Ivayla Apostolova

Correlation of Inflammation Assessed by 18F-FDG PET, Active Mineral Deposition Assessed by 18F-Fluoride PET, and Vascular Calcification in Atherosclerotic Plaque: A Dual-Tracer PET/CT Study

Formation and progression of atherosclerotic plaque is a dynamic and complex process involving various pathophysiologic steps including inflammation and calcification. The purpose of this study was to compare macrophage activity as determined by 18F-FDG PET and ongoing mineral deposition as measured by 18F-sodium fluoride PET in atherosclerotic plaque and to correlate these findings with calcified plaque burden as assessed by CT. Methods: Forty-five patients were examined by whole-body 18F-FDG PET, 18F-sodium fluoride PET, and CT. Tracer uptake in various arterial segments was analyzed both qualitatively and semiquantitatively by measuring the blood-pool–corrected standardized uptake value (target-to-background ratio [TBR]). The pattern of tracer uptake in atherosclerotic lesions was compared after color-coded multistudy image fusion of PET and CT studies. The Fisher exact test and the Spearman correlation coefficient rs were used for statistical analysis of image-based results and cardiovascular risk factors. Intra- and interrater reproducibility were evaluated using the Cohen κ. Results: 18F-sodium fluoride uptake was observed at 105 sites in 27 (60%) of the 45 study patients, and mean TBR was 2.3 ± 0.7. 18F-FDG uptake was seen at 124 sites in 34 (75.6%) patients, and mean TBR was 1.5 ± 0.3. Calcified atherosclerotic lesions were observed at 503 sites in 34 (75.6%) patients. Eighty-one (77.1%) of the 105 lesions with marked 18F-sodium fluoride uptake and only 18 (14.5%) of the 124 lesions with 18F-FDG accumulation were colocalized with arterial calcification. Coincident uptake of both 18F-sodium fluoride and 18F-FDG was observed in only 14 (6.5%) of the 215 arterial lesions with radiotracer accumulation. Conclusion: PET/CT with 18F-FDG and 18F-sodium fluoride may allow evaluation of distinct pathophysiologic processes in atherosclerotic lesions and might provide information on the complex interactions involved in formation and progression of atherosclerotic plaque.

Comparative Effectiveness of 18f-fdg Pet/ct Versus Whole-body Mri for Detection of Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis Type 1

Purpose The aim of this study was to compare the diagnostic performance of 18F-fluorodeoxyglucose (FDG) PET/CT and whole-body MRI for the detection of malignant peripheral nerve sheath tumors (MPNSTs) in patients with neurofibromatosis type 1, and to evaluate a panel of imaging-based criteria serving that purpose. Patients and Methods Thirty-one patients were examined by whole-body MRI and 18F-FDG PET/CT. A panel of imaging-based criteria including tumor region, size, shape, margin definition, contrast enhancement, heterogeneity before and after contrast, intratumoral lobulation, target sign, and mean and maximum standardized uptake values (SUVs) were evaluated. A SUVmax cut-off value of 3.5 was used for lesion analysis. Histopathologic evaluation and/or clinical follow-up served as the reference standard. Results 18F-FDG PET/CT had a sensitivity of 100%, whereas MRI had a sensitivity of 66.7%. On PET/CT, tumor size (P < 0.005), SUVmax (P < 0.0001), SUVmean (P < 0.0001), and tracer uptake heterogeneity (P = 0.002) were significantly associated with MPNSTs. On MRI, intratumoral lobulation (P < 0.02), ill-defined margins (P = 0.007), and irregular enhancement on T1-weighted imaging (P < 0.001) were significantly associated with MPNSTs. Conclusions Both PET/CT and whole-body MRI may distinguish benign and malignant PNSTs, but PET/CT has higher sensitivity for that purpose. Imaging-based criteria for identification of MPNSTs on both modalities were identified. False-positive results, requiring biopsy or clinical follow-up, may be reduced by using a combination of MRI and PET derived markers, but only at the price of reduced sensitivity.

