DNA damage and repair in peripheral blood mononuclear cells after internal ex vivo irradiation of patient blood with 131I.

AIM: The aim of this study was to provide a systematic approach to characterize DNA damage induction and repair in isolated peripheral blood mononuclear cells (PBMCs) after internal ex vivo irradiation with [131I]NaI. In this approach, we tried to mimic ex vivo the irradiation of patient blood in the first hours after radioiodine therapy. MATERIAL AND METHODS: Blood of 33 patients of two centres was collected immediately before radioiodine therapy of differentiated thyroid cancer (DTC) and split into two samples. One sample served as non-irradiated control. The second sample was exposed to ionizing radiation by adding 1 ml of [131I]NaI solution to 7 ml of blood, followed by incubation at 37 °C for 1 h. PBMCs of both samples were isolated, split in three parts each and (i) fixed in 70% ethanol and stored at - 20 °C directly (0 h) after irradiation, (ii) after 4 h and (iii) 24 h after irradiation and culture in RPMI medium. After immunofluorescence staining microscopically visible co-localizing γ-H2AX + 53BP1 foci were scored in 100 cells per sample as biomarkers for radiation-induced double-strand breaks (DSBs). RESULTS: Thirty-two of 33 blood samples could be analysed. The mean absorbed dose to the blood in all irradiated samples was 50.1 ± 2.3 mGy. For all time points (0 h, 4 h, 24 h), the average number of γ-H2AX + 53BP1 foci per cell was significantly different when compared to baseline and the other time points. The average number of radiation-induced foci (RIF) per cell after irradiation was 0.72 ± 0.16 at t = 0 h, 0.26 ± 0.09 at t = 4 h and 0.04 ± 0.09 at t = 24 h. A monoexponential fit of the mean values of the three time points provided a decay rate of 0.25 ± 0.05 h-1, which is in good agreement with data obtained from external irradiation with γ- or X-rays. CONCLUSION: This study provides novel data about the ex vivo DSB repair in internally irradiated PBMCs of patients before radionuclide therapy. Our findings show, in a large patient sample, that efficient repair occurs after internal irradiation with 50 mGy absorbed dose, and that the induction and repair rate after 131I exposure is comparable to that of external irradiation with γ- or X-rays.

Developing and implementing a multi-modality imaging optimization study in paediatric radiology: Experience and recommendations from an IAEA coordinated research project.

Optimization of imaging examinations is a key requirement of both the International and European Basic Safety Standards, and the focus of much international activity. Although methodologies are well established in principle, there continues to be a variety of practical issues both in collecting and interpreting dose and image quality data and in making successful interventions to optimize exposures. A Coordinated Research Project, involving institutes from ten different countries, was established by the IAEA to assess the efficacy of recommended optimization methodologies in the field of paediatric radiology and to derive practical guidance on their implementation. The steps followed in this process were identification of the imaging process to be investigated (abdomen and chest x-rays, micturating cysto-urethrograms, and brain & thorax CT scans); collection of dose and image quality data; evaluation and comparison of the data between institutes and to standards; identification and implementation of interventions for optimization; and re-evaluation of dose and image quality parameters. The project succeeded both in achieving effective interventions for optimization of specific imaging tasks in individual institutes and in identifying key issues with potential to handicap this process. The main area in which problems were encountered was in the collation of reliable dose and image quality data. The reasons for this were explored and a series of recommendations have been made, summarized into 'ten practical tips' for optimization to assist institutes, particularly those in the early stages of addressing optimization issues.

α-Particle-induced DNA damage tracks in peripheral blood mononuclear cells of [223Ra]RaCl2-treated prostate cancer patients.

PURPOSE: One therapy option for prostate cancer patients with bone metastases is the use of [223Ra]RaCl2. The α-emitter 223Ra creates DNA damage tracks along α-particle trajectories (α-tracks) in exposed cells that can be revealed by immunofluorescent staining of γ-H2AX+53BP1 DNA double-strand break markers. We investigated the time- and absorbed dose-dependency of the number of α-tracks in peripheral blood mononuclear cells (PBMCs) of patients undergoing their first therapy with [223Ra]RaCl2. METHODS: Multiple blood samples from nine prostate cancer patients were collected before and after administration of [223Ra]RaCl2, up to 4 weeks after treatment. γ-H2AX- and 53BP1-positive α-tracks were microscopically quantified in isolated and immuno-stained PBMCs. RESULTS: The absorbed doses to the blood were less than 6 mGy up to 4 h after administration and maximally 16 mGy in total. Up to 4 h after administration, the α-track frequency was significantly increased relative to baseline and correlated with the absorbed dose to the blood in the dose range < 3 mGy. In most of the late samples (24 h - 4 weeks after administration), the α-track frequency remained elevated. CONCLUSION: The γ-H2AX+53BP1 assay is a potent method for detection of α-particle-induced DNA damages during treatment with or after accidental incorporation of radionuclides even at low absorbed doses. It may serve as a biomarker discriminating α- from ß-emitters based on damage geometry.

