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Determination of gamma camera calibration factors for quantitation of therapeutic radioisotopes Zhao, Wei; Esquinas, Pedro L; Hou, Xinchi; Uribe, Carlos F; Gonzalez, Marjorie; Beauregard, Jean-Mathieu; Dewaraja, Yuni K; Celler, Anna May 2, 2018

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ORIGINAL RESEARCH Open AccessDetermination of gamma cameracalibration factors for quantitation oftherapeutic radioisotopesWei Zhao1,2* , Pedro L. Esquinas1,2, Xinchi Hou2, Carlos F. Uribe3, Marjorie Gonzalez4, Jean-Mathieu Beauregard5,6,Yuni K. Dewaraja7 and Anna Celler2* Correspondence: wzhao910@phas.ubc.ca1Department of Physics andAstronomy, University of BritishColumbia, Vancouver, BC, Canada2Medical Imaging Research Group,Department of Radiology, Universityof British Columbia, Vancouver, BC,CanadaFull list of author information isavailable at the end of the articleAbstractBackground: Camera calibration, which translates reconstructed count map intoabsolute activity map, is a prerequisite procedure for quantitative SPECT imaging.Both planar and tomographic scans using different phantom geometries have beenproposed for the determination of the camera calibration factor (CF). However, thereis no consensus on which approach is the best. The aim of this study is to evaluateall these calibration methods, compare their performance, and propose a practicaland accurate calibration method for SPECT quantitation of therapeutic radioisotopes.Twenty-one phantom experiments (Siemens Symbia SPECT/CT) and 12 Monte Carlosimulations (GATE v6.1) using three therapy isotopes (131I, 177Lu, and 188Re) havebeen performed. The following phantom geometries were used: (1) planar scans ofpoint source in air (PS), (2) tomographic scans of insert(s) filled with activity placed innon-radioactive water (HS + CB), (3) tomographic scans of hot insert(s) in radioactivewater (HS + WB), and (4) tomographic scans of cylinders uniformly filled with activity(HC). Tomographic data were reconstructed using OSEM with CT-based attenuationcorrection and triple energy window (TEW) scatter correction, and CF was determinedusing total counts in the reconstructed image, while for planar scans, the photopeakcounts, corrected for scatter and background with TEW, were used. Additionally, forsimulated data, CF obtained from primary photons only was analyzed.Results: For phantom experiments, CF obtained from PS and HS + WB agreed towithin 6% (below 3% if experiments performed on the same day are considered).However, CF from HS + CB exceeded those from PS by 4–12%. Similar trend was foundin simulation studies. Analysis of CFs from primary photons helped us to understandthis discrepancy. It was due to underestimation of scatter by the TEW method, furtherenhanced by attenuation correction. This effect becomes less important when thesource is distributed over the entire phantom volume (HS + WB and HC).Conclusions: Camera CF could be determined using planar scans of a point source,provided that the scatter and background contributions are removed, for exampleusing the clinically available TEW method. This approach is simple and yet provides CFwith sufficient accuracy (~ 5%) to be used in clinics for radiotracer quantification.Keywords: Gamma camera calibration, TEW, Quantification, Iodine-131, Lutetium-177,Rhenium-188EJNMMI Physics© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 InternationalLicense (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, andindicate if changes were made.Zhao et al. EJNMMI Physics  (2018) 5:8 https://doi.org/10.1186/s40658-018-0208-9BackgroundIn single-photon emission computed tomography (SPECT), quantification of radio-tracer distribution has recently become an increasingly important component of manyclinical studies [1, 2]. In particular, quantitative SPECT can be very helpful in the diag-nosis of multi-vessel heart disease and assessment of myocardial blood flow reserve [3],as well as in quantitative evaluation of the lungs, kidneys, brain [4] and other organs.However, the most important role activity quantitation has to play is in the targetedradionuclide therapies (TRT) [5]. The assessment of tumor burden, prediction of po-tentially critical organs and normal tissue toxicities, and calculation of the radiationdose are all necessary elements of the personalized, image-based therapy planning aswell as evaluation of patient’s response to this therapy. They all require accurate absolutequantification of the amount of the radioactive material that is localized in tumor(s) andcritical organs and characterization of its changes over time (biokinetics) [6, 7].There are three essential steps, which have to be performed for quantification ofSPECT images. The first step involves quantitative SPECT reconstructions. Since thedata acquired in projections are affected by physical phenomena such as photonattenuation and scatter, collimator blurring, camera dead-time and partial volume ef-fects; in order to get