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Purpose As α-emitters for radiopharmaceutical therapies are administered systemically by intravenous injection, blood will be irradiated by α-particles that induce clustered DNA double-strand breaks (DSBs). Here, we investigated the induction and repair of DSB damage in peripheral blood mononuclear cells (PBMCs) as a function of the absorbed dose to the blood following internal ex vivo irradiation with [223Ra]RaCl2. Methods Blood samples of ten volunteers were irradiated by adding [223Ra]RaCl2 solution with different activity concentrations resulting in absorbed doses to the blood of 3 mGy, 25 mGy, 50 mGy and 100 mGy. PBMCs were isolated, divided in three parts and either fixed directly (d-samples) or after 4 h or 24 h culture. After immunostaining, the induced γ-H2AX α-tracks were counted. The time-dependent decrease in α-track frequency was described with a model assuming a repair rate R and a fraction of non-repairable damage Q. Results For 25 mGy, 50 mGy and 100 mGy, the numbers of α-tracks were significantly increased compared to baseline at all time points. Compared to the corresponding d-samples, the α-track frequency decreased significantly after 4 h and after 24 h. The repair rates R were (0.24 ± 0.05) h−1 for 25 mGy, (0.16 ± 0.04) h−1 for 50 mGy and (0.13 ± 0.02) h−1 for 100 mGy, suggesting faster repair at lower absorbed doses, while Q-values were similar. Conclusion The results obtained suggest that induction and repair of the DSB damage depend on the absorbed dose to the blood. Repair rates were similar to what has been observed for irradiation with low linear energy transfer.

[223Ra]RaCl2 and [224Ra]RaCl2 are bone seekers, emitting high LET, and short range (< 100 μm) alpha-particles. Both radionuclides show similar decay properties; the total alpha energies are comparable (223Ra: ≈28 MeV, 224Ra: ≈26 MeV). [224Ra]RaCl2 has been used from the mid-1940s until 1990 for treating different bone and joint diseases with activities of up to approximately 50 MBq [224Ra]RaCl2. In 2013 [223Ra]RaCl2 obtained marketing authorization by the FDA and by the European Union for the treatment of metastatic prostate cancer with an activity to administer of 0.055 MBq per kg body weight for six cycles. For intravenous injections in humans a model calculation using the biokinetic model of ICRP67 shows a ratio of organ absorbed dose coefficients (224Ra:223Ra) between 0.37 (liver) and 0.97 except for the kidneys (2.27) and blood (1.57). For the red marrow as primary organ-at-risk, the ratio is 0.57. The differences are mainly caused be the differing half-lives of the decay products of both radium isotopes. Both radionuclides show comparable DNA damage patterns in peripheral blood mononuclear cells after internal ex-vivo irradiation. Data on the long-term radiation-associated side effects are only available for treatment with [224Ra]RaCl2. Two epidemiological studies followed two patient groups treated with [224Ra]RaCl2 for more than 25 years. One of them was the “Spiess study”, a cohort of 899 juvenile patients who received several injections of [224Ra]RaCl2 with a mean specific activity of 0.66 MBq/kg. Another patient group of ankylosing spondylitis patients was treated with 10 repeated intravenous injections of [224Ra]RaCl2, 1 MBq each, 1 week apart. In total 1,471 of these patients were followed-up in the “Wick study”. In both studies, an increased cancer mortality by leukemia and solid cancers was observed. Similar considerations on long-term effects likely apply to [223Ra]RaCl2 as well since the biokinetics are similar and the absorbed doses in the same range. However, this increased risk will most likely not be observed due to the much shorter life expectancy of prostate cancer patients treated with [223Ra]RaCl2.

