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Purpose Ra-223 dichloride (223Ra, Xofigo®) is used for treatment of patients suffering from castration-resistant metastatic prostate cancer. The objective of this work was to apply the most recent biokinetic model for radium and its progeny to show their radiopharmacokinetic behaviour. Organ absorbed doses after intravenous injection of 223Ra were estimated and compared to clinical data and data of an earlier modelling study. Methods The most recent systemic biokinetic model of 223Ra and its progeny, developed by the International Commission on Radiological Protection (ICRP), as well as the ICRP human alimentary tract model were applied for the radiopharmacokinetic modelling of Xofigo® biodistribution in patients after bolus administration. Independent kinetics were assumed for the progeny of 223Ra. The time activity curves for 223Ra were modelled and the time integrated activity coefficients, $$ \overset{\sim }{a}\left({r}_S,{T}_D\right), $$ a ~ r S T D , in the source regions for each progeny were determined. For estimating the organ absorbed doses, the Specific Absorbed Fractions (SAF) and dosimetric framework of ICRP were used together with the aforementioned $$ \overset{\sim }{a}\left({r}_S,{T}_D\right) $$ a ~ r S T D values. Results The distribution of 223Ra after injection showed a rapid plasma clearance and a low urinary excretion. Main elimination was via faeces. Bone retention was found to be about 30% at 4 h post-injection. Similar tendencies were observed in clinical trials of other authors. The highest absorbed dose coefficients were found for bone endosteum, liver and red marrow, followed by kidneys and colon. Conclusion The biokinetic modelling of 223Ra and its progeny may help to predict their distributions in patients after administration of Xofigo®. The organ dose coefficients of this work showed some variation to the values reported from clinical studies and an earlier compartmental modelling study. The dose to the bone endosteum was found to be lower by a factor of ca. 3 than previously estimated.

Purpose The objective of this study was to evaluate the image degrading factors in quantitative 177Lu SPECT imaging when using both main gamma photopeak energies. Methods Phantom measurements with two different vials containing various calibrated activities in air or water were performed to derive a mean calibration factor (CF) for large and small volumes of interest (VOIs). In addition, Monte Carlo simulations were utilized to investigate the effect of scatter energy window width, scatter correction method, such as effective scatter source estimation (ESSE) and triple energy window (TEW), and attenuation map on the quantification of 177Lu. Results: The measured mean CF using large and small VOIs in water was 4.50 ± 0.80 and 4.80 ± 0.72 cps MBq−1, respectively. Simulations showed a reference CF of 3.3 cps MBq−1 for the water-filled phantom considering all photons excluding scattered events. By using the attenuation map generated for 190 keV photons, the calculated CFs for 113 keV and 208 keV are 10% lower than by using the weighted mean energy of 175 keV for 177Lu. The calculated CF using the TEW correction was 17% higher than using the ESSE method for a water-filled phantom. However, our findings showed that an appropriate scatter window combination can reduce this difference between TEW and ESSE methods. Conclusions The present work implies that choosing a suitable width of scatter energy windows can reduce uncertainties in radioactivity quantification. It is suggested to generate the attenuation map at 113 keV and 208 keV, separately. Furthermore, using small VOIs is suggested in CF calculation.