quantitatively accurate images, all these factors must be properlycompensated for during the reconstruction process. Fortunately, in the past few de-cades, considerable technical advancement has been achieved in both SPECT hardwareand data processing software. Particularly, with the introduction of hybrid SPECT/CTimaging systems and the development of statistical iterative reconstruction algorithms,quantitative reconstructions have become available for the majority of the commercialSPECT/CT cameras [8–10].The second step is to apply camera calibration factor (CF) to the reconstructed images,which will translate the three-dimensional (3D) count maps into 3D activity maps. It isimportant to stress at this point that CF provides only a numerical coefficient necessaryfor this “translation”. The value of CF depends on the energy of the measured photons;therefore, it is radioisotope specific and represents the joint sensitivity of the camera andthe collimator for detection of a particular isotope’s emissions in the energy window(s)that is used for data acquisition. Please note that the value of CF might be influenced bythe potential errors in dose calibrator readings when measuring the activity.Finally, in order to obtain a quantitative value of the activity contained in any particu-lar volume of tissue (for example in an organ or a tumor), the third step involving seg-mentation of this activity map must be performed. As segmented volumes will beaffected by partial volume effects (PVE), for accurate activity quantification, appropriatePVE correction methods must be applied [11]. For example, one such method wouldbe to use experimentally determined recovery coefficients (RC) [12, 13].The most reliable method to determine CF of the camera is to perform an experi-mental measurement using an accurately calibrated radioactive source. Consideringthat quantitative reconstruction methods generate images from primary photons (PP)(as quantitative reconstruction has already removed the scattered photons and cor-rected for losses due to attenuation), CF must relate these PP images to the activitywhich produced them.Different camera calibration methods have been proposed, but there is still no con-sensus which method is the best. Some researchers use planar scans of a small (point-Zhao et al. EJNMMI Physics  (2018) 5:8 Page 2 of 16like) source (PS) placed in air at a certain distance (usually 20–30 cm) from the colli-mator surface [14–19]. This is a simple method where the CF is directly calculatedfrom the acquired planar images. Care must be taken, however, that photon scatter isaccounted for and that attenuation in the source and source support are minimized.Different small-volume geometries ranging from a vial to a syringe [15, 18]and a smallcontainer [14] to a petri dish (following NEMA protocol for camera sensitivity test[19]) have been employed. Some researchers even performed tomographic scans ofsuch a point source [16]; however, it is not clear what would be the advantage of suchacquisition.Alternatively, tomographic scans of large cylindrical phantoms containing accuratelymeasured amounts of radioactive materials have been proposed [12, 13, 20–26]. Thisapproach is more cumbersome, especially when radioisotopes with long half-livesare used. However, its rationale is that the geometry of the extended calibrationphantom better models the body of a patient and the physical effects (photonattenuation and scatter) which occur in patients’ acquisitions. Therefore, all ap-proximations (and potential inaccuracies) due to the clinical reconstruction methodwhich may affect the accuracy of patient images will be replicated in the recon-structed images of the calibration phantom. The geometries which have been usedin the extended phantom experiments can be divided into three categories: (a)small container(s) filled with activity (hot sources (HS)) placed in the large cylinderfilled with non-radioactive water (cold background (CB)) [13, 22, 23, 26], (b) smallcontainer(s) with activity placed in the large cylinder filled with radioactive water(warm background (WB)) [21], and (c) large cylinders with no inserts, filleduniformly with activity (hot-cylinder (HC)) [12].The purpose of the present study is to evaluate all these methods, compare theirperformance and check if, and under what conditions, the planar calibration andtomographic calibration produce equivalent results. A large series of phantomexperiments, as well as extensive simulation studies, have been performed. Theobjective of the simulations (done with GATE Monte Carlo program [27]) was togenerate the true CF values, and to investigate and understand the physical effects,which may be responsible for the discrepancies observed between CFs obtainedusing different experimental methods. Three popular therapeutic radioisotopes(emitting beta particles and also gamma radiation) were investigated, namely, 131I,177Lu and 188Re.MethodsOur study was composed of two parts: (1) phantom experiments and (2) Monte