Excretion analysis is the established method for detection of incorporated alpha-emitting radionuclides, but it is laborious and time consuming. We sought a simplified method in which changes in gene expression might be measured in human peripheral blood to detect incorporated radionuclides. Such an approach could be used to quickly determine internal exposure in instances of a radiological dispersal device or a radiation accident.We evaluated whole blood samples from five patients with castration-resistant prostate cancer and multiple bone metastases (without visceral or nodal involvement), who underwent treatment with the alpha emitting isotope Radium-223 dichloride (Ra-223, XofigoFirstly, we conducted whole genome screening of mRNAs (mRNA seq) and small RNAs (small RNA seq) using next generation sequencing in one patient at eight different time points during all six cycles of Ra-223-therapy. We identified 1900 mRNAs and 972 small RNAs (222 miRNAs) that were differentially up- or down-regulated during follow-up after the first treatment with Ra-223. Overall candidate RNA species inclusion criteria were a general (≥|2|-fold) change or with peaking profiles (≥|5|-fold) at specific points in time. Next we chose 72 candidate mRNAs and 101 small RNAs (comprising 29 miRNAs) for methodologic (This proof of concept provides support for the applicability of gene expression measurements to detect internalized alpha-emitting radionuclides, but further work is needed with a larger sample size. While our approach has merit for internal deposition monitoring, it was complicated by the severe clinical condition of the patients we studied.

This review presents efforts in Europe over the last few years with respect to standardization of quantitative imaging and dosimetry and comprises the results of several European research projects on practices regarding radiopharmaceutical therapies (RPTs). Because the European Union has regulatory requirements concerning dosimetry in RPTs, the European Association of Nuclear Medicine released a position paper in 2021 on the use of dosimetry under these requirements. The importance of radiobiology for RPTs is elucidated in another position paper by the European Association of Nuclear Medicine. Furthermore, how dosimetry interacts with clinical requirements is described, with several clinical examples. In the future, more efforts need to be undertaken to increase teaching and standardization efforts and to incorporate radiobiology for further individualizing patient treatment, with the aim of improving the outcome and safety of RPTs.

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.

To establish a dose-response relationship between radiation-induced DNA damage and the corresponding absorbed doses in blood irradiated with radionuclides in solution under ex vivo conditions, the absorbed dose coefficient for 1 ml for 1 h internal ex vivo irradiation of peripheral blood (dThe Monte Carlo simulation reproduces the irradiation geometry of a blood sample of 7 ml mixed with 1 ml of a water equivalent radioactive solution in an 8 ml vial. The simulation was performed for ten different radionuclides:The values of dThis study provides a comprehensive set of absorbed dose coefficients for 1 ml for 1 h internal ex vivo irradiation of peripheral blood in a special vial geometry and radionuclides typically used in Nuclear Medicine. Furthermore, the method proposed by this work can be easily adapted to a variety of internal irradiation conditions and serve as a reference for future studies.

Aim Recent advancements in PET technology have brought with it significant improvements in PET performance and image quality. In particular, the extension of the axial field of view of PET systems, and the introduction of semiconductor technology into the PET detector, initially for PET/MR, and more recently available long-field-of-view PET/CT systems (≥ 25 cm) have brought a step change improvement in the sensitivity of PET scanners. Given the requirement to limit paediatric doses, this increase in sensitivity is extremely welcome for the imaging of children and young people. This is even more relevant with PET/MR, where the lack of CT exposures brings further dose reduction benefits to this population. In this short article, we give some details around the benefits around new PET technology including PET/MR and its implications on the EANM paediatric dosage card. Material and methods Reflecting on EANM adult guidance on injected activities, and making reference to bed overlap and the concept of MBq.min bed−1 kg−1, we use published data on image quality from PET/MR systems to update the paediatric dosage card for PET/MR and extended axial field of view (≥ 25 cm) PET/CT systems. However, this communication does not cover the expansion of paediatric dosing for the half-body and total-body scanners that have recently come to market. Results In analogy to the existing EANM dosage card, new parameters for the EANM paediatric dosage card were developed (class B, baseline value: 10.7 MBq, minimum recommended activity 10 MBq). The recommended administered activities for the systems considered in this communication range from 11 MBq [18F]FDG for a child with a weight of 3 kg to 149 MBq [18F]FDG for a paediatric patient weight of 68 kg, assuming a scan of 3 min per bed position. The mean effective dose over all ages (1 year and older) is 2.85 mSv. Conclusion With this, recommendations for paediatric dosing are given for systems that have not been considered previously.

