Validation of a multiwell γ-counter for measuring high-pressure liquid chromatography metabolite profiles

Objectives: The purpose of this study was to verify the accuracy and reproducibility of a multiwell counter to assess its suitability for use within human PET studies in which metabolizing 11C tracers are used. Such tracers often require metabolite analysis for deriving plasma metabolite-corrected input curves. High-pressure liquid chromatography (HPLC) with on-line activity measurement is often unreliable for later plasma samples due to the poor sensitivity of the on-line activity detector. Fraction collector obtained HPLC samples that are counted in a separate high-sensitivity well counter can be an alternative to overcome poor counting statistics. Methods: Several experiments to evaluate background counting, reproducibility, and linearity were performed to validate the accuracy, precision, and detection limits of the well counter. In addition, measurements on a series of samples resembling activity profiles as seen within human 11C-flumazenil studies were performed to evaluate the performance of the well counter for clinically relevant data. Results: The tests proved that the well counter detection limit, linearity, and reproducibility were more than sufficient in circumstances as seen during patient studies for samples with both high and low activity. Conclusion: The use of a multiwell counter is a good alternative for the on-line activity detector of the HPLC, allowing derivation of plasma metabolite fractions with high accuracy and reproducibility

Validation of a multiwell gamma-counter for measuring high-pressure liquid chromatography metabolite profiles

OBJECTIVES: The purpose of this study was to verify the accuracy and reproducibility of a multiwell counter to assess its suitability for use within human PET studies in which metabolizing (11)C tracers are used. Such tracers often require metabolite analysis for deriving plasma metabolite-corrected input curves. High-pressure liquid chromatography (HPLC) with on-line activity measurement is often unreliable for later plasma samples due to the poor sensitivity of the on-line activity detector. Fraction collector obtained HPLC samples that are counted in a separate high-sensitivity well counter can be an alternative to overcome poor counting statistics. METHODS: Several experiments to evaluate background counting, reproducibility, and linearity were performed to validate the accuracy, precision, and detection limits of the well counter. In addition, measurements on a series of samples resembling activity profiles as seen within human (11)C-flumazenil studies were performed to evaluate the performance of the well counter for clinically relevant data. RESULTS: The tests proved that the well counter detection limit, linearity, and reproducibility were more than sufficient in circumstances as seen during patient studies for samples with both high and low activity. CONCLUSION: The use of a multiwell counter is a good alternative for the on-line activity detector of the HPLC, allowing derivation of plasma metabolite fractions with high accuracy and reproducibility

Calibration of PET/CT scanners for multicenter studies on differentiated thyroid cancer with 124I

Background: Studies on imaging of differentiated thyroid cancer (DTC) using 124I often require a multicenter approach, as the prevalence of DTC is low. Calibration of participating scanners is required to obtain comparable quantification. As determination of a well-defined range of recovery coefficients is complicated for various reasons, a simpler approach based on the assumption that the iodine uptake is highly focal with a background that significantly lacks radioactivity might be more efficient. For each scanner, a linear conversion between known and observed activity can be derived, allowing quantification that can be traced to a common source for all scanners within one study-protocol. The aim of this paper is to outline a procedure using this approach in order to set up a multicenter calibration of PET/CT scanners for 124I. Methods: A cylindrical polyethylene phantom contained six 2-ml vials with reference activities of ~2, 10, 20, 100, 400, and 2000 kBq, produced by dilution from a known activity. The phantom was scanned twice on PET/CT scanners of participating centers within 1 week. For each scanner, the best proportional and linear fit between measured and known activities were derived and based on statistical analyses of the results of all scanners; it was determined which fit should be applied. In addition, a Bland-Altman analysis was done on calibrated activities with respect to reference activities to asses the relative precision of the scanners. Results: Nine Philips (vendor A) and nine Siemens (vendor B) PET/CT scanners were calibrated in a time period of 3 days before and after the reference time. No significant differences were detected between the two subsequent scans on any scanner. Six fitted intercepts of vendor A were significantly different from zero, so the linear model was used. Intercepts ranged from −8 to 26 kBq and slopes ranged from 0.80 to 0.98. Bland-Altman analysis of calibrated and reference activities showed that the relative error of calibrated activities was smaller than that of uncalibrated activities. Conclusions: A simplified multicenter calibration procedure for PET/CT scans that show highly focal uptake and negligible background is feasible and results in more precise quantification. Our procedure can be used in multicenter 124I PET scans focusing on (recurrent) DTC

Calibration of PET/CT scanners for multicenter studies on differentiated thyroid cancer with I-124