Carlosimulations. In both parts, 131I, 177Lu and 188Re radioisotopes were used, and in total,21 experimental scans and 12 simulation runs were performed. The information aboutthe isotopes’ half-lives, their most intensive gamma emissions and maximum and meanenergy of their beta emission, is provided in Table 1.Phantom experimentsFor each isotope, the data were acquired using the following three experimental config-urations (see Fig. 1 and Table 2):Zhao et al. EJNMMI Physics  (2018) 5:8 Page 3 of 16A. Planar acquisition of a small source suspended in air (PS; Table 2: experiments #1,#6–7, and #15–17)B. Tomographic (SPECT/CT) acquisition of hot inserts (spheres and/or cylinders)placed in non-radioactive water (HS + CB; Table 2: experiments #2–3, #8–9, and#18–19)C. Tomographic (SPECT/CT) acquisition of the same set of hot inserts placed inradioactive water (HS + WB; Table 2: experiments #4–5, #10–13, and #20–21)Additionally, for 177Lu, the following fourth configuration was used:D. Tomographic (SPECT/CT) acquisition of a cylindrical phantom filled with uniformactivity (HC; Table 2: experiment #14)All data acquisitions were performed using Symbia SPECT/CT cameras (SiemensHealthineers, Germany). The acquisitions #6–13 for 177Lu and #15–21 for 188Re wereperformed at the Vancouver General Hospital, Nuclear Medicine Department, Vancouver(Canada). Experiments with 131I (acquisitions #1–5) were done at the Department ofRadiology, University of Michigan Medical School, Ann Arbor (USA). And finally, the177Lu acquisition #14 was performed at the Department of Radiology and NuclearMedicine, Université Laval, Quebec (Canada). The acquisition conditions, theTable 1 Decay characteristics of 131I [34], 177Lu [35], and 188Re [36]Isotope Half-life Strongest γ emissionsEγ [keV] (Iγ [%])aMean β energyEmean [keV]Max β energyEmax [keV]131I 8.03 days 284 (6.1) 181.9 970.8364 (81.5)637 (7.2)723 (1.8)177Lu 6.65 days 113 (6.2) 134.2 498.3208 (10.4)188Re 17.00 h 155 (15.6) 763 2120.4478 (1.1)633 (1.4)aOnly gammas with intensities higher than 1% were listedFig. 1 Examples of experimental configurations used in planar (a) and tomographic (b) acquisitionsZhao et al. EJNMMI Physics  (2018) 5:8 Page 4 of 16camera model, the collimators, and the total activities used in the experiments arespecified in Table 2.For experiments performed using configuration A, the volume of the point sourcewas always equal to or less than 1 mL. In each case, a syringe containing the pointsource was suspended in air between the detectors and it was equally spaced from eachcollimator surface (Fig. 1a and Table 2). The scan duration ranged from 5 to 20 min.For tomographic acquisitions, cylindrical phantoms with hot spherical and/orcylindrical inserts were used (Fig. 1b and Table 2). The total volume of the hot insertsvaried between experiments and ranged from 58 to 560 mL, while the volume of thecylinder was about 6 L (Jaszczak phantom) and 10 L (Elliptical Thorax phantom). Inthe experiments where inserts were placed in the hot background, the ratio of sphereto background activity concentration was always close to 6:1 (which corresponds tothat often observed in clinical studies).For each phantom configuration and each experiment, the total activity in thephantom was sufficiently low that the camera did not display any dead timeeffects. For all scans, the projection data were acquired in three abutting energywindows, namely the 20% photopeak window (PW), the lower scatter window(LSW) and the upper scatter window (USW). The data in these three windowswere subsequently used to perform triple energy window (TEW) scatter correction.The acquisition times ranged from 8 to 40s per projection with a total of 60–96projection (30–48 camera stops). Table 3 provides energy window settings used inTable 2 Parameters of acquisitions and source activities used in phantom experimentsExperimentnumberIsotope Camera andcollimatorNumber ofprojectionsExperimentalconfigurationTotal phantomactivity [MBq]Source-collimatordistance [cm]1 131I Symbia T and HE 1 A ➔ PS 24.35 252 60 B ➔ HS + CB 16.02 Non-circular orbit3 20.764 C ➔ HS + WB 89.545 203.866 177Lu Symbia T and ME 1 A ➔ PS 11.70 367 13.10 358 90 B ➔ HS + CB 446.79 Non-circular orbit9 277.5010 C ➔ HS + WB 681.2611 489.0812 2486.6013 2459.8914 96 D ➔ HC 659.6015 188Re Symbia T and HE 1 A ➔ PS 14.15 3016 16.25 1317 119.02 1318 90 B ➔ HS + CB 664.0 Non-circular orbit19 554.020 C ➔ HS + WB 491.021 1193.0Zhao et al. EJNMMI Physics  (2018) 5:8 Page 5 of 16our experiments and simulations (for 177Lu, only the 208 keV photopeak wasused).Monte Carlo simulation experimentsThe Geant4 Applications for Tomographic Emission (GATE version 6.1 [27]) MonteCarlo code was used for the simulated experiments. The Siemens SymbiaT dual headSPECT imaging system was modeled. The system geometry (detector, collimator andshielding) used in our simulations was identical to that described and validated in ourprevious study [28].The emission energy spectra of the three isotopes, which have complex decayschemes, are built-in into GATE and included accurate modeling of β− and gammaemissions. The simulated radionuclides were distributed uniformly within their respect-ive source volume, as described in the next paragraph.For each radionuclide, four phantom configurations (analogous to those used in theexperiments) were simulated:I. Point source (1-mL sphere) in airII. 