An international multi-center investigation on the accuracy of radionuclide calibrators in nuclear medicine theranostics

An international multi-center investigation on the accuracy of radionuclide calibrators in nuclear medicine theranostics | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Original research An international multi-center investigation on the accuracy of radionuclide calibrators in nuclear medicine theranostics Clarita Saldarriaga Vargas, Matthias Bauwens, Ivo NA Pooters, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-41572/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Nov, 2020 Read the published version in EJNMMI Physics → Version 2 posted 4 You are reading this latest preprint version Show more versions Abstract Background: Personalized molecular radiotherapy based on theragnostics requires accurate quantification of the amount of radiopharmaceutical activity administered to patients both in diagnostic and therapeutic applications. This international multi-center study aims to investigate the clinical measurement accuracy of radionuclide calibrators for 7 radionuclides used in theragnostics: 99m Tc, 111 In, 123 I, 124 I, 131 I, 177 Lu and 90 Y. Methods: In total, 32 radionuclide calibrators from 8 hospitals located in the Netherlands, Belgium and Germany were tested. For each radionuclide, a set of four samples comprising two clinical containers (10-mL glass vial and 3-mL syringe) with two filling volumes were measured. The reference value of each sample was determined by two certified radioactivity calibration centers (SCK CEN and JRC) using two secondary standard ionization chambers. The deviation in measured activity with respect to the reference value was determined for each radionuclide and each measurement geometry. In addition, the combined systematic deviation of activity measurements in a theragnostic setting was evaluated for 5 clinically-relevant theragnostic pairs: 131 I/ 123 I, 131 I/ 124 I, 177 Lu/ 111 In, 90 Y/ 99m Tc and 90 Y/ 111 In. Results: For 99m Tc, 131 I, and 177 Lu, a small minority of measurements were not within ±5% range from the reference activity (percentage of measurements not within range: 99m Tc: 6%, 131 I: 14%, 177 Lu: 24%) and almost none were outside ±10% range. However, for 111 In, 123 I, 124 I and 90 Y more than half of all measurements were not accurate within ±5% range ( 111 In: 51%, 123 I: 83%, 124 I: 63%, 90 Y: 61%) and not all were within ±10% margin ( 111 In: 22%, 123 I: 35%, 124 I: 15%, 90 Y: 25%). A large variability in measurement accuracy was observed between radionuclide calibrator systems, type of sample container (vial vs syringe), and source-geometry calibration/correction settings used. Consequently, we observed large combined deviations (percentage deviation > ±10%) for the investigated theragnostic pairs, in particular for 90 Y/ 111 In, 131 I/ 123 I and 90 Y/ 99m Tc. Conclusions: Our study shows that substantial over- or under-estimation of therapeutic patient doses are likely to occur in a theragnostic setting due to errors in the assessment of radioactivity with radionuclide calibrators. These findings underline the importance of thorough validation of radionuclide calibrator systems for each clinically-relevant radionuclide and sample geometry. Nuclear Medicine & Medical Imaging activity measurement radionuclide calibrator accuracy theranostics Figures Figure 1 Figure 1 Figure 2 Figure 2 Figure 3 Figure 3 Figure 4 Figure 4 Introduction In the last decades, the application of personalized molecular radiotherapy using theragnostics has gained a lot of interest in nuclear medicine [1,2]. Theragnostic approaches aim to optimize molecular radiotherapy for individual patients using pre-therapeutic diagnostic imaging. In particular, assessment of the therapeutic absorbed dose to malignant tissue and to organs at risk based on these images facilitates a personalized therapeutic activity approach. These approaches require accurate quantification of the activity administered to patients both in diagnostic and therapeutic applications. Accurate activity calibration of radionuclide imaging equipment such as SPECT and PET cameras is also essential in theragnostics, to enable an accurate estimation of radiopharmaceutical uptake in patient tissues. In practice, radionuclide activity calibrators are used to measure the radiopharmaceutical activity to be administered to patients, and are often the reference instrument for calibrating SPECT and PET systems. Radionuclide calibrators are typically provided with factory-set calibration factors for a variety of clinically-relevant radionuclides. Usually, the calibration factors are calculated from energy-dependent sensitivity curves, determined experimentally on a dedicated reference device using well-calibrated traceable sources in standard containers [3]. In-factory calibration of medical devices is usually limited to a small subset of (long-lived) radionuclides to ensure proper response of each device with respect to the reference device. However, due to manufacturing tolerances in device specifications, variations in response among radionuclide calibrators of same model can occur, particularly in the low photon-energy range, which is generally not tested in the factory. Moreover, sample geometries used in clinical practice differ in shape, size, material and filling volume from the standard container geometries used for activity calibrations. Since radionuclide calibrator measurements are sensitive to changes in system and sample measurement geometry [4,5], the validity of generic factory-set calibration factors is not guaranteed for clinically-used radionuclides and sample geometries. Therefore, several international guidelines recommend a thorough validation of radionuclide calibrator accuracy for all clinically-used radionuclides and sample geometries during acceptance testing [6-8]. These guidelines typically recommend a measurement accuracy of ±5-10% for diagnostic and ±5% for therapeutic radionuclides. However, although practice varies widely across Europe, more often than not radionuclide calibrators are clinically implemented without such validation due to a lack of available certified activity standards of (short-lived) clinically-used radionuclides, expertise and time/costs required to perform this validation. In fact, a multi-center study investigating the radionuclide calibrator measurement accuracy among 15 Belgian hospitals performed between 2013 and 2015 revealed that none of the participating centers assessed the accuracy of clinically-used radionuclides [9]. Several studies [9-15] have reported on the measurement accuracy of various individual diagnostic and therapeutic radionuclides, and demonstrated large measurement deviations (> ±10%), particularly for 111 In, 68 Ga, 123 I and 90 Y. However, no study has reported on the combined error of radiopharmaceutical activity measurements with radionuclide calibrators in the increasing application of personalized molecular radiotherapy based on a theragnostic approach. Therefore, we performed an international multi-center study on the clinical measurement accuracy of 32 radionuclide calibrators (7 different types from 4 vendors) for a comprehensive set of theragnostic radionuclides: imaging tracers 99m Tc, 111 In, 123 I and 124 I, and their therapeutic companions 90 Y, 177 Lu and 131 I. Additionally, the combined deviation of activity measurements in a theragnostic setting was evaluated for 5 clinically-relevant theragnostic pairs: 131 I/ 123 I and 131 I/ 124 I, which are used mostly for treatment of thyroid disorders such as differentiated thyroid cancer and hyperthyroidism; 177 Lu/ 111 In and 90 Y/ 111 In, used for peptide receptor radionuclide therapy of neuroendocrine neoplasms and prostate cancer; and 90 Y/ 99m Tc, used in the treatment of liver tumors and metastases with 90 Y microspheres [1,2,16]. Methods Stock solution preparation The radionuclides were obtained from various suppliers: [ 99m Tc]-NaTcO 4 , [ 123 I]-NaI and [ 131 I]-NaI from GE Healthcare (Eindhoven, The Netherlands), [ 124 I]-NaI from BV Cyclotron VU (Amsterdam, The Netherlands), [ 177 Lu]-LuCl 3 from IDB Holland (Baarle-Nassau, The Netherlands), and [ 111 In]-InCl 3 and [ 90 Y]-YCl 3 from Curium (Petten, The Netherlands). [ 177 Lu]-LuCl 3 , [ 111 In]-InCl 3 , [ 90 Y]-YCl 3, [ 131 I]-NaI and [ 124 I]-NaI stock solutions and samples were prepared within 24 hours of the first day of the intercomparison measurements, which took place over three consecutive days. Due to their shorter half-life, [ 99m Tc]-NaTcO 4 and [ 123 I]-NaI solutions were prepared at each measurement day. For each radionuclide, a stock solution was prepared with approximately 10 MBq·mL -1 on the first measurement day. Stock solutions were prepared using sterile water (Baxter, Netherlands) in a borosilicate glass container and immediately after preparation dispensed into samples to avoid precipitations. Evaluation of radionuclidic impurities Each stock solution was checked for radionuclidic impurities by high-resolution gamma-ray spectrometry using a high-purity germanium detector (GR1018; Mirion Technologies, Georgia, USA) as described in the supplemental material. No short- or long-lived radionuclidic impurities were found for 99m Tc, 111 In, 131 I and 90 Y. For 123 I and 124 I, trace amounts of 125 I were observed with a maximum radionuclidic impurity of 0.030% and 0.037%, respectively. For 177 Lu, trace amounts of 177m Lu were observed with a maximum radionuclidic impurity of 0.017%. Minimum detectable activities of potential impurities not detected ( 99 Mo, 114m In, 121 Te, 88 Y) and the effect of (potential) impurities on a radionuclide calibrator, are reported in the supplemental material (Table S1) [17]. Determination of reference activity The reference (true) activity concentration of each stock solution was determined by the Belgian Nuclear Research Centre SCK CEN (Mol, Belgium) in collaboration with the Joint Research Centre (Geel, Belgium), which is specialized in primary and secondary standardization of radioactivity [18]. Reference activity measurements were performed using two secondary standard ionization chambers: a Fidelis (Southern-Scientific, Henfield, UK) and an ISOCAL-III (Vinten Instruments, UK). The latter is consistent with radioactivity standards from the JRC [9]. Both chambers are of the same design and use calibration factors traceable to the primary standards of activity of the UK National Physical Laboratory (NPL). From each stock solution, three 10-mL Type 1+ Schott vials (SCHOTT AG Pharmaceutical Systems, Mainz, Germany) [19] were filled with 4 mL of solution (calibration geometry specified for the Fidelis), and their activities were assayed in both reference chambers. With the exception of 90 Y, the reference activity of each Schott vial was determined from the mean of the activities measured with both the Fidelis and the ISOCAL, and the gravimetrically-determined mass of stock solution in the vial. All activity measurements were corrected for background signal and for radioactive decay to a common reference time using the half-life values published in the NuDat database version 2.8 [20]. Additionally, before determination of the average value, the activity measurements were corrected for linearity, radionuclide impurities (significant only for ( 177m Lu/) 177 Lu measurements) and for deviations in response against the NPL master chamber (see supplementary Table S2). For the latter correction, radionuclide- and chamber-dependent correction factors were estimated from the NPL acceptance testing data of each system (corrections < 1.1% for the gamma emitters and 14.5% for the 90 Y Fidelis measurements), as described in the supplementary data [21]. With the exception of 90 Y, the Fidelis and ISOCAL systems agreed within ±0.7% in Schott vial activity measurements. For 90 Y, however, a difference in response of approximately 10% was observed between both systems. On the basis of this discrepancy and the lack of experimental data to correct the response of the ISOCAL against the NPL master chamber for pure beta emitters, the reference activity concentration of the 90 Y stock solution was derived from activity measurements with the Fidelis only.The reference activity concentration of the radionuclide stock solution was then determined as the mean of the activity concentrations from the three Schott vials. The expanded uncertainty (95% confidence level) in the reference activity concentrations of the stock solutions was: 2.0% for 99m Tc, 1.7% for 111 In, 2.2% for 123 I, 2.0% for 124 I, 1.1% for 131 I, 1.2% for 177 Lu and 6.9% for 90 Y, see supplementary Table S3. Sample preparation From each stock solution, a set of four samples comprising two different clinical containers each with two filling volumes were prepared: two 3-mL Luer-lock syringes (Terumo Europe, Leuven, Belgium) filled with 1 mL and 3 mL of solution, and two 11-mL TechneVial glass vials (Curium, Petten, The Netherlands) filled with 1 mL and 10 mL of solution. Each syringe was sealed with a combi-stopper (Braun, The Netherlands). The content mass of each sample was verified gravimetrically, by weighing the sample before and after filling with an analytical balance (XS105DU/M; Mettler-Toledo, Tiel, The Netherlands). The reference activity ( A ref ) of each sample was calculated by multiplying the content mass with the stock solution reference activity concentration. As the uncertainty in sample mass measurements was negligible compared to the uncertainty in radioactivity concentration, the relative uncertainty of the sample reference activity ( u ref ) was approximately equal to the relative uncertainty of the stock solution activity concentration. Due to transport logistics, for one hospital separate sets of samples (a 3-mL syringe filled with 3 mL and a TechneVial filled with 10 mL of stock solution) were prepared for all radionuclides. Clinical activity measurements Sample measurements were performed on a total of 32 radionuclide calibrator systems of 8 university hospitals located in the Netherlands, Belgium and Germany. Of all systems, 4 were manufactured by Capintec Inc (Florham Park, USA), 11 by former MED Nuklear-Medizintechnik (now Nuvia Instruments, Dresden, Germany), 1 by PTW-Freiburg (Freiburg, Germany), and 16 by former Veenstra Instruments (now Comecer Netherlands, Joure, Netherlands) (see supplemental Table S4). If applicable, measurements were performed using hospital-specific calibration settings and sample geometry corrections. Otherwise, standard factory settings were used (see supplementary Tables S5-S11). The standard (automatic) measurement (averaging) time of the calibrator was used. Three activity readings ( n =3) were taken sequentially, without moving the sample, at intervals of several seconds (dependent on observed system response time). The calibrator reading was left to settle (typically for about 15 to 30 seconds) before the first reading was taken. The range of the sample activities at the moment of clinical measurements are indicated in Table 1. Each measurement was corrected for background signal and radioactive decay. For each measurement triplet the average net activity ( Ā m ) and standard deviation ( SD ) were calculated. The statistical measurement uncertainty ( u m ) was estimated at the 95% confidence level (coverage factor k =4.30 for a t -distribution with two ( n -1) degrees of freedom), as follows: Net activities were not corrected for the presence