The Importance of Uncertainty Analysis and Traceable Measurements in Routine Quantitative 90Y-PET Molecular Radiotherapy: A Multicenter Experience.

Molecular Radiation Therapy (MRT) is a valid therapeutic option for a wide range of malignancies, such as neuroendocrine tumors and liver cancers. In its practice, it is generally acknowledged that there is a need to evaluate the influence of different factors affecting the accuracy of dose estimates and to define the actions necessary to maintain treatment uncertainties at acceptable levels. The present study addresses the problem of uncertainty propagation in 90Y-PET quantification. We assessed the quantitative accuracy in reference conditions of three PET scanners (namely, Siemens Biograph mCT, Siemens Biograph mCT flow, and GE Discovery DST) available at three different Italian Nuclear Medicine centers. Specific aspects of uncertainty within the quantification chain have been addressed, including the uncertainty in the calibration procedure. A framework based on the Guide to the Expression of Uncertainty in Measurement (GUM) approach is proposed for modeling the uncertainty in the quantification processes, and ultimately, an estimation of the uncertainty achievable in clinical conditions is reported.

The international reference system for beta-particle emitting radionuclides: Validation through the pilot study CCRI(II)-P1.Co-60.

The Bureau International des Poids et Mesures (BIPM) is developing a new transfer instrument to extend its centralized services for assessing the international equivalence of radioactive standards to new radionuclides. A liquid scintillation counter using the triple/double coincidence ratio method is being studied and tested in the CCRI(II)-P1.Co-60 pilot study. The pilot study, involving 13 participating laboratories with primary calibration capabilities, validated the approach against the original international reference system based on ionization chambers, which has been in operation since 1976. The results are in agreement and an accuracy suitable for purpose, below 5×10-4, is achieved. The pilot study also reveals an issue when impurities emitting low-energy electrons are present in the standard solution, which have a different impact on liquid scintillation counting compared to other primary measurement methods.

Intercomparison of Radon Flux Monitors at Low and at High Radium Content Areas under Field Conditions.

Interlaboratory exercises are a good tool to compare the response of different systems to the same quantity and to identify possible inconsistencies between them. One of the main goals of the EMPIR 19ENV01 traceRadon project is to harmonize radon flux measurements based on different systems and methodologies. In the framework of the traceRadon Project, two radon flux intercomparison campaigns were carried out in October 2021 at high and at low radon source areas. Four institutions participated in the field intercomparison exercises with their own systems. Every system was based on a specific radon monitor (diffusion or pump mode) and an accumulation chamber (with manual or automatic opening). Radon fluxes were calculated by each participant using both exponential and linear fittings of the radon activity concentration measured over time within the accumulation chambers. The results of this study show mainly: (i) the exponential approach is not advisable due to the variability of the radon flux and the leakage of the systems during long-time measurements; (ii) the linear approach should be applied to minimize the measurement period in agreement with the time response and sensitivity of the monitors; (iii) radon flux measured at high radon source areas (radium content of about 800 Bq kg-1) risks being underestimated because of the influence of advective effects; (iv) radon flux measured at low radon source areas (radium content of about 30 Bq kg-1) may present large uncertainties if sensitive radon monitors with pump mode are not used.

Absorbed dose measurements from a 90Y radionuclide liquid solution using LiF:Mg,Cu,P thermoluminescent dosimeters.

In the last few years there has been an increasing interest in the measurement of the absorbed dose from radionuclides, with special attention devoted to molecular radiotherapy treatments. In particular, the determination of the absorbed dose from beta emitting radionuclides in liquid solution poses a number of issues when dose measurements are performed using thermoluminescent dosimeters (TLD). Finite volume effect, i.e. the exclusion of radioactivity from the volume occupied by the TLD is one of these. Furthermore, TLDs need to be encapsulated into some kind of waterproof envelope that unavoidably contributes to beta particle attenuation during the measurement. The purpose of this study is twofold: I) to measure the absorbed dose to water, Dw, using LiF:Mg,Cu,P chips inside a PMMA cylindrical phantom filled with a homogenous 90YCl3 aqueous solution II) to assess the uncertainty budget related to Dw measurements. To this purpose, six cylindrical PMMA phantoms were manufactured at ENEA. Each phantom can host a waterproof PMMA stick containing 3 TLD chips encapsulated by a polystyrene envelope. The cylindrical phantoms were manufactured so that the radioactive liquid environment surrounds the whole stick. Finally, Dw measurements were compared with Monte Carlo (MC) calculations. The measurement of absorbed dose to water from 90YCl3 radionuclide solution using LiF:Mg,Cu,P TLDs turned out to be a viable technique, provided that all necessary correction factors are applied. Using this method, a relative combined standard uncertainty in the range 3.1-3.7% was obtained on each Dw measurement. The major source of uncertainty was shown to be TLDs calibration, with associated uncertainties in the range 0.7-2.2%. Comparison of measured and MC-calculated absorbed dose per emitted beta particle provided good results, with the two quantities being in the ratio 1.08.