100-mL spherical source placed in the center of a cylinder filled with non-radioactive waterIII.100-mL spherical source placed in the center of a cylinder filled withradioactive waterIV.Cylinder filled with uniform activityIn all simulation experiments, the phantoms were placed at the center of the field ofview (FOV) of the camera. The distance from the source to each of the collimatorsurfaces was equal to 25 cm. The cylindrical phantom used in these simulations hadthe same dimensions as that used in the experiments. Although multiple inserts withdifferent sizes were used in the phantom experiments, while only a single sphere wasused in the simulations, the characteristics of photons recorded by the camera whenusing this simple phantom model were very similar to those from the experiments,providing us with information sufficient to explain discrepancies in CF valuesobtained by different methods.The total number of decays (Ntot) simulated for each phantom configuration and cor-responding activities (assuming in each case 5 min acquisition time) are listed in Table 4(Ntot was selected so that the total number of photons detected in PW was more thanTable 3 Energy window settings for 131I [37], 177Lu [38], and 188Re [39] used in the experimentalacquisitions and in the simulationsIsotope Photopeak window (PW)[keV]Lower scatter window (LSW)[keV]Upper scatter window (USW)[keV]Center Range Center Range Center Range131I 364 328–400 317 306–328 411 400–422177Lua 208 187–229 167 146–187 249 229–270188Re 155 140–171 136 132–140 175 171–178aFor experiments acquired at Quebec (experiment D), the range of LSW and USW were 166–187 and229–250, respectivelyZhao et al. EJNMMI Physics  (2018) 5:8 Page 6 of 1615,000 in order to ensure errors are < 1%). For each simulation experiment, the projec-tion images corresponding to the true primary photons and the total photons recordedin the photopeak window (PW), as well as those recorded in the two scatter windows(LSW and USW), were generated.For all phantom configurations, only one planar projection was simulated for each ofthe photopeak windows (PW) and for each of the two scatter energy windows (LSWand USW). Benefiting from the cylindrical symmetry of the simulated phantoms, thetomographic images were created by replicating these single projections 90 times withPoisson noise added to the data.Image reconstructionThe images from the experimentally acquired tomographic projection datasets, as wellas these from simulations, were reconstructed using in-house developed software pack-ages (MIRG software [29] for 177Lu and 188Re, UM software [30] for 131I). In all cases,the OSEM algorithm (see Table 5 for details), with CT-based attenuation correctionand TEW scatter correction [31, 32], was employed.Additionally, 177Lu datasets were reconstructed using the Siemens software availableon the camera (Flash3D) [20]. By definition, these reconstructions included resolutionrecovery (RR) correction. This correction, however, should have no effect on the totalnumber of counts recorded in the reconstructed image. Therefore, CFs obtained fromimages reconstructed with and without RR should be considered to be equivalent. Inall cases, the matrix size was 128 × 128 × 128 with the pixel size equal to 4.79 mm.Table 4 Total number of decays used in the simulation experiments. Additionally, for eachradioisotope, activities (in MBq) corresponding to these simulations, assuming 5-min acquisitiontimes, are provided (in brackets)Ntot (total activity [MBq])Isotope Conf. A ➔ PS Conf. B ➔ HS + CB Conf. Ca ➔ HS + WB Conf. D ➔ HC131I 5E8 (1.7) 1E9 (3.3) Sphere 2.6E8 (0.9) 3E9 (10)Bkg 2.7E9 (9)177Lu 1E9 (3.3) 2E9 (6.7) Sphere 1.7E9 (5.7) 2E10 (66.7)Bkg 1.8E10 (60)188Re 3.5E8 (1.2) 2E9 (6.7) Sphere 1.1E9 (3.7) 1.2E10 (40)Bkg 1.2E10 (40)aThe number in decays in the sphere and the background was specified so that the ratio of activity concentrations wasequal to 6Table 5 Parameters used in the reconstructions of images from experimental and simulatedtomographic data (experiments performed using configurations HS + CB, HS + HB and HC)Isotope Reconstruction Iterations Subsets131I UM Software [30] 35 6177Lua MIRG qSPECT [29] 6 10Siemens Flash3D [20] 6 10188Re MIRG qSPECT [29] 6 10aFor the reconstruction of phantom experiment D (performed at Quebec), 12 subsets which were used as thetomographic data were collected with 96 projectionsZhao et al. EJNMMI Physics  (2018) 5:8 Page 7 of 16Moreover, for each isotope and each phantom configuration, the images were recon-structed from the simulated data corresponding to the primary photons only. In thiscase, no scatter correction