of radionuclidic impurities (if any). minimum A ref - maximum A ref (25 th percentile) (MBq) Radionuclide Syringe 1 mL Syringe 3 mL Vial 1 mL Vial 10 mL 99m Tc 3.9-18.5 (6.7) 10.3-44.3 (18.1) 4.3-18.0 (7.1) 34.1-147.8 (58.6) 111 In 5.3-9.5 (5.7) 14.4-25.6 (15.4) 5.9-10.5 (6.3) 48.1-85.6 (51.4) 123 I 6.7-17.6 (9.6) 17.6-47.5 (25.2) 7.8-19.9 (11.1) 60.7-161.6 (86.6) 124 I 6.8-10.3 (7.1) 10.8-25.4 (17.4) 7.9-12.0 (8.3) 35.0-85.7 (58.6) 90 Y 17.3-38.8 (18.7) 20.4-94.3 (45.2) 14.4-32.4 (15.6) 67.4-312.4 (149.7) 131 I 10.8-13.4 (11.1) 20.4-31.5 (26.0) 13.1-16.2 (13.4) 66.8-105.7 (87.3) 177 Lu 8.9-12.5 (9.2) 17.8-34.2 (25.2) 10.4-14.4 (10.7) 57.9-111.4 (82.0) Table 1. Sample reference activities (minimum-maximum (25 th percentile)) at the moment of clinical activity measurements. Evaluation of performance Individual radionuclides The radionuclide calibrator measurement accuracy was determined as the percentage deviation of the average measured activity Ā m with respect to the sample reference activity A ref . For each radionuclide and sample geometry, the typical accuracy and reliability of activity measurements was described in terms of the median and the inter-quartile range (IQR) values of the measurement percentage deviations of all systems pooled together. Similarly, these metrics were used to assess the manufacturer dependence of measurement accuracy and inter-system variability. Sample geometry effects were evaluated by comparing the measurement deviations of the syringe and vial samples with similar filling volume (syringe 1 mL vs vial 1 mL, syringe 3 mL vs vial 10 mL). Theragnostic pairs Finally, since patient tissue doses are proportional to the amount of therapeutic activity administered and in a theragnostic approach the amount of therapeutic activity is based on diagnostic imaging, the combined systematic percentage deviation (bias) that would be associated to therapeutic doses ( E D ) was calculated for the theragnostic pairs 131 I/ 123 I, 131 I/ 124 I, 177 Lu/ 111 In, 90 Y/ 99m Tc and 90 Y/ 111 In, as follows: Results Data analysis In total, 32 radionuclide calibrator systems were investigated. If no calibration setting was available for a specific radionuclide (see supplemental Tables S4-S10), that radionuclide was not measured on that system. One system (E1) appeared defective as it systematically underestimated the activity (typically by more than 10%) of all samples (see Figure 1). Therefore, this system was excluded from further analysis. This resulted in a total of 745 activity measurement datasets for further analysis. An overview of the intercomparison results is provided in Figure 1 as box-whisker plots of the percentage deviations from all analyzed radionuclide calibrator measurements. Figures 2 and 3 show the individual percentage deviations grouped per manufacturer (excluding defective/invalid measurements), for the diagnostic and therapeutic radionuclides, respectively. Table 2 indicates the percentage of activity measurements that exceeded a given range of deviation from the reference activity. Deviating measurements (%) Radionuclide Sample type ±5% ±10% Nr. measurement datasets Nr. systems tested 99m Tc syringes 3.6 0.0 55 28 vials 9.1 0.0 55 28 111 In syringes 61.5 25.0 52 26 vials 40.4 19.2 52 26 123 I syringes 67.9 34.0 53 27 vials 98.1 35.8 53 27 124 I syringes 36.2 12.8 47 25 vials 89.4 17.0 47 25 90 Y syringes 74.5 27.3 55 29 vials 47.3 23.6 55 29 131 I syringes 10.7 3.6 56 30 vials 18.2 1.8 55 29 177 Lu syringes 18.2 0.0 55 29 vials 29.1 0.0 55 29 Table 2. Percentage of activity measurements that exceed a given deviation from the reference activity Diagnostic radionuclides 99m Tc For 99m Tc only 6% (7/110) of all measurements were not within ±5% of the reference value. No dataset showed deviations larger than ±10%. For all sample configurations, the median deviation was within 3.2% from the reference value and there was little spread in measurement deviations (largest IQR 4%), indicating a good and reproducible measurement accuracy for 99m Tc. With a median difference of less than ±2% in measurement deviations between syringes and vials (IQR 3%), the dependency on container type was mostly small. 111 In A substantial amount of the 111 In measurements did not meet the recommended accuracy of ±5% (51%; 53/104), nor the less strict limit of ±10% (22%; 23/104). Although the median deviation of all systems was within 3.5% from the reference value for all sample types, the IQR ranged up to 12%. Additionally, the measurement accuracy often depended on sample container, with a median difference between syringes and vials of ±8% (IQR 14%). Typically, this was most pronounced for systems that did not incorporate any correction for measurement geometry ( i.e. Capintec systems, D3, E3, E4, G1-G3). However, even systems with sample geometry calibration/correction settings were not always accurate within ±5% or ±10% (Isomed F3-F6). 123 I The majority of the 123 I measurements did not meet the recommended ±5% accuracy limit (83%; 88/106). Moreover, a substantial amount of measurements did not meet the ±10% limit either (35%; 37/106). For all the samples, the median deviation of all systems was within 7.4% from the reference value, and the largest IQR was 30%. Furthermore, we observed a large dependence on sample type with a median difference between syringes and vials of ±17% (IQR 16%). Typically, systems without sample geometry corrections tended to overestimate the activity in syringes but underestimate the activity in vials, whereas the opposite trend was observed for systems that did incorporate sample geometry corrections. 124 I A substantial amount of the 124 I measurements did not meet the recommended ±5% (63%; 59/94) nor the less-strict limit of ±10% (15%; 14/94). For all the samples, the median deviation of all systems was within 4.9% from the reference value, and the largest IQR was 16%. Additionally, with a median difference between syringes and vials of ±10% (IQR 8%), 124 I showed a substantial sensitivity to sample geometry. Syringe measurements showed a rather small overestimation in measured activity (largest median deviation of 4.8%) with a relatively small IQR (maximum 6%). For vials, however, the accuracy typically depended on whether the system used sample-specific calibration/correction settings (median deviation of all vial measurements of 9.1%) or not (-6.3%). Therapeutic radionuclides 131 I For 131 I 14% (16/111) and 3% (3/111) of all activity measurements were not within ±5% and ±10% of the reference values, respectively. For all the samples, the median deviation of all systems was within 1.1% from the reference value, and the largest IQR was 7%. Furthermore, with a median difference of less than ±2% between the deviations of syringes and vials (IQR 3%), sample geometry effects were mostly small. 177 Lu A substantial amount of all 177 Lu measurements did not meet the recommended ±5% (24%; 26/110) criterion. However, no dataset showed deviations exceeding the ±10% limit. For all the samples, the median deviation was within 3.7% from the reference value. All IQR values were within 4%, indicating a fair to good reproducible measurement accuracy. Moreover, with a median difference of approximately ±1% between the deviations of syringes and vials (IQR 2%), sample geometry effects were small. 90 Y The majority of the 90 Y measurements did not meet the recommended ±5% accuracy limit (61%; 67/110). Moreover, a substantial amount of measurements did not meet the ±10% limit (26%; 28/110). We observed a large variability in measurement accuracy depending on the system (type) and manufacturer. Isomed systems, using specific calibration settings for each sample configuration, often showed very large underestimation (>30%) of the 90 Y reference activity, most pronounced for syringes, with IQR values up to 45%. Additionally, we found a large variability in performance between systems of the same type using identical calibration factors ( e.g. A1 vs F1). Moreover, with a median difference between the deviations for syringes and vials of ±33% (IQR 30%), geometry effects were very large. Instead, the other radionuclide systems typically performed better, particularly for vials. For all sample configurations, the mean deviations were within 3.5%, and the largest IQR was 12%. With a median difference in measurement deviations between syringes and vials of ±6% (IQR 8%), geometry effects were much smaller compared to the Isomed systems. Interestingly, two systems resulted in unexpectedly high deviations from the reference activity: Isomed D1 (maximum deviation 158%) and Veenstra H2 (maximum deviation 424%). Theragnostic pairs Figure 4 shows the combined systematic percentage deviations for the theragnostic pairs considered ( 131 I/ 123 I, 131 I/ 124 I, 177 Lu/ 111 In, 90 Y/ 99m Tc, 90 Y/ 111 In), when both radionuclides are measured on the same device with the same sample geometry. The combined deviations of the theragnostic pairs show substantial variability in measurement accuracy between systems and manufacturers with a dependency on calibration/correction setting and sample geometry. Generally speaking, roughly half of all investigated theragnostic combinations would introduce a bias in the therapeutic dose larger than ±5%, and for one quarter of these combinations in a bias larger than ±10% (Table 3). This performance is even worse when activity measurements in different containers are combined: of all administrations two thirds would introduce a bias larger than ±5% and one third larger than ±10% (data not shown). Deviating measurements (%) Theragnostic pair Sample type ±5% ±10% ±20% Nr. pairs of measurement datasets Nr. systems tested 131 I/ 123 I syringes 64.2 41.5 1.9 53 27 vials 75.0 25.0 7.7 52 26 131 I/ 124 I syringes 44.7 4.3 0.0 47 25 vials 47.8 4.3 0.0 46 24 177 Lu/ 111 In syringes 55.8 25.0 0.0 52 26 vials 30.8 15.4 5.8 52 26 90 Y/ 99m Tc syringes 67.9 32.1 26.4 53 27 vials 52.8 20.8 13.2 53 27 90 Y/ 111 In syringes 57.7 50.0 26.9 52 26 vials 65.4 42.3 19.2 52 26 Table 2. Percentage of theragnostic activity measurements that exceed a given deviation from the reference activities. Discussion Administering the correct amount of therapeutic activity to patients is of utmost importance in personalized molecular radiotherapy. Typically, (inter)national guidelines recommend stricter accuracy demands (±5%) for therapeutic than for diagnostic radionuclides (±5-10%) [6-8]. However, in case of theragnostics, where the therapeutic activity is optimized based on pre-therapeutic dosimetry/uptake calculations using diagnostic imaging, accurate quantification of the diagnostic activity is of equal importance as accurate therapeutic activity quantification. Therefore, to prevent introducing a substantial error in the therapeutic doses delivered to patients, we advocate to apply the ±5% accuracy limit also for diagnostic radionuclides in a theragnostic setting. In our study we found one radionuclide calibrator (E1) that showed large deviations (> 10% underestimations) for all radionuclides, therefore appearing to be malfunctioning. This system was recently installed and was not yet (fully) validated nor released for clinical use. These observations indicate that extensive validation of all clinically-used radionuclides is of vital importance. Individual radionuclides This intercomparison shows that radionuclide calibrator measurements of 99m Tc, still the workhorse of nuclear medicine, are (nearly) always correct, in agreement with values reported in literature [9,14]. The same cannot be said for the other diagnostic radionuclides evaluated. For 111 In, 123 I and 124 I measurement deviations frequently exceeded the ±5% and often even the ±10% limits. This is in agreement with values reported in literature for 111 In and 123 I [9,10,12]. To the best of our knowledge, no multi-center data are available on the typical accuracy of 124 I clinical activity measurements. In particular, these radionuclides ( 111 In, 123 I and 124 I) show a large dependence on sample geometry (particularly sample container) caused by self-absorption of the emitted low-energy X-rays within the sample itself. Consequently, accurate activity measurement of these radionuclides requires specific calibration or correction factors for the sample geometry [22,23]. When factory settings dedicated to specific sample configurations are available, they must be experimentally verified prior to clinical use, as they might not be accurate for the specific containers used locally. This was the case for many activity measurements of 123 I, 111 In and 124 I. Alternatively, selective absorption of low-energy X-rays using a copper/aluminum filter is an effective method to minimize the variability in activity measurements caused by sample geometry [23,24]. In this intercomparison a copper filter was available for two systems, but appropriate calibration factors for measurements with filter had yet to be determined. Regarding the therapeutic radionuclides, 177 Lu measurements were almost always within ±5% from the reference activity, and never deviated by more than ±10%, in agreement with values previously reported for Capintec systems [13]. A tendency to overestimate the reference activity values by typically a few percent was observed, which might (partially) be attributed to the calibrators being sensitive to the presence of the 177m Lu impurity. Our study presents new data for 177 Lu, particularly on the accuracy of medical calibrators from different suppliers, and using clinical sample configurations. Similar as for 177 Lu, the majority of calibrators were accurate for measuring 131 I albeit with a slightly higher deviation (sometimes > ±5%, rarely > ±10%). This is in agreement with values reported in literature [15]. In contrast, for 90 Y some systems showed incorrect measurements to an unacceptable level: the deviation ranged from a 72% underestimation to a 424% overestimation. Indeed, in literature large measurement errors up to ±50% have been reported [13]. In particular, although all Isomed devices used factory-set corrections for sample geometry, they were highly sensitive to the sample container and volume of solution and large measurement deviations were observed. Also, two systems (D1 and H2) showed extremely high overestimations for the syringe measurements, but not for the vials. Interestingly, this effect was not observed for other systems of the same type and with the same (factory-set) calibration factors. Most likely, in these two systems high-energy beta radiation was able to reach the ionization chamber in the syringe samples but not in the vial samples. Indeed, the radionuclide calibrator response to high-energy beta particles is highly sensitive to even small variations in the material and design specifications of the measurement set-up [4]. This clearly indicates the importance of extensive validation of each individual system for each radionuclide and clinically-used sample geometry. Theragnostic applications The present study sets the first reference on typical combined errors associated to clinical radiopharmaceutical activity measurements in a theragnostic setting. Considering 5 clinically-relevant theragnostic pairs ( 131 I/ 123 I, 131 I/ 124 I, 177 Lu/ 111 In, 90 Y/ 99m Tc, 90 Y/ 111 In), this intercomparison study showed that poor accuracy in radionuclide calibrator activity measurements of therapeutic and diagnostic radionuclides can introduce a relatively large (> ±10%) bias in the therapeutic