Asphericity of pretherapeutic tumour FDG uptake provides independent prognostic value in head-and-neck cancer

AbstractObjectiveTo propose a novel measure, namely the ‘asphericity’ (ASP), of spatial irregularity of FDG uptake in the primary tumour as a prognostic marker in head-and-neck cancer.MethodsPET/CT was performed in 52 patients (first presentation, n = 36; recurrence, n = 16). The primary tumour was segmented based on thresholding at the volume-reproducible intensity threshold after subtraction of the local background. ASP was used to characterise the deviation of the tumour’s shape from sphere symmetry. Tumour stage, tumour localisation, lymph node metastases, distant metastases, SUVmax, SUVmean, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were also considered. The association of overall (OAS) and progression-free survival (PFS) with these parameters was analysed.ResultsCox regression revealed high SUVmax [hazard ratio (HR) = 4.4/7.4], MTV (HR = 4.6/5.7), TLG (HR = 4.8/8.9) and ASP (HR = 7.8/7.4) as significant predictors with respect to PFS/OAS in case of first tumour manifestation. The combination of high MTV and ASP showed very high HRs of 22.7 for PFS and 13.2 for OAS. In case of recurrence, MTV (HR = 3.7) and the combination of MTV/ASP (HR = 4.2) were significant predictors of PFS.ConclusionsASP of pretherapeutic FDG uptake in the primary tumour improves the prediction of tumour progression in head-and-neck cancer at first tumour presentation.Key Points•Asphericity (ASP) characterises the spatial heterogeneity of FDG uptake in tumours • ASP is a promising prognostic parameter in head-and-neck cancer • ASP is useful for identification of high-risk patients with head-and-neck cancer

Effects of behavioral therapy or pharmacotherapy on brain glucose metabolism in subjects with obsessive-compulsive disorder as assessed by brain FDG PET

This prospective study investigated the effect of pharmacotherapy (PT) and cognitive behavioral therapy (CBT) on cerebral glucose metabolism in adults with obsessive-compulsive disorder (OCD). Dynamic positron emission tomography (PET) of the brain with F-18-fluorodeoxyglucose (FDG) was performed before and after treatment in 16 subjects diagnosed for OCD for at least 2 years (PT: n=7). Pre-to-post-treatment change of scaled local metabolic rate of glucose (SLMRGlc) was assessed separately in therapy responders and non-responders. Correlation was tested between SLMRGlc change and change of OCD, depression, or anxiety symptoms. SLMRGlc increased in the right caudate after successful therapy. The increase tended to correlate with the improvement of OCD symptom severity. The finding of increased local caudate activity after successful therapy is in contrast to most previous studies. Possible explanations include effects of therapy on concomitant depression symptoms and/or the large proportion of early-onset OCD in the present sample.

Increased evidence for the prognostic value of primary tumor asphericity in pretherapeutic FDG PET for risk stratification in patients with head and neck cancer

PurposeIn a previous study, we demonstrated the first evidence that the asphericity (ASP) of pretherapeutic FDG uptake in the primary tumor provides independent prognostic information in patients with head and neck cancer. The aim of this work was to confirm these results in an independent patient group examined at a different site.MethodsFDG-PET/CT was performed in 37 patients. The primary tumor was delineated by an automatic algorithm based on adaptive thresholding. For the resulting ROIs, the metabolically active part of the tumor (MTV), SUVmax, SUVmean, total lesion glycolysis (TLG) and ASP were computed. Univariate Cox regression with respect to progression free survival (PFS) and overall survival (OS) was performed. For survival analysis, patients were divided in groups of high and low risk according to the parameter cut-offs defined in our previous work. In a second step, the cut-offs were adjusted to the present data. Univariate and multivariate Cox regression was performed for the pooled data consisting of the current and the previously described patient group (N = 68). In multivariate Cox regression, clinically relevant parameters were included.ResultsUnivariate Cox regression using the previously published cut-off values revealed TLG (hazard ratio (HR) = 3) and ASP (HR = 3) as significant predictors for PFS. For OS MTV (HR = 2.7) and ASP (HR = 5.9) were significant predictors. Using the adjusted cutoffs MTV (HR = 2.9/3.3), TLG (HR = 3.1/3.3) and ASP (HR = 3.1/5.9) were prognostic for PFS/OS. In the pooled data, multivariate Cox regression revealed a significant prognostic value with respect to PFS/OS for MTV (HR = 2.3/2.1), SUVmax (HR = 2.1/2.5), TLG (HR = 3.5/3.6), and ASP (HR = 3.4/4.4).ConclusionsOur results confirm the independent prognostic value of ASP of the pretherapeutic FDG uptake in the primary tumor in patients with head and neck cancer. Moreover, these results demonstrate that ASP can be determined unambiguously across different sites.

