REPLY: We thank Drs. Thie, Laffon, and Marthan for their response on our paper ([1][1]). In this study, we tried to comprehensively investigate the repeatability of various whole-body 18F-FDG uptake metrics and assess the influence of several correction methods to normalize 18F-FDG uptake. In
There is increased interest in various new quantitative uptake metrics beyond SUV in oncologic PET/CT studies. The purpose of this study was to investigate the variability and test–retest ratio (TRT) of metabolically active tumor volume (MATV) measurements and several other new quantitative metrics in non–small cell lung cancer using 18F-FDG PET/CT with different segmentation methods, user interactions, uptake intervals, and reconstruction protocols. Methods: Ten patients with advanced non–small cell lung cancer received 2 series of 2 whole-body 18F-FDG PET/CT scans at 60 min after injection and at 90 min after injection. PET data were reconstructed with 4 different protocols. Eight segmentation methods were applied to delineate lesions with and without a tumor mask. MATV, SUVmax, SUVmean, total lesion glycolysis, and intralesional heterogeneity features were derived. Variability and repeatability were evaluated using a generalized-estimating-equation statistical model with Bonferroni adjustment for multiple comparisons. The statistical model, including interaction between uptake interval and reconstruction protocol, was applied individually to the data obtained from each segmentation method. Results: Without masking, none of the segmentation methods could delineate all lesions correctly. MATV was affected by both uptake interval and reconstruction settings for most segmentation methods. Similar observations were obtained for the uptake metrics SUVmax, SUVmean, total lesion glycolysis, homogeneity, entropy, and zone percentage. No effect of uptake interval was observed on TRT metrics, whereas the reconstruction protocol affected the TRT of SUVmax. Overall, segmentation methods showing poor quantitative performance in one condition showed better performance in other (combined) conditions. For some metrics, a clear statistical interaction was found between the segmentation method and both uptake interval and reconstruction protocol. Conclusion: All segmentation results need to be reviewed critically. MATV and other quantitative uptake metrics, as well as their TRT, depend on segmentation method, uptake interval, and reconstruction protocol. To obtain quantitative reliable metrics, with good TRT performance, the optimal segmentation method depends on local imaging procedure, the PET/CT system, or reconstruction protocol. Rigid harmonization of imaging procedure and PET/CT performance will be helpful in mitigating this variability.
Change in (18)F-FDG uptake may predict response to anticancer treatment. The PERCIST suggest a threshold of 30% change in SUV to define partial response and progressive disease. Evidence underlying these thresholds consists of mixed stand-alone PET and PET/CT data with variable uptake intervals and no consensus on the number of lesions to be assessed. Additionally, there is increasing interest in alternative (18)F-FDG uptake measures such as metabolically active tumor volume and total lesion glycolysis (TLG). The aim of this study was to comprehensively investigate the repeatability of various quantitative whole-body (18)F-FDG metrics in non-small cell lung cancer (NSCLC) patients as a function of tracer uptake interval and lesion selection strategies.Eleven NSCLC patients, with at least 1 intrathoracic lesion 3 cm or greater, underwent double baseline whole-body (18)F-FDG PET/CT scans at 60 and 90 min after injection within 3 d. All (18)F-FDG-avid tumors were delineated with an 50% threshold of SUVpeak adapted for local background. SUVmax, SUVmean, SUVpeak, TLG, metabolically active tumor volume, and tumor-to-blood and -liver ratios were evaluated, as well as the influence of lesion selection and 2 methods for correction of uptake time differences.The best repeatability was found using the SUV metrics of the averaged PERCIST target lesions (repeatability coefficients < 10%). The correlation between test and retest scans was strong for all uptake measures at either uptake interval (intraclass correlation coefficient > 0.97 and R(2) > 0.98). There were no significant differences in repeatability between data obtained 60 and 90 min after injection. When only PERCIST-defined target lesions were included (n = 34), repeatability improved for all uptake values. Normalization to liver or blood uptake or glucose correction did not improve repeatability. However, after correction for uptake time the correlation of SUV measures and TLG between the 60- and 90-min data significantly improved without affecting test-retest performance.This study suggests that a 15% change of SUVmean/SUVpeak at 60 min after injection can be used to assess response in advanced NSCLC patients if up to 5 PERCIST target lesions are assessed. Lower thresholds could be used in averaged PERCIST target lesions (<10%).
