Activity standard and calibrations for 227Th with ingrowing progeny.

Thorium-227 was separated from its progeny and standardized for activity by the triple-to-double coincidence ratio (TDCR) method of liquid scintillation counting. Confirmatory liquid scintillation-based measurements were made using efficiency tracing with 3H and live-timed anticoincidence counting (LTAC). The separation time and the efficiency of the separation were confirmed by gamma-ray spectrometry. Calibrations for reentrant pressurized ionization chambers, including commercial radionuclide calibrators, and a well-type NaI(Tl) detector are discussed.

Liquid scintillation efficiencies, gamma-ray emission intensities, and half-life for Gd-153.

Gadolinium-153 was standardized for activity by live-timed anticoincidence counting and an ampoule was submitted to the international reference system (SIR). Absolute emission intensities for the main γ rays were determined with calibrated high-purity germanium (HPGe) and lithium-drifted silicon (Si(Li)) detectors. A revised decay scheme is indicated, with no probability of direct electron capture to the 153Eu ground state. Triple-to-double coincidence ratio (TDCR) efficiency curves indicate that the revised decay scheme is consistent with experiment. Half-life measurements agree with a previous NIST determination and show no sensitivity to chemical environment.

Comparison of calibration coefficients for a vinten ionization chamber simulated using four Monte Carlo methods.

The Vinten 671 ionization chamber (VIC) was modelled using Monte Carlo (MC) programs EGSnrc, Penelope, and TOPAS. Several national measurement institutes have VICs with well-characterized response relationships and have measured calibration coefficients for many radionuclides. Twelve radionuclides with various decay emissions were assessed as well as 14 monoenergetic photon sources and 10 monoenergetic electron sources. Calibration coefficients were calculated based on the energy deposited in the simulated VIC nitrogen gas volume and compared to experimental values from the literature.

Primary standardization of 212Pb activity by liquid scintillation counting.

An activity standard for 212Pb in equilibrium with its progeny was realized, based on triple-to-double coincidence ratio (TDCR) liquid scintillation (LS) counting. A Monte Carlo-based approach to estimating uncertainties due to nuclear decay data (branching ratios, beta endpoint energies, γ-ray energies, and conversion coefficients for 212Pb and 208Tl) led to combined standard uncertainties ≤ 0.20 %. Confirmatory primary measurements were made by LS efficiency tracing with tritium and 4παß(LS)-γ(NaI(Tl)) anticoincidence counting. The standard is discussed in relation to current approaches to 212Pb activity calibration. In particular, potential biases encountered when using inappropriate radionuclide calibrator settings are discussed.

Dosimetry for Radiopharmaceutical Therapy: Current Practices and Commercial Resources.

With the ongoing dramatic growth of radiopharmaceutical therapy, research and development in internal radiation dosimetry continue to advance both at academic medical centers and in industry. The basic paradigm for patient-specific dosimetry includes administration of a pretreatment tracer activity of the therapeutic radiopharmaceutical; measurement of its time-dependent biodistribution; definition of the pertinent anatomy; integration of the measured time-activity data to derive source-region time-integrated activities; calculation of the tumor, organ-at-risk, and/or whole-body absorbed doses; and prescription of the therapeutic administered activity. This paper provides an overview of the state of the art of patient-specific dosimetry for radiopharmaceutical therapy, including current methods and commercially available software and other resources.

Ra-224 activity, half-life, and 241 keV gamma ray absolute emission intensity: A NIST-NPL bilateral comparison.

The national metrology institutes for the United Kingdom (UK) and the United States of America (USA) have compared activity standards for 224Ra, an α-particle emitter of interest as the basis for therapeutic radiopharmaceuticals. Solutions of 224RaCl2 were assayed by absolute methods, including digital coincidence counting and triple-to-double coincidence ratio liquid scintillation counting. Ionization chamber and high-purity germanium (HPGe) γ-ray spectrometry calibrations were compared; further, a solution was shipped between laboratories for a direct comparison by HPGe spectrometry. New determinations of the absolute emission intensity for the 241 keV γ ray (Iγ = 4.011(16) per 100 disintegrations of 224Ra) and of the 224Ra half-life (T1/2 = 3.6313(14) d) are presented and discussed in the context of previous measurements and evaluations.

Overcoming Barriers to Radiopharmaceutical Therapy (RPT): An Overview From the NRG-NCI Working Group on Dosimetry of Radiopharmaceutical Therapy.