Purpose Ra-223-Dichloride (223Ra, Xofigo®) is used for treatment of patients suffering from castration-resistant metastatic prostate cancer. The objective of this work was to apply the most recent biokinetic model for radium and its progeny and dosimetric framework developed by the International Commission on Radiological Protection (ICRP) and to show their radiopharmacokinetic behaviour. Organ absorbed and equivalent doses after intravenous injection of 223Ra were estimated and compared to clinical data and other modelling study. Methods The most recent ICRP systemic biokinetic model of 223Ra and its progeny as well as the ICRP human alimentary tract model were applied for the radiopharmacokinetic modelling of Xofigo® biodistribution in patients after bolus administration. Independent kinetics was assumed for the progeny of 223Ra. The time activity curves for 223Ra were modelled and the time integrated activity coefficients, in the source regions for each progeny were determined. For estimating the organ absorbed doses, the Specific Absorbed Fractions (SAF) and dosimetric framework of ICRP were used together with the aforementioned values to estimate the organ absorbed and equivalent doses. Results The distribution of 223Ra after injection showed a rapid plasma clearance and a low urinary excretion. Main elimination was via faeces. Bone retention was found to be about 30% at 4 h post-injection. Similar tendencies were observed in clinic trials. The highest absorbed dose coefficients were found for bone endosteum, liver, and red marrow, followed by kidneys and colon. Conclusion The biokinetic modelling of 223Ra and its progeny may help to predict their distributions in patients after administration of Xofigo®. The organ dose coefficients of this work showed some variation to the values from clinical studies and of a previous compartmental modelling study. The dose to the bone endosteum was found to be lower by a factor of ca. 3 than previously estimated.

Purpose Ra-223 dichloride (223Ra, Xofigo®) is used for treatment of patients suffering from castration-resistant metastatic prostate cancer. The objective of this work was to apply the most recent biokinetic model for radium and its progeny to show their radiopharmacokinetic behaviour. Organ absorbed doses after intravenous injection of 223Ra were estimated and compared to clinical data and data of an earlier modelling study. Methods The most recent systemic biokinetic model of 223Ra and its progeny, developed by the International Commission on Radiological Protection (ICRP), as well as the ICRP human alimentary tract model were applied for the radiopharmacokinetic modelling of Xofigo® biodistribution in patients after bolus administration. Independent kinetics were assumed for the progeny of 223Ra. The time activity curves for 223Ra were modelled and the time integrated activity coefficients, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \overset{\sim }{a}\left({r}_S,{T}_D\right), $$\end{document}a~rSTD, in the source regions for each progeny were determined. For estimating the organ absorbed doses, the Specific Absorbed Fractions (SAF) and dosimetric framework of ICRP were used together with the aforementioned \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \overset{\sim }{a}\left({r}_S,{T}_D\right) $$\end{document}a~rSTD values. Results The distribution of 223Ra after injection showed a rapid plasma clearance and a low urinary excretion. Main elimination was via faeces. Bone retention was found to be about 30% at 4 h post-injection. Similar tendencies were observed in clinical trials of other authors. The highest absorbed dose coefficients were found for bone endosteum, liver and red marrow, followed by kidneys and colon. Conclusion The biokinetic modelling of 223Ra and its progeny may help to predict their distributions in patients after administration of Xofigo®. The organ dose coefficients of this work showed some variation to the values reported from clinical studies and an earlier compartmental modelling study. The dose to the bone endosteum was found to be lower by a factor of ca. 3 than previously estimated. Supplementary Information The online version contains supplementary material available at 10.1186/s40658-021-00388-1.

Double tracer studies in healthy human volunteers with stable isotopes of cerium citrate were performed with the aim of investigating the gastro-intestinal absorption of cerium (Ce), its plasma clearance and urinary excretion. In the present work, results of the clearance of Ce in blood plasma are shown after simultaneous intravenous and oral administration of a Ce tracer. Inductively coupled plasma mass spectrometry was used to determine the tracer concentrations in plasma. The results show that about 80% of the injected Ce citrate cleared from the plasma within the 5 mins post-administration. The data obtained are compared to a revised biokinetic model of Ce, which was initially developed by the International Commission on Radiological Protection (ICRP). The measured plasma clearance of Ce citrate was mostly consistent with that predicted by the ICRP biokinetic model. Furthermore, in an effort to quantify the uncertainty of the model prediction, the laboratory animal data on which the ICRP biokinetic Ce model is based, was analyzed. The measured plasma clearance and its uncertainty was also compared to the plasma clearance uncertainty predicted by the model. It was found that the measured plasma clearance during the first 15 min after administration is in a good agreement with the modelled plasma clearance. In general, the measured clearance falls inside the 95% confidence interval predicted by the biokinetic model.