[EN] The purpose of the EANM Dosimetry Committee is to provide recommendations and guidance to scientists and clinicians on patient-specific dosimetry. Radiopharmaceuticals labelled with lutetium-177 (177Lu) are increasingly used for therapeutic applications, in particular for the treatment of metastatic neuroendocrine tumours using ligands for somatostatin receptors and prostate adenocarcinoma with small-molecule PSMA-targeting ligands. This paper provides an overview of reported dosimetry data for these therapies and summarises current knowledge about radiation-induced side effects on normal tissues and dose-effect relationships for tumours. Dosimetry methods and data are summarised for kidneys, bone marrow, salivary glands, lacrimal glands, pituitary glands, tumours, and the skin in case of radiopharmaceutical extravasation. Where applicable, taking into account the present status of the field and recent evidence in the literature, guidance is provided. The purpose of these recommendations is to encourage the practice of patient-specific dosimetry in therapy with 177Lu-labelled compounds. The proposed methods should be within the scope of centres offering therapy with 177Lu-labelled ligands for somatostatin receptors or small-molecule PSMA. Open access funding provided by Lund University. Economic support was granted by the Swedish Cancer Society (180747, 211754Pj01H) and Mrs. Berta Kamprad's Foundation (BKS-2020-13) (Sjogreen Gleisner).

Executive SummaryWith an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine.

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 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 β-emitters based on damage geometry.

The aim of this review is to provide an overview of the most recent technologic developments in state-of-the-art equipment and tools for dosimetry in radionuclide therapies. This includes, but is not restricted to, calibration methods for imaging systems. In addition, a summary of new developments that consider the influence of small-scale dosimetry and of biologic effects on radionuclide therapies is given. Finally, the current limitations of patient-specific dosimetry such as bone-marrow dosimetry or dosimetry of α-emitters are discussed.

ZusammenfassungDie Biodosimetrie leistet einen wichtigen Beitrag zum Verständnis der Wirkung ionisierender Strahlung. Ziel dieser Übersichtsarbeit ist es daher, Methoden und Ergebnisse der Biodosimetrie und deren Zusammenhang mit der physikalischen Dosimetrie vorzustellen. Die Daten dieser Arbeit wurden aus Veröffentlichungen nach 1995 erhoben. Die dabei verwendeten Methoden sind hauptsächlich die Analyse dizentrischer Chromosomen, der Mikrokern-Assay, sowie der γ-H2AX-Assay in Lymphozyten. Die Mehrzahl der Daten wurde während Radioiodtherapien erhoben. Etwa die Hälfte der Veröffentlichungen bezog die Ergebnisse nur auf die verabreichte Aktivität. Dosis-Wirkungsbeziehungen konnten nur in wenigen Arbeiten hergestellt werden. Insbesondere anhand der Daten, die mittels des γ-H2AX-Assays gewonnen wurden, konnte die Dosisabhängigkeit und der zeitliche Verlauf der DNA-Schadensantwort in vitro und in vivo mit ß–-Emittern gezeigt werden. Weitere Arbeiten sind nötig, um die Reparatur von DNA-Schäden und deren Zusammenhang mit der Energiedosis nach nuklearmedizinischer Diagnostik und Therapie, insbesondere auch mit α-Strahlern, noch besser beschreiben zu können.

Purpose The aim of this study was to investigate the time- and dose-dependency of DNA double-strand break (DSB) induction and repair in peripheral blood leucocytes of prostate cancer patients during therapy with 177Lu-PSMA. Methods Blood samples from 16 prostate cancer patients receiving their first 177Lu-PSMA therapy were taken before and at seven time-points (between 1 h and 96 h) after radionuclide administration. Absorbed doses to the blood were calculated using integrated time–activity curves of the blood and the whole-body. For DSB quantification, leucocytes were isolated, fixed in ethanol and immunostained with γ-H2AX and 53BP1 antibodies. Colocalizing foci of both DSB markers were manually counted in a fluorescence microscope. Results The average number of radiation-induced foci (RIF) per cell increased within the first 4 h after administration, followed by a decrease indicating DNA repair. The number of RIF during the first 2.6 h correlated linearly with the absorbed dose to the blood (R2 = 0.58), in good agreement with previously published in-vitro data. At late time-points (48 h and 96 h after administration), the number of RIF correlated linearly with the absorbed dose rate (R2 = 0.56). In most patients, DNA DSBs were repaired effectively. However, in some patients RIF did not disappear completely even 96 h after administration. Conclusion The general pattern of the time- and dose-dependent induction and disappearance of RIF during 177Lu-PSMA therapy is similar to that of other radionuclide therapies.