Brain perfusion SPECT in the mouse: Normal pattern according to gender and age

Regional cerebral blood flow (rCBF) is a useful surrogate marker of neuronal activity and a parameter of primary interest in the diagnosis of many diseases. The increasing use of mouse models spawns the demand for in vivo measurement of rCBF in the mouse. Small animal SPECT provides excellent spatial resolution at adequate sensitivity and is therefore a promising tool for imaging the mouse brain. This study evaluates the feasibility of mouse brain perfusion SPECT and assesses the regional pattern of normal Tc-99m-HMPAO uptake and the impact of age and gender. Whole-brain kinetics was compared between Tc-99m-HMPAO and Tc-99m-ECD using rapid dynamic planar scans in 10 mice. Assessment of the regional uptake pattern was restricted to the more suitable tracer, HMPAO. Two HMPAO SPECTs were performed in 18 juvenile mice aged 7.5 ± 1.5weeks, and in the same animals at young adulthood, 19.1 ± 4.0 weeks (nanoSPECT/CTplus, general purpose mouse apertures: 1.2kcps/MBq, 0.7mm FWHM). The 3-D MRI Digital Atlas Database of an adult C57BL/6J mouse brain was used for region-of-interest (ROI) analysis. SPECT images were stereotactically normalized using SPM8 and a custom made, left-right symmetric HMPAO template in atlas space. For testing lateral asymmetry, each SPECT was left-right flipped prior to stereotactical normalization. Flipped and unflipped SPECTs were compared by paired testing. Peak brain uptake was similar for ECD and HMPAO: 1.8 ± 0.2 and 2.1 ± 0.6 %ID (p=0.357). Washout after the peak was much faster for ECD than for HMPAO: 24 ± 7min vs. 4.6 ± 1.7h (p=0.001). The general linear model for repeated measures with gender as an intersubject factor revealed an increase in relative HMPAO uptake with age in the neocortex (p=0.018) and the hippocampus (p=0.012). A decrease was detected in the midbrain (p=0.025). Lateral asymmetry, with HMPAO uptake larger in the left hemisphere, was detected primarily in the neocortex, both at juvenile age (asymmetry index AI=2.7 ± 1.7%, p=0.000) and at young adult age (AI=2.4 ± 1.7%, p=0.000). Gender had no effect on asymmetry. Voxel-wise testing confirmed the ROI-based findings. In conclusion, high-resolution HMPAO SPECT is a promising technique for measuring rCBF in preclinical research. It indicates lateral asymmetry of rCBF in the mouse brain as well as age-related changes during late maturation. ECD is not suitable as tracer for brain SPECT in the mouse because of its fast clearance from tissue indicating an interspecies difference in esterase activity between mice and humans.

Comparative evaluation of SUV, tumor-to-blood standard uptake ratio (SUR), and dual time point measurements for assessment of the metabolic uptake rate in FDG PET