Multicentre Trials on Standardised Quantitative Imaging and Dosimetry for Radionuclide Therapies.

The aim of this review is to summarise the efforts undertaken so far to compare or standardise quantitative imaging with gamma cameras across centres for multicentre trials in radionuclide therapies. Overall, 10 studies were identified, five of which were set up as a multicentre effort for standardising and comparing methods for quantitative imaging. One study used positron emission tomography imaging with 124I. In the remaining studies, measurements were carried out with planar imaging, single photon emission computed tomography/computed tomography (SPECT/CT) or a combination of both. Three studies used radioactive calibration sources that were traceable to national standards. Most of the studies were set up in the framework of multicentre clinical trials in an effort to obtain comparable quantification across sites. The use of state-of-the-art SPECT/CT systems and reconstructions has emerged as the method of choice for dosimetry in clinical trials for radionuclide therapies.

Paediatric nuclear medicine practice: an international survey by the IAEA.

PURPOSE: The International Atomic Energy Agency (IAEA) decided to initiate a survey to evaluate the current status of the practice of paediatric nuclear medicine worldwide, with the focus mainly on low and middle-income countries specifically in Latin America, Eastern Europe, Africa and Asia. This investigation sought to determine if the practice in paediatric nuclear medicine in these countries differed from that indicated by the survey of the Nuclear Medicine Global Initiative (NMGI) and if nuclear medicine practitioners were following established paediatric nuclear medicine guidelines. METHODS: A total of 133 institutes took part in the survey from 62 different IAEA member states within Africa (29), Asia (39), Europe (29) and Latin America (36). The four most frequent conventional (single-photon) nuclear medicine procedures were 99mTc labelled MDP, DSMA, MAG3 and pertechnetate thyroid scans. In addition, 46 centres provided data on FDG PET/CT, including exposure data for the CT component. Nearly half of the sites (48%) perform less than 200 paediatric nuclear medicine studies per year, while 11% perform more than 1000 such studies per year. RESULTS: Administered activities largely exceeded the recommendations for most of the sites for DMSA, MAG3 and pertechnetate, while compliance with international standards was somehow better for MDP studies. For FDG PET, the results were more uniform than for conventional nuclear medicine procedures. However, the use of CT in PET/CT for paediatric nuclear medicine revealed a high variability and, in some cases, high, dose-length product (DLP) values. This observation indicates that further attention is warranted for optimizing clinical practice in FDG PET/CT. CONCLUSIONS: Overall, in most parts of the world, efforts have been undertaken to comply either with the EANM dosage card or with the North American Consensus Guidelines. However, variability in the practice of paediatric nuclear medicine still exists. The results of this survey provide valuable recommendations for a path towards global standardization of determining the amount of activity to be administered to children undergoing nuclear medicine procedures.

ICRP Publication 140: Radiological Protection in Therapy with Radiopharmaceuticals.

Radiopharmaceuticals are increasingly used for the treatment of various cancers with novel radionuclides, compounds, tracer molecules, and administration techniques. The goal of radiation therapy, including therapy with radiopharmaceuticals, is to optimise the relationship between tumour control probability and potential complications in normal organs and tissues. Essential to this optimisation is the ability to quantify the radiation doses delivered to both tumours and normal tissues. This publication provides an overview of therapeutic procedures and a framework for calculating radiation doses for various treatment approaches. In radiopharmaceutical therapy, the absorbed dose to an organ or tissue is governed by radiopharmaceutical uptake, retention in and clearance from the various organs and tissues of the body, together with radionuclide physical half-life. Biokinetic parameters are determined by direct measurements made using techniques that vary in complexity. For treatment planning, absorbed dose calculations are usually performed prior to therapy using a trace-labelled diagnostic administration, or retrospective dosimetry may be performed on the basis of the activity already administered following each therapeutic administration. Uncertainty analyses provide additional information about sources of bias and random variation and their magnitudes; these analyses show the reliability and quality of absorbed dose calculations. Effective dose can provide an approximate measure of lifetime risk of detriment attributable to the stochastic effects of radiation exposure, principally cancer, but effective dose does not predict future cancer incidence for an individual and does not apply to short-term deterministic effects associated with radiopharmaceutical therapy. Accident prevention in radiation therapy should be an integral part of the design of facilities, equipment, and administration procedures. Minimisation of staff exposures includes consideration of equipment design, proper shielding and handling of sources, and personal protective equipment and tools, as well as education and training to promote awareness and engagement in radiological protection. The decision to hold or release a patient after radiopharmaceutical therapy should account for potential radiation dose to members of the public and carers that may result from residual radioactivity in the patient. In these situations, specific radiological protection guidance should be provided to patients and carers.