Radiopharmaceutical therapy (RPT) continues to demonstrate tremendous potential in improving the therapeutic gains in radiation therapy by specifically delivering radiation to tumors that can be well assessed in terms of dosimetry and imaging. Dosimetry in external beam radiation therapy is standard practice. This is not the case, however, in RPT. This NRG (acronym formed from the first letter of the 3 original groups: National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group)-National Cancer Institute Working Group review describes some of the challenges to improving RPT. The main priorities for advancing the field include (1) developing and adopting best practice guidelines for incorporating patient-specific dosimetry for RPT that can be used at both large clinics with substantial resources and more modest clinics that have limited resources, (2) establishing and improving strategies for introducing new radiopharmaceuticals for clinical investigation, (3) developing approaches to address the radiophobia that is associated with the administration of radioactivity for cancer therapy, and (4) solving the financial and logistical issues of expertise and training in the developing field of RPT.

Calorimetry in Computed Tomography Beams.

A portable calorimeter for direct realization of absorbed dose in medical computed tomography (CT) procedures was constructed and tested in a positron emission tomography (PET) CT scanner. The calorimeter consists of two small thermistors embedded in a polystyrene (PS) cylindrical "core" (1.5 cm diameter) that can be inserted into a cylindrical high-density polyethylene (HDPE) phantom (30 cm diameter). The cylindrical design of core and phantom allows coaxial alignment of the system with the scanner rotation axis, which is necessary to minimize variations in dose that would otherwise occur as the X-ray source is rotated during scanning operations. The core can be replaced by a cylindrical ionization chamber for comparing dose measurement results. Measurements using the core and a calibrated thimble ionization chamber were carried out in a beam of 6 MV X-rays from a clinical accelerator and in 120 kV X-rays from a CT scanner. Doses obtained from the calorimeter and chamber in the 6 MV beam exhibited good agreement over a range of dose rates from 0.8 Gy/min to 4 Gy/min, with negligible excess heat. For the CT beam, as anticipated for these X-ray energies, the calorimeter response was complicated by excess heat from device components. Analyses done in the frequency domain and time domain indicated that excess heat increased calorimetric temperature rise by a factor of about 15. The calorimeter's response was dominated by dose to the thermistor, which contains high-atomic-number elements. Therefore, for future construction of calorimeters for CT beams, lower-atomic-number temperature sensors will be needed. These results serve as a guide for future alternative design of calorimeters toward a calorimetry absorbed dose standard for diagnostic CT.

203/212Pb Theranostic Radiopharmaceuticals for Image-guided Radionuclide Therapy for Cancer.

Receptor-targeted image-guided Radionuclide Therapy (TRT) is increasingly recognized as a promising approach to cancer treatment. In particular, the potential for clinical translation of receptor-targeted alpha-particle therapy is receiving considerable attention as an approach that can improve outcomes for cancer patients. Higher Linear-energy Transfer (LET) of alpha-particles (compared to beta particles) for this purpose results in an increased incidence of double-strand DNA breaks and improved-localized cancer-cell damage. Recent clinical studies provide compelling evidence that alpha-TRT has the potential to deliver a significantly more potent anti-cancer effect compared with beta-TRT. Generator-produced 212Pb (which decays to alpha emitters 212Bi and 212Po) is a particularly promising radionuclide for receptor-targeted alpha-particle therapy. A second attractive feature that distinguishes 212Pb alpha-TRT from other available radionuclides is the possibility to employ elementallymatched isotope 203Pb as an imaging surrogate in place of the therapeutic radionuclide. As direct non-invasive measurement of alpha-particle emissions cannot be conducted using current medical scanner technology, the imaging surrogate allows for a pharmacologically-inactive determination of the pharmacokinetics and biodistribution of TRT candidate ligands in advance of treatment. Thus, elementally-matched 203Pb labeled radiopharmaceuticals can be used to identify patients who may benefit from 212Pb alpha-TRT and apply appropriate dosimetry and treatment planning in advance of the therapy. In this review, we provide a brief history on the use of these isotopes for cancer therapy; describe the decay and chemical characteristics of 203/212Pb for their use in cancer theranostics and methodologies applied for production and purification of these isotopes for radiopharmaceutical production. In addition, a medical physics and dosimetry perspective is provided that highlights the potential of 212Pb for alpha-TRT and the expected safety for 203Pb surrogate imaging. Recent and current preclinical and clinical studies are presented. The sum of the findings herein and observations presented provide evidence that the 203Pb/212Pb theranostic pair has a promising future for use in radiopharmaceutical theranostic therapies for cancer.

Primary standardization of 224Ra activity by liquid scintillation counting.