doses delivered to patients in theragnostic applications. Such errors should be minimized as much as practically possible, therefore the recommendation to apply a standard ±5% accuracy limit to calibrator activity measurements of both therapeutic and diagnostic radionuclides. The best way to limit the error in the administration of activity is to ensure accurate and reproducible activity measurements of both radionuclides involved in the theragnostic application. This can be achieved by proper evaluation of the accuracy of the measurement settings of the calibrators for the radionuclides and sample configurations found in clinical practice, together with an assessment of other sources of uncertainty in the activity measurements and proper maintenance through a quality assurance program [6]. These procedures may lead to re-calibration of the device or determination of appropriate correction factors, and optimization of the source configurations ( e.g. choice of container) or other measurement settings or procedures used for activity measurements. After all, the error in the assessment of patient administered activities is only one of the several sources of uncertainty in the dosimetry process [25]. Minimizing its contribution to the overall uncertainty is the best starting point towards patient treatment optimization in molecular radiotherapy. Uncertainties in the clinical activity measurements of this study As reported in detail by Gadd et al [5], radioactivity measurements using radionuclide calibrators are affected by different sources of uncertainty, including: the accuracy of calibration factors, sample geometry effects, photon-emitting radionuclide impurities, background variability, system non-linear response, short-term response variability, reproducibility of sample position, influence of external shielding, etc. These uncertainty components are dependent on the specific measurement set-up (calibrator unit and its accessories, shielding, local background field), the radionuclide and/or the level of activity (ionization current) being measured. In this study the clinical measurement accuracy of radionuclide calibrators was tested for 7 radionuclides used in theragnostics, each in 4 sample configurations. The effect of the sample type of container (syringe vs vial) was evaluated. As previously addressed, this effect was a significant source of variability in the activity measurements of all the radionuclides, with the magnitude of the effect (median) being large (> ±5%) for 90 Y, 123 I, 111 In and 124 I, mostly small (±2%) for 131 I and 99m Tc, and small (±1%) for 177 Lu. The influence of the short-term response variability in the activity measurements was reduced by taking the average of three consecutive activity readings. Although the measurement statistical uncertainty u m was within 0.7% for the large majority (> 75%) of the activity datasets, which indicates a good short-term measurement reproducibility; it is not negligible and in a clinical setting (where an average value is generally not estimated) would cause a spread in the activity assessment. The background reading was subtracted from all activity measurements. Yet, the uncertainty due to background variability was not assessed. This uncertainty can have an important bearing in the measurement of low activities and radionuclides with a low response per unit activity, such as 90 Y. In this study the highest background-to-sample reading ratios were obtained, as expected, with the vials with 1 mL (samples with low activity), and were ≤ 3.7% for 90 Y, 1.7% for 177 Lu and 0.9% for the other radionuclides. For the vials filled with 10 mL (samples with the highest activity) background fractions were considerably lower (less or equal to 0.6% for 90 Y and 0.2% for the other radionuclides). Assuming a high uncertainty of 10% in the background measurement, the potential error introduced in the estimated net activities of the low-activity vial samples of this study would be ≤ ±0.38% ( 90 Y), ±0.17% ( 177 Lu) and ±0.09% (other radionuclides). Although such potential error is not negligible for 90 Y and 177 Lu, it is much lower compared to the measurement deviations observed in this intercomparison for the vial and syringe samples with 1-3 mL, suggesting that it is not the main cause of the spread in 90 Y and 177 Lu measurements of the samples with the lowest activities. For the other samples and radionuclides the potential error from the background uncertainty is negligible. All radionuclide solutions were checked for the presence of photon-emitting impurities by high-resolution gamma spectrometry. Impurities were detected only in 123 I ( 125 I), 124 I ( 125 I) and 177 Lu ( 177m Lu). From these impurities, only the 177m Lu impurity has a significant effect on activity measurements in a radionuclide calibrator (0.51% over-response for the Fidelis). Since the activities measured with the hospital calibrators were not corrected for this effect, this remains a source of uncertainty in the 177 Lu intercomparison results. Information regarding other sources of uncertainty was not gathered from the participating hospitals. Yet, hospitals were encouraged to make a more detailed uncertainty assessment for their activity measurements, since this is essential to evaluate the agreement with the reference values and determine which corrective actions are needed to improve the accuracy and reliability of their activity measurements. In general, that assessment should be within the practical reach of hospitals, since most of the sources of error mentioned above can be quantified by following a thorough quality control program [5,6,8]. Study limitations It should be noted that not all the calibrator systems tested were clinically used to measure all the radionuclides considered in this study. Since hospitals may validate a device only for the specific radionuclides used in their clinical practice, some specific results of this study may not fully represent the local (hospital) measurement capability. Clinical activity measurements can bear additional uncertainties beyond those accounted in this study. The amounts of activities administered to patients in nuclear medicine theragnostics are in the range of tens to several hundred MBq for imaging studies and a couple to several GBq for therapeutic purposes, whereas in this study the sample activities were in the range of 4–162 MBq for diagnostic radionuclides and 9–312 MBq for therapeutic radionuclides (see values per radionuclide in Table 1). Linearity effects, which are typically in the range of ± 1% to few percent [3,5], become more important for the much broader range of activities measured in clinical applications. Also, in clinical practice therapeutic and diagnostic radionuclides are often not measured using the same (sample) measurement geometry. For instance, 90 Y is often assayed using manufacturer-supplied vials and/or acrylic shields. Indeed, the (combined) errors in theragnostic activity measurements will depend on the specific measurement settings used for each radionuclide. Moreover, the response of a radionuclide calibrator to 90 Y also depends on the physicochemical form of the 90 Y compound [26]. In this study 90 Y samples were prepared based on a 90 Y chloride aqueous solution. Yet, in liver radioembolization procedures, which represent the main clinical application of the theragnostic pair 90 Y/ 99m Tc, 90 Y is administered to patients in the form of suspensions of resin/glass microspheres. Activity measurements of 90 Y microspheres may require the use of different calibration factors and present further challenges whose associated errors might not be reflected in the overall measurement performance obtained here using 90 Y chloride. Conclusion This intercomparison showed that, while 99m Tc, 131 I and 177 Lu activity measurements are mostly accurate, there is still significant room for improvement for 111 In, 123 I, 124 I and 90 Y. For these radionuclides, the radionuclide calibrator response is particularly sensitive to the sample and detector geometry. Consequently, substantial over- or under-dosing (> ±10%) of therapeutic administrations is likely to occur in a theragnostic setting. A key message from this intercomparison is that, prior to clinical release, radionuclide calibration factors and sample geometry correction factors should be verified for each radionuclide and sample configuration used in practice. A unified international standard for testing and calibrating medical radionuclide calibrators is pressingly needed to boost the implementation of quantitative accuracy in nuclear medicine theragnostics. Abbreviations IQR: inter-quartile range; JRC: Joint Research Centre; NPL: National Physical Laboratory; PET: positron emission tomography; SCK CEN: Belgian Nuclear Research Centre; SD: standard deviation; SPECT: single photon emission computed tomography. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and material The data that support the findings of this study are available from the corresponding author RW upon reasonable request and with permission of the institution where measurement data was acquired. Competing interests The authors declare that they have no competing interests. Funding This study was funded by Maastricht University Medical Center and the Belgian Nuclear Research Centre. Authors' contributions RW, MB, CSV, MG, FMM and JEW contributed to the conception and design of the study. RW, CSV, INAP, SMBP, MS, WJ, AV, FHPV, SLMV and PC acquired (part of) the radionuclide calibrator data. CSV and SP determined the reference activity of the samples. CSV, RW and MB analyzed and interpreted the intercomparison data and drafted the manuscript. All authors critically revised the manuscript. Acknowledgements The authors kindly thank IDB Holland for providing 177 Lu without charge, Andrew Fenwick (NPL) for the helpful discussions regarding the activity standardizations, Reid Townson (National Research Council Canada) for providing simulation data on the reference chambers energy dependence, Mikael Hult (JRC) for logistic support, and GE Healthcare for providing packing materials without charge. Authors' information 1 Radiation Protection Dosimetry and Calibrations, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium; [email protected] . 2 In vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel, Jette, Belgium. 3 Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands. 4 European Commission, Joint Research Centre (JRC), Geel, Belgium. 5 Department of Radiology, Nuclear Medicine and Anatomy, Radboudumc, Nijmegen, The Netherlands. 6 Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. 7 Department of Nuclear Medicine, University of Duisburg-Essen, Essen, Germany. 8 Department of Nuclear Medicine, University Hospital RWTH Aachen University, Aachen, Germany. 9 Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. 10 Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. 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Vienna: International Atomic Energy Agency; 2006. Busemann Sokole E, Plachcínska A, Britten A; EANM Physics Committee. Acceptance testing for nuclear medicine instrumentation. Eur J Nucl Med Mol Imaging. 2010;37:672-681. The selection, use, calibration and quality assurance of radionuclide calibrators used in nuclear medicine, Report of AAPM Task Group 181. College Park: American Association of Physicists in Medicine; 2012. Saldarriaga Vargas C, Rodríguez Pérez S, Baete K, Pommé S, Paepen J, Van Ammel R, et al. Intercomparison of 99m Tc, 18 F and 111 In activity measurements with radionuclide calibrators in Belgian hospitals. Phys Med. 2018;45:134-142. Bauwens M, Pooters I, Cobben R, Vissera M, Schnerra R, Mottaghy F, et al. A comparison of four radionuclide dose calibrators using various radionuclides and measurement geometries clinically used in nuclear medicine. Phys Med. 2019;60:14-21. Bailey DL, Hofman MS, Forwood NJ, O’Keefe GJ, Scott AM, van Wyngaardt WM, et al. Accuracy of dose calibrators for 68 Ga PET imaging: unexpected findings in a multicenter clinical pretrial assessment. J Nucl Med. 2018;59(4):636-638. Ferreira KM, Fenwick AJ. 123 I intercomparison exercises: Assessment of measurement capabilities in UK hospitals. Appl Radiat Isot. 2018;134:108-111. Fenwick A, Baker M, Ferreira K, Keightley J. Comparison of 90 Y and 177 Lu measurement capability in UK and European hospitals. Appl Radiat Isot. 2014;87:10-13. MacMahon D, Townley J, Bakhshandeiar E, Harms AV. Comparison of Tc-99m measurements in UK hospitals, 2006, NPL Report DQL-RN 018. Teddington: National Physical Laboratory; 2007. Ciocanel M, Keightley JD, Scott CJ, Woods MJ. Intercomparisons of 131 I solution and capsule sources in UK hospitals, 1999, NPL report CIRM 31. Teddington: National Physical Laboratory; 1999. Stokke C, Minguez Gabiña P, Solný P, Cicone F, Sandström M, Sjögreen Gleisner K, et al. Dosimetry-based treatment planning for molecular radiotherapy: a summary of the 2017 report from the Internal Dosimetry Task Force. EJNMMI Phys. 2017;4(1):27. doi:10.1186/s40658-017-0194-3. Determination of the detection limit and decision threshold for ionizing radiation measurements — Part 3: Fundamentals and application to counting measurements by high resolution gamma spectrometry, without the influence of sample treatment, EN ISO 11929-3:2000. Geneva: International Organization for Standardization; 2000. Pommé S. Methods from primary standardization of activity. Metrologia. 2007;44:17-26. Injection Containers and Accessories. Injection Vials Made of Glass Tubing, EN ISO 8362-1:2009. Geneva: International Organization for Standardization; 2010. Brookhaven National Laboratory, https://www.nndc.bnl.gov/nudat2/. Accessed 15 October 2020. Townson R, Tessier F, Galea R. EGSnrc calculation of activity calibration factors for the Vinten ionization chamber. Appl Radiat Isot. 2018;134:100-104. Peitl PK, Tomse P, Kroseli M, Socana A, Hojkera S, Pecar S, et al. Influence of radiation source geometry on determination of 111 In and 90 Y activity of radiopharmaceuticals. Nucl Med Commun. 2009;30(10):807-814. Beattie BJ, Pentlow KS, O'Donoghue J, Humm JL. A recommendation for revised dose calibrator measurement procedures for 89 Zr and 124 PLoS One. 2014; 9(9): e106868. Kowalsky RJ, Johnston RE. Dose calibrator assay of iodine-123 and indium-111 with a copper filter. J Nucl Med Technol. 1998;26(2):94-98. Gear JI, Cox MG, Gustafsson J, Sjögreen Gleisner K, Murray I, Glatting G, et al. EANM practical guidance on uncertainty analysis for molecular radiotherapy absorbed dose calculations. Eur J Nucl Med Mol Imaging. 