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.

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.

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.

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.

Recombinant human thyrotropin: safety and quality of life evaluation.

Recombinant human TSH (rhTSH) (thyrotropin alfa, Genzyme Co.) has been developed to improve the management of patients with differentiated thyroid cancer, who need radioiodine (131I) for treatment or follow-up diagnosis. Data available from published series involving approximately 500 patients prove that rhTSH is safe and that mostly unspecific non-severe side effects may occur (e.g. nausea, vomiting, headache or fatigue and dizziness). Tumor swelling which has been occasionally observed after rhTSH injection is a phenomenon well known from the past attributed to endogenous TSH stimulation after thyroid hormone withdrawal (THW) and can be prevented or alleviated by concomitant administration of glucocorticoids. The absorbed dose to the tumor after preparation of 131I therapy with rhTSH as compared to THW is not statistically different. The radiation dose to the blood and the remainder, however, is significantly lower if rhTSH is used instead of THW which is a strong argument in favor of rhTSH. Most importantly, the quality of life (QOL) after rhTSH is preserved as compared to THW where symptoms of hypothyroidism significantly impair QOL. Last but not least, more convenient scheduling of patients and shorter duration of time to be spent in the radioprotective ward are further arguments in favor of rhTSH.

EANM Dosimetry Committee guidance document: good practice of clinical dosimetry reporting.

Many recent publications in nuclear medicine contain data on dosimetric findings for existing and new diagnostic and therapeutic agents. In many of these articles, however, a description of the methodology applied for dosimetry is lacking or important details are omitted. The intention of the EANM Dosimetry Committee is to guide the reader through a series of suggestions for reporting dosimetric approaches. The authors are aware of the large amount of data required to report the way a given clinical dosimetry procedure was implemented. Another aim of this guidance document is to provide comprehensive information for preparing and submitting publications and reports containing data on internal dosimetry. This guidance document also contains a checklist which could be useful for reviewers of manuscripts submitted to scientific journals or for grant applications. In addition, this document could be used to decide which data are useful for a documentation of dosimetry results in individual patient records. This may be of importance when the approval of a new radiopharmaceutical by official bodies such as EMA or FDA is envisaged.

(131)I therapy in patients with benign thyroid disease does not conclusively lead to a higher risk of subsequent malignancies.

UNLABELLED: Due to its excellent tolerability and low incidence of side effects, 131I therapy has been the treatment of choice for benign thyroid diseases for over 60 years. A potentially increased risk of malignancies due to this therapy is however still subject of debate. AIM: To review the literature pertaining to 131I therapy of benign thyroid diseases in order to establish whether there is an increased incidence of, or increased mortality due to malignancies of the thyroid or other organs. METHODS: In order to allow for sufficient long-term follow-up time after 131I therapy, only literature after 1990 was reviewed. Two criteria were applied to consider an increased incidence of malignancies linked to 131I therapy: a) there should be a latency period of at least 5 years between 131I therapy and the observation of an increased risk b) an elevated risk should increase with increasing radiation exposure. RESULTS: A total of 7 studies reporting cancer incidence and / or mortality in 4 different patient collectives spanning a total of 54510 patients over an observation period varying from 2-49 years were found. Although some studies detected a slightly increased risk for malignancies of the thyroid or the digestive system, others did not find these effects - while other studies even reported a slightly lower risk of malignant (thyroid) disease after 131I therapy for benign thyroid diseases. CONCLUSION: As over 60 years of experience has thus far failed to produce conclusive evidence to the contrary, it can be concluded that there is no increased risk of malignancies after 131I therapy for benign thyroid disease.

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.

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.

[Dosimetry of short-ranged radionuclides]. / Dosimetrie offener Radionuklide mit kurzer Reichweite.

More and more targeted radiotherapies (TRT) are carried out with pure beta-emitters such as 90Y. Normally fixed activities are administered without considering the individual biokinetics increasing the risk of under- or overdosing. In addition, it would be helpful to obtain additional data on dose-response relationships for further optimization of TRTs. Therefore, post-therapeutic dosimetry using quantitative imaging becomes more important. For an optimization of TRTs additional aspects such as the changing dose rate and radiobiological considerations need to be taken into account. This paper provides an overview on bremsstrahlung imaging modalities after therapies with pure beta-emitters. In addition, new dosimetric methods are described which consider dose rate and fractionation of treatment.

Joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma.

Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/oropharyngeal squamous cell carcinoma (OSCC), and the decision of whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method for determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histologic nodal staging and avoids overtreating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This document is designed to outline the current best practice guidelines for the provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. Preparation of this guideline was carried out by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial (SENT) Committee.

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.

Intra- and interobserver variability of thyroid volume measurements in healthy adults by 2D versus 3D ultrasound.

UNLABELLED: Thyroid volume measurement by ultrasonography (US) is essential in numerous clinical diagnostic and therapeutic fields. While known to be limited, the accuracy and precision of two-dimensional (2D) US thyroid volume measurement have not been thoroughly characterized. OBJECTIVE: We sought to assess the intra- and interobserver variability, accuracy and precision of thyroid volume determination by conventional 2D US in healthy adults using reference volumes determined by three-dimensional (3D) US. Design, METHODS: In a prospective blinded trial, thyroid volumes of ten volunteers were determined repeatedly by nine experienced sonographers using conventional 2D US (ellipsoid model). The values obtained were statistically compared to the so-called true volumes determined by 3D US (multiplanar approximation), the so-called gold standard, to estimate systematic errors and relative deviations of individual observers. RESULTS: The standard error of measurement (SEM) for one observer and successive measurements (intraobserver variability), was 14%, and for different observers and repeated measurements (interobserver variability), 17%. The minimum relative thyroid volume change significantly different at the 95% level was 39% for the same observer and 46% for different observers. Regarding accuracy, the mean value of the differences showed a significant thyroid volume overestimation (17%, p < 0.01) by 2D relative to 3D US. CONCLUSION: 2D US is appropriate for routine thyroid volumetry. Nevertheless, the so-called human factor (random error) should be kept in mind and correction is needed for methodical bias (systematic error). Further efforts are required to improve the accuracy and precision of 2D US thyroid volumetry by optimizing the underlying geometrical modeling or by the application of 3D US.