An acute limbic-cerebellar syndrome was seen in six industrial workers who inhaled trimethyltin (TMT). Clinical features included hearing loss, disorientation, confabulation, amnesia, aggressiveness, hyperphagia, disturbed sexual behavior, complex partial and tonic-clonic seizures, nystagmus, ataxia, and mild sensory neuropathy. Severity paralleled maximal urinary organotin levels. One patient died and two remained seriously disabled.
Radiolabeled prostate-specific membrane antigen (PSMA) PET has demonstrated promising results for prostate cancer (PCa) imaging. Quantification of PSMA radiotracer uptake is desired as it enables reliable interpretation of PET images, use of PSMA uptake as an imaging biomarker for tumor characterization, and evaluation of treatment effects. The aim of this study was to perform a full pharmacokinetic analysis of 2-(3-(1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL), a second-generation 18F-labeled PSMA ligand. On the basis of the pharmacokinetic analysis (reference method), simplified methods for quantification of 18F-DCFPyL uptake were validated. Methods: Eight patients with metastasized PCa were included. Dynamic PET acquisitions were performed at 0–60 and 90–120 min after injection of a median dose of 313 MBq of 18F-DCFPyL (range, 292–314 MBq). Continuous and manual arterial blood sampling provided calibrated plasma tracer input functions. Time–activity curves were derived for each PCa metastasis, and 18F-DCFPyL kinetics were described using standard plasma input tissue-compartment models. Simplified methods for quantification of 18F-DCFPyL uptake (SUVs; tumor-to-blood ratios [TBRs]) were correlated with kinetic parameter estimates obtained from full pharmacokinetic analysis. Results: In total, 46 metastases were evaluated. A reversible 2-tissue-compartment model was preferred for 18F-DCFPyL kinetics in 59% of the metastases. The observed k4 was small, however, resulting in nearly irreversible kinetics during the course of the PET study. Hence, k4 was fixated (0.015) and net influx rate, Ki, was preferred as the reference kinetic parameter. Whole-blood TBR provided an excellent correlation with Ki from full kinetic analysis (R2 = 0.97). This TBR could be simplified further by replacing the blood samples with an image-based, single measurement of blood activity in the ascending aorta (image-based TBR, R2 = 0.96). SUV correlated poorly with Ki (R2 = 0.47 and R2 = 0.60 for SUV normalized to body weight and lean body mass, respectively), most likely because of deviant blood activity concentrations (i.e., tumor tracer input) in patients with higher tumor volumes. Conclusion:18F-DCFPyL kinetics in PCa metastases are best described by a reversible 2-tissue-compartment model. Image-based TBRs were validated as a simplified method to quantify 18F-DCFPyL uptake and might be applied to clinical, whole-body PET scans. SUV does not provide reliable quantification of 18F-DCFPyL uptake.
Severity of abdominal obesity and possibly levels of metabolic activity of abdominal visceral adipose tissue (VAT) are associated with an increased risk for cardiovascular disease (CVD). In this context, the purpose of the current study was to evaluate the reproducibility and repeatability of a semi-automated method for assessment of the metabolic activity of VAT using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET)/x-ray computed tomography (CT). Ten patients with lung cancer who underwent two baseline whole-body [18F]FDG PET/low-dose (LD) CT scans within 1 week were included. Abdominal VAT was automatically segmented using CT between levels L1–L5. The initial CT-based segmentation was further optimized using PET data with a standardized uptake value (SUV) threshold approach (range 1.0–2.5) and morphological erosion (range 0–5 pixels). The [18F]FDG uptake in SUV that was measured by the automated method was compared with manual analysis. The reproducibility and repeatability were quantified using intraclass correlation coefficients (ICCs). The metabolic assessment of VAT on [18F]FDG PET/LDCT scans expressed as SUVmean, using an automated method showed high inter and intra observer (all ICCs > 0.99) and overall repeatability (ICC = 0.98). The manual method showed reproducible inter observer (all ICCs > 0.92), but less intra observer (ICC = 0.57) and less overall repeatability (ICC = 0.78) compared with the automated method. Our proposed semi-automated method provided reproducible and repeatable quantitative analysis of [18F]FDG uptake in VAT. We expect this method to aid future research regarding the role of VAT in development of CVD.