14 MeV Neutrons for 99Mo/99mTc Production: Experiments, Simulations and Perspectives.

BACKGROUND: the gamma-emitting radionuclide Technetium-99m (99mTc) is still the workhorse of Single Photon Emission Computed Tomography (SPECT) as it is used worldwide for the diagnosis of a variety of phatological conditions. 99mTc is obtained from 99Mo/99mTc generators as pertechnetate ion, which is the ubiquitous starting material for the preparation of 99mTc radiopharmaceuticals. 99Mo in such generators is currently produced in nuclear fission reactors as a by-product of 235U fission. Here we investigated an alternative route for the production of 99Mo by irradiating a natural metallic molybdenum powder using a 14-MeV accelerator-driven neutron source. METHODS: after irradiation, an efficient isolation and purification of the final 99mTc-pertechnetate was carried out by means of solvent extraction. Monte Carlo simulations allowed reliable predictions of 99Mo production rates for a newly designed 14-MeV neutron source (New Sorgentina Fusion Source). RESULTS: in traceable metrological conditions, a level of radionuclidic purity consistent with accepted pharmaceutical quality standards, was achieved. CONCLUSIONS: we showed that this source, featuring a nominal neutron emission rate of about 1015 s-1, may potentially supply an appreciable fraction of the current 99Mo global demand. This study highlights that a robust and viable solution, alternative to nuclear fission reactors, can be accomplished to secure the long-term supply of 99Mo.

Results of the CCRI(II)-S12.H-3 supplementary comparison: Comparison of methods for the calculation of the activity and standard uncertainty of a tritiated-water source measured using the LSC-TDCR method.

A comparison of calculations of the activity of a 3H2O liquid scintillation source using the same experimental data set collected at the LNE-LNHB with a triple-to-double coincidence ratio (TDCR) counter was completed. A total of 17 laboratories calculated the activity and standard uncertainty of the LS source using the files with experimental data provided by the LNE-LNHB. The results as well as relevant information on the computation techniques are presented and analysed in this paper. All results are compatible, even if there is a significant dispersion between the reported uncertainties. An output of this comparison is the estimation of the dispersion of TDCR measurement results when measurement conditions are well defined.

Phantom validation of quantitative Y-90 PET/CT-based dosimetry in liver radioembolization.

BACKGROUND: PET/CT has recently been shown to be a viable alternative to traditional post-infusion imaging methods providing good quality images of 90Y-laden microspheres after selective internal radiation therapy (SIRT). In the present paper, first we assessed the quantitative accuracy of 90Y-PET using an anthropomorphic phantom provided with lungs, liver, spine, and a cylindrical homemade lesion located into the hepatic compartment. Then, we explored the accuracy of different computational approaches on dose calculation, including (I) direct Monte Carlo radiation transport using Raydose, (II) Kernel convolution using Philips Stratos, (III) local deposition algorithm, (IV) Monte Carlo technique (MCNP) considering a uniform activity distribution, and (V) MIRD (Medical Internal Radiation Dose) analytical approach. Finally, calculated absorbed doses were compared with those obtained performing measurements with LiF:Mg,Cu,P TLD chips in a liquid environment. RESULTS: Our results indicate that despite 90Y-PET being likely to provide high-resolution images, the 90Y low branch ratio, along with other image-degrading factors, may produce non-uniform activity maps, even in the presence of uniform activity. A systematic underestimation of the recovered activity, both for the tumor insert and for the liver background, was found. This is particularly true if no partial volume correction is applied through recovery coefficients. All dose algorithms performed well, the worst case scenario providing an agreement between absorbed dose evaluations within 20%. Average absorbed doses determined with the local deposition method are in excellent agreement with those obtained using the MIRD and the kernel-convolution dose calculation approach. Finally, absorbed dose assessed with MC codes are in good agreement with those obtained using TLD in liquid solution, thus confirming the soundness of both calculation approaches. This is especially true for Raydose, which provided an absorbed dose value within 3% of the measured dose, well within the stated uncertainties. CONCLUSIONS: Patient-specific dosimetry is possible even in a scenario with low true coincidences and high random fraction, as in 90Y-PET imaging, granted that accurate absolute PET calibration is performed and acquisition times are sufficiently long. Despite Monte Carlo calculations seeming to outperform all dose estimation algorithms, our data provide a strong argument for encouraging the use of the local deposition algorithm for routine 90Y dosimetry based on PET/CT imaging, due to its simplicity of implementation.

(18)F primary standard at ENEA-INMRI by three absolute techniques and calibration of a well-type IG11 ionization chamber.