was required so only attenuation correction was included inthe reconstruction. The attenuation maps used in all reconstructions of the simulateddata were generated using cylindrical phantom shapes filled with narrow-beam attenu-ation coefficients.Determination of camera calibration factorThe camera calibration factor (CF) can be determined using the following generalformula:CF ¼ CA tð1Þwhere C is the number of photons emitted by the source having the activity A and re-corded by the camera in time t. This general formula formed the bases of all our dataprocessing; the details of calculations are summarized in Table 6. For simulated data,the product of activity and time was replaced by the total number of decays.Planar acquisitions (experimental and simulated configurations—PS)For planar acquisitions, the CF was directly calculated from the acquired planar images;no reconstruction was required. The counts collected in the entire field of view of thecamera were employed and CPWSC corresponding to the PW counts corrected forscatter using the TEW method was used.Table 6 Techniques used in CF determination from the experimental and simulated dataConfig. CF DefinitionsCounts Time ActivityPhantom experimentsA CFPWSC Count in PW corrected for scatterusing TEW: CPWSCScan time: t Small sourceactivity: AB CFBR Total counts in the imagereconstructed with AC + SC: CRNumber of projectionsmultiplied by the projectionduration: nptpTotal activity inspheres: AC CFCR Total phantomactivity(spheres+bkg): AD CFDR Total activity inphantom: ASimulation experimentsA CFPWSCsim Count in PW corrected for scatter usingTEW: CPWSCsimTotal number of simulated decays: NtotCFPPsim Primary photons simulated in PW: CPPsimB CFBRsim Total counts in the image that wasreconstructed from PW with AC + SC: CRsimNumber of projections multiplied by numberof decays simulated in each projection: npNtotCFBRPPsim Total counts in the image reconstructedfrom primary photons only with AC: CRPPsimC CFCRsim Total counts in the image that wasreconstructed from PW with AC + SC: CRsimCFCRPPsim Total counts in the image reconstructedfrom primary photons only with AC: CRPPsimD CFDRsim Total counts in the image that wasreconstructed from PW with AC + SC: CRsimZhao et al. EJNMMI Physics  (2018) 5:8 Page 8 of 16Additionally, our simulated data provided us with the estimate of the number ofprimary photons. This allowed us to calculate CPPsim (the “true” CF), which was notaffected by approximations related to the TEW scatter correction.Tomographic acquisitions (experimental and simulated configurations—HS + CB, HS +HB and HC)For tomographic phantom experiments, the total numbers of counts, summed over theentire 3D image, were used to determine the CFs corresponding to each isotope andeach phantom configuration.Additionally, for simulated data, the CF factors were calculated using the imagesreconstructed from primary photons only (see Table 6).In Table 6, the CF symbols corresponding to the values obtained from planar data aremarked with subscript PW for “photopeak window” and PWSC for “photopeak windowscatter corrected”; CF obtained from tomographic data are marked with subscript R for“reconstructed” and superscript B, C or D indicating configuration of the phantom. Fur-thermore, the CF obtained from simulated data was labeled with subscript sim, whileCF calculated from primary photons only are additionally marked with subscript PP.ResultsFigure 2 presents the energy spectra for the three investigated radioisotopes, generatedby our GATE simulations. The phantoms used in these simulations corresponded to apoint source scanned in air (blue line), a 100-mL sphere filled with activity placed atthe center of a cylinder filled with cold (black line) and warm (red line) water.Tables 7 and 8 summarize the CF values obtained using all planar and tomographicconfigurations (as outlined in Table 6) from simulations and phantom experiments, re-spectively. Additionally, these results are presented in a graphical form in Figs. 3 and 4.Since the CF values for 177Lu data obtained from MIRG and Siemens reconstructionsagreed to within 3%, only CF from MIRG reconstructions were used in the subsequentanalysis.In order to facilitate comparison of CFs obtained from different experiments withdifferent phantom configurations, the CF values in Figs. 3 and 4 are presented in rela-tive units. For simulated data, shown in Fig. 4a, CF obtained from primary photonsrecorded in the photopeak window of the planar acquisition of a point source wereconsidered to be the “true” CF values and were set to 1. For the experimental dataFig. 