BackgroundWe have demonstrated recently that the tumor-to-blood standard uptake ratio (SUR) is superior to tumor standardized uptake value (SUV) as a surrogate of the metabolic uptake rate Km of fluorodeoxyglucose (FDG), overcoming several of the known shortcomings of the SUV approach: excellent linear correlation of SUR and Km from Patlak analysis was found using dynamic imaging of liver metastases. However, due to the perfectly standardized uptake period used for SUR determination and the comparatively short uptake period, these results are not automatically valid and applicable for clinical whole-body examinations in which the uptake periods (T) are distinctly longer and can vary considerably. Therefore, the aim of this work was to investigate the correlation between SUR derived from clinical static whole-body scans and Km-surrogate derived from dual time point (DTP) measurements.MethodsDTP 18F-FDG PET/CT was performed in 90 consecutive patients with histologically proven non-small cell lung cancer (NSCLC). In the PET images, the primary tumor was delineated with an adaptive threshold method. For determination of the blood SUV, an aorta region of interest (ROI) was delineated manually in the attenuation CT and transferred to the PET image. Blood SUV was computed as the mean value of the aorta ROI. SUR values were computed as ratio of tumor SUV and blood SUV. SUR values from the early time point of each DTP measurement were scan time corrected to 75 min postinjection (SURtc). As surrogate of Km, we used the SUR(T) slope, Kslope, derived from DTP measurements since it is proportional to the latter under the given circumstances. The correlation of SUV and SURtc with Kslope was investigated. The prognostic value of SUV, SURtc, and Kslope for overall survival (OS) and progression-free survival (PFS) was investigated with univariate Cox regression in a homogeneous subgroup (N=31) treated with primary chemoradiation.ResultsCorrelation analysis revealed for both, SUV and SURtc, a clear linear correlation with Kslope (P<0.001). Correlation SUR vs. Kslope was considerably stronger than correlation SUV vs. Kslope (R2=0.92 and R2=0.69, respectively, P<0.001). Univariate Cox regression revealed SURtc and Kslope as significant prognostic factors for PFS (hazard ratio (HR) =3.4/ P=0.017 and HR =4.3/ P=0.020, respectively). For SUV, no significant effect was found. None of the investigated parameters was prognostic for OS.ConclusionsScan-time-corrected SUR is a significantly better surrogate of tumor FDG metabolism in clinical whole-body PET compared to SUV. The very high linear correlation of SUR and DTP-derived Kslope (which is proportional to actual Km) implies that for histologically proven malignant lesions, FDG-DTP does not provide added value in comparison to the SUR approach in NSCLC.

An investigation of the relation between tumor-to-liver ratio (TLR) and tumor-to-blood standard uptake ratio (SUR) in oncological FDG PET

BackgroundThe standardized uptake value (SUV) is the nearly exclusive means for quantitative evaluation of clinical [18F-]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) whole body investigations. However, the SUV methodology has well-known shortcomings. In this context, it has been recognized that at least part of the problems can be eliminated if tumor SUV is normalized to the SUV of a reference region in the liver (tumor-to-liver [TLR] ratio). In recent publications, we have systematically investigated the tumor-to-blood SUV ratio (SUR) for normalization of tumor SUVs which in our view offers principal advantages in comparison to TLR. The aim of this study was a comprehensive comparison of TLR and SUR in terms of quantification of tumor lesions.Methods18F-FDG PET/CT was performed in 424 patients (557 scans) with different tumor entities prior to radio(chemo)therapy. In the PET images, SUVmax of the primary tumor was determined. SUVliver was calculated in the inferior right lobe of the liver. SUVblood was determined by manually delineating the aorta in the low-dose CT. TLR and SUR were computed and scan time corrected to 60 min p.i. (TLRtc and SURtc). Correlation analysis was performed for SUVliver vs. SUVblood, TLR vs. SUR, SUVliver/SUVblood vs. SUVblood,SURtc/TLR vs. SURtc, and SURtc/TLRtc vs. SURtc. Variability of the respective ratios was assessed via histogram analysis. The prognostic value of TLR and TLRtc for distant metastases-free survival (DM) was investigated with univariate Cox regression in a homogeneous subgroup (N = 130) and compared to previously published results for SUV and SURtc.ResultsCorrelation analysis revealed a linear correlation of SUVliver vs. SUVblood (R 2=0.83) and of TLR vs. SURtc (R2=0.92). The SUVliver/SUVblood ratio (mean ± s.d.) was 1.47 ± 0.18. For the SURtc/TLR ratio, we obtained 1.14 ± 0.21 and for the SURtc/TLRtc ratio 1.38 ± 0.17. Survival analysis revealed TLR and TLRtc as significant prognostic factors for DM (hazard ratio [HR] = 3.3 and HR = 3, respectively). Both hazard ratios are lower than that of SURtc (HR = 4.1) although this reduction does not reach statistical significance for the given limited group size. HRs of TLR and SURtc are both significantly higher than HR of SUV (HR = 2.2).ConclusionsSuitability of the liver as surrogate of arterial tracer supply for SUV normalization via TLR computation is limited. Further studies in sufficiently large patient groups are required to better characterize the relative performance of SUV, TLR, and SUR in different settings.

Nerve Sheath Tumors in Neurofibromatosis Type 1: Assessment of Whole-Body Metabolic Tumor Burden Using F-18-FDG PET/CT.