2018;45(13):2456-2474. Ferreira KM, Fenwick AJ, Arinc A, Johansson LC. Standardization of 90 Y and determination of calibration factors for 90 Y microspheres (resin) for the NPL secondary ionization chamber and a Capintec CRC-25R. Appl Radiat Isot. 2016;109:226-230. Supplementary Files 20201030supplementaldatarevised.pdf 20201030supplementaldatarevised.pdf Cite Share Download PDF Status: Published Journal Publication published 23 Nov, 2020 Read the published version in EJNMMI Physics → Version 2 posted Editorial decision: Accept 08 Nov, 2020 Editor assigned by journal 03 Nov, 2020 Submission checks completed at journal 03 Nov, 2020 Editor invited by journal 03 Nov, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Additionally, the percentage deviations from defective measurements excluded from the analysis and box-whisker plots are shown as data points.","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-41572/v2/826984e57ed555edf65e7d25.jpg"},{"id":3507006,"identity":"c8087ac2-9dbe-4381-831a-fa9589a53c94","added_by":"auto","created_at":"2020-11-11 10:33:57","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":130581,"visible":true,"origin":"","legend":"Percentage deviations of all the activity measurements used for analysis, for each system tested, for the diagnostic radionuclides. A: 99mTc, B: 111In, C: 123I, D: 124I. Systems using sample geometry calibration/correction factors are labeled with an asterisk (*).","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-41572/v2/12dff904e5707eb5b7416c80.jpg"},{"id":3507001,"identity":"a0fbb97a-4b01-4862-a20b-e0f2e1af2569","added_by":"auto","created_at":"2020-11-11 10:33:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":130581,"visible":true,"origin":"","legend":"Percentage deviations of all the activity measurements used for analysis, for each system tested, for the diagnostic radionuclides. A: 99mTc, B: 111In, C: 123I, D: 124I. Systems using sample geometry calibration/correction factors are labeled with an asterisk (*).","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-41572/v2/5bffe4123dda77b1cb23fb57.jpg"},{"id":3507007,"identity":"8ae7867d-86f3-4f64-b5fd-a09cfd8b5f00","added_by":"auto","created_at":"2020-11-11 10:33:58","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":95800,"visible":true,"origin":"","legend":"Percentage deviations of all the activity measurements used for analysis, for each system tested, for the therapeutic radionuclides. A: 131I, B: 177Lu, C: 90Y (data not shown: D1 syringe 1 mL 158.2%, D1 syringe 3 mL 94.0%, H2 syringe 1 mL 423.9%; H2 syringe 3 mL 383.6%). Systems using sample geometry calibration/correction factors are labeled with an asterisk (*).","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-41572/v2/a06e21d13e5b0c62a403be9c.jpg"},{"id":3507002,"identity":"4438f19b-768e-4fe4-8228-857d42ff92b7","added_by":"auto","created_at":"2020-11-11 10:33:52","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":95800,"visible":true,"origin":"","legend":"Percentage deviations of all the activity measurements used for analysis, for each system tested, for the therapeutic radionuclides. A: 131I, B: 177Lu, C: 90Y (data not shown: D1 syringe 1 mL 158.2%, D1 syringe 3 mL 94.0%, H2 syringe 1 mL 423.9%; H2 syringe 3 mL 383.6%). Systems using sample geometry calibration/correction factors are labeled with an asterisk (*).","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-41572/v2/4ff1abe46834c76da3352cb9.jpg"},{"id":3507008,"identity":"96234c50-5b02-4845-99a6-b95eb18f1ce8","added_by":"auto","created_at":"2020-11-11 10:33:58","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":165689,"visible":true,"origin":"","legend":"Percentage combined deviations for the theragnostic radionuclide pairs considered, when both radionuclides are measured on the same device and using the same sample geometry. A: 131I/123I, B: 131I/124I, C: 177Lu/111In, D: 90Y/111In, E: 90Y/99mTc. ","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-41572/v2/e2b871dd737f1f0c803bb75b.jpg"},{"id":3507003,"identity":"16e2b2e1-ab52-4470-a3d0-096b000afb87","added_by":"auto","created_at":"2020-11-11 10:33:52","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":165689,"visible":true,"origin":"","legend":"Percentage combined deviations for the theragnostic radionuclide pairs considered, when both radionuclides are measured on the same device and using the same sample geometry. A: 131I/123I, B: 131I/124I, C: 177Lu/111In, D: 90Y/111In, E: 90Y/99mTc. 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Theragnostic approaches aim to optimize molecular radiotherapy for individual patients using pre-therapeutic diagnostic imaging. In particular, assessment of the therapeutic absorbed dose to malignant tissue and to organs at risk based on these images facilitates a personalized therapeutic activity approach. These approaches require accurate quantification of the activity administered to patients both in diagnostic and therapeutic applications. Accurate activity calibration of radionuclide imaging equipment such as SPECT and PET cameras is also essential in theragnostics, to enable an accurate estimation of radiopharmaceutical uptake in patient tissues.\u003c/p\u003e\n\u003cp\u003eIn practice, radionuclide activity calibrators are used to measure the radiopharmaceutical activity to be administered to patients, and are often the reference instrument for calibrating SPECT and PET systems. Radionuclide calibrators are typically provided with factory-set calibration factors for a variety of clinically-relevant radionuclides. Usually, the calibration factors are calculated from energy-dependent sensitivity curves, determined experimentally on a dedicated reference device using well-calibrated traceable sources in standard containers [3]. In-factory calibration of medical devices is usually limited to a small subset of (long-lived) radionuclides to ensure proper response of each device with respect to the reference device. However, due to manufacturing tolerances in device specifications, variations in response among radionuclide calibrators of same model can occur, particularly in the low photon-energy range, which is generally not tested in the factory. Moreover, sample geometries used in clinical practice differ in shape, size, material and filling volume from the standard container geometries used for activity calibrations. Since radionuclide calibrator measurements are sensitive to changes in system and sample measurement geometry [4,5], the validity of generic factory-set calibration factors is not guaranteed for clinically-used radionuclides and sample geometries.\u003c/p\u003e\n\u003cp\u003eTherefore, several international guidelines recommend a thorough validation of radionuclide calibrator accuracy for all clinically-used radionuclides and sample geometries during acceptance testing [6-8]. These guidelines typically recommend a measurement accuracy of \u0026plusmn;5-10% for diagnostic and \u0026plusmn;5% for therapeutic radionuclides. However, although practice varies widely across Europe, more often than not \u0026nbsp;radionuclide calibrators are clinically implemented without such validation due to a lack of available certified activity standards of (short-lived) clinically-used radionuclides, expertise and time/costs required to perform this validation. In fact, a multi-center study investigating the radionuclide calibrator measurement accuracy among 15 Belgian hospitals performed between 2013 and 2015 revealed that none of the participating centers assessed the accuracy of clinically-used radionuclides [9].\u003c/p\u003e\n\u003cp\u003eSeveral studies [9-15] have reported on the measurement accuracy of various individual diagnostic and therapeutic radionuclides, and demonstrated large measurement deviations (\u0026gt; \u0026plusmn;10%), particularly for \u003csup\u003e111\u003c/sup\u003eIn, \u003csup\u003e68\u003c/sup\u003eGa, \u003csup\u003e123\u003c/sup\u003eI and \u003csup\u003e90\u003c/sup\u003eY. However, no study has reported on the combined error of radiopharmaceutical activity measurements with radionuclide calibrators in the increasing application of personalized molecular radiotherapy based on a theragnostic approach. Therefore, we performed an international multi-center study on the clinical measurement accuracy of 32 radionuclide calibrators (7 different types from 4 vendors) for a comprehensive set of theragnostic radionuclides: imaging tracers \u003csup\u003e99m\u003c/sup\u003eTc, \u003csup\u003e111\u003c/sup\u003eIn, \u003csup\u003e123\u003c/sup\u003eI and \u003csup\u003e124\u003c/sup\u003eI, and their therapeutic companions \u003csup\u003e90\u003c/sup\u003eY, \u003csup\u003e177\u003c/sup\u003eLu and \u003csup\u003e131\u003c/sup\u003eI. Additionally, the combined deviation of activity measurements in a theragnostic setting was evaluated for 5 clinically-relevant theragnostic pairs: \u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e123\u003c/sup\u003eI and \u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e124\u003c/sup\u003eI, which are used mostly for treatment of thyroid disorders such as differentiated thyroid cancer and hyperthyroidism; \u003csup\u003e177\u003c/sup\u003eLu/\u003csup\u003e111\u003c/sup\u003eIn and \u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e111\u003c/sup\u003eIn, used for peptide receptor radionuclide therapy of neuroendocrine neoplasms and prostate cancer; and \u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e99m\u003c/sup\u003eTc, used in the treatment of liver tumors and metastases with \u003csup\u003e90\u003c/sup\u003eY microspheres [1,2,16].\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStock solution preparation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe radionuclides were obtained from various suppliers: [\u003csup\u003e99m\u003c/sup\u003eTc]-NaTcO\u003csub\u003e4\u003c/sub\u003e, [\u003csup\u003e123\u003c/sup\u003eI]-NaI and [\u003csup\u003e131\u003c/sup\u003eI]-NaI from GE Healthcare (Eindhoven, The Netherlands), [\u003csup\u003e124\u003c/sup\u003eI]-NaI from BV Cyclotron VU (Amsterdam, The Netherlands), [\u003csup\u003e177\u003c/sup\u003eLu]-LuCl\u003csub\u003e3\u003c/sub\u003e from IDB Holland (Baarle-Nassau, The Netherlands), and [\u003csup\u003e111\u003c/sup\u003eIn]-InCl\u003csub\u003e3\u003c/sub\u003e and [\u003csup\u003e90\u003c/sup\u003eY]-YCl\u003csub\u003e3\u003c/sub\u003e from Curium (Petten, The Netherlands).\u003c/p\u003e\n\u003cp\u003e[\u003csup\u003e177\u003c/sup\u003eLu]-LuCl\u003csub\u003e3\u003c/sub\u003e, [\u003csup\u003e111\u003c/sup\u003eIn]-InCl\u003csub\u003e3\u003c/sub\u003e, [\u003csup\u003e90\u003c/sup\u003eY]-YCl\u003csub\u003e3, \u003c/sub\u003e[\u003csup\u003e131\u003c/sup\u003eI]-NaI and [\u003csup\u003e124\u003c/sup\u003eI]-NaI stock solutions and samples were prepared within 24 hours of the first day of the intercomparison measurements, which took place over three consecutive days. Due to their shorter half-life, [\u003csup\u003e99m\u003c/sup\u003eTc]-NaTcO\u003csub\u003e4 \u003c/sub\u003eand [\u003csup\u003e123\u003c/sup\u003eI]-NaI solutions were prepared at each measurement day. For each radionuclide, a stock solution was prepared with approximately 10 MBq\u0026middot;mL\u003csup\u003e-1\u003c/sup\u003e on the first measurement day. Stock solutions were prepared using sterile water (Baxter, Netherlands) in a borosilicate glass container and immediately after preparation dispensed into samples to avoid precipitations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEvaluation of radionuclidic impurities\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach stock solution was checked for radionuclidic impurities by high-resolution gamma-ray spectrometry using a high-purity germanium detector (GR1018; Mirion Technologies, Georgia, USA) as described in the supplemental material. No short- or long-lived radionuclidic impurities were found for \u003csup\u003e99m\u003c/sup\u003eTc, \u003csup\u003e111\u003c/sup\u003eIn, \u003csup\u003e131\u003c/sup\u003eI \u0026nbsp;and \u003csup\u003e90\u003c/sup\u003eY. For \u003csup\u003e123\u003c/sup\u003eI and \u003csup\u003e124\u003c/sup\u003eI, trace amounts of \u003csup\u003e125\u003c/sup\u003eI were observed with a maximum radionuclidic impurity of 0.030% and 0.037%, respectively. For \u003csup\u003e177\u003c/sup\u003eLu, trace amounts of \u003csup\u003e177m\u003c/sup\u003eLu were observed with a maximum radionuclidic impurity of 0.017%. Minimum detectable activities of potential impurities not detected (\u003csup\u003e99\u003c/sup\u003eMo, \u003csup\u003e114m\u003c/sup\u003eIn, \u003csup\u003e121\u003c/sup\u003eTe, \u003csup\u003e88\u003c/sup\u003eY) and the effect of (potential) impurities on a radionuclide calibrator, are reported in the supplemental material (Table S1) [17].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDetermination of reference activity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe reference (true) activity concentration of each stock solution was determined by the Belgian Nuclear Research Centre SCK CEN (Mol, Belgium) in collaboration with the Joint Research Centre (Geel, Belgium), which is specialized in primary and secondary standardization of radioactivity [18]. Reference activity measurements were performed using two secondary standard ionization chambers: a Fidelis (Southern-Scientific, Henfield, UK) and an ISOCAL-III (Vinten Instruments, UK). The latter is consistent with radioactivity standards from the JRC [9]. Both chambers are of the same design and use calibration factors traceable to the primary standards of activity of the UK National Physical Laboratory (NPL).\u003c/p\u003e\n\u003cp\u003eFrom each stock solution, three 10-mL Type 1+ Schott vials (SCHOTT AG Pharmaceutical Systems, Mainz, Germany) [19] were filled with 4 mL of solution (calibration geometry specified for the Fidelis), and their activities were assayed in both reference chambers. With the exception of \u003csup\u003e90\u003c/sup\u003eY, the reference activity of each Schott vial was determined from the mean of the activities measured with both the Fidelis and the ISOCAL, and the gravimetrically-determined mass of stock solution in the vial. All activity measurements were corrected for background signal and for radioactive decay to a common reference time using the half-life values published in the NuDat database version 2.8 \u0026nbsp;[20]. Additionally, before determination of the average value, the activity measurements were corrected for linearity, radionuclide impurities (significant only for (\u003csup\u003e177m\u003c/sup\u003eLu/)\u003csup\u003e177\u003c/sup\u003eLu measurements) and for deviations in response against the NPL master chamber (see supplementary Table S2). For the latter correction, radionuclide- and chamber-dependent correction factors were estimated from the NPL acceptance testing data of each system (corrections \u0026lt; 1.1% for the gamma emitters and 14.5% for the \u003csup\u003e90\u003c/sup\u003eY Fidelis measurements), as described in the supplementary data [21].\u003c/p\u003e\n\u003cp\u003eWith the exception of \u003csup\u003e90\u003c/sup\u003eY, the Fidelis and ISOCAL systems agreed within \u0026plusmn;0.7% in Schott vial activity measurements. For \u003csup\u003e90\u003c/sup\u003eY, however, a difference in response of approximately 10% was observed between both systems. On the basis of this discrepancy and the lack of experimental data to correct the response of the ISOCAL against the NPL master chamber for pure beta emitters, the reference activity concentration of the \u003csup\u003e90\u003c/sup\u003eY stock solution was derived from activity measurements with the Fidelis only.The reference activity concentration of the radionuclide stock solution was then determined as the mean of the activity concentrations from the three Schott vials. The expanded uncertainty (95% confidence level) in the reference activity concentrations of the stock solutions was: 2.0% for \u003csup\u003e99m\u003c/sup\u003eTc, 1.7% for \u003csup\u003e111\u003c/sup\u003eIn, 2.2% for \u003csup\u003e123\u003c/sup\u003eI, 2.0% for \u003csup\u003e124\u003c/sup\u003eI, 1.1% for \u003csup\u003e131\u003c/sup\u003eI, 1.2% for \u003csup\u003e177\u003c/sup\u003eLu and 6.9% for \u003csup\u003e90\u003c/sup\u003eY, see supplementary Table S3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample preparation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom each stock solution, a set of four samples comprising two different clinical containers each with two filling volumes were prepared: two 3-mL Luer-lock syringes (Terumo Europe, Leuven, Belgium) filled with 1 mL and 3 mL of solution, and two 11-mL TechneVial glass vials (Curium, Petten, The Netherlands) filled with 1 mL and 10 mL of solution. Each syringe was sealed with a combi-stopper (Braun, The Netherlands). The content mass of each sample was verified gravimetrically, by weighing the sample before and after filling with an analytical balance (XS105DU/M; Mettler-Toledo, Tiel, The Netherlands). The reference activity (\u003cem\u003eA\u003c/em\u003e\u003csub\u003eref\u003c/sub\u003e) of each sample was calculated by multiplying the content mass with the stock solution reference activity concentration. As the uncertainty in sample mass measurements was negligible compared to the uncertainty in radioactivity concentration, the relative uncertainty of the sample reference activity (\u003cem\u003eu\u003c/em\u003e\u003csub\u003eref\u003c/sub\u003e) was approximately equal to the relative uncertainty of the stock solution activity concentration.