2 Simulated energy spectra as would be acquired by the SPECT camera from emissions of 131I, 177Lu,and 188Re. For each isotope, a point source scanned in air (blue line) and a 100-mL hot sphere placed atthe center of a 20-cm diameter cylindrical phantom filled with non-radioactive water (black line) and warm(red line) water were simulatedZhao et al. EJNMMI Physics  (2018) 5:8 Page 9 of 16presented in Fig. 3 and for simulations shown in Fig. 4b, the data were normalizedusing counts in the planar acquisition of a point source corrected for scatter, i.e.CFPWSC and CFPWSCsim, respectively.DiscussionThe spectra presented in Fig. 2 allow us to evaluate the contribution of scatteredphotons to the photopeak energy window for different phantom configurations. Whilescatter component in point source (PS) scans of 177Lu is relatively low, for 131I and188Re, the photons from high-energy gamma transitions, which were scattered mostlyin the camera and its components, substantially increase the background. This observa-tion supports our claim that scatter correction should be performed when CF is derivedfrom the data obtained using planar scans of point sources. The scatter correctionmethod, which is the most popular in clinics, is TEW. Besides being simple and easy toimplement, TEW allows us to correct not only for self-scattered photons, but also forhigh-energy scatter and other background.Further analysis of the data presented in Fig. 2 confirms that scatter correctionshould be included in all tomographic image reconstructions. All energy spectra for HS+ CB and HS + WB phantom configurations that were used in our tomographic acqui-sitions, and which model patient scans better than point sources, display large scatterbackground under the photopeaks.Table 7 Experimental camera CF determined using different phantom configurationsExperiment number Isotope Experimental configuration CF [cps/MBq] Mean CF value [cps/MBq]1 131I A ➔ PS 58.32 58.32 B ➔ HS + CB 59.94 60.53 61.104 C ➔ HS + WB 56.91 55.05 53.056 177Lu A ➔ PS 9.94 9.47 8.938 B ➔ HS + CB 11.04 10.59 9.8710 C ➔ HS + WB 9.75 9.511 9.6812 9.8413 8.9014 D ➔ HC 10.10 10.115 188Re A ➔ PS 15.8 16.516 17.5617 15.9918 B ➔ HS + CB 18.64 18.519 18.2620 C ➔ HS + WB 15.09 15.521 15.95Zhao et al. EJNMMI Physics  (2018) 5:8 Page 10 of 16For all isotopes (131I, 177Lu and 188Re), the experimental CFs (summarized in Fig. 3and Table 7) show relatively good agreement between CFPWSC obtained from planarscans corrected for scatter and CFCR obtained from tomographic scans performed usinghot sources placed in warm background (HS + WB). These CF values agree to within6%. The agreement usually improves (to below 3%) when CF obtained from the experi-ments performed on the same day are considered. This improvement may be attributedto the fact that for the same-day experiments, all errors in activity determination areminimized, as the activity measurements are performed using the same vial and samedose calibrator settings. However, the differences between CFPWSC and CFBR (HS + CB)values are much larger, for 177Lu and 188Re even reaching 12%.The explanation of all these effects can be provided by the analysis of our MC simu-lation results. Firstly, as expected, when considering only primary photons, for allradioisotopes, CFs obtained from planar scans (CFPPsim) and those reconstructed fromtomographic data (with attenuation correction) agree to within 1–3% (see Table 8 andFig. 4a). Such small differences may be caused by statistical fluctuations and smallapproximations in attenuation correction used in reconstructions of simulated tomo-graphic data (voxelized attenuation maps were used in reconstructions, while in GATEanalytical shapes are used).However, larger discrepancies, similar to those observed in experimental data, arefound when comparing CFs obtained from simulated PS scans corrected for scatterCFPWSCsim and simulated tomographic scans (Table 8 and Fig. 4b). The differencesbetween CFPWSCsim and both CFCRsim and CFDRsim remain below 5%, while CFCRsim andCFDRsim agree with each other to within 1%. However, the differences between CFPWSCsimand CFBRsim increase to 12–16%. These effects are caused by the approximations of theTEW scatter correction method, which can be visualized when considering the shapesof the profiles presented in Fig. 5.Table 8 Camera CF obtained using simulated dataIsotope Configuration A [cps/MBq]Configuration B [cps/MBq]Configuration C [cps/MBq]Configuration D [cps/MBq]CFPWSCsim CFPPsim CFBRsim CFBRPPsim CFCRsim CFCRPPsim CFDRsim CFDRPPsim131I 65.74 66.51 69.23 65.55 67.05 67.63 66.54 67.04177Lu 11.18 11.33 12.44 11.32 11.49 11.59 11.51 11.54188Re 17.60 18.37 20.47 17.98 18.29 18.77 18.51 18.98Fig. 3 Summary of CF obtained experimentally using different phantom configurations. The data werenormalized using counts in the planar acquisition of a point source corrected for scatter with TEWZhao et al. EJNMMI Physics  (2018) 5:8 Page 11 of 16Simulated spectra presented in Fig. 5 correspond to the phantom configuration B(HS + CB). The graphs compare the shapes of the photopeak, the true scatter compo-nent observed in PW and the scatter estimated by the TEW method using countsrecorded in LSW + USW. Counts in the three regions were analyzed. Spectra presentedin Fig. 5b correspond to counts recorded in the source ROI, and Fig. 5a shows the loca-tion of the source ROI drawn in the projection images of each isotope. Spectra in Fig. 5ccorrespond to counts recorded in the background region around the source, and Fig. 5dFig. 4 Summary of CF obtained from simulated phantom experiments performed using different phantomconfigurations. a shows CFs obtained from primary photons only normalized using CFPPsim, while CFsshown in b were calculated using total counts recorded in the photopeak window corrected for scatterwith TEW and normalized using CFPWSCsimFig. 