The objective of this study was to evaluate the image degrading factors in quantitativePhantom measurements with two different vials containing various calibrated activities in air or water were performed to derive a mean calibration factor (CF) for large and small volumes of interest (VOIs). In addition, Monte Carlo simulations were utilized to investigate the effect of scatter energy window width, scatter correction method, such as effective scatter source estimation (ESSE) and triple energy window (TEW), and attenuation map on the quantification ofThe measured mean CF using large and small VOIs in water was 4.50 ± 0.80 and 4.80 ± 0.72 cps MBqThe present work implies that choosing a suitable width of scatter energy windows can reduce uncertainties in radioactivity quantification. It is suggested to generate the attenuation map at 113 keV and 208 keV, separately. Furthermore, using small VOIs is suggested in CF calculation.

Proton transfer reaction mass spectrometry (PTR-MS) has been used to analyze the volatile organic compounds (VOCs) emitted by in-vitro cultured human cells. For this purpose, two pairs of cancerous and non-cancerous human cell lines were selected:1. lung epithelium cells A-549 and retinal pigment epithelium cells hTERT-RPE1, cultured in different growth media; and 2. squamous lung carcinoma cells EPLC and immortalized human bronchial epithelial cells BEAS2B, cultured in identical growth medium. The VOCs in the headspace of the cell cultures were sampled: 1. online by drawing off the gas directly from the culture flask; and 2. by accumulation of the VOCs in PTFE bags connected to the flask for at least 12 h. The pure media were analyzed in the same way as the corresponding cells in order to provide a reference. Direct comparison of headspace VOCs from flasks with cells plus medium and from flasks with pure medium enabled the characterization of cell-line-specific production or consumption of VOCs. Among all identified VOCs in this respect, the most outstanding compound was m/z = 45 (acetaldehyde) revealing significant consumption by the cancerous cell lines but not by the non-cancerous cells. By applying multivariate statistical analysis using 42 selected marker VOCs, it was possible to clearly separate the cancerous and non-cancerous cell lines from each other.

Volatile organic compounds (VOCs) from breath can successfully be used to diagnose disease-specific pathological alterations in metabolism. However, the exact origin and underlying biochemical pathways that could be mapped to VOC signatures are mainly unknown. There is a knowledge gap regarding the contribution of tissues, organs, the gut microbiome, and exogenous factors to the "sum signal" from breath samples. Animal models for human disease such as mutant mice provide the possibility to reproduce genetic predisposition to disease, thereby allowing the in-depth analysis of metabolic and biochemical functions. We hypothesized that breath VOCs can be traced back to origins and organ-specific metabolic functions by combining breath concentrations with systemic levels detected in different organs and biological media (breath, blood, faeces and urine). For this we fed C57Bl/6N mice a grain-based chow or a purified low-fat diet, thereby modifying the emission of methanol in breath whereas acetone levels were unaffected. We then measured headspace concentrations of both VOCs in ex-vivo samples of several biological media. Especially cecum content was identified as a likely source of systemic methanol, whereas liver showed highest acetone concentrations. Our findings are a first step to the systemic mapping of VOC patterns to metabolic functions in mice because differences between VOCs could be traced to different sources in the body. As a future aim, different levels of so-called omics technologies (genomics, proteomics, metabolomics, and breathomics) could be mapped to metabolic pathways in multiple tissues deepening our understanding of VOC metabolism and possibly leading to early non-invasive biomarkers for human pathologies.

The accidental release of radioactive isotopes of strontium, mainly (90)Sr, into the environment and its transfer into the biosphere results in an internal radiation exposure of the affected population. In order to obtain reliable estimates of the committed dose due to an intake of Sr radionuclides, reliable information on its metabolic behaviour inside the human body is needed, i.e. biokinetic data on fractional uptake from contaminated foodstuffs, distribution to and retention in different organs and tissues of the human body. Such information can be obtained by tracer kinetic investigations. The committed effective dose is dependent on the fractional intestinal absorption of the ingested activity (f(1) value). The International Commission on Radiological Protection in its publication ICRP 67 adopted an f(1) value of 0.3 for adults. This study is aimed at investigating if the value corresponds with the actual uptake from contaminated foodstuffs. Aqueous solutions and contaminated vegetables, i.e. cress and salad (lettuce) were used as test materials. For this purpose, the methodology for intrinsic labelling of foodstuffs described in part 1 was applied. For aqueous solutions, a mean f(1) value of 0.63+/-0.14 (mean +/- SD) was obtained by administering 1 mg of strontium. The uptake of Sr from cress intrinsically labelled with about 1 mg Sr almost corresponds to that from aqueous solutions (f(1)=0.62+/-0.10), but from lettuce it is reduced by a factor of 2 (f(1)=0.27+/-0.08).

Breath gas analysis in humans proved successful in identifying disease states and assessing metabolic functions in a non-invasive way. While many studies report diagnostic capability using volatile organic compounds (VOC) in breath, the inter-individual variability even in healthy human cohorts is rather large and not completely understood in its biochemical origin. Laboratory mice are the predominant animal model system for human disorders and are analysed under highly standardized and controlled conditions. We established a novel setup to monitor VOCs as biomarkers for disease in the breath gas of non-anesthetized, non-restrained mice using a proton transfer reaction mass spectrometer with time of flight detection. In this study, we implemented breath gas analysis in a dietary intervention study in C57BL/6J mice with the aim to assess the variability in VOC signatures due to a change in the diet matrix. Mice were fed a standard laboratory chow and then exposed to four semi-purified low- or high-fat diets for four weeks. Random forest (RF++) was used to identify VOCs that specifically respond to the diet matrix change. Interestingly, we found that the change from a chow diet to semi-purified diets resulted in a considerable drop of several VOC levels. Our results suggest that the diet matrix impacts VOC signatures and the underlying metabolic functions and may be one source of variability in exhaled volatiles.

The phenotyping of genetic mouse models for human disorders may greatly benefit from breath gas analysis as a noninvasive tool to identify metabolic alterations in mice. Phenotyping screens such as the German Mouse Clinic demand investigations in unrestrained mice. Therefore, we adapted a breath screen in which exhaled volatile organic compounds (VOCs) were online monitored by proton transfer reaction mass spectrometry (hs-PTR-MS). The source strength of VOCs was derived from the dynamics in the accumulation profile of exhaled VOCs of a single mouse in a respirometry chamber. A careful survey of the accumulation revealed alterations in the source strength due to confounders, e.g., urine and feces. Moreover changes in the source strength of humidity were triggered by changes in locomotor behavior as mice showed a typical behavioral pattern from activity to settling down in the course of subsequent accumulation profiles. We demonstrated that metabolic changes caused by a dietary intervention, e.g., after feeding a high-fat diet (HFD) a sample of 14 male mice, still resulted in a statistically significant shift in the source strength of exhaled VOCs. Applying a normalization which was derived from the distribution of the source strength of humidity and accounted for varying locomotor behaviors improved the shift. Hence, breath gas analysis may provide a noninvasive, fast access to monitor the metabolic adaptation of a mouse to alterations in energy balance due to overfeeding or fasting and dietary macronutrient composition as well as a high potential for systemic phenotyping of mouse mutants, intervention studies, and drug testing in mice.

The radioactive isotopes of strontium, mainly (90)Sr, which are common fission products, may significantly contribute to the internal exposure of the population in case of their accidental release into the environment and transfer to the food chain. For (90)Sr, the internal radiation dose is significantly dependent on the fractional absorption of the ingested activity (f(1)-value). Human data on the absorption of dietary strontium and of soluble forms of the element give values ranging from about 0.15 to 0.45 (up to 1.0) for adults. The International Commission on Radiological Protection (ICRP) has adopted f(1)-values of 0.6 for children of less than 1 year of age, 0.4 for children between 1 and 15 years and 0.3 for adolescents above 15 years of age. This study was aimed at investigating how far these values correspond to the actual uptake of strontium from contaminated foodstuffs. A methodology is presented that has been developed for preparing foodstuffs intrinsically labelled with stable isotopes and that will be used in tracer kinetic investigations. The results show that cress and salad can be adequately labelled, i.e. a strontium concentration of 1.36+/-0.47 g per kg of cress (wet weight) and of 0.29+/-0.04 g per kg of salad (wet weight) may be obtained within 15 days and 24 days, respectively. For the biokinetic investigations on humans, applying stable isotopes of Sr as tracers, about 0.1-1 mg strontium is required per volunteer, i.e. a few grams of the edible parts of the labelled material are sufficient.

The radioactive isotopes of strontium, mainly 90Sr, which are common fission products, may significantly contribute to the internal exposure of the population in case of their accidental release into the environment and transfer to the food chain. For 90Sr, the internal radiation dose is significantly dependent on the fractional absorption of the ingested activity (f1-value). Human data on the absorption of dietary strontium and of soluble forms of the element give values ranging from about 0.15 to 0.45 (up to 1.0) for adults. The International Commission on Radiological Protection (ICRP) has adopted f1-values of 0.6 for children of less than 1 year of age, 0.4 for children between 1 and 15 years and 0.3 for adolescents above 15 years of age. This study was aimed at investigating how far these values correspond to the actual uptake of strontium from contaminated foodstuffs. A methodology is presented that has been developed for preparing foodstuffs intrinsically labelled with stable isotopes and that will be used in tracer kinetic investigations. The results show that cress and salad can be adequately labelled, i.e. a strontium concentration of 1.36±0.47 g per kg of cress (wet weight) and of 0.29±0.04 g per kg of salad (wet weight) may be obtained within 15 days and 24 days, respectively. For the biokinetic investigations on humans, applying stable isotopes of Sr as tracers, about 0.1–1 mg strontium is required per volunteer, i.e. a few grams of the edible parts of the labelled material are sufficient.

Breath gas analysis is a promising technology in the frame of medical diagnostics. By identifying disease-specific biomarkers in the breath of patients, a non-invasive and easy method for early diagnosis or therapy monitoring might be developed. However, to verify this potential and develop diagnostic tools based on breath gas analysis one essential prerequisite is a low variability in measurement of exhaled volatile organic compounds. Therefore, a study has been undertaken in order to identify possible artefacts within the application of a breath gas test in practice, for which the breath gas is analysed by proton transfer reaction-mass spectrometry (PTR-MS). After validating the low instrumental variability by repeatedly measuring standard gas, the variability of breath gas sampling has been evaluated. The latter has been carried out by measuring single breath gas samples (mixed expiratory breath) collected over different periods of time such as 1 min (10 volunteers, 4 breath gas samples each), 1 h (10 volunteers, 11 breath gas samples each) and several days (11 volunteers, 10 breath gas samples each). The breath gas samples were collected in Teflon bags and consecutively measured with PTR-MS. It was found that those samples collected within 1 min and 1 h show a low variability. This was, however, not the case for samples being collected over longer periods of time (15-70 days). Under these circumstances, many volatile organic compounds (VOCs) showed significant day-to-day variation in concentration, although the breath collection had been performed under the same conditions (similar sampling time, sampling technique, sample storage time, measurement conditions, etc). This large variation might be assigned to the influence of room air VOCs, which have been investigated in this work, or with other parameters which will be discussed. It was also found that the variability in the measurement of exhaled concentrations of methanol, acetone and isoprene within different individuals (inter individual variability) is much higher than differences in the same volunteer (intra individual variability) measured over a longer time interval.