lesions was 100%, the specificity was 82%, the PPV was 92% and the negative predictive value (NPV) was 100%. Using combined PET/CT angiography the findings were concordant with invasive angiography in 32/33 patients and at a patient level, the sensitivity was 96%, the specificity was 100%, the PPV was 100% and the NPV was 91%. CONCLUSION: The use of integrated cardiac PET/64-detector CT angiography is feasible and appears to improve some aspects of the diagnostic performance of 64-detector coronary artery angiography in detecting coronary artery disease.

Magnetic resonance texture analysis utility in differentiating intraparenchymal neurosarcoidosis from primary central nervous system lymphoma: a preliminary analysis.

PURPOSE: Neurosarcoidosis and primary central nervous system lymphomas, although distinct disease entities, can both have overlapping neuroimaging findings. The purpose of our preliminary study was to assess if magnetic resonance texture analysis can differentiate parenchymal mass-like neurosarcoidosis granulomas from primary central nervous system lymphomas. METHODS: A total of nine patients was evaluated, four with parenchymal neurosarcoidosis granulomas and five with primary central nervous system lymphomas. Magnetic resonance texture analysis was performed with commercial software using a filtration histogram technique. Texture features of different sizes and variations in signal intensity were extracted at six different spatial scale filters, followed by feature quantification using statistical and histogram parameters and 36 features were analysed for each sequence (T1-weighted, T2-weighted, fluid-attenuated inversion recovery, diffusion-weighted, apparent diffusion coefficient, T1-post contrast). The non-parametric Mann-Whitney test was used to evaluate the differences between different texture parameters. RESULTS: The differences in distribution of entropy on T2-weighted imaging, apparent diffusion coefficient and T1-weighted post-contrast images were statistically significant on all spatial scale filters. Magnetic resonance texture analysis using medium and coarse spatial scale filters was especially useful in discriminating neurosarcoidosis from primary central nervous system lymphomas for mean, mean positive pixels, kurtosis, and skewness on diffusion-weighted imaging ( P < 0.004-0.030). At spatial scale filter 5, entropy on T2-weighted imaging ( P = 0.001) was the most useful discriminator with a cut-off value of 6.12 ( P = 0.001, area under the curve (AUC)-1, sensitivity (Sn)-100%, specificity (Sp)-100%), followed by kurtosis and skewness on diffusion-weighted imaging with a cut-off value of -0.565 ( P = 0.011, AUC-0.97, Sn-100%, Sp-83%) and-0.365 ( P = 0.008, AUC-0.98, Sn-100%, Sp-100%) respectively. CONCLUSION: Filtration histogram-based magnetic resonance texture analysis appears to be a promising modality to distinguish parenchymal neurosarcoidosis granulomas from primary central nervous system lymphomas.

Multifunctional imaging signature for V-KI-RAS2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in colorectal cancer.

UNLABELLED: This study explores the potential for multifunctional imaging to provide a signature for V-KI-RAS2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutations in colorectal cancer. METHODS: This prospective study approved by the institutional review board comprised 33 patients undergoing PET/CT before surgery for proven primary colorectal cancer. Tumor tissue was examined histologically for presence of the KRAS mutations and for expression of hypoxia-inducible factor-1 (HIF-1) and minichromosome maintenance protein 2 (mcm2). The following imaging parameters were derived for each tumor: (18)F-FDG uptake ((18)F-FDG maximum standardized uptake value [SUVmax]), CT texture (expressed as mean of positive pixels [MPP]), and blood flow measured by dynamic contrast-enhanced CT. A recursive decision tree was developed in which the imaging investigations were applied sequentially to identify tumors with KRAS mutations. Monte Carlo analysis provided mean values and 95% confidence intervals for sensitivity, specificity, and accuracy. RESULTS: The final decision tree comprised 4 decision nodes and 5 terminal nodes, 2 of which identified KRAS mutants. The true-positive rate, false-positive rate, and accuracy (95% confidence intervals) of the decision tree were 82.4% (63.9%-93.9%), 0% (0%-10.4%), and 90.1% (79.2%-96.0%), respectively. KRAS mutants with high (18)F-FDG SUVmax and low MPP showed greater frequency of HIF-1 expression (P = 0.032). KRAS mutants with low (18)F-FDG SUV(max), high MPP, and high blood flow expressed mcm2 (P = 0.036). CONCLUSION: Multifunctional imaging with PET/CT and recursive decision-tree analysis to combine measurements of tumor (18)F-FDG uptake, CT texture, and perfusion has the potential to identify imaging signatures for colorectal cancers with KRAS mutations exhibiting hypoxic or proliferative phenotypes.

Tumor heterogeneity and permeability as measured on the CT component of PET/CT predict survival in patients with non-small cell lung cancer.

PURPOSE: We prospectively examined the role of tumor textural heterogeneity on positron emission tomography/computed tomography (PET/CT) in predicting survival compared with other clinical and imaging parameters in patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: The feasibility study consisted of 56 assessed consecutive patients with NSCLC (32 males, 24 females; mean age 67 ± 9.7 years) who underwent combined fluorodeoxyglucose (FDG) PET/CT. The validation study population consisted of 66 prospectively recruited consecutive consenting patients with NSCLC (37 males, 29 females; mean age, 67.5 ± 7.8 years) who successfully underwent combined FDG PET/CT-dynamic contrast-enhanced (DCE) CT. Images were used to derive tumoral PET/CT textural heterogeneity, DCE CT permeability, and FDG uptake (SUVmax). The mean follow-up periods were 22.6 ± 13.3 months and 28.5± 13.2 months for the feasibility and validation studies, respectively. Optimum threshold was determined for clinical stage and each of the above biomarkers (where available) from the feasibility study population. Kaplan-Meier analysis was used to assess the ability of the biomarkers to predict survival in the validation study. Cox regression determined survival factor independence. RESULTS: Univariate analysis revealed that tumor CT-derived heterogeneity (P < 0.001), PET-derived heterogeneity (P = 0.003), CT-derived permeability (P = 0.002), and stage (P < 0.001) were all significant survival predictors. The thresholds used in this study were derived from a previously conducted feasibility study. Tumor SUVmax did not predict survival. Using multivariable analysis, tumor CT textural heterogeneity (P = 0.021), stage (P = 0.001), and permeability (P < 0.001) were independent survival predictors. These predictors were independent of patient treatment. CONCLUSIONS: Tumor stage and CT-derived textural heterogeneity were the best predictors of survival in NSCLC. The use of CT-derived textural heterogeneity should assist the management of many patients with NSCLC.

The flow-metabolic phenotype of primary colorectal cancer: assessment by integrated 18F-FDG PET/perfusion CT with histopathologic correlation.

UNLABELLED: The aim of this study was to assess the in vivo flow-metabolic phenotype in primary colorectal cancer with integrated (18)F-FDG PET/perfusion CT and its relationship to gold standard histopathologic assessment of angiogenesis and hypoxia. METHODS: 45 patients (26 male and 19 female; mean age, 67.6 y) with primary colorectal cancer underwent integrated (18)F-FDG PET/perfusion CT, deriving tumor glucose metabolism (maximum standardized uptake value) and regional blood flow. From this cohort, 35 underwent surgery subsequently, without intervening neoadjuvant treatment, allowing histopathologic correlation with tumor stage, CD105 microvessel density, vascular endothelial growth factor (VEGF), glucose transporter protein 1 (Glut-1), and hypoxia-inducible factor 1 expression. RESULTS: The flow-metabolic ratio was significantly lower for tumors with higher VEGF (3.65 vs. 5.98; P = 0.01) or hypoxia-inducible factor 1 expression (3.63 vs. 5.48; P = 0.04) versus tumors with lower expression. There were significant negative correlations between the tumor flow-metabolic ratio and VEGF expression (r = -0.55, P = 0.0008), indicating that tumors with low blood flow but higher metabolism were associated with higher VEGF expression. Flow and metabolism were coupled in higher-stage (stage III/IV) tumors but not lower-stage tumors (stage I/II) (r = 0.47, P = 0.03, vs. r = 0.09, P = 0.65, respectively. CONCLUSION: Tumors with a low-flow-high-metabolism phenotype demonstrated higher VEGF expression and may reflect a more angiogenic phenotype.

Investigating vulnerable atheroma using combined (18)F-FDG PET/CT angiography of carotid plaque with immunohistochemical validation.

UNLABELLED: Inflammation and angiogenesis are hypothesized to be important factors contributing to plaque vulnerability, whereas calcification is suggested to confer stability. To investigate this in vivo, we combined CT angiography and PET and compared the findings with immunohistochemistry for patients undergoing carotid endarterectomy. METHODS: Twenty-one consecutive patients (18 men, 3 women; mean age ± SD, 68.3 ± 7.3) undergoing carotid endarterectomy were recruited for combined carotid (18)F-FDG PET/CT angiography. Plaque (18)F-FDG uptake was quantified with maximum standardized uptake value, and CT angiography quantified percentage plaque composition (calcium and lipid). Surgical specimens underwent ex vivo CT aiding image registration, followed by immunohistochemical staining for CD68 (macrophage density) and vascular endothelial growth factor (angiogenesis). Relationships between imaging and immunohistochemistry were assessed with Spearman rank correlation and multivariable regression. RESULTS: The mean (±SD) surgically excised carotid plaque (18)F-FDG metabolism was 2.4 (±0.5) versus 2.2 (±0.3) contralaterally (P = 0.027). There were positive correlations between plaque (18)F-FDG metabolism and immunohistochemistry with CD68 (ρ = 0.55; P = 0.011) and vascular endothelial growth factor (ρ = 0.47; P = 0.031). There was an inverse relationship between plaque (18)F-FDG metabolism and plaque percentage calcium composition on CT (ρ = -0.51; P = 0.018) and between calcium composition and immunohistochemistry with CD68 (ρ = -0.57; P = 0.007). Regression showed that maximum standardized uptake value and calcium composition were independently significant predictors of angiogenesis, and calcium composition was a predictor of macrophage density. CONCLUSION: We provide in vivo evidence that increased plaque metabolism is associated with increased biomarkers of angiogenesis and inflammation, whereas plaque calcification is inversely related to PET and histologic biomarkers of inflammation.