Targeted alpha-particle therapy: imaging, dosimetry, and radiation protection.

Systemic or locoregionally administered alpha-particle emitters are highly potent therapeutic agents used in oncology that are fundamentally novel in their mechanism and, most likely, overcome radiation resistance as the alpha particles emitted have a short range and a high linear energy transfer. The use of alpha emitters in a clinic environment requires extra measures with respect to imaging, dosimetry, and radiation protection. This is shown for the example of 223Ra dichloride therapy. After intravenous injection, 223Ra leaves the blood and is taken up rapidly in bone and bone metastases; it is mainly excreted via the intestinal tract. 223Ra can be imaged in patients with a gamma camera. Dosimetry shows that, after a series of six treatments for a 70-kg person with an overall administered activity of 23 MBq, 223Ra results in an absorbed alpha dose of approximately 17 Gy to the bone endosteum and approximately 1.7 Gy to the red bone marrow. During administration, special care must be taken to ensure that no spill is present on the skin of either the patient or staff. Due to the low dose rate, the treatment is normally performed on an outpatient basis; the patient and carers should receive written instructions about the therapy and radiation protection.

Biokinetics, dosimetry, and radiation risk in infants after 99mTc-MAG3 scans.

BACKGROUND: Renal scans are among the most frequent exams performed on infants and toddlers. Due to the young age, this patient group can be classified as a high-risk group with a higher probability for developing stochastic radiation effects compared to adults. As there are only limited data on biokinetics and dosimetry in this patient group, the aim of this study was to reassess the dosimetry and the associated radiation risk for infants undergoing 99mTc-MAG3 renal scans based on a retrospective analysis of existing patient data. Consecutive data were collected from 20 patients younger than 20 months (14 males; 6 females) with normal renal function undergoing 99mTc-MAG3 scans. To estimate the patient-specific organ activity, a retrospective calibration was performed based on a set of two 3D-printed infant kidneys filled with known activities. Both phantoms were scanned at different positions along the anteroposterior axis inside a water phantom, providing depth- and size-dependent attenuation correction factors for planar imaging. Time-activity curves were determined by drawing kidney, bladder, and whole-body regions-of-interest for each patient, and subsequently applying the calibration factor for conversion of counts to activity. Patient-specific time-integrated activity coefficients were obtained by integrating the organ-specific time-activity curves. Absorbed and effective dose coefficients for each patient were assessed with OLINDA/EXM for the provided newborn and 1-year-old model. The risk estimation was performed individually for each of the 20 patients with the NCI Radiation Risk Assessment Tool. RESULTS: The mean age of the patients was 7.0 ± 4.5 months, with a weight between 5 and 12 kg and a body size between 60 and 89 cm. The injected activities ranged from 12 to 24 MBq of 99mTc-MAG3. The patients' organ-specific mean absorbed dose coefficients were 0.04 ± 0.03 mGy/MBq for the kidneys and 0.27 ± 0.24 mGy/MBq for the bladder. The mean effective dose coefficient was 0.02 ± 0.02 mSv/MBq. Based on the dosimetry results, an evaluation of the excess lifetime risk for the development of radiation-induced cancer showed that the group of newborns has a risk of 16.8 per 100,000 persons, which is about 12% higher in comparison with the 1-year-old group with 14.7 per 100,000 persons (all values are given as mean plus/minus one standard deviation except otherwise specified). CONCLUSION: In this study, we retrospectively derived new data on biokinetics and dosimetry for infants with normal kidney function after undergoing renal scans with 99mTc-MAG3. In addition, we analyzed the associated age- and gender-specific excess lifetime risk due to ionizing radiation. The radiation-associated stochastic risk increases with the organ doses, taking age- and gender-specific influences into account. Overall, the lifetime radiation risk associated with the 99mTc-MAG3 scans is very low in comparison to the general population risk for developing cancer.