(18)F-clofarabine, a nucleotide purine analog, is a substrate for deoxycytidine kinase (dCK), a key enzyme in the deoxyribonucleoside salvage pathway. (18)F-clofarabine might be used to measure dCK expression and thus serve as a predictive biomarker for tumor responses to dCK-dependent prodrugs or small-molecule dCK inhibitors, respectively. As a prerequisite for clinical translation, we determined the human whole-body and organ dosimetry of (18)F-clofarabine. Methods: Five healthy volunteers were injected intravenously with 232.4 ± 1.5 MBq of (18)F-clofarabine. Immediately after tracer injection, a dynamic scan of the entire chest was acquired for 30 min. This was followed by 3 static whole-body scans at 45, 90, and 135 min after tracer injection. Regions of interest were drawn around multiple organs on the CT scan and copied to the PET scans. Organ activity was determined and absorbed dose was estimated with OLINDA/EXM software. Results: The urinary bladder (critical organ), liver, kidney, and spleen exhibited the highest uptake. For an activity of 250 MBq, the absorbed doses in the bladder, liver, kidney, and spleen were 58.5, 6.6, 6.3, and 4.3 mGy, respectively. The average effective dose coefficient was 5.1 mSv. Conclusion: Our results hint that (18)F-clofarabine can be used safely in humans to measure tissue dCK expression. Future studies will determine whether (18)F-clofarabine may serve as a predictive biomarker for responses to dCK-dependent prodrugs or small-molecule dCK inhibitors.

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.

This review mainly focuses on the dosimetry methodology which includes consideration of the number and time points of scans, imaging methodology, methods for integrating time-activity curves and calculating absorbed doses. (177)Lu-labelled compounds show many advantages for dosimetry assessments due to attractive physical properties which comprise low abundance of photons for sufficient post-therapy imaging, a clearly separated gamma peak at 208 keV, and a low range of beta particles. The most up-to-date results of absorbed dose calculations for the kidneys, bone marrow, and tumors are provided. The absorbed doses reported for radiopeptide therapies using (177)Lu labelled compounds taken from clinical studies show a high variability, presumably because of the different applied methodologies.

UnlabelledProstate-specific membrane antigen (PSMA) is a promising target for diagnosis and treatment of prostate cancer. EuK-Subkff-(68)Ga-DOTAGA ((68)Ga-PSMA Imaging & Therapy [PSMA I&T]) is a recently introduced PET tracer for imaging PSMA expression in vivo. Whole-body distribution and radiation dosimetry of this new probe were evaluated.MethodsFive patients with a history of prostate cancer were injected intravenously with 91-148 MBq of (68)Ga-PSMA I&T (mean ± SD, 128 ± 23 MBq). After an initial series of rapid whole-body scans, 3 static whole-body scans were acquired at 1, 2, and 4 h after tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM.ResultsInjection of 150 MBq of (68)Ga-PSMA I&T resulted in an effective dose of 3.0 mSv. The kidneys were the critical organ (33 mGy), followed by the urinary bladder wall and spleen (10 mGy each), salivary glands (9 mGy each), and liver (7 mGy).Conclusion(68)Ga-PSMA I&T exhibits a favorable dosimetry, delivering organ doses that are comparable to (kidneys) or lower than those delivered by (18)F-FDG.

68Ga-pentixafor is a promising PET tracer for imaging the expression of the human chemokine receptor 4 (CXCR4) in vivo. The whole-body distribution and radiation dosimetry of 68Ga-pentixafor were evaluated. Methods: Five multiple-myeloma patients were injected intravenously with 90–158 MBq of 68Ga-pentixafor (mean ± SD, 134 ± 25 MBq), and a series of 3 rapid multiple-bed-position whole-body scans were acquired immediately afterward. Subsequently, 4 static whole-body scans followed at 30 min, 1 h, 2 h, and 4 h after administration of the radiopharmaceutical. Venous blood samples were obtained. Time-integrated activity coefficients were determined from multiexponential regression of organ region-of-interest data normalized to the administered activity, for example, the time-dependent percentages of the injected activity per organ. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM. Results: The effective dose based on 150 MBq of 68Ga-pentixafor was 2.3 mSv. The highest organ-absorbed doses (for 150 MBq injected) were found in the urinary bladder wall (12.2 mGy), spleen (8.1 mGy), kidneys (5.3 mGy), and heart wall (4.0 mGy). Other organ mean absorbed doses were as follows: 2.7 mGy, liver; 2.1 mGy, red marrow; 1.7 mGy, testes; and 1.9 mGy, ovaries. Conclusion:68Ga-pentixafor exhibits a favorable dosimetry, delivering absorbed doses to organs that are lower than those delivered by 18F-FDG– or 68Ga-labeled somatostatin receptor ligands.