Background: Studies on imaging of differentiated thyroid cancer (DTC) using 124I often require a multicenter approach, as the prevalence of DTC is low. Calibration of participating scanners is required to obtain comparable quantification. As determination of a well-defined range of recovery coefficients is complicated for various reasons, a simpler approach based on the assumption that the iodine uptake is highly focal with a background that significantly lacks radioactivity might be more efficient. For each scanner, a linear conversion between known and observed activity can be derived, allowing quantification that can be traced to a common source for all scanners within one study-protocol. The aim of this paper is to outline a procedure using this approach in order to set up a multicenter calibration of PET/CT scanners for 124I. Methods: A cylindrical polyethylene phantom contained six 2-ml vials with reference activities of ~2, 10, 20, 100, 400, and 2000 kBq, produced by dilution from a known activity. The phantom was scanned twice on PET/CT scanners of participating centers within 1 week. For each scanner, the best proportional and linear fit between measured and known activities were derived and based on statistical analyses of the results of all scanners; it was determined which fit should be applied. In addition, a Bland-Altman analysis was done on calibrated activities with respect to reference activities to asses the relative precision of the scanners. Results: Nine Philips (vendor A) and nine Siemens (vendor B) PET/CT scanners were calibrated in a time period of 3 days before and after the reference time. No significant differences were detected between the two subsequent scans on any scanner. Six fitted intercepts of vendor A were significantly different from zero, so the linear model was used. Intercepts ranged from −8 to 26 kBq and slopes ranged from 0.80 to 0.98. Bland-Altman analysis of calibrated and reference activities showed that the relative error of calibrated activities was smaller than that of uncalibrated activities. Conclusions: A simplified multicenter calibration procedure for PET/CT scans that show highly focal uptake and negligible background is feasible and results in more precise quantification. Our procedure can be used in multicenter 124I PET scans focusing on (recurrent) DTC

Multicenter Harmonization of Zr-89 PET/CT Performance

This study investigated the feasibility of quantitative accuracy and harmonized image quality in Zr-89-PET/CT multicenter studies. Methods: Five PET/CT scanners from 3 vendors were included. Zr-89 activity was measured in a central dose calibrator before delivery. Local activity assays were based on volume as well as on the local dose calibrator. Accuracy and image noise were determined from a cross calibration experiment. Image quality was assessed from recovery coefficients derived from different volume-of-interest (VOI) methods (VOIA50%, based on a 3-dimensional isocontour at 50% of the maximum voxel value with local background correction; VOImax, based on the voxel with the highest uptake; and VOI3Dpeak, based on a spheric VOI of 1.2-cm diameter positioned so as to maximize the enclosed average). PET images were analyzed before and after postreconstruction smoothing, applied to match image noise. Results: PET/CT accuracy and image noise ranged from -3% to 10% and from 13% to 22%, respectively. VOI3Dpeak produced the most reproducible recovery coefficients. After calibration of the local dose calibrator to the central dose calibrator, differences between the local activity assays were within 6%. Conclusion: This study showed that quantitative accuracy and harmonized image quality can be reached in Zr-89 PET/CT multicenter studies

Toward prediction of efficacy of chemotherapy:a proof of concept study in lung cancer patients using [¹¹C]docetaxel and positron emission tomography

PURPOSE: Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and a microdose of radiolabeled docetaxel ([(11)C]docetaxel). The objective of this study was to investigate whether a [(11)C]docetaxel PET microdosing study could predict tumor uptake of therapeutic doses of docetaxel.EXPERIMENTAL DESIGN: Docetaxel-naïve lung cancer patients underwent 2 [(11)C]docetaxel PET scans; one after bolus injection of [(11)C]docetaxel and another during combined infusion of [(11)C]docetaxel and a therapeutic dose of docetaxel (75 mg·m(-2)). Compartmental and spectral analyses were used to quantify [(11)C]docetaxel tumor kinetics. [(11)C]docetaxel PET measurements were used to estimate the area under the curve (AUC) of docetaxel in tumors. Tumor response was evaluated using computed tomography scans.RESULTS: Net rates of influx (Ki) of [(11)C]docetaxel in tumors were comparable during microdosing and therapeutic scans. [(11)C]docetaxel AUCTumor during the therapeutic scan could be predicted reliably using an impulse response function derived from the microdosing scan together with the plasma curve of [(11)C]docetaxel during the therapeutic scan. At 90 minutes, the accumulated amount of docetaxel in tumors was less than 1% of the total infused dose of docetaxel. [(11)C]docetaxel Ki derived from the microdosing scan correlated with AUCTumor of docetaxel (Spearman ρ = 0.715; P = 0.004) during the therapeutic scan and with tumor response to docetaxel therapy (Spearman ρ = -0.800; P = 0.010).CONCLUSIONS: Microdosing data of [(11)C]docetaxel PET can be used to predict tumor uptake of docetaxel during chemotherapy. The present study provides a framework for investigating the PET microdosing concept for radiolabeled anticancer drugs in patients.</p