A new (18)F primary standardization carried out at ENEA-INMRI by three different absolute techniques, i.e. 4πγNaI(Tl)γ high-efficiency counting, TDCR and 4πß(LS)-γ[NaI(Tl)] coincidence counting method, allowed the calibration of a fixed well-reentrant IG11 ionization chamber (IC), with an uncertainty lower than 1%, and to check the calibration factor of a portable well-type IC NPL-CRC model, previously calibrated. By the new standard the ENEA-INMRI was linked to the BIPM International Reference System (SIR) through the BIPM SIR Transfer Instrument (SIRTI).

A prototype of a portable TDCR system at ENEA.

A prototype of a portable liquid scintillation counting system based on the Triple-to-Double Coincidence Ratio (TDCR) technique was developed at ENEA-INMRI in the framework of the European Metrofission project. The new device equipped with the CAEN digitizers was tested for the activity measurements of pure ß-emitters ((99)Tc and (63)Ni). The list-mode data recorded by the digitizers were analyzed by software implemented in the CERN ROOT environment, which allows the application of pulse shape discrimination using the new device.

Bilateral comparison between PTB and ENEA to check the performance of a commercial TDCR system for activity measurements.

The only commercial TDCR counter from Hidex Oy (Finland), comprising three photomultiplier tubes, was tested at the two National Metrology Institutes (NMIs) PTB and ENEA. To this end, the two NMIs purchased a Hidex 300 SL TDCR counter (METRO version) each and carried out various tests at their laboratories. In addition, the two institutions agreed to organize a bilateral comparison in order to acquire information on the reproducibility of the results obtained with the counters. To achieve this, PTB prepared some (89)Sr liquid scintillation samples, which were first measured in various counters at PTB and then shipped to ENEA for comparative measurements. The aim of this paper is to summarize the findings on the counter characteristics and adjustments. In addition, the results of the bilateral comparison between PTB and ENEA are presented and the results from various commercial counters using the CIEMAT/NIST efficiency tracing and the TDCR method are discussed.

Construction and implementation of a TDCR system at ENEA.

A new 4π (LS) TDCR system was built at ENEA-INMRI. Three photomultiplier tubes, arranged in a planar 120° geometry around a spherical optical chamber, were directly linked to a CAEN Desktop Digitizer DT5720. This module, based on the Field Programmable Gate Array (FPGA) technology for real time Digital Pulse Processing (DPP), allowed to replace all the classical TDCR electronics by only one device. The activity of (3)H and (63)Ni standard sources were successfully measured by the new detector.

A full digital approach to the TDCR method.

Current state of the art solutions based on the Triple to Double Coincidence Ratio method are generally large size, heavy-weight and not transportable systems. This is due, on one side, to large detectors and scintillation chambers and, on the other, to bulky analog electronics for data acquisition. CAEN developed a new, full digital approach to TDCR technique based on a portable, stand-alone, high-speed multichannel digitizer, on-board Digital Pulse Processing and dedicated DAQ software that emulates the well-known MAC3 analog board.

Experimental determination of the radionuclide calibrator setting for Technesium-99m, by using a primary standardisation method.

BACKGROUND: A new 99mTc national standard has been developed at the Italian National Metrology Institute for Ionizing Radiation quantities of ENEA (ENEA-INMRI). METHODS: The stock radioactive solution was prepared at the Ospedale Pediatrico Bambino Gesù (OPBG) and standardized at the ENEA-INMRI by using the 4pigamma absolute measurement method. The new standard was used to calibrate the dose calibrator of the OPBG Nuclear Medicine Unit (NMU) and the ENEA-INMRI portable ionization chamber which was employed as the secondary standard measurement system to calibrate the dose calibrator of another Italian nuclear medicine unit. RESULTS AND CONCLUSION: Remarkable improvement of measurement accuracy was achieved. The importance of traceable calibrations is underlined. Specific comments are made about quality control performance and measurement accuracy for the instrumentation used in nuclear medicine units of paediatric hospitals.

A national campaign for coincidence-summing correction in gamma-ray spectrometry.

A national campaign was carried out in Italy for the application of coincidence-summing correction in gamma-ray spectrometry. Twelve laboratories, belonging to the National Environmental Radioactivity Surveillance Network, took part in the campaign. They are equipped with gamma-ray spectrometry systems based on p- and n-type HPGe detectors with different relative efficiencies. A simplified procedure was used for coincidence-summing correction. This procedure requires a single-photon, single-nuclide source to measure the peak-to-total efficiency ratio at just one photon energy value. All the laboratories were given a 137Cs standard source for total efficiency determination, and a 134Cs source in the same geometry whose activity they had to determine. The results show the usefulness of the procedure. The average deviation of all the laboratory results from the ENEA-INMRI reference value was reduced from -12% before correction to +1% after correction. The paper gives a description of the different organisational aspects of the campaign, reports the results obtained and draws conclusions in which the gain in measurement accuracy is evaluated in the light of the effort required for each participant to perform the correction.