In 2005, the term theragnostics (theranostics) was introduced for describing the use of imaging for therapy planning in radiation oncology. In nuclear medicine, this expression describes the use of tracers for predicting the absorbed doses in molecular radiotherapy and, thus, the safety and efficacy of a treatment. At present, the most successful groups of isotopes for this purpose are 123I/124I/131I, 68Ga/177Lu, and 111In/86Y/90Y. The purpose of this review is to summarize available data on the dosimetry and dose-response relationships of several theranostic compounds, with a special focus on radioiodine therapy for differentiated thyroid cancer and peptide receptor radionuclide therapy. These are treatment modalities for which dose-response relationships for healthy tissues and tumors have been demonstrated. In addition, available data demonstrate that posttherapeutic dosimetry after a first treatment cycle predicts the absorbed doses in further cycles. Both examples show the applicability of the concept of theranostics in molecular radiotherapies. Nevertheless, unanswered questions need to be addressed in clinical trials incorporating dosimetry-related concepts for determining the amount of therapeutic activity to be administered.

International audience; The “intended purpose” in all therapeutic exposures is treatment efficacy against malignant disease. The optimization principle (as low as reasonably achievable, ALARA) of article 56, when applied in a therapy situation, states that absorbed doses to nontarget tissues should be kept reasonably low, but not so low as to lose efficacy. We think that this applies above all to the fight against life-threatening cancer. As a consequence, we believe that to adhere to the optimization principle in oncological patients, nuclear medicine therapy should be based on individualized dosimetry.

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.

In recent years internal dosimetry added valuable information on the diagnostic and therapeutic use of radionuclide imaging and therapy of neuroendocrine tumors.

This review compiles and analyzes the available dosimetry data of [ 68 Ga] labeled compounds. Dosimetry data are given for [ 68 Ga]DOTA-NOC, TOC, TATE, and NODAGA-RGDyK. The number of PET-scans with [ 68 Ga]DOTA-compounds for imaging neuroendocrine tumors is increasing because [ 68 Ga] has a higher affinity to somatostatin receptors (SSTR) in comparison to comparable [ 111 In]-compounds. In addition, the better image resolution of the PET images provides improved diagnostics. Despite its widespread use literature on dosimetry of [ 68 Ga]-labeled radiopharmaceuticals is sparse. In some cases the description of the underlying methodology is missing or human data are gained from the extrapolation of animal experiments. More and better documented dosimetry data will further promote the use of these promising new agents.

Die Koregistrierung von CT-Daten im Rahmen nuklearmedizinischer Untersuchungen erlaubt eine direkte Korrelation anatomischer und funktioneller Informationen. Szintigrafische Befunde konnen so prazise lokalisiert und die Dignitat unklarer CT-Befunde aufgrund funktioneller Daten beurteilt werden. Bei zahlreichen onkologischen Fragestellungen konnte eine Uberlegenheit der Hybridtechnik gegenuber separat durchgefuhrter anatomischer und funktioneller Untersuchungen gezeigt werden. Die Einfuhrung der PET/CT in die klinische Diagnostik hat aufgrund einer hohen diagnostischen Treffsicherheit zu einer Anderung des Diagnose-Algorithmus einiger solider Tumoren und hamatologischer Neoplasien gefuhrt. Bezuglich SPECT/CT konnte eine verbesserte Diagnostik von Knochenmetastasen, neuroendokrinen Tumoren und von Wachterlymphknoten bei Erstdiagnose eines Mammakarzinoms oder malignen Melanoms belegt werden. Die Anzahl der mittels Hybridgeraten durchgefuhrten Untersuchungen gehort zu den am schnellsten wachsenden unter den bildgebenden Verfahren in der Medizin. Mit zunehmender Untersuchungsfrequenz ruckt die Minimierung der Strahlenexposition immer mehr in den Fokus und der Untersuchungsablauf wird kontinuierlich optimiert. Viele onkologische Fragestellungen konnen bereits mit einer ’low-dose´-PET/CT- oder -SPECT/CT-Untersuchung hinreichend beantwortet werden. Durch die Verwendung der neuesten Geratetechnik kann die Strahlenexposition sowohl seitens der CT als auch durch die applizierte Aktivitat der Radiopharmaka wesentlich beeinflusst werden. Dieser Artikel soll eine Ubersicht uber die mit Hybriduntersuchungen verbundene Strahlenexposition geben und zeigen, wie diese bereits heute signifikant reduziert werden kann. Entscheidend ist, dass ionisierende Strahlung nur bei eindeutigen klinischen Fragestellungen zum Einsatz kommen darf.