Recommended administered activities for (68)Ga-labelled peptides in paediatric nuclear medicine.

PURPOSE: The aim of this study was to establish a method for determining administered activities for (68)Ga-labelled peptides. Dose calculations were based on the weight-independent effective dose model proposed by the EANM paediatric dosage card for use in paediatric nuclear medicine. METHODS: Previously published time-integrated activity coefficients for (68)Ga-DOTATATE, (68)Ga-DOTATOC and (68)Ga-pentixafor were used to calculate age-independent effective doses. Consequently, the corresponding weight-dependent effective dose coefficients were rescaled according to the formalism of the EANM dosage card to determine the radiopharmaceutical class of  (68)Ga-labelled peptides ("multiples") and to calculate the baseline activities based on an upper limit for administered activity (185 MBq) in an adult. RESULTS: All calculated normalization factors suggest that the (68)Ga-labelled peptides are class "B" radiopharmaceuticals. The baseline activity for all compounds is 12.8 MBq. In analogy to (18)F-fluoride, we recommend a minimum activity of 14 MBq. CONCLUSION: For paediatric nuclear medicine applications involving (68)Ga-labelled peptides, we suggest determining administered activities based on the formalism proposed in this work. The corresponding effective doses from these procedures will remain age-independent.

SPECT- and PET-based patient-tailored treatment in neuroendocrine tumors: a comprehensive multidisciplinary team approach.

The overexpression of somatostatin receptors on the tumor cell surface of neuroendocrine tumors (NETs) detected by multimodal functional imaging modalities such as SPECT and PET tracers constitutes a therapeutic option using targeting radiolabeled compounds. We will introduce the theranostic concept in general, explain in more detail its development in NETs, and discuss available SPECT and PET tracers regarding their potential for diagnostic imaging, visualization of target expression, and treatment tailoring. Moreover, we will discuss the currently available peptide receptor radionuclide therapy principles and compare them to previously published studies. Finally, we will discuss which new concepts will most likely influence the theranostic treatment approach in NETs in the future.

The absorbed dose to blood from blood-borne activity.

The radiation absorbed dose to blood and organs from activity in the blood is relevant for nuclear medicine dosimetry and for research in biodosimetry. The present study provides coefficients for the average absorbed dose rates to the blood from blood-borne activity for radionuclides frequently used in targeted radiotherapy and in PET diagnostics. The results were deduced from published data for vessel radius-dependent dose rate coefficients and reasonable assumptions on the blood-volume distribution as a function of the vessel radius. Different parts of the circulatory system were analyzed separately. Vessel size information for heart chambers, aorta, vena cava, pulmonary artery, and capillaries was taken from published results of morphometric measurements. The remaining blood not contained in the mentioned vessels was assumed to reside in fractal-like vascular trees, the smallest branches of which are the arterioles or venules. The applied vessel size distribution is consistent with recommendations of the ICRP on the blood-volume distribution in the human. The resulting average absorbed dose rates to the blood per nuclear disintegration per milliliter (ml) of blood are (in 10(-11) Gy·s(-1)·Bq(-1)·ml) Y-90: 5.58, I-131: 2.49, Lu-177: 1.72, Sm-153: 2.97, Tc-99m: 0.366, C-11: 4.56, F-18: 3.61, Ga-68: 5.94, I-124: 2.55. Photon radiation contributes 1.1-1.2·10(-11) Gy·s(-1)·Bq(-1)·ml to the total dose rate for positron emitters but significantly less for the other nuclides. Blood self-absorption of the energy emitted by ß-particles in the whole blood ranges from 37% for Y-90 to 80% for Tc-99m. The correspondent values in vascular trees, which are important for the absorbed dose to organs, range from 30% for Y-90 to 82% for Tc-99m.

The limit of detection in scintigraphic imaging with I-131 in patients with differentiated thyroid carcinoma.