A standard for activity of 224Ra in secular equilibrium with its progeny has been developed, based on triple-to-double coincidence ratio (TDCR) liquid scintillation (LS) counting. The standard was confirmed by efficiency tracing and 4παß(LS)-γ(NaI(Tl)) anticoincidence counting, as well as by 4πγ ionization chamber and NaI(Tl) measurements. Secondary standard ionization chambers were calibrated with an expanded uncertainty of 0.62% (k = 2). Calibration settings were also determined for a 5 mL flame-sealed ampoule on several commercial reentrant ionization chambers (dose calibrators).

Two determinations of the Ge-68 half-life.

In nuclear medicine, 68Ge is used to generate 68Ga for imaging by positron emission tomography (PET) and sealed sources containing 68Ge/68Ga in equilibrium have been adopted as long-lived calibration surrogates for the more common PET nuclide, 18F. We prepared several 68Ge sources for measurement on a NaI(Tl) well counter and a pressurized ionization chamber, following their decay for 110 weeks (≈ 2.8 half-lives). We determined values for the 68Ge half-life of T1/2 = 271.14(15) d and T1/2 = 271.07(12) d from the NaI(Tl) well counter and ionization chamber measurements, respectively. These are in accord with the current Decay Data Evaluation Project (DDEP) recommended value of T1/2 = 270.95(26) d and we discuss the expected impact of our measurements on this value.

Automated cassette-based production of high specific activity [203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer.

A method for preparation of Pb-212 and Pb-203 labeled chelator-modified peptide-based radiopharmaceuticals for cancer imaging and radionuclide therapy has been developed and adapted for automated clinical production. Pre-concentration and isolation of radioactive Pb2+ from interfering metals in dilute hydrochloric acid was optimized using a commercially-available Pb-specific chromatography resin packed in disposable plastic columns. The pre-concentrated radioactive Pb2+ is eluted in NaOAc buffer directly to the reaction vessel containing chelator-modified peptides. Radiolabeling was found to proceed efficiently at 85°C (45min; pH 5.5). The specific activity of radiolabeled conjugates was optimized by separation of radiolabeled conjugates from unlabeled peptide via HPLC. Preservation of bioactivity was confirmed by in vivo biodistribution of Pb-203 and Pb-212 labeled peptides in melanoma-tumor-bearing mice. The approach has been found to be robustly adaptable to automation and a cassette-based fluid-handling system (Modular Lab Pharm Tracer) has been customized for clinical radiopharmaceutical production. Our findings demonstrate that the Pb-203/Pb-212 combination is a promising elementally-matched radionuclide pair for image-guided radionuclide therapy for melanoma, neuroendocrine tumors, and potentially other cancers.

Multi-centre evaluation of accuracy and reproducibility of planar and SPECT image quantification: An IAEA phantom study.

Accurate quantitation of activity provides the basis for internal dosimetry of targeted radionuclide therapies. This study investigated quantitative imaging capabilities at sites with a variety of experience and equipment and assessed levels of errors in activity quantitation in Single-Photon Emission Computed Tomography (SPECT) and planar imaging. Participants from 9 countries took part in a comparison in which planar, SPECT and SPECT with X ray computed tomography (SPECT-CT) imaging were used to quantify activities of four epoxy-filled cylinders containing 133Ba, which was chosen as a surrogate for 131I. The sources, with nominal volumes of 2, 4, 6 and 23mL, were calibrated for 133Ba activity by the National Institute of Standards and Technology, but the activity was initially unknown to the participants. Imaging was performed in a cylindrical phantom filled with water. Two trials were carried out in which the participants first estimated the activities using their local standard protocols, and then repeated the measurements using a standardized acquisition and analysis protocol. Finally, processing of the imaging data from the second trial was repeated by a single centre using a fixed protocol. In the first trial, the activities were underestimated by about 15% with planar imaging. SPECT with Chang's first order attenuation correction (Chang-AC) and SPECT-CT overestimated the activity by about 10%. The second trial showed moderate improvements in accuracy and variability. Planar imaging was subject to methodological errors, e.g., in the use of a transmission scan for attenuation correction. The use of Chang-AC was subject to variability from the definition of phantom contours. The project demonstrated the need for training and standardized protocols to achieve good levels of quantitative accuracy and precision in a multicentre setting. Absolute quantification of simple objects with no background was possible with the strictest protocol to about 6% with planar imaging and SPECT (with Chang-AC) and within 2% for SPECT-CT.

Natural Uranium Radioactivity Solution Standard: SRM 4321d.