The aim of this study was to synthesize and preclinically evaluate anSeveral conditions for the labeling ofQuantitative labeling yields could be achieved with97 % radiochemical purity. The

Background 177Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of 177Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications. Results 177Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq 177Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of 177Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels. Conclusions The 177Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range. Electronic supplementary material The online version of this article (doi:10.1186/s13550-016-0204-9) contains supplementary material, which is available to authorized users.

Diagnostic nuclear medicine procedures imply the administration of activity levels that do not lead to the appearance of radiation deterministic effects. Effects to be expected, if at all, are stochastic effects of ionizing radiation. The assessment of adverse health effects from exposure of ionizing radiation in the dose range commonly encountered in clinical (and pediatric) diagnostic nuclear medicine is based on epidemiological and biological data. Most of the data on the effects on human health after exposure to ionizing radiation comes from the Life Span Study of the survivors of the bombings of Hiroshima and Nagasaki, as reported by the Radiation Effects Research Foundation [18, 22–24]. In addition, there are few data on the stochastic radiation risk after treatment of thyroid diseases with radioiodine [10, 21, 26, 31]. However, there is no clear evidence that there is an increase in cancer risk associated with I-131 therapy [31]. No such data are available concerning the potential cancer risk of diagnostic nuclear medicine.

Radioguided surgery requires a significant amount of technology for its implementation. As a result, surgeons working in this field must have a basic know-how that extends beyond the standard surgical training and covers the relevant physics. Within this chapter we have tried to synthesize the background knowledge needed for a complete understanding of the most important aspects and processes. The terminology and the explanations target people just starting in the field, and the contents should prove readily intelligible as long as the complete chapter is read.

The use of radioactive substances for sentinel lymph node (SLN) biopsy needs consideration on how to optimize radiation safety issues. In this chapter an overview on basic radiation-related quantities, definitions, and on patient dosimetry is given. Values of absorbed and effective doses are provided for patients, the staff in the operation theater and in the pathology department, and for waste disposal. For radiolocalization of SLN with Tc-99m, the dose to the patients and the exposure of the staff are low; for radiopharmaceuticals with longer half-lives and/or positron emitters, individual monitoring of staff exposure and contamination should be considered for larger patient numbers.

The aim of the study was to investigate DNA double-strand break (DSB) formation and its correlation to the absorbed dose to the blood in patients with surgically treated differentiated thyroid cancer undergoing their first radioiodine therapy for remnant ablation. Methods: Twenty patients were included in this study. At least 7 peripheral blood samples were obtained before and between 0.5 and 120 h after administration of radioiodine. From the time–activity curves of the blood and the whole body, residence times for the blood self-irradiation and the irradiation from the whole body were determined. Peripheral blood lymphocytes were isolated, ethanol-fixed, and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was analyzed as a function of the absorbed dose to the blood and compared with an in vitro calibration curve for 131I and 177Lu established previously in our institution. Results: The average number of radiation-induced foci (RIF) per cell increased over the first 3 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 2 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time points, RIF numbers diminished, along with dropping dose rates, indicating progression of DNA repair. Individual patient data were characterized by a linear dose-dependent increase and a biexponential response function describing a fast and a slow repair component. Conclusion: With the experimental results and model calculations presented in this work, a dose–response relationship is demonstrated, and an analytic function describing the time course of the in vivo damage response after internal irradiation of patients with 131I is established.