Purpose To determine the metabolically active whole-body tumor volume (WB-MTV) on F-18-fluorodeoxyglucose positron emission tomography/computed tomography (F-18-FDG PET/CT) in individuals with neurofibromatosis type 1 (NF1) using a three-dimensional (3D) segmentation and computerized volumetry technique, and to compare PET WB-MTV between patients with benign and malignant peripheral nerve sheath tumors (PNSTs). Patients and Methods Thirty-six NF1 patients (18 patients with malignant PNSTs and 18 age- and sex-matched controls with benign PNSTs) were examined by F-18-FDG PET/CT. WB-MTV, whole-body total lesion glycolysis (WB-TLG) and a set of semi-quantitative imaging-based parameters were analyzed both on a per-patient and a per-lesion basis. Results On a per-lesion basis, malignant PNSTs demonstrated both a significantly higher MTV and TLG than benign PNSTs (p < 0.0001). On a per-patient basis, WB-MTV and WB-TLG were significantly higher in patients with malignant PNSTs compared to patients with benign PNSTs (p < 0.001). ROC analysis showed that MTV and TLG could be used to differentiate between benign and malignant tumors. Conclusions WB-MTV and WB-TLG may identify malignant change and may have the potential to provide a basis for investigating molecular biomarkers that correlate with metabolically active disease manifestations. Further evaluation will determine the potential clinical impact of these PET-based parameters in NF1.

Test-retest variability of lesion SUV and lesion SUR in 18F-FDG PET: an analysis of data from two prospective multicenter trials

Quantitative assessment of radio- and chemotherapy response with 18F-FDG whole-body PET has attracted increasing interest in recent years. In most published work, SUV has been used for this purpose. In the context of therapy response assessment, the reliability of lesion SUVs, notably their test–retest stability, thus becomes crucial. However, a recent study demonstrated substantial test–retest variability (TRV) in SUVs. The purpose of the present study was to investigate whether the tumor-to-blood SUV ratio (SUR) can improve TRV in tracer uptake. Methods: 73 patients with advanced non–small cell lung cancer from the prospective multicenter trials ACRIN 6678 (n = 34) and MK-0646-008 (n = 39) were included in this study. All patients underwent two 18F-FDG PET/CT investigations on two different days (time difference, 3.6 ± 2.1 d; range, 1–7 d) before therapy. For each patient, up to 7 tumor lesions were evaluated. For each lesion, SUVmax and SUVpeak were determined. Blood SUV was determined as the mean value of a 3-dimensional aortic region of interest that was delineated on the attenuation CT image and transferred to the PET image. SURs were computed as the ratio of tumor SUV to blood SUV and were uptake time–corrected to 75 min after injection. TRV was quantified as 1.96 multiplied by the root-mean-square deviation of the fractional paired differences in SUV and SUR. The combined effect of blood normalization and uptake time correction was inspected by considering RTRV (TRVSUR/TRVSUV), a ratio reflecting the reduction in the TRV in SUR relative to SUV. RTRV was correlated with the group-averaged-value difference (δ) in CFmean (δCFmean) of the quantity δCF = |CF – 1|, where CF is the numeric factor that converts individual ratios of paired SUVs into corresponding SURs. This correlation analysis was performed by successively increasing a threshold value δCFmin and computing δCFmean and RTRV for the remaining subgroup of patients/lesions with δCF ≥ δCFmin. Results: The group-averaged TRVSUV and TRVSUR were 32.1 and 29.0, respectively, which correspond to a reduction of variability in SUR by an RTRV factor of 0.9 in comparison to SUV. This rather marginal improvement can be understood to be a consequence of the atypically low intrasubject variability in blood SUV and uptake time and the accordingly small δCF values in the investigated prospective study groups. In fact, subgroup analysis with increasing δCFmin thresholds revealed a pronounced negative correlation (Spearman ρ = −0.99, P < 0.001) between RTRV and δCFmean, where RTRV ≈ 0.4 in the δCFmin = 20% subgroup, corresponding to a more than 2-fold reduction of TRVSUR compared with TRVSUV. Conclusion: Variability in blood SUV and uptake time has been identified as a causal factor in the TRV in lesion SUV. Therefore, TRV in lesion uptake measurements can be reduced by replacing SUV with SUR as the uptake measure. The improvement becomes substantial for the level of variability in blood SUV and uptake time typically observed in the clinical context.