A new natural uranium solution standard has been produced and will be disseminated by the National Institute of Standards and Technology (NIST) as Standard Reference Material 4321d. The standard is certified for the massic activities of 234U, 235U, and 238U in solution, and it is based on isotopic mass data for the metallic Certified Reference Material (CRM) 112-A (originally issued as SRM 960) that was obtained from THE U.S. Department of Energy, New Brunswick Laboratory. The metallic CRM was chemically cleaned, dissolved, and gravimetrically diluted to prepare a master solution, which was quantitatively dispensed into 5 mL aliquots that were contained within flame-sealed glass ampoules for each SRM unit. Homogeneity among SRM units, verifying solution homogeneity, was substantiated by photonic-emission integral counting with a NaI(Tl) well counter. Confirmatory measurements were performed by liquid scintillation counting for the total massic activity, and by isotope dilution α spectrometry for the 234U and 238U massic activities.

Comparison of (14)C liquid scintillation counting at NIST and NRC Canada.

An informal bilateral comparison of (14)C liquid scintillation (LS) counting at the National Research Council of Canada (NRC) and the National Institute of Standards and Technology (NIST) has been completed. Two solutions, one containing (14)C-labeled sodium benzoate and one containing (14)C-labeled n-hexadecane, were measured at both laboratories. Despite observed LS cocktail instabilities, the two laboratories achieved accord in their standardizations of both solutions. At the conclusion of the comparison, the beta spectrum used for efficiency calculations was identified as inadequate and the data were reanalyzed with different inputs, improving accord.

Impact of Recent Change in the National Institute of Standards and Technology Standard for 18F on the Relative Response of 68Ge-Based Mock Syringe Dose Calibrator Standards.

UNLABELLED: As a result of a recent change in the National Institute of Standards and Technology (NIST) activity standard for (18)F, we have determined new relative response ratios for a (68)Ge solid epoxy mock syringe source used in activity calibrators as a long-lived substitute for (18)F. New standardized solutions of each radionuclide were used to determine the response ratios while maintaining traceability to national standards. This work updates our previously published data from 2010. METHODS: Following our previously published methodology, solution-filled mock syringe sources, identical in geometry to the solid (68)Ge epoxy calibration source currently on the market, were prepared using NIST-calibrated solutions of (68)GeCl4 and (18)F-FDG and directly compared in several models of activity calibrators to determine empirically the relative response ratios for these 2 radionuclides. RESULTS: The new relative response ratios measured in this study reflect the change in (18)F activity measurements that arise from the recent -4% change in the NIST activity standard. The results allow the (68)Ge activity of the mock syringe source to be expressed in terms of equivalent (18)F activity, with a relative combined standard uncertainty of about 0.8% for the activity calibrators used in this study. CONCLUSION: This work revises our previously derived relative response ratios for (18)F and (68)Ge by -3.7%, allowing users of the commercial mock syringe surrogate source to calibrate their activity calibrators in a way that is consistent with the recent change in the NIST (18)F standard.

Secondary standards for ²²³Ra revised.

Dose calibrator dial settings reported by NIST in 2010 (ARI, v. 68, p. 1367) are now known to give erroneously low (by 10%) activity readings. The original determinations were based on a chain of calibrations; a broken link in this chain was recently discovered. New calibration factors (i.e., dial settings), directly linked to updated NIST primary standards, are reported here. In addition, the raw data used to derive the factors reported in 2010 are revisited. The validity of the reevaluation is established via comparison with the new experiments and revised calibration factors for numerous clinical geometries are reported. The main conclusions of the 2010 report regarding geometry effects remain valid.

Dose calibrator manufacturer-dependent bias in assays of ¹²³I.

Calibration factors for commercial ionization chambers (i.e. dose calibrators) were determined for a solution of (123)I; the activity was based on the 1976 NBS standard. A link between the NIST standard and the International Reference System (SIR) was established. The two major U.S. dose calibrator manufacturers recommend oppositely biased calibration factors, giving a spread of 11.3% in measured activities. With modern quantitative imaging techniques capable of ≤10% accuracy, this bias for a SPECT nuclide is highly significant.

A Review of NIST Primary Activity Standards for (18)F: 1982 to 2013.

The new NIST activity standardization for (18)F, described in 2014 in Applied Radiation and Isotopes (v. 85, p. 77), differs from results obtained between 1998 and 2008 by 4 %. The new results are considered to be very reliable; they are based on a battery of robust primary measurement techniques and bring the NIST standard into accord with other national metrology institutes. This paper reviews all ten (18)F activity standardizations performed at NIST from 1982 to 2013, with a focus on experimental variables that might account for discrepancies. We have identified many possible sources of measurement bias and eliminated most of them, but we have not adequately accounted for the 1998-2008 results.