5 The energy spectra obtained from the simulations of the phantom scanned in configuration B (HS + CB).The counts recorded in the photopeak window and correspond to the ROI drawn on the projection images:around the hot object (column b), in the background surrounding this ROI (column c), and in the entire image(column d). Column a shows the simulated PW projections. The hot object ROI was placed inside the red circlewhile the background ROI comprised all counts found on the outside of the red circleZhao et al. EJNMMI Physics  (2018) 5:8 Page 12 of 16shows spectra of counts recorded in the entire image (these counts were used for theCF determination). Please note that Fig. 5c for 131I contains a small peak correspondingto septal penetration of the collimator by 364 keV photons.The analysis of these graphs clearly demonstrates that for all isotopes, the TEWmethod (area under the red line) underestimates the true scatter (marked by the blueline) in the source ROI region while overestimates it in the background region. As aresult, the source region seems to have more counts, while counts in the backgroundaround the source seem to be lower than they should be. This “surplus” is furtherenhanced by the attenuation correction, which boosts the excess of counts in thesource region, because it is located in the center of the phantom where attenuation cor-rection is the highest.On the other hand, when scatter correction is done by subtracting projections, beforeimage reconstruction, the overestimation of scatter counts in the background maypotentially create negative counts. However, in our reconstructions, these negativecounts could not occur because the TEW scatter estimate was included in the denom-inator of the OSEM formula. As a result, the total number of reconstructed countsused for CF calculation is higher than the truth and also higher than that determinedfrom planar scans. This effect is relatively smaller for phantom configurations in whichactivity is distributed over the entire phantom (HS + WB and HC).Additionally, please note that although CFs determined experimentally and obtainedfrom simulations are quite similar, CF from simulations exceed experimental values by3–10%. In our opinion, these differences should be attributed to approximations madein the simulated camera model [28] and inaccuracies in dose calibrator measurementsof source activities.At this point, it is important to emphasize that the CF value, as defined in our study,corresponds purely to the camera efficiency for given radioisotope, collimator andenergy window settings. It does not depend on the camera and image resolution, thesize and shape of the imaged object, the signal-to-background ratio and other factors.Although some authors propose to combine CF and RC into a single calibration coeffi-cient [33], such approach would be very challenging, as it is impossible to design a cali-bration experiment which would model every patient geometry and every activitydistribution. More importantly, in order to account for these different conditions, sucha “combined” approach would require not a single value of CF, but a large table ofvalues, which additionally would depend on the segmentation method that was used togenerate RC.This is not to say that the proposed CF allows us to avoid the challenges related toimage segmentation. Still, the activity maps, which are obtained by multiplying patientimages (i.e. count-maps) by CF, must be segmented if one wants to get activity in anyparticular volume. The advantage of the proposed method is that CF determined usinga single planar scan can be repeatedly applied to many patient studies, as long as theywere acquired using the same camera, collimator, radioisotope and energy windowsettings. It has been shown that, under normal exploitation conditions, the camerasensitivity (thus this CF) will remain unchanged over a long period of time [18].Actually, another observation from this study (and also from our previous experi-ence) is that often calibration experiments performed using the same type of camera(from the same manufacturer) and same acquisition protocols (collimator and energyZhao et al. EJNMMI Physics  (2018) 5:8 Page 13 of 16window settings) but located in different Nuclear Medicine departments (often even indifferent countries) result in very similar values of CFs. This fact may be illustrated bythe experimental CFs for 177Lu phantom configuration C and D, which agree well(within 6%) in spite of the fact that one of these studies was done using Siemenscamera located in