\u003c/p\u003e\n\u003cp\u003eDue to transport logistics, for one hospital separate sets of samples (a 3-mL syringe filled with 3 mL and a TechneVial filled with 10 mL of stock solution) were prepared for all radionuclides.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical activity measurements \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSample measurements were performed on a total of 32 radionuclide calibrator systems of 8 university hospitals located in the Netherlands, Belgium and Germany. Of all systems, 4 were manufactured by Capintec Inc (Florham Park, USA), 11 by former MED Nuklear-Medizintechnik (now Nuvia Instruments, Dresden, Germany), 1 by PTW-Freiburg (Freiburg, Germany), and 16 by former Veenstra Instruments (now Comecer Netherlands, Joure, Netherlands) (see supplemental Table S4).\u003c/p\u003e\n\u003cp\u003eIf applicable, measurements were performed using hospital-specific calibration settings and sample geometry corrections. Otherwise, standard factory settings were used (see supplementary Tables S5-S11). The standard (automatic) measurement (averaging) time of the calibrator was used. Three activity readings (\u003cem\u003en\u003c/em\u003e=3) were taken sequentially, without moving the sample, at intervals of several seconds (dependent on observed system response time). The calibrator reading was left to settle (typically for about 15 to 30 seconds) before the first reading was taken. \u0026nbsp;The range of the sample activities at the moment of clinical measurements are indicated in Table 1. Each measurement was corrected for background signal and radioactive decay. For each measurement triplet the average net activity (\u003cem\u003eĀ\u003csub\u003em\u003c/sub\u003e\u003c/em\u003e) and standard deviation (\u003cem\u003eSD\u003c/em\u003e) were calculated. The statistical measurement uncertainty (\u003cem\u003eu\u003csub\u003em\u003c/sub\u003e\u003c/em\u003e) was estimated at the 95% confidence level (coverage factor \u003cem\u003ek\u003c/em\u003e=4.30 for a \u003cem\u003et\u003c/em\u003e-distribution with two (\u003cem\u003en\u003c/em\u003e-1) degrees of freedom), as follows:\u003c/p\u003e\u003cp\u003e\u003cimg 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activities were not corrected for the presence of radionuclidic impurities (if any).\u003c/p\u003e\n\u003ctable style=\"width: 4.5e+2pt;border: none;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:73.15pt;border:none;border-top:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width:380.45pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003eminimum A\u003csub\u003eref\u003c/sub\u003e - maximum A\u003csub\u003eref\u003c/sub\u003e (25\u003csup\u003eth\u003c/sup\u003e percentile) (MBq)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:73.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003eRadionuclide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003eSyringe 1 mL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003eSyringe 3 mL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003eVial 1 mL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cstrong\u003eVial 10 mL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:73.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003csup\u003e99m\u003c/sup\u003eTc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e3.9-18.5 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e10.3-44.3 (18.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e4.3-18.0 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e34.1-147.8 (58.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:73.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003csup\u003e111\u003c/sup\u003eIn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e5.3-9.5 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e14.4-25.6 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e5.9-10.5 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e48.1-85.6 (51.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:73.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003csup\u003e123\u003c/sup\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e6.7-17.6 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e17.6-47.5 (25.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e7.8-19.9 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e60.7-161.6 (86.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:73.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003csup\u003e124\u003c/sup\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e6.8-10.3 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e10.8-25.4 (17.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e7.9-12.0 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e35.0-85.7 (58.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:73.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003csup\u003e90\u003c/sup\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e17.3-38.8 (18.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e20.4-94.3 (45.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e14.4-32.4 (15.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e67.4-312.4 (149.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:73.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003csup\u003e131\u003c/sup\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e10.8-13.4 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e20.4-31.5 (26.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e13.1-16.2 (13.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.15pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e66.8-105.7 (87.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:73.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003csup\u003e177\u003c/sup\u003eLu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e8.9-12.5 (9.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e17.8-34.2 (25.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.1pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e10.4-14.4 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:95.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.25in;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e57.9-111.4 (82.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cp style='margin-top:12.0pt;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cstrong\u003e\u003cem\u003eTable 1.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eSample reference activities (minimum-maximum (25\u003csup\u003eth\u003c/sup\u003e percentile)) at the moment of clinical activity measurements.\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\u003cbr\u003e\n\u003cp\u003e\u003cstrong\u003eEvaluation of performance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIndividual radionuclides\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe radionuclide calibrator measurement accuracy was determined as the percentage deviation of the average measured activity \u003cem\u003eĀ\u003csub\u003em\u003c/sub\u003e\u003c/em\u003e with respect to the sample reference activity \u003cem\u003eA\u003c/em\u003e\u003csub\u003eref\u003c/sub\u003e.\u003c/p\u003e\n\u003cp\u003eFor each radionuclide and sample geometry, the typical accuracy and reliability of activity measurements was described in terms of the median and the inter-quartile range (IQR) values of the measurement percentage deviations of all systems pooled together. Similarly, these metrics were used to assess the manufacturer dependence of measurement accuracy and inter-system variability. Sample geometry effects were evaluated by comparing the measurement deviations of the syringe and vial samples with similar filling volume (syringe 1 mL \u003cem\u003evs\u003c/em\u003e vial 1 mL, syringe 3 mL \u003cem\u003evs\u003c/em\u003e vial 10 mL).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTheragnostic\u003c/em\u003e\u003cem\u003e pairs\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFinally, since patient tissue doses are proportional to the amount of therapeutic activity administered and in a theragnostic approach the amount of therapeutic activity is based on diagnostic imaging, the combined systematic percentage deviation (bias) that would be associated to therapeutic doses (\u003cem\u003eE\u003csub\u003eD\u003c/sub\u003e\u003c/em\u003e) was calculated for the theragnostic pairs \u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e123\u003c/sup\u003eI, \u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e124\u003c/sup\u003eI, \u003csup\u003e177\u003c/sup\u003eLu/\u003csup\u003e111\u003c/sup\u003eIn, \u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e99m\u003c/sup\u003eTc and \u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e111\u003c/sup\u003eIn, as follows:\u003c/p\u003e\u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eData analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn total, 32 radionuclide calibrator systems were investigated. If no calibration setting was available for a specific radionuclide (see supplemental Tables S4-S10), that radionuclide was not measured on that system. One system (E1) appeared defective as it systematically underestimated the activity (typically by more than 10%) of all samples (see Figure 1). Therefore, this system was excluded from further analysis. This resulted in a total of 745 activity measurement datasets for further analysis.\u003c/p\u003e\n\u003cp\u003eAn overview of the intercomparison results is provided in Figure 1 as box-whisker plots of the percentage deviations from all analyzed radionuclide calibrator measurements. Figures 2 and 3 show the individual percentage deviations grouped per manufacturer (excluding defective/invalid measurements), for the diagnostic and therapeutic radionuclides, respectively. Table 2 indicates the percentage of activity measurements that exceeded a given range of deviation from the reference activity.\u003c/p\u003e\u003ctable style=\"width: 4.5e+2pt;border: none;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-top:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-top:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:150.15pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003eDeviating measurements (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;border:none;border-top:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;border:none;border-top:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:42.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003eRadionuclide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:42.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003eSample type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.8pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:42.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u0026plusmn;5%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:75.35pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:42.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u0026plusmn;10%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:42.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003eNr. measurement datasets\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:42.5pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003eNr. systems tested\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003csup\u003e99m\u003c/sup\u003eTc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003evials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e9.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003csup\u003e111\u003c/sup\u003eIn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e61.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003evials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e40.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e19.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003csup\u003e123\u003c/sup\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e67.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e34.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003evials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e98.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e35.8\u003c/p\u003e\n \u003c/td\u003e\n 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\u003ctd style=\"width:74.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e36.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e12.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003evials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e89.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e17.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003csup\u003e90\u003c/sup\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e74.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e27.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003evials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e47.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e23.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003csup\u003e131\u003c/sup\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003evials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e18.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003csup\u003e177\u003c/sup\u003eLu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e18.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003evials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74.8pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e29.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75.35pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:69.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:15px;line-height:115%;font-family:\"Calibri\",sans-serif;'\u003eTable 2.\u0026nbsp;\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u003cspan style='font-size:15px;line-height:115%;font-family:\"Calibri\",sans-serif;'\u003ePercentage of activity measurements that exceed a given deviation from the reference activity\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cbr\u003e\u003cp\u003e\u003cstrong\u003eDiagnostic radionuclides\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003csup\u003e99m\u003c/sup\u003e\u003c/em\u003e\u003cem\u003eTc\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFor \u003csup\u003e99m\u003c/sup\u003eTc only 6% (7/110) of all measurements were not within \u0026plusmn;5% of the reference value. No dataset showed deviations larger than \u0026plusmn;10%. For all sample configurations, the median deviation was within 3.2% from the reference value and there was little spread in measurement deviations (largest IQR 4%), indicating a good and reproducible measurement accuracy for \u003csup\u003e99m\u003c/sup\u003eTc.