Radioiodine scintigraphy influences staging and treatment in patients with differentiated thyroid carcinoma. The limit of detection for fractional uptake in an iodine avid focus in a scintigraphic image was determined from the number of lesion net counts and the count density of the tissue background. The count statistics were used to calculate the diagnostic activity required to elevate the signal from a lesion with a given uptake significantly above a homogeneous background with randomly distributed counts per area. The dependences of the minimal uptake and the minimal size of lesions visible in a scan on several parameters of influence were determined by linking the typical biokinetics observed in iodine avid tissue to the lesion mass and to the absorbed dose received in a radioiodine therapy. The detection limits for fractional uptake in a neck lesion of a typical patient are about 0.001% after therapy with 7000 MBq, 0.01% for activities typically administered in diagnostic assessments (74-185 MBq), and 0.1% after the administration of 10 MBq I-131. Lesions at the limit of detection in a diagnostic scan with biokinetics eligible for radioiodine therapy are small with diameters of a few millimeters. Increasing the diagnostic activity by a factor of 4 reduces the diameter of visible lesions by 25% or about 1 mm. Several other determinants have a comparable or higher influence on the limit of detection than the administered activity; most important are the biokinetics in both blood pool and target tissue and the time of measurement. A generally valid recommendation for the timing of the scan is impossible as the time of the highest probability to detect iodine avid tissue depends on the administered activity as well as on the biokinetics in the lesion and background in the individual patient.

Self-irradiation of the blood from selected nuclides in nuclear medicine.

Nuclear medicine dosimetry and research in biodosimetry often require the knowledge of the absorbed dose to the blood. This study provides coefficients for the absorbed dose rates to the blood related to the activity concentration in the blood as a function of the vessel radius for radionuclides commonly used in targeted radiotherapy and in PET-diagnostics: C-11, F-18, Ga-68, Y-90, Tc-99 m, I-124, I-131, and Lu-177. The energy deposition patterns after nuclear disintegrations in blood vessel lumina (cylinders homogeneously filled with blood) with radii from 0.01 to 25.0 mm were simulated with the Monte-Carlo radiation transport code MCNPX. An additional contribution from photon radiation from activity in blood in the remainder of the body was taken into account based on a reasonable blood distribution model. The fraction of energy absorbed from non-penetrating radiation in the blood is low in thin blood vessels but approaches the total energy emitted by particles with increasing lumen radius. For photon radiation, irradiation to blood in small vessels is almost completely due to radioactive decays in distant blood distributed throughout the body, whereas the contribution from activity in the vessel becomes dominant for lumen radii exceeding 13 mm. The dependences of the absorbed dose rates on the lumen radius can be described with good accuracy by empirical functions which can be used to determine the absorbed doses to the blood and to the surrounding tissue.

Molecular radiotherapy: the NUKFIT software for calculating the time-integrated activity coefficient.

PURPOSE: Calculation of the time-integrated activity coefficient (residence time) is a crucial step in dosimetry for molecular radiotherapy. However, available software is deficient in that it is either not tailored for the use in molecular radiotherapy and/or does not include all required estimation methods. The aim of this work was therefore the development and programming of an algorithm which allows for an objective and reproducible determination of the time-integrated activity coefficient and its standard error. METHODS: The algorithm includes the selection of a set of fitting functions from predefined sums of exponentials and the choice of an error model for the used data. To estimate the values of the adjustable parameters an objective function, depending on the data, the parameters of the error model, the fitting function and (if required and available) Bayesian information, is minimized. To increase reproducibility and user-friendliness the starting values are automatically determined using a combination of curve stripping and random search. Visual inspection, the coefficient of determination, the standard error of the fitted parameters, and the correlation matrix are provided to evaluate the quality of the fit. The functions which are most supported by the data are determined using the corrected Akaike information criterion. The time-integrated activity coefficient is estimated by analytically integrating the fitted functions. Its standard error is determined assuming Gaussian error propagation. The software was implemented using MATLAB. RESULTS: To validate the proper implementation of the objective function and the fit functions, the results of NUKFIT and SAAM numerical, a commercially available software tool, were compared. The automatic search for starting values was successfully tested for reproducibility. The quality criteria applied in conjunction with the Akaike information criterion allowed the selection of suitable functions. Function fit parameters and their standard error estimated by using SAAM numerical and NUKFIT showed differences of <1%. The differences for the time-integrated activity coefficients were also <1% (standard error between 0.4% and 3%). In general, the application of the software is user-friendly and the results are mathematically correct and reproducible. An application of NUKFIT is presented for three different clinical examples. CONCLUSIONS: The software tool with its underlying methodology can be employed to objectively and reproducibly estimate the time integrated activity coefficient and its standard error for most time activity data in molecular radiotherapy.