Vancouver and the other camera in Quebec City.ConclusionsAccurate determination of the gamma camera CF is critical for quantitative imaging totranslate counts in the reconstructed images into activity values. However, currently,there is no consensus about the calibration method, both planar and tomographic scanshave been performed and the resulting CF applied in research and clinical studies.We have shown that planar acquisition of a point-like source provides CF very closeto those obtained from tomographic images (reconstructed with attenuation and scattercorrections) of a phantom where the activity is distributed over the entire volume (withor without the hot object(s) in its center). The value of CF determined using these twoapproaches agree to within 3% when experiments are performed on the same day andto 6% for experiments done over the period of several months. Usually, such phantomconfiguration is considered to be a good approximation of activity distribution encoun-tered in clinical patient studies. However, our analysis suggests that, for all investigatedradiotherapy isotopes, the camera calibration based on a planar scan of a point sourcemust include scatter correction. This is because photopeak windows for 131I and 188Re,and to a lesser degree for 177Lu, contain important component from scattered high-energy gamma emissions (and septal penetration for 131I).Additionally, our experiments indicate that camera calibration performed usingtomographic scan of a source(s) placed in non-radioactive (cold) background may over-estimate CF by more than 10%. Thus, the use of this method is not recommended fordetermination of the camera CF. Analysis of simulations helped us to understand thatthis rather large discrepancy is due to approximations made by the TEW scatter correc-tion, even further enhanced by attenuation correction performed during imagereconstruction.Based on these considerations, we conclude that camera CF may be confidentlydetermined using planar scans of the point source, provided that the backgroundcontribution to the photopeak is removed, for example using the TEW method. Theapproach is simple and easy to perform and provides CF with sufficient accuracy(~ 5%) to be used in clinical quantitative imaging studies. The proposed method isgeneral and is expected to provide good results for other isotopes than thosereported here.Abbreviations3D: Three-dimensional; CB: Cold background; CF: Calibration factor; FOV: Field of view; GATE: Geant4 Applications forTomographic Emission; HC: Hot cylinder; HS: Hot sources; LSW: Lower scatter window; PP: Primary photons; PS: Pointsource; PVE: Partial volume effects; PW: Photopeak window; RC: Recovery coefficients; ROI: Region of interest;RR: Resolution recovery; SPECT: Single photon emission computed tomography; TEW: Triple energy window;TRT: Targeted radionuclide therapies; USW: Upper scatter window; WB: Warm backgroundAcknowledgmentsThe publication of this article was supported by funds of the European Association of Nuclear Medicine (EANM).FundingThe funding for the project has been provided by the Canadian Institutes of Health Research (CIHR) grant MOP-142233 and the Natural Sciences and Engineering Research Council (NSERC) Discovery grant RGPIN-2017-04914.Zhao et al. EJNMMI Physics  (2018) 5:8 Page 14 of 16Additionally, one of the authors (YKD) would like to acknowledge grant support from R01 EB022075 awarded by theNational Institute of Health, USA.Availability of data and materialsThe phantom images and the simulated phantom data are stored in the Medical Imaging Research Group Server,Vancouver, Canada.Authors’ contributionsWZ was responsible for the acquisitions, reconstructions, and data analysis and participated in the study design withAC, and AC, PE, and XH assisted with the acquisitions and analysis of data. MG and CU assisted with the acquisitions inVancouver, Canada. JMB assisted with the acquisitions in Quebec, Canada. YKD assisted with the acquisitions inMichigan, USA. All authors read and approved the manuscript.Authors’ informationYuni K Dewaraja/consultant/MIM Software Inc., Cleveland, USA.Carlos F Uribe/postdoctoral fellow/GE Healthcare/Data Driven Gating/Monetary.Ethics approval and consent to participateNot applicable.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Author details1Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada. 2Medical ImagingResearch Group, Department of Radiology, University of British Columbia, Vancouver, BC, Canada. 3Department ofMolecular Oncology, BC Cancer Research Center, Vancouver, BC, Canada. 4Vancouver Coastal Health Authority,Vancouver, BC, Canada. 5Department of Medical Imaging, CHU de Quebec-Université Laval, Quebec City, QC, Canada.6Department of Radiology and Nuclear Medicine, Université Laval, Quebec City, QC, Canada. 7Department ofRadiology, University of Michigan Medical School, Ann Arbor, MI, USA.Received: 19 October 2017 Accepted: 23 February 2018References1. 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