\u003c/p\u003e\n\u003cp\u003eWith a median difference of less than \u0026plusmn;2% in measurement deviations between syringes and vials (IQR 3%), the dependency on container type was mostly small.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003csup\u003e111\u003c/sup\u003e\u003c/em\u003e\u003cem\u003eIn\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA substantial amount of the \u003csup\u003e111\u003c/sup\u003eIn measurements did not meet the recommended accuracy of \u0026plusmn;5% (51%; 53/104), nor the less strict limit of \u0026plusmn;10% (22%; 23/104). Although the median deviation of all systems was within 3.5% from the reference value for all sample types, the IQR ranged up to 12%.\u003c/p\u003e\n\u003cp\u003eAdditionally, the measurement accuracy often depended on sample container, with a median difference \u0026nbsp;between syringes and vials of \u0026plusmn;8% (IQR 14%). Typically, this was most pronounced for systems that did not incorporate any correction for measurement geometry (\u003cem\u003ei.e.\u003c/em\u003e Capintec systems, D3, E3, E4, G1-G3). However, even systems with sample geometry calibration/correction settings were not always accurate within \u0026plusmn;5% or \u0026plusmn;10% (Isomed F3-F6).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003csup\u003e123\u003c/sup\u003e\u003c/em\u003e\u003cem\u003eI\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe majority of the \u003csup\u003e123\u003c/sup\u003eI measurements did not meet the recommended \u0026plusmn;5% accuracy limit (83%; 88/106). Moreover, a substantial amount of measurements did not meet the \u0026plusmn;10% limit either (35%; 37/106). For all the samples, the median deviation of all systems was within 7.4% from the reference value, and the largest IQR was 30%. Furthermore, we observed a large dependence on sample type with a median difference between syringes and vials of \u0026plusmn;17% (IQR 16%).\u003c/p\u003e\n\u003cp\u003eTypically, systems without sample geometry corrections tended to overestimate the activity in syringes but underestimate the activity in vials, whereas the opposite trend was observed for systems that did incorporate sample geometry corrections.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003csup\u003e124\u003c/sup\u003e\u003c/em\u003e\u003cem\u003eI\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA substantial amount of the \u003csup\u003e124\u003c/sup\u003eI measurements did not meet the recommended \u0026plusmn;5% (63%; 59/94) nor the less-strict limit of \u0026plusmn;10% (15%; 14/94). For all the samples, the median deviation of all systems was within 4.9% from the reference value, and the largest IQR was 16%. Additionally, with a median difference between syringes and vials of \u0026plusmn;10% (IQR 8%), \u003csup\u003e124\u003c/sup\u003eI showed a substantial sensitivity to sample geometry. Syringe measurements showed a rather small overestimation in measured activity (largest median deviation of 4.8%) with a relatively small IQR (maximum 6%). For vials, however, the accuracy typically depended on whether the system used sample-specific calibration/correction settings (median deviation of all vial measurements of 9.1%) or not (-6.3%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTherapeutic radionuclides\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003csup\u003e131\u003c/sup\u003e\u003c/em\u003e\u003cem\u003eI\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFor \u003csup\u003e131\u003c/sup\u003eI 14% (16/111) and 3% (3/111) of all activity measurements were not within \u0026plusmn;5% and \u0026plusmn;10% of the reference values, respectively. For all the samples, the median deviation of all systems was within 1.1% from the reference value, and the largest IQR was 7%. Furthermore, with a median difference of less than \u0026plusmn;2% between the deviations of syringes and vials (IQR 3%), sample geometry effects were mostly small.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003csup\u003e177\u003c/sup\u003e\u003c/em\u003e\u003cem\u003eLu\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA substantial amount of all \u003csup\u003e177\u003c/sup\u003eLu measurements did not meet the recommended \u0026plusmn;5% (24%; 26/110) criterion. However, no dataset showed deviations exceeding the \u0026plusmn;10% limit. For all the samples, the median deviation was within 3.7% from the reference value. All IQR values were within 4%, indicating a fair to good reproducible measurement accuracy. Moreover, with a median difference of approximately \u0026plusmn;1% between the deviations of syringes and vials (IQR 2%), sample geometry effects were small.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003csup\u003e90\u003c/sup\u003e\u003c/em\u003e\u003cem\u003eY\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe majority of the \u003csup\u003e90\u003c/sup\u003eY measurements did not meet the recommended \u0026plusmn;5% accuracy limit (61%; 67/110). Moreover, a substantial amount of measurements did not meet the \u0026plusmn;10% limit (26%; 28/110). We observed a large variability in measurement accuracy depending on the system (type) and manufacturer.\u003c/p\u003e\n\u003cp\u003eIsomed systems, using specific calibration settings for each sample configuration, often showed very large underestimation (\u0026gt;30%) of the \u003csup\u003e90\u003c/sup\u003eY reference activity, most pronounced for syringes, with IQR values up to 45%. Additionally, we found a large variability in performance between systems of the same type using identical calibration factors (\u003cem\u003ee.g.\u003c/em\u003e A1 \u003cem\u003evs\u003c/em\u003e F1). Moreover, with a median difference between the deviations for syringes and vials of \u0026plusmn;33% (IQR 30%), geometry effects were very large.\u003c/p\u003e\n\u003cp\u003eInstead, the other radionuclide systems typically performed better, particularly for vials. For all sample configurations, the mean deviations were within 3.5%, and the largest IQR was 12%. With a median difference in measurement deviations between syringes and vials of \u0026plusmn;6% (IQR 8%), geometry effects were much smaller compared to the Isomed systems.\u003c/p\u003e\n\u003cp\u003eInterestingly, two systems resulted in unexpectedly high deviations from the reference activity: Isomed D1 (maximum deviation 158%) and Veenstra H2 (maximum deviation 424%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTheragnostic \u003c/strong\u003e\u003cstrong\u003epairs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 4 shows the combined systematic percentage deviations for the theragnostic pairs considered (\u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e123\u003c/sup\u003eI, \u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e124\u003c/sup\u003eI, \u003csup\u003e177\u003c/sup\u003eLu/\u003csup\u003e111\u003c/sup\u003eIn, \u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e99m\u003c/sup\u003eTc, \u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e111\u003c/sup\u003eIn), when both radionuclides are measured on the same device with the same sample geometry.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe combined deviations of the theragnostic pairs show substantial variability in measurement accuracy between systems and manufacturers with a dependency on calibration/correction setting and sample geometry. Generally speaking, roughly half of all investigated theragnostic combinations would introduce a bias in the therapeutic dose larger than \u0026plusmn;5%, and for one quarter of these combinations in a bias larger than \u0026plusmn;10% (Table 3). This performance is even worse when activity measurements in different containers are combined: of all administrations two thirds would introduce a bias larger than \u0026plusmn;5% and one third larger than \u0026plusmn;10% (data not shown).\u003c/p\u003e\u003ctable style=\"width: 4.5e+2pt;border: none;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-top:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-top:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width:149.65pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003eDeviating measurements (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.0pt;border:none;border-top:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;border:none;border-top:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:45.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003eTheragnostic pair\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:45.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003eSample type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.85pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:45.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u0026plusmn;5%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.9pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:45.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u0026plusmn;10%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.9pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:45.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u0026plusmn;20%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:45.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003eNr. pairs of measurement datasets\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:45.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003eNr. systems tested\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e123\u003c/sup\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.85pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e64.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e41.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003evials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.85pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e75.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e7.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e124\u003c/sup\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.85pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e44.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp 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none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp 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style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.85pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e55.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp 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style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003evials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.85pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e30.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e15.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp 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style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.85pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e67.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e32.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e26.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003evials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.85pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e52.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e20.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e13.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e111\u003c/sup\u003eIn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003esyringes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.85pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e57.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e50.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;padding: 0in 5.4pt;height: 17.25pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e26.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:17.25pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:78.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:74.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003evials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.85pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e65.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e42.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49.9pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e19.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-top:12.0pt;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cem\u003eTable 2.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003ePercentage of theragnostic activity measurements that exceed a given deviation from the reference activities.\u003c/em\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:10.0pt;margin-left:0in;line-height:115%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAdministering the correct amount of therapeutic activity to patients is of utmost importance in personalized molecular radiotherapy. Typically, (inter)national guidelines recommend stricter accuracy demands (\u0026plusmn;5%) for therapeutic than for diagnostic radionuclides (\u0026plusmn;5-10%) [6-8]. However, in case of theragnostics, where the therapeutic activity is optimized based on pre-therapeutic dosimetry/uptake calculations using diagnostic imaging, accurate quantification of the diagnostic activity is of equal importance as accurate therapeutic activity quantification. Therefore, to prevent introducing a substantial error in the therapeutic doses delivered to patients, we advocate to apply the \u0026plusmn;5% accuracy limit also for diagnostic radionuclides in a theragnostic setting.\u003c/p\u003e\n\u003cp\u003eIn our study we found one radionuclide calibrator (E1) that showed large deviations (\u0026gt; 10% underestimations) for all radionuclides, therefore appearing to be malfunctioning. This system was recently installed and was not yet (fully) validated nor released for clinical use. These observations indicate that extensive validation of all clinically-used radionuclides is of vital importance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIndividual radionuclides\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis intercomparison shows that radionuclide calibrator measurements of \u003csup\u003e99m\u003c/sup\u003eTc, still the workhorse of nuclear medicine, are (nearly) always correct, in agreement with values reported in literature [9,14]. The same cannot be said for the other diagnostic radionuclides evaluated. For \u003csup\u003e111\u003c/sup\u003eIn, \u003csup\u003e123\u003c/sup\u003eI and \u003csup\u003e124\u003c/sup\u003eI measurement deviations frequently exceeded the \u0026plusmn;5% and often even the \u0026plusmn;10% limits. This is in agreement with values reported in literature for \u003csup\u003e111\u003c/sup\u003eIn and \u003csup\u003e123\u003c/sup\u003eI [9,10,12]. To the best of our knowledge, no multi-center data are available on the typical accuracy of \u003csup\u003e124\u003c/sup\u003eI clinical activity measurements. In particular, these radionuclides (\u003csup\u003e111\u003c/sup\u003eIn, \u003csup\u003e123\u003c/sup\u003eI and \u003csup\u003e124\u003c/sup\u003eI) show a large dependence on sample geometry (particularly sample container) caused by self-absorption of the emitted low-energy X-rays within the sample itself. Consequently, accurate activity measurement of these radionuclides requires specific calibration or correction factors for the sample geometry [22,23]. When factory settings dedicated to specific sample configurations are available, they must be experimentally verified prior to clinical use, as they might not be accurate for the specific containers used locally. This was the case for many activity measurements of \u003csup\u003e123\u003c/sup\u003eI, \u003csup\u003e111\u003c/sup\u003eIn and \u003csup\u003e124\u003c/sup\u003eI. Alternatively, selective absorption of low-energy X-rays using a copper/aluminum filter is an effective method to minimize the variability in activity measurements caused by sample geometry [23,24]. In this intercomparison a copper filter was available for two systems, but appropriate calibration factors for measurements with filter had yet to be determined.