How to obtain the image-derived blood concentration from 89Zr-immuno-PET scans

Abstract Background PET scans using zirconium-89 labelled monoclonal antibodies (89Zr-mAbs), known as 89Zr-immuno-PET, are made to measure uptake in tumour and organ tissue. Uptake is related to the supply of 89Zr-mAbs in the blood. Measuring activity concentrations in blood, however, requires invasive blood sampling. This study aims to identify the best delineation strategy to obtain the image-derived blood concentration (IDBC) from 89Zr-immuno-PET scans. Methods PET imaging and blood sampling of two 89Zr-mAbs were included, 89Zr-cetuximab and 89Zr-durvalumab. For seven patients receiving 89Zr-cetuximab, PET scans on 1–2 h, 2 and 6 days post-injection (p.i.) were analysed. Five patients received three injections of 89Zr-durvalumab. The scanning protocol for the first two injections consisted of PET scanning on 2, 5 and 7 days p.i. and for the third injection only on 7 days p.i. Blood samples were drawn with every PET scan and the sample-derived blood concentration (SDBC) was used as gold standard for the IDBC. According to an in-house developed standard operating procedure, the aortic arch, ascending aorta, descending aorta and left ventricle were delineated. Bland–Altman analyses were performed to assess the bias (mean difference) and variability (1.96 times the standard deviation of the differences) between IDBC and SDBC. Results Overall, the activity concentration obtained from the IDBC was lower than from the SDBC. When comparing IDBC with SDBC, variability was smallest for the ascending aorta (20.3% and 17.0% for 89Zr-cetuximab and 89Zr-durvalumab, respectively). Variability for the other regions ranged between 17.9 and 30.8%. Bias for the ascending aorta was − 10.9% and − 11.4% for 89Zr-cetuximab and 89Zr-durvalumab, respectively. Conclusions Image-derived blood concentrations should be obtained from delineating the ascending aorta in 89Zr-immuno-PET scans, as this results in the lowest variability with respect to sample-derived blood concentrations

Validation of simplified uptake measures against dynamic Patlak Ki for quantification of lesional 89Zr-Immuno-PET antibody uptake

Purpose: Positron emission tomography imaging of zirconium-89-labelled monoclonal antibodies (89Zr-Immuno-PET) allows for visualisation and quantification of antibody uptake in tumours in vivo. Patlak linearization provides distribution volume (VT) and nett influx rate (Ki) values, representing reversible and irreversible uptake, respectively. Standardised uptake value (SUV) and tumour-to-plasma/tumour-to-blood ratio (TPR/TBR) are often used, but their validity depends on the comparability of plasma kinetics and clearances. This study assesses the validity of SUV, TPR and TBR against Patlak Ki for quantifying irreversible 89Zr-Immuno-PET uptake in tumours. Methods: Ten patients received 37 MBq 10 mg 89Zr-anti-EGFR with 500 mg/m2 unlabelled mAbs. Five patients received two doses of 37 MBq 89Zr-anti-HER3: 8–24 mg for the first administration and 24 mg–30 mg/kg for the second. Seven tumours from four patients showed 89Zr-anti-EGFR uptake, and 18 tumours from five patients showed 89Zr-anti-HER3 uptake. SUVpeak, TPRpeak and TBRpeak values were obtained from one to six days p.i. Patlak linearization was applied to tumour time activity curves and plasma samples to obtain Ki. Results: For 89Zr-anti-EGFR, there was a small variability along the linear regression line between SUV (− 0.51–0.57), TPR (− 0.06‒0.11) and TBR (− 0.13‒0.16) on day 6 versus Ki. Similar doses of 89Zr-anti-HER3 showed similar variability for SUV (− 1.3‒1.0), TPR (− 1.1‒0.53) and TBR (− 1.5‒0.72) on day 5 versus Ki. However, for the second administration of 89Zr-anti-HER3 with a large variability in administered mass doses, SUV showed a larger variability (− 1.4‒2.3) along the regression line with Ki, which improved when using TPR (− 0.38–0.32) or TBR (− 0.56‒0.46). Conclusion: SUV, TPR and TBR at late time points were valid for quantifying irreversible lesional 89Zr-Immuno-PET uptake when constant mass doses were administered. However, for variable mass doses, only TPR and TBR provided reliable values for irreversible uptake, but not SUV, because SUV does not take patient and mass dose-specific plasma clearance into account