For diagnostic dosimetry in nuclear medicine, quantitative imaging and activity measurements of blood and urine samples are essential. This is followed by the calculation of the absorbed organ doses and the effective dose. To achieve this, a correct temporal sampling and the use of adequate procedures to integrate the time-activity curves to obtain the total number of decays in the source organs (the time-integrated activity coefficients, TIACs) are prerequisites. If the TIACs are known, a calculation of the absorbed doses is performed by applying the “MIRD formalism”: D = TIAC · A 0 · S D: the mean absorbed dose to a target from a source region. A 0 : administered activity S: mean absorbed dose per unit cumulated activity in the target region. The S-values used for diagnostics are still based on mathematical phantoms. Although, the ICRP in its publication 103 requires the use of a set of gender-specific realistic voxel phantoms, the S-values for isotopes, however, are not yet made publicly available. For diagnostics the effective dose is the main protection quantity. It is calculated using the tissue weighting factors established by the ICRP in the publications ICRP60 and ICRP103. The effective dose, however, is only intended to calculate the risk for an age-independent reference person, not the individual risk. It is a protection quantity and is related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation.

This review mainly focuses on the dosimetry methodology which includes consideration of the number and time points of scans, imaging methodology, methods for integrating time-activity curves and calculating absorbed doses. (177)Lu-labelled compounds show many advantages for dosimetry assessments due to attractive physical properties which comprise low abundance of photons for sufficient post-therapy imaging, a clearly separated gamma peak at 208 keV, and a low range of beta particles. The most up-to-date results of absorbed dose calculations for the kidneys, bone marrow, and tumors are provided. The absorbed doses reported for radiopeptide therapies using (177)Lu labelled compounds taken from clinical studies show a high variability, presumably because of the different applied methodologies.

Purpose The impact on patients’ health of radiopharmaceuticals in nuclear medicine diagnostics has not until now been evaluated systematically in a European context. Therefore, as part of the EU-funded Project PEDDOSE.NET (www.peddose.net), we review and summarize the current knowledge on biokinetics and dosimetry of commonly used diagnostic radiopharmaceuticals. Methods A detailed literature search on published biokinetic and dosimetric data was performed mostly via PubMed (www.ncbi.nlm.nih.gov/pubmed). In principle the criteria for inclusion of data followed the EANM Dosimetry Committee guidance document on good clinical reporting. Results Data on dosimetry and biokinetics can be difficult to find, are scattered in various journals and, especially in paediatric nuclear medicine, are very scarce. The data collection and calculation methods vary with respect to the time-points, bladder voiding, dose assessment after the last data point and the way the effective dose was calculated. In many studies the number of subjects included for obtaining biokinetic and dosimetry data was fewer than ten, and some of the biokinetic data were acquired more than 20 years ago. Conclusion It would be of interest to generate new data on biokinetics and dosimetry in diagnostic nuclear medicine using state-of-the-art equipment and more uniform dosimetry protocols. For easier public access to dosimetry data for diagnostic radiopharmaceuticals, a database containing these data should be created and maintained. Electronic supplementary material The online version of this article (doi:10.1007/s00259-011-1904-z) contains supplementary material, which is available to authorized users.

Purpose The aim of the study was to investigate DNA double strand break (DSB) formation and its correlation with the absorbed dose to the blood lymphocytes of patients undergoing their first peptide receptor radionuclide therapy (PRRT) with 177Lu-labelled DOTATATE/DOTATOC. Methods The study group comprised 16 patients receiving their first PRRT. At least six peripheral blood samples were obtained before, and between 0.5 h and 48 h after radionuclide administration. From the time–activity curves of the blood and the whole body, residence times for blood self-irradiation and whole-body irradiation were determined. Peripheral blood lymphocytes were isolated, fixed with ethanol and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was determined as a function of the absorbed dose to the blood and compared with an in vitro calibration curve established in our laboratory with 131I and 177Lu. Results The average number of radiation-induced foci (RIF) per cell increased over the first 5 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 5 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time-points the number of RIF decreased, indicating progression of DNA repair. Conclusion Measurements of RIF and the absorbed dose to the blood after systemic administration of 177Lu may be used to obtain data on the individual dose–response relationships in vivo. Individual patient data were characterized by a linear dose-dependent increase and an exponential decay function describing repair. Electronic supplementary material The online version of this article (doi:10.1007/s00259-015-3083-9) contains supplementary material, which is available to authorized users.

PurposeThe aim of this study was to synthesize and preclinically evaluate an 18F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined.MethodsSeveral conditions for the labeling of 18F-PSMA-11 via 18F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed.ResultsQuantitative labeling yields could be achieved with >97% radiochemical purity. The 18F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p