We evaluated the impact of pre-therapeutic hematopoiesis on survival, hematotoxicity (HT) and number of 223Radium (223Ra) treatments in patients with metastatic castration-resistant prostate cancer.Hemoglobin-levels (Hb), the number of platelets (Plts), leukocytes (Leuk), and survival data were collected in 56 patients treated with 223Ra. Pre-therapeutic hematopoiesis as well as adverse events during and after therapy were scored (grade 0-4) according to the CTCAE recommendations. The association of pre-therapeutic hematopoiesis, survival, HT and numbers of 223Ra cycles was analyzed.Median survival in all patients was 69.9 weeks; 77% of patients had pre-existing impaired Hb (1.7% grade 3, 12.5% grade 2, 62.5% grade 1). 8/56 (14.3%) had impaired Plt (grade 1) Maximum toxicity (Tox) grades of patients during treatment were grade 4 (Hb 1.7%; Plt 1.7%), grade 3 (Hb 14.3%; Plt 7.1%; Leu 7.1%), grade 2 (Hb 33.9%; Plt 7.1%; Leu 23.2%), grade 1 (Hb 46.4%; Plt 17.9%; Leu 23.2%) and grade 0 (Hb 5.4%; Plt 66.1%; Leu 44.6%). Interestingly, patients with thrombocytopenia had a significantly shorter survival compared to those with normal Plt levels (21 weeks vs not reached; P<0.003). As expected patients with pre-therapeutic low Hb-level (<10g/dL) had a significantly shorter survival compared to those with Hb-level >10g/dL (28 weeks vs not reached, P<0.004), whereas survival of patients with mildly impaired Hb (>10 but <13.5g/dL) did not differ from patients with normal levels of Hb (X vs. Y, P=...). Also patients with impaired Hb also developed significantly more grade 3 and 4 HT (Hb <10g/dL: 42.9 vs 14.3%, P<0.001; Plt <150G/mL: 25.0% vs 6.3%; P=0.002) and received significantly fewer treatment cycles (Hb<10g/dL: 5.1 vs 5.8, P<0.04; Plt <150G/mL: 3.4 vs 5.6; P<0.001). Neither extent of bone metastases nor previous chemotherapy were associated with survival, number of 223Ra cycles and HT.Patients with metastatic castration-resistant prostate cancer and impaired hematopoiesis, in particular thrombocytopenia and anemia, before 223Ra therapy suffer from significantly more high-grade HT, shorter survival and receive significantly fewer 223Ra treatments. Therefore, Hb-levels and platelet counts are essential parameters for adequate patient selection for 223Ra therapy.
158 Objectives [18F]fluoroazomycin-arabinoside ([18F]FAZA) is a PET tracer, proposed for quantifying tumour hypoxia. However, as hypoxia is associated with decreased perfusion, delivery of [18F]FAZA might be compromised, potentially disturbing the association between tissue hypoxia and [18F]FAZA uptake. This study aimed to gain insight in the relationship between tumour perfusion and [18F]FAZA uptake. Methods Eight patients with non-small cell lung cancer (NSCLC) underwent dynamic [15O]H2O and [18F]FAZA scans with arterial sampling. Parametric analyses were performed to generate quantitative 3D images of both perfusion and volume of distribution (VT) of [18F]FAZA. Next, multiparametric classification was performed by classifying voxels as low and high perfusion and/or low and high VT using median tumour values across each scan. By combining these initial classifications, voxels were allocated to 4 categories (low perfusion-low VT, low perfusion-high VT, high perfusion-low VT and high perfusion-high VT). Results 11 malignant lesions were identified in 8 patients. Average perfusion and VT across all lesions were 0.46±0.20 mL/mL/min and 0.95±0.31, respectively. The average of all median values across all lesions were 0.38±0.15 mL/mL/min and 0.87±0.18 for perfusion and VT, respectively. Multiparametric analysis suggested that classified voxels were clustered rather than randomly distributed. Several intralesional areas could be identified where VT of [18F]FAZA was inversely related to perfusion. Also distinct areas could be seen where perfusion and VT were either both decreased or increased. Conclusions Spatial variation of [18F]FAZA uptake is not necessarily inversely related with perfusion. Decreased perfusion might thus result in perfusion limited delivery of [18F]FAZA. In conclusion, multiparametric evaluation of the spatial distribution of both perfusion and [18F]FAZA uptake may be essential for understanding the [18F]FAZA signal.
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