Einflussgrößen der Nephrotoxizität eines Radiotracers am Beispiel der Radioimmuntherapie mit 188Re-anti-CD66

Die Nephrotoxizität ist die wichtigste Nebenwirkung bei Applikation von Radioimmunkonjugaten zur Konditionierung des Knochenmarks bei der Leukämiebehandlung. Die Auswirkungen der Unsicherheiten bei der Dosisbestimmung der Niere, insbesondere durch individuelle Nierenmasse und regionale Aktivitätsunterschiede, wurden untersucht. Die biologische Strahlenwirkung wurde als Biologisch Effektive Dosis unter Berücksichtigung des Zeitverlaufs der Dosisapplikation quantifiziert. Berechnungen wurden neben 188Rhenium auch für andere therapierelevante Radionuklide durchgeführt

Correction of scan time dependence of standard uptake values in oncological PET

BACKGROUND: Standard uptake values (SUV) as well as tumor-to-blood standard uptake ratios (SUR) measured with [ (18)F-]fluorodeoxyglucose (FDG) PET are time dependent. This poses a serious problem for reliable quantification since variability of scan start time relative to the time of injection is a persistent issue in clinical oncological Positron emission tomography (PET). In this work, we present a method for scan time correction of, both, SUR and SUV. METHODS: Assuming irreversible FDG kinetics, SUR is linearly correlated to K(m) (the metabolic rate of FDG), where the slope only depends on the shape of the arterial input function (AIF) and on scan time. Considering the approximately invariant shape of the AIF, this slope (the ‘Patlak time’) is an investigation independent function of scan time. This fact can be used to map SUR and SUV values from different investigations to a common time point for quantitative comparison. Additionally, it turns out that modelling the invariant AIF shape by an inverse power law is possible which further simplifies the correction procedure. The procedure was evaluated in 15 fully dynamic investigations of liver metastases from colorectal cancer and 10 dual time point (DTP) measurements. From each dynamic study, three ‘static scans’ at T=20,35,and 55 min post injection (p.i.) were created, where the last scan defined the reference time point to which the uptake values measured in the other two were corrected. The corrected uptake values were then compared to those actually measured at the reference time. For the DTP studies, the first scan (acquired at (78.1 ± 15.9) min p.i.) served as the reference, and the uptake values from the second scan (acquired (39.2 ± 9.9) min later) were corrected accordingly and compared to the reference. RESULTS: For the dynamic data, the observed difference between uncorrected values and values at reference time was (-52±4.5)% at T=20 min and (-31±3.7)% at T=35 min for SUR and (-30±6.6)% at T=20 min and (-16±4)% at T=35 min for SUV. After correction, the difference was reduced to (-2.9±6.6)% at T=20 min and (-2.7±5)% at T=35 min for SUR and (1.9% ± 6.2)% at T=20 min and (1.7 ± 3.3)% at T=35 min for SUV. For the DTP studies, the observed differences of SUR and SUV between late and early scans were (48 ± 11)% and (24 ± 8.4)%, respectively. After correction, these differences were reduced to (2.6 ± 6.9)% and (-2.4±7.3)%, respectively. CONCLUSION: If FDG kinetics is irreversible in the targeted tissue, correction of SUV and SUR for scan time variability is possible with good accuracy. The correction distinctly improves comparability of lesion uptