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.

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.

Integrated 18F-fluorodeoxyglucose-positron emission tomography/dynamic contrast-enhanced computed tomography to phenotype non-small cell lung carcinoma.

We applied modern molecular and functional imaging to the pretreatment assessment of lung cancer using combined dynamic contrast-enhanced computed tomography (DCE-CT) and (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) to phenotype tumors. Seventy-four lung cancer patients were prospectively recruited for (18)F-FDG-PET/DCE-CT using PET/64-detector CT. After technical failures, there were 64 patients (35 males, 29 females; mean age [± SD] 67.5 ± 7.9 years). DCE-CT yielded tumor peak enhancement (PE) and standardized perfusion value (SPV). The uptake of (18)F-FDG quantified on PET as the standardized uptake value (SUV(max)) assessed tumor metabolism. The median values for SUV(max) and SPV were used to define four vascular-metabolic phenotypes. There were associations (Spearman rank correlation [rs]) between tumor size and vascular-metabolic parameters: SUV(max) versus size (rs  =  .40, p  =  .001) and SUV/PE versus size (r  =  .43, p < .001). Patients with earlier-stage (I-IIA, n  =  30) disease had mean (± SD) SUV/PE 0.36 ± 0.28 versus 0.56 ± 0.32 in later-stage (stage IIB-IV, n  =  34) disease (p  =  .007). The low metabolism with high vascularity phenotype was significantly more common among adenocarcinomas (p  =  .018), whereas the high metabolism with high vascularity phenotype was more common among squamous cell carcinomas (p  =  .024). Other non-small cell lung carcinoma tumor types demonstrated a high prevalence of the high metabolism with low vascularity phenotype (p  =  .028). We show that tumor subtypes have different vascular-metabolic associations, which can be helpful clinically in managing lung cancer patients to hone targeted therapy.

Defining the role of PET-CT in staging early breast cancer.

INTRODUCTION: Currently, there is a lack of data on the role of combined positron emission tomography-computed tomography (PET-CT) in the staging of early invasive primary breast cancer. We therefore evaluated the role of (18)F-fluorodeoxyglucose ((18)F-FDG)-PET-CT in this patient population. METHODS: We prospectively recruited 70 consecutive patients (69 women, one man; mean age, 61.9 ± 8.1 years) with early primary breast cancer for staging with (18)F-FDG-PET-CT. All PET-CT images were interpreted by two readers (independently of each other). A third reader adjudicated any discrepancies. All readers had ≥5 years of specific experience. Ethics board approval and informed consent were obtained. RESULTS: The mean clinical follow-up was 22.7 ± 12.6 months. The primary tumor was identified with PET-CT in 64 of 70 patients. Of the unidentified lesions, surgical pathology revealed two intraductal carcinomas, one invasive tubular carcinoma, and three invasive lobular carcinomas. Undiagnosed multifocal breast disease was shown in seven of 70 patients. PET-CT identified avid axillary lymph nodes in 19 of 70 patients, compared with 24 of 70 confirmed during surgery. There were four patients who were axillary node positive on PET but had no axillary disease at surgery. Five patients were reported with avid metastases. Two of those patients were treated for metastatic disease (nodal, lung, and liver in one and bone metastases in the other) following further imaging and clinical assessment. In the other three patients, lesions (lung, n = 1; pleural, n = 1; paratrachael node, n = 1) were subsequently diagnosed as benign lesions. CONCLUSION: Integrated (18)F-FDG-PET-CT may have a role in staging patients presenting with early breast cancer.

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.

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.

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.

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.

Distribution pattern of 68Ga-DOTATATE in disease-free patients.

PURPOSE: 68Ga-DOTA-DPhe1,Tyr3-octreotate (68Ga-DOTATATE) is a somatostatin analogue that shows high affinity for somatostatin receptor subtype 2 (sst2) and has been used for imaging neuroendocrine tumours. However, normal uptake patterns and potential pitfalls have not been described with this high-sensitivity radiotracer. The aim of this study was therefore to outline the normal distribution pattern of 68Ga-DOTATATE in disease-free patients, to provide standardized uptake values (SUVs) of various organs and to compare our results with the current knowledge on sst2 receptor expression in vitro. METHODS: 68Ga-DOTATATE PET/computed tomography was performed in 42 patients (15 men and 27 women). Approximately 145 MBq of tracer was injected intravenously and imaging was performed using a GE Discovery ST PET/computed tomography scanner. SUVs were calculated on the reconstructed images for various organs. RESULTS: 68Ga-DOTATATE uptake was noted in the sst2-expressing organs such as pituitary, thyroid, stomach wall, spleen, adrenals, kidneys, pancreas and prostate and in the liver and salivary glands, with excreted activity in the bowel and in the pelvicalyceal system of the kidneys and urinary bladder. The SUVs ranged from 0.1 to 48.8 in the organs considered. Potential pitfalls in interpreting the 68Ga-DOTATATE uptake in organs such as thyroid, pancreas lymph nodes and bowel were identified. CONCLUSION: This study shows the distribution pattern of 68Ga-DOTATATE outlines the range of SUVs for various organs in disease-free patients and identifies some of the potential pitfalls encountered during imaging.

Assessment of left ventricular function at rest using rubidium-82 myocardial perfusion PET: comparison of four software algorithms with simultaneous 64-slice coronary CT angiography.

OBJECTIVE: Left ventricular function is prognostically important. Our aim was to validate different algorithms' measurements with rubidium-82 PET, using computed tomography (CT) acquired simultaneously on hybrid imaging. METHODS: Fifty patients (33 men, 17 women, mean age 59 years SD 12) referred for coronary artery disease evaluation underwent rubidium-82 PET myocardial perfusion scintigraphy and 64-slice CT coronary angiography simultaneously on hybrid PET/CT. Left ventricular ejection fraction, end-systolic volume and end-diastolic volume from quantitative gated PET at rest, were calculated using quantitative gated single-photon emission computed tomography (QGS), Emory Cardiac Toolbox (ECT), Myometrix and CardIQ Physio software and then compared with CT. The paired t-test and Bland-Altman plots were used for analysis. RESULTS: There was no significant difference between CT and both QGS and ECT for calculating ESV. Otherwise there were significant differences (t-test, P<0.05) between CT coronary angiography and all other software algorithms in calculating systolic and diastolic volumes. Bland-Altman analysis revealed a bias towards underestimating end-diastolic volume with mean differences of 32.3, 34.8, 42.6 and 35.7 ml for QGS, ECT, Myometrix and CardIQ Physio, respectively. The limits of agreement (mean bias+/-1.96 SD) for left ventricular ejection fraction (%) were 8.5+/-21.0, 12.9+/-21.0, 3.5+/-18.9 and 5.6+/-17.1, for QGS, ECT, Myometrix and CardIQ Physio, respectively. CONCLUSION: The systematic error (or mean bias) of the Myometrix algorithm is the smallest, and CardIQ Physio shows the least statistical error (or limits of agreement) when calculating ejection fraction from rubidium-82 myocardial perfusion PET, compared with QGS and ECT. The wide limits of agreement between the different algorithms mean that they are not interchangeable.

Metabolic-flow relationships in primary breast cancer: feasibility of combined PET/dynamic contrast-enhanced CT.

PURPOSE: To assess the feasibility and first experience of combined (18)F-FDG-PET)/dynamic contrast-enhanced (DCE) CT in evaluating breast cancer. METHODS: Nine consecutive female patients (mean age 64.2 years, range 52-74 years) with primary breast carcinoma were prospectively recruited for combined (18)F-FDG PET/DCE-CT. Dynamic CT data were used to calculate a range of parameters of tumour vascularity, and tumour (18)F-FDG uptake (standardized uptake value, SUVmax) was used as a metabolic indicator. RESULTS: One tumour did not enhance and was excluded. The mean tumour SUVmax was 7.7 (range 2.4-26.1). The mean values for tumour perfusion, perfusion normalized to cardiac output, standard perfusion value (SPV) and permeability were 41 ml/min per 100 g (19-59 ml/min per 100 g), 0.56%/100 g (0.33-1.09%/100 g), 3.6 (2.5-5.9) and 0.15/min (0.09-0.30/min), respectively. Linear regression analysis showed a positive correlation between tumour SUV and tumour perfusion normalized to cardiac output (r=0.55, p=0.045) and a marginal correlation between tumour SUV and tumour SPV (r=0.19, p=0.065). There were no significant correlations between tumour SUV and tumour perfusion (r=0.29, p=0.401) or permeability (r=0.03, p=0.682). CONCLUSION: The first data from combined (18)F-FDG-PET/DCE-CT in breast cancer are reported. The technique was successful in eight of nine patients. Breast tumour metabolic and vascular parameters were consistent with previous data from (15)O-H(2)O-PET.

CT coronary angiography: quantitative assessment of myocardial perfusion using test bolus data-initial experience.

The aim of this study is to quantify myocardial perfusion during coronary CT angiography using data from a modified timing test-bolus acquisition. Institutional review board approval and informed consent were obtained. Nineteen patients with suspected coronary artery disease underwent combined coronary CT angiography and cardiac (82)Rubidium-PET perfusion. Prior to the CT angiogram a retrospectively ECG-gated dynamic test bolus was obtained following 25 mls of IV contrast medium injected at 5 ml/s. Images were acquired every 1.5 s for 30 s using 4 x 1.25-mm slices at 120 kV, 35 mAs. Regions of interest were drawn to delineate the myocardium and aorta on the resulting transaxial images. Time density curves were created and perfusion calculated using two simple approaches: maximum-slope method and peak method. In patients with normal PET myocardial perfusion, the mean (SD) resting myocardial perfusion estimated by CT using the maximum-slope method was 0.89 (+/-0.27) ml/min/g and 0.93 (+/-0.21) ml/min/g at end-systole and end-diastole, respectively, and 0.69 (+/-0.11) ml/min/g and 0.79 (+/-0.19) at end-systole and end-diastole, respectively, for the peak method. Thus quantification of myocardial perfusion from a routine coronary CT angiography test bolus is possible. CT-derived myocardial perfusion values are consistent with published values derived from other techniques.

Cardiac 82Rubidium PET/CT: initial European experience.

PURPOSE: Myocardial perfusion with PET/CT has advantages over conventional SPECT. We describe our initial European experience using (82)Rubidium-PET/CT, as part of a clinical myocardial perfusion service. METHODS: We studied the first 100 patients (64 male; 36 female, mean age = 60: SD +/-12.5y, mean body mass index = 30: SD +/-6.9kg/m( 2 )) who underwent (82)Rubidium cardiac PET/CT in our institution. Thirty patients had recently undergone coronary angiography. Patients underwent imaging during adenosine infusion and at rest. Images were acquired over 5 minutes using a GE-PET/CT instrument. Image quality was described as good, adequate or inadequate. Images were reported patient-by-patient by a minimum of five nuclear medicine physicians. A segment-by-segment analysis (17-segment model) was also performed. RESULTS: Image quality was good in 77%, adequate 23% and inadequate 0%. There was no statistical difference in image quality between obese and non-obese patients (Fisher's exact test, p = 0.2864). 59% had normal perfusion studies, 29% had inducible ischaemia, 12% had myocardial infarction (11% with super added ischaemia). There was reduced (82)Rubidium uptake in 132/1700 segments during stress. There was reduced (82)Rubidium uptake at rest in 42/1700 segments. The (82)Rubidium PET/CT findings were consistent with the angiographic findings in 28/30 cases. CONCLUSION: We show that, even from initial use of (82)Rubidium, it is possible to perform myocardial perfusion studies quickly with good image quality, even in the obese. The PET findings correlated well in the third of the cases where angiography was available. As such, (82)Rubidium cardiac PET/CT is likely to be an exciting addition to the European nuclear physician/ cardiologist's radionuclide imaging arsenal.