\u003c/p\u003e\n\u003cp\u003eRegarding the therapeutic radionuclides, \u003csup\u003e177\u003c/sup\u003eLu measurements were almost always within \u0026plusmn;5% from the reference activity, and never deviated by more than \u0026plusmn;10%, in agreement with values previously reported for Capintec systems [13]. A tendency to overestimate the reference activity values by typically a few percent was observed, which might (partially) be attributed to the calibrators being sensitive to the presence of the \u003csup\u003e177m\u003c/sup\u003eLu impurity. Our study presents new data for \u003csup\u003e177\u003c/sup\u003eLu, particularly on the accuracy of medical calibrators from different suppliers, and using clinical sample configurations. Similar as for \u003csup\u003e177\u003c/sup\u003eLu, the majority of calibrators were accurate for measuring \u003csup\u003e131\u003c/sup\u003eI albeit with a slightly higher deviation (sometimes \u0026gt; \u0026plusmn;5%, rarely \u0026gt; \u0026plusmn;10%). This is in agreement with values reported in literature [15]. In contrast, for \u003csup\u003e90\u003c/sup\u003eY some systems showed incorrect measurements to an unacceptable level: the deviation ranged from a 72% underestimation to a 424% overestimation. Indeed, in literature large measurement errors up to \u0026plusmn;50% have been reported [13]. In particular, although all Isomed devices used factory-set corrections for sample geometry, they were highly sensitive to the sample container and volume of solution and large measurement deviations were observed. Also, two systems (D1 and H2) showed extremely high overestimations for the syringe measurements, but not for the vials. Interestingly, this effect was not observed for other systems of the same type and with the same (factory-set) calibration factors. Most likely, in these two systems high-energy beta radiation was able to reach the ionization chamber in the syringe samples but not in the vial samples. Indeed, the radionuclide calibrator response to high-energy beta particles is highly sensitive to even small variations in the material and design specifications of the measurement set-up [4]. This clearly indicates the importance of extensive validation of each individual system for each radionuclide and clinically-used sample geometry.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTheragnostic applications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study sets the first reference on typical combined errors associated to clinical radiopharmaceutical activity measurements in a theragnostic setting. Considering 5 clinically-relevant theragnostic pairs (\u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e123\u003c/sup\u003eI, \u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e124\u003c/sup\u003eI, \u003csup\u003e177\u003c/sup\u003eLu/\u003csup\u003e111\u003c/sup\u003eIn, \u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e99m\u003c/sup\u003eTc, \u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e111\u003c/sup\u003eIn), this intercomparison study showed that poor accuracy in radionuclide calibrator activity measurements of therapeutic and diagnostic radionuclides can introduce a relatively large (\u0026gt; \u0026plusmn;10%) bias in the therapeutic doses delivered to patients in theragnostic applications. Such errors should be minimized as much as practically possible, therefore the recommendation to apply a standard \u0026plusmn;5% accuracy limit to calibrator activity measurements of both therapeutic and diagnostic radionuclides.\u003c/p\u003e\n\u003cp\u003eThe best way to limit the error in the administration of activity is to ensure accurate and reproducible activity measurements of both radionuclides involved in the theragnostic application. This can be achieved by proper evaluation of the accuracy of the measurement settings of the calibrators for the radionuclides and sample configurations found in clinical practice, together with an assessment of other sources of uncertainty in the activity measurements and proper maintenance through a quality assurance program [6]. These procedures may lead to re-calibration of the device or determination of appropriate correction factors, and optimization of the source configurations (\u003cem\u003ee.g.\u003c/em\u003e choice of container) or other measurement settings or procedures used for activity measurements. After all, the error in the assessment of patient administered activities is only one of the several sources of uncertainty in the dosimetry process [25]. Minimizing its contribution to the overall uncertainty is the best starting point towards patient treatment optimization in molecular radiotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUncertainties in the clinical activity measurements of this study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs reported in detail by Gadd \u003cem\u003eet al\u003c/em\u003e [5], radioactivity measurements using radionuclide calibrators are affected by different sources of uncertainty, including: the accuracy of calibration factors, sample geometry effects, photon-emitting radionuclide impurities, background variability, system non-linear response, short-term response variability, reproducibility of sample position, influence of external shielding, etc. These uncertainty components are dependent on the specific measurement set-up (calibrator unit and its accessories, shielding, local background field), the radionuclide and/or the level of activity (ionization current) being measured.\u003c/p\u003e\n\u003cp\u003eIn this study the clinical measurement accuracy of radionuclide calibrators was tested for 7 radionuclides used in theragnostics, each in 4 sample configurations.\u003c/p\u003e\n\u003cp\u003eThe effect of the sample type of container (syringe \u003cem\u003evs\u003c/em\u003e vial) was evaluated. As previously addressed, this effect was a significant source of variability in the activity measurements of all the radionuclides, with the magnitude of the effect (median) being large (\u0026gt; \u0026plusmn;5%) for \u003csup\u003e90\u003c/sup\u003eY, \u003csup\u003e123\u003c/sup\u003eI, \u003csup\u003e111\u003c/sup\u003eIn and \u003csup\u003e124\u003c/sup\u003eI, mostly small (\u0026plusmn;2%) for \u003csup\u003e131\u003c/sup\u003eI and \u003csup\u003e99m\u003c/sup\u003eTc, and small (\u0026plusmn;1%) for \u003csup\u003e177\u003c/sup\u003eLu.\u003c/p\u003e\n\u003cp\u003eThe influence of the short-term response variability in the activity measurements was reduced by taking the average of three consecutive activity readings. Although the measurement statistical uncertainty \u003cem\u003eu\u003c/em\u003e\u003csub\u003em\u003c/sub\u003e was within 0.7% for the large majority (\u0026gt; 75%) of the activity datasets, which indicates a good short-term measurement reproducibility; it is not negligible and in a clinical setting (where an average value is generally not estimated) would cause a spread in the activity assessment.\u003c/p\u003e\n\u003cp\u003eThe background reading was subtracted from all activity measurements. Yet, the uncertainty due to background variability was not assessed. This uncertainty can have an important bearing in the measurement of low activities and radionuclides with a low response per unit activity, such as \u003csup\u003e90\u003c/sup\u003eY. In this study the highest background-to-sample reading ratios were obtained, as expected, with the vials with 1 mL (samples with low activity), and were \u0026le; 3.7% for \u003csup\u003e90\u003c/sup\u003eY, 1.7% for \u003csup\u003e177\u003c/sup\u003eLu and 0.9% for the other radionuclides. For the vials filled with 10 mL (samples with the highest activity) background fractions were considerably lower (less or equal to 0.6% for \u003csup\u003e90\u003c/sup\u003eY and 0.2% for the other radionuclides). Assuming a high uncertainty of 10% in the background measurement, the potential error introduced in the estimated net activities of the low-activity vial samples of this study would be \u0026le; \u0026plusmn;0.38% (\u003csup\u003e90\u003c/sup\u003eY), \u0026plusmn;0.17% (\u003csup\u003e177\u003c/sup\u003eLu) and \u0026plusmn;0.09% (other radionuclides). Although such potential error is not negligible for \u003csup\u003e90\u003c/sup\u003eY and \u003csup\u003e177\u003c/sup\u003eLu, it is much lower compared to the measurement deviations observed in this intercomparison for the vial and syringe samples with 1-3 mL, suggesting that it is not the main cause of the spread in \u003csup\u003e90\u003c/sup\u003eY and \u003csup\u003e177\u003c/sup\u003eLu measurements of the samples with the lowest activities. For the other samples and radionuclides the potential error from the background uncertainty is negligible.\u003c/p\u003e\n\u003cp\u003eAll radionuclide solutions were checked for the presence of photon-emitting impurities by high-resolution gamma spectrometry. Impurities were detected only in \u003csup\u003e123\u003c/sup\u003eI (\u003csup\u003e125\u003c/sup\u003eI), \u003csup\u003e124\u003c/sup\u003eI (\u003csup\u003e125\u003c/sup\u003eI) and \u003csup\u003e177\u003c/sup\u003eLu (\u003csup\u003e177m\u003c/sup\u003eLu). From these impurities, only the \u003csup\u003e177m\u003c/sup\u003eLu impurity has a significant effect on activity measurements in a radionuclide calibrator (0.51% over-response for the Fidelis). Since the activities measured with the hospital calibrators were not corrected for this effect, this remains a source of uncertainty in the \u003csup\u003e177\u003c/sup\u003eLu intercomparison results.\u003c/p\u003e\n\u003cp\u003eInformation regarding other sources of uncertainty was not gathered from the participating hospitals. Yet, hospitals were encouraged to make a more detailed uncertainty assessment for their activity measurements, since this is essential to evaluate the agreement with the reference values and determine which corrective actions are needed to improve the accuracy and reliability of their activity measurements. In general, that assessment should be within the practical reach of hospitals, since most of the sources of error mentioned above can be quantified by following a thorough quality control program [5,6,8].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy limitations \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt should be noted that not all the calibrator systems tested were clinically used to measure all the radionuclides considered in this study. Since hospitals may validate a device only for the specific radionuclides used in their clinical practice, some specific results of this study may not fully represent the local (hospital) measurement capability.\u003c/p\u003e\n\u003cp\u003eClinical activity measurements can bear additional uncertainties beyond those accounted in this study. The amounts of activities administered to patients in nuclear medicine theragnostics are in the range of tens to several hundred MBq for imaging studies and a couple to several GBq for therapeutic purposes, whereas in this study the sample activities were in the range of 4\u0026ndash;162 MBq for diagnostic radionuclides and 9\u0026ndash;312 MBq for therapeutic radionuclides (see values per radionuclide in Table 1). Linearity effects, which are typically in the range of \u0026plusmn; 1% to few percent [3,5], become more important for the much broader range of activities measured in clinical applications. Also, in clinical practice therapeutic and diagnostic radionuclides are often not measured using the same (sample) measurement geometry. For instance, \u003csup\u003e90\u003c/sup\u003eY is often assayed using manufacturer-supplied vials and/or acrylic shields. Indeed, the (combined) errors in theragnostic activity measurements will depend on the specific measurement settings used for each radionuclide. Moreover, the response of a radionuclide calibrator to \u003csup\u003e90\u003c/sup\u003eY also depends on the physicochemical form of the \u003csup\u003e90\u003c/sup\u003eY compound [26]. In this study \u003csup\u003e90\u003c/sup\u003eY samples were prepared based on a \u003csup\u003e90\u003c/sup\u003eY chloride aqueous solution. Yet, in liver radioembolization procedures, which represent the main clinical application of the theragnostic pair \u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e99m\u003c/sup\u003eTc, \u003csup\u003e90\u003c/sup\u003eY is administered to patients in the form of suspensions of resin/glass microspheres. Activity measurements of \u003csup\u003e90\u003c/sup\u003eY microspheres may require the use of different calibration factors and present further challenges whose associated errors might not be reflected in the overall measurement performance obtained here using \u003csup\u003e90\u003c/sup\u003eY chloride.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis intercomparison showed that, while \u003csup\u003e99m\u003c/sup\u003eTc, \u003csup\u003e131\u003c/sup\u003eI and \u003csup\u003e177\u003c/sup\u003eLu activity measurements are mostly accurate, there is still significant room for improvement for \u003csup\u003e111\u003c/sup\u003eIn, \u003csup\u003e123\u003c/sup\u003eI, \u003csup\u003e124\u003c/sup\u003eI and \u003csup\u003e90\u003c/sup\u003eY. For these radionuclides, the radionuclide calibrator response is particularly sensitive to the sample and detector geometry. Consequently, substantial over- or under-dosing (\u0026gt; \u0026plusmn;10%) of therapeutic administrations is likely to occur in a theragnostic setting. A key message from this intercomparison is that, prior to clinical release, radionuclide calibration factors and sample geometry correction factors should be verified for each radionuclide and sample configuration used in practice. A unified international standard for testing and calibrating medical radionuclide calibrators is pressingly needed to boost the implementation of quantitative accuracy in nuclear medicine theragnostics.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eIQR: inter-quartile range; JRC: Joint Research Centre; NPL: National Physical Laboratory; PET: positron emission tomography; SCK CEN: Belgian Nuclear Research Centre; SD: standard deviation; SPECT: single photon emission computed tomography.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author RW upon reasonable request and with permission of the institution where measurement data was acquired.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by Maastricht University Medical Center and the Belgian Nuclear Research Centre.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRW, MB, CSV, MG, FMM and JEW contributed to the conception and design of the study. RW, CSV, INAP, SMBP, MS, WJ, AV, FHPV, SLMV and PC acquired (part of) the radionuclide calibrator data. CSV and SP determined the reference activity of the samples. CSV, RW and MB analyzed and interpreted the intercomparison data and drafted the manuscript. All authors critically revised the manuscript. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors kindly thank IDB Holland for providing \u003csup\u003e177\u003c/sup\u003eLu without charge, Andrew Fenwick (NPL) for the helpful discussions regarding the activity standardizations, Reid Townson (National Research Council Canada) for providing simulation data on the reference chambers energy dependence, Mikael Hult (JRC) for logistic support, and GE Healthcare for providing packing materials without charge.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eRadiation Protection Dosimetry and Calibrations, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium; [email protected]. \u003csup\u003e2\u003c/sup\u003eIn vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel, Jette, Belgium. \u003csup\u003e3\u003c/sup\u003eDepartment of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands. \u003csup\u003e4\u003c/sup\u003eEuropean Commission, Joint Research Centre (JRC), Geel, Belgium. \u003csup\u003e5\u003c/sup\u003eDepartment of Radiology, Nuclear Medicine and Anatomy, Radboudumc, Nijmegen, The Netherlands. \u003csup\u003e6\u003c/sup\u003eDepartment of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. \u003csup\u003e7\u003c/sup\u003eDepartment of Nuclear Medicine, University of Duisburg-Essen, Essen, Germany. \u003csup\u003e8\u003c/sup\u003eDepartment of Nuclear Medicine, University Hospital RWTH Aachen University, Aachen, Germany. \u003csup\u003e9\u003c/sup\u003eDepartment of Radiology, Leiden University Medical Center, Leiden, The Netherlands. \u003csup\u003e10\u003c/sup\u003eDepartment of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEberlein U, Cremonesi M, Lassmann M. Individualized dosimetry for theragnostics: necessary, nice to have, or counterproductive? J Nucl Med. 2017;58:97S-103S.\u003c/li\u003e\n\u003cli\u003eHerrmann K, Schwaiger M, Lewis JS, Solomon SB, McNeil BJ, Baumann M, et al. Radiotheranostics: a roadmap for future development. Lancet Oncol. 2020;21(3):e146-e156. doi:10.1016/S1470-2045(19)30821-6.\u003c/li\u003e\n\u003cli\u003eCRC-25R owner\u0026rsquo;s manual. Florham Park: Capintec Inc; 2017.\u003c/li\u003e\n\u003cli\u003eLaedermann JP, Valley JF, Bulling S, Bochud FO. Monte Carlo calculation of the sensitivity of a commercial dose calibrator to gamma and beta radiation. Med Phys. 2004;31(6):1614-1622.\u003c/li\u003e\n\u003cli\u003eGadd R, Baker M, Nijran KS, Owens S, Thomson W, Woods MJ, et al. Protocol for establishing and maintaining the calibration of medical radionuclide calibrators and their quality control, measurement good practice guide no. 93. Teddington: National Physical Laboratory; 2006.\u003c/li\u003e\n\u003cli\u003eQuality assurance for radioactivity measurement in nuclear medicine, Technical reports series no 454. Vienna: International Atomic Energy Agency; 2006.\u003c/li\u003e\n\u003cli\u003eBusemann Sokole E, Plachc\u0026iacute;nska A, Britten A; EANM Physics Committee. Acceptance testing for nuclear medicine instrumentation. Eur J Nucl Med Mol Imaging. 2010;37:672-681.\u003c/li\u003e\n\u003cli\u003eThe selection, use, calibration and quality assurance of radionuclide calibrators used in nuclear medicine, Report of AAPM Task Group 181. College Park: American Association of Physicists in Medicine; 2012.\u003c/li\u003e\n\u003cli\u003eSaldarriaga Vargas C, Rodr\u0026iacute;guez P\u0026eacute;rez S, Baete K, Pomm\u0026eacute; S, Paepen J, Van Ammel R, et al. Intercomparison of \u003csup\u003e99m\u003c/sup\u003eTc, \u003csup\u003e18\u003c/sup\u003eF and \u003csup\u003e111\u003c/sup\u003eIn activity measurements with radionuclide calibrators in Belgian hospitals. Phys Med. 2018;45:134-142.\u003c/li\u003e\n\u003cli\u003eBauwens M, Pooters I, Cobben R, Vissera M, Schnerra R, Mottaghy F, et al. A comparison of four radionuclide dose calibrators using various radionuclides and measurement geometries clinically used in nuclear medicine. Phys Med. 2019;60:14-21.\u003c/li\u003e\n\u003cli\u003eBailey DL, Hofman MS, Forwood NJ, O\u0026rsquo;Keefe GJ, Scott AM, van Wyngaardt WM, et al. Accuracy of dose calibrators for \u003csup\u003e68\u003c/sup\u003eGa PET imaging: unexpected findings in a multicenter clinical pretrial assessment. J Nucl Med. 2018;59(4):636-638.\u003c/li\u003e\n\u003cli\u003eFerreira KM, Fenwick AJ. \u003csup\u003e123\u003c/sup\u003eI intercomparison exercises: Assessment of measurement capabilities in UK hospitals. Appl Radiat Isot. 2018;134:108-111.\u003c/li\u003e\n\u003cli\u003eFenwick A, Baker M, Ferreira K, Keightley J. Comparison of \u003csup\u003e90\u003c/sup\u003eY and \u003csup\u003e177\u003c/sup\u003eLu measurement capability in UK and European hospitals. Appl Radiat Isot. 2014;87:10-13.\u003c/li\u003e\n\u003cli\u003eMacMahon D, Townley J, Bakhshandeiar E, Harms AV. Comparison of Tc-99m measurements in UK hospitals, 2006, NPL Report DQL-RN 018. Teddington: National Physical Laboratory; 2007.\u003c/li\u003e\n\u003cli\u003eCiocanel M, Keightley JD, Scott CJ, Woods MJ. Intercomparisons of \u003csup\u003e131\u003c/sup\u003eI solution and capsule sources in UK hospitals, 1999, NPL report CIRM 31. Teddington: National Physical Laboratory; 1999.\u003c/li\u003e\n\u003cli\u003eStokke C, Minguez Gabi\u0026ntilde;a P, Soln\u0026yacute; P, Cicone F, Sandstr\u0026ouml;m M, Sj\u0026ouml;green Gleisner K, et al. Dosimetry-based treatment planning for molecular radiotherapy: a summary of the 2017 report from the Internal Dosimetry Task Force. EJNMMI Phys. 2017;4(1):27. doi:10.1186/s40658-017-0194-3.\u003c/li\u003e\n\u003cli\u003eDetermination of the detection limit and decision threshold for ionizing radiation measurements \u0026mdash; Part 3: Fundamentals and application to counting measurements by high resolution gamma spectrometry, without the influence of sample treatment, EN ISO 11929-3:2000. Geneva: International Organization for Standardization; 2000.\u003c/li\u003e\n\u003cli\u003ePomm\u0026eacute; S. Methods from primary standardization of activity. Metrologia. 2007;44:17-26.\u003c/li\u003e\n\u003cli\u003eInjection Containers and Accessories. Injection Vials Made of Glass Tubing, EN ISO 8362-1:2009. Geneva: International Organization for Standardization; 2010.\u003c/li\u003e\n\u003cli\u003eBrookhaven National Laboratory, https://www.nndc.bnl.gov/nudat2/. Accessed 15 October 2020.\u003c/li\u003e\n\u003cli\u003eTownson R, Tessier F, Galea R. EGSnrc calculation of activity calibration factors for the Vinten ionization chamber. Appl Radiat Isot. 2018;134:100-104.\u003c/li\u003e\n\u003cli\u003ePeitl PK, Tomse P, Kroseli M, Socana A, Hojkera S, Pecar S, et al. Influence of radiation source geometry on determination of \u003csup\u003e111\u003c/sup\u003eIn and \u003csup\u003e90\u003c/sup\u003eY activity of radiopharmaceuticals. Nucl Med Commun. 2009;30(10):807-814.\u003c/li\u003e\n\u003cli\u003eBeattie BJ, Pentlow KS, O'Donoghue J, Humm JL. A recommendation for revised dose calibrator measurement procedures for \u003csup\u003e89\u003c/sup\u003eZr and \u003csup\u003e124\u003c/sup\u003e PLoS One. 2014; 9(9): e106868.\u003c/li\u003e\n\u003cli\u003eKowalsky RJ, Johnston RE. Dose calibrator assay of iodine-123 and indium-111 with a copper filter. J Nucl Med Technol. 1998;26(2):94-98.\u003c/li\u003e\n\u003cli\u003eGear JI, Cox MG, Gustafsson J, Sj\u0026ouml;green Gleisner K, Murray I, Glatting G, et al. EANM practical guidance on uncertainty analysis for molecular radiotherapy absorbed dose calculations. Eur J Nucl Med Mol Imaging. 2018;45(13):2456-2474.\u003c/li\u003e\n\u003cli\u003eFerreira KM, Fenwick AJ, Arinc A, Johansson LC. Standardization of \u003csup\u003e90\u003c/sup\u003eY and determination of calibration factors for \u003csup\u003e90\u003c/sup\u003eY microspheres (resin) for the NPL secondary ionization chamber and a Capintec CRC-25R. Appl Radiat Isot. 2016;109:226-230.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-physics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejph","sideBox":"Learn more about [EJNMMI Physics](http://ejnmmiphys.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejph/default.aspx","title":"EJNMMI Physics","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"activity measurement, radionuclide calibrator, accuracy, theranostics","lastPublishedDoi":"10.21203/rs.3.rs-41572/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-41572/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Personalized molecular radiotherapy based on theragnostics requires accurate quantification of the amount of radiopharmaceutical activity administered to patients both in diagnostic and therapeutic applications. This international multi-center study aims to investigate the clinical measurement accuracy of radionuclide calibrators for 7 radionuclides used in theragnostics: \u003csup\u003e99m\u003c/sup\u003eTc, \u003csup\u003e111\u003c/sup\u003eIn, \u003csup\u003e123\u003c/sup\u003eI, \u003csup\u003e124\u003c/sup\u003eI, \u003csup\u003e131\u003c/sup\u003eI, \u003csup\u003e177\u003c/sup\u003eLu and \u003csup\u003e90\u003c/sup\u003eY.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In total, 32 radionuclide calibrators from 8 hospitals located in the Netherlands, Belgium and Germany were tested. For each radionuclide, a set of four samples comprising two clinical containers (10-mL glass vial and 3-mL syringe) with two filling volumes were measured. The reference value of each sample was determined by two certified radioactivity calibration centers (SCK CEN and JRC) using two secondary standard ionization chambers. The deviation in measured activity with respect to the reference value was determined for each radionuclide and each measurement geometry. In addition, the combined systematic deviation of activity measurements in a theragnostic setting was evaluated for 5 clinically-relevant theragnostic pairs: \u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e123\u003c/sup\u003eI, \u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e124\u003c/sup\u003eI, \u003csup\u003e177\u003c/sup\u003eLu/\u003csup\u003e111\u003c/sup\u003eIn, \u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e99m\u003c/sup\u003eTc and \u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e111\u003c/sup\u003eIn.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e For\u0026nbsp;\u003csup\u003e99m\u003c/sup\u003eTc,\u0026nbsp;\u003csup\u003e131\u003c/sup\u003eI, and\u0026nbsp;\u003csup\u003e177\u003c/sup\u003eLu, a small minority of measurements were not within ±5% range from the reference activity (percentage of measurements not within range: \u003csup\u003e99m\u003c/sup\u003eTc: 6%,\u0026nbsp;\u003csup\u003e131\u003c/sup\u003eI: 14%,\u0026nbsp;\u003csup\u003e177\u003c/sup\u003eLu: 24%) and almost none were outside ±10% range. However, for\u0026nbsp;\u003csup\u003e111\u003c/sup\u003eIn,\u0026nbsp;\u003csup\u003e123\u003c/sup\u003eI,\u0026nbsp;\u003csup\u003e124\u003c/sup\u003eI and\u0026nbsp;\u003csup\u003e90\u003c/sup\u003eY more than half of all measurements were not accurate within ±5% range (\u003csup\u003e111\u003c/sup\u003eIn: 51%,\u0026nbsp;\u003csup\u003e123\u003c/sup\u003eI: 83%,\u0026nbsp;\u003csup\u003e124\u003c/sup\u003eI: 63%,\u0026nbsp;\u003csup\u003e90\u003c/sup\u003eY: 61%) and not all were within ±10% margin (\u003csup\u003e111\u003c/sup\u003eIn: 22%,\u0026nbsp;\u003csup\u003e123\u003c/sup\u003eI: 35%,\u0026nbsp;\u003csup\u003e124\u003c/sup\u003eI: 15%,\u0026nbsp;\u003csup\u003e90\u003c/sup\u003eY: 25%). A large variability in measurement accuracy was observed between radionuclide calibrator systems, type of sample container (vial\u0026nbsp;\u003cem\u003evs\u003c/em\u003e\u0026nbsp;syringe), and source-geometry calibration/correction settings used. Consequently, we observed large combined deviations (percentage deviation \u0026gt; ±10%) for the investigated theragnostic pairs, in particular for\u0026nbsp;\u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e111\u003c/sup\u003eIn,\u0026nbsp;\u003csup\u003e131\u003c/sup\u003eI/\u003csup\u003e123\u003c/sup\u003eI and\u0026nbsp;\u003csup\u003e90\u003c/sup\u003eY/\u003csup\u003e99m\u003c/sup\u003eTc.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Our study shows that substantial over- or under-estimation of therapeutic patient doses are likely to occur in a theragnostic setting due to errors in the assessment of radioactivity with radionuclide calibrators. These findings underline the importance of thorough validation of radionuclide calibrator systems for each clinically-relevant radionuclide and sample geometry.\u003c/p\u003e","manuscriptTitle":"An international multi-center investigation on the accuracy of radionuclide calibrators in nuclear medicine theranostics","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2020-11-11 10:33:49","doi":"10.21203/rs.3.rs-41572/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2020-11-09T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-11-04T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-11-03T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-11-03T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-physics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejph","sideBox":"Learn more about [EJNMMI Physics](http://ejnmmiphys.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejph/default.aspx","title":"EJNMMI Physics","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-07-16 19:18:14","doi":"10.21203/rs.3.rs-41572/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2020-09-25T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-09-16T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2020-08-31T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-08-20T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2020-08-14T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-08-12T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-07-15T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-07-15T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-07-14T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-07-09T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-physics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejph","sideBox":"Learn more about [EJNMMI Physics](http://ejnmmiphys.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejph/default.aspx","title":"EJNMMI Physics","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"33f028bf-725f-4cce-a30f-47ba6ee55347","owner":[],"postedDate":"November 11th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":167728,"name":"Nuclear Medicine \u0026 Medical Imaging"}],"tags":[],"updatedAt":"2020-11-29T15:04:10+00:00","versionOfRecord":{"articleIdentity":"rs-41572","link":"https://doi.org/10.1186/s40658-020-00338-3","journal":{"identity":"ejnmmi-physics","isVorOnly":false,"title":"EJNMMI Physics"},"publishedOn":"2020-11-23 15:02:35","publishedOnDateReadable":"November 23rd, 2020"},"versionCreatedAt":"2020-11-11 10:33:49","video":"","vorDoi":"10.1186/s40658-020-00338-3","vorDoiUrl":"https://doi.org/10.1186/s40658-020-00338-3","workflowStages":[]},"version":"v2","identity":"rs-41572","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-41572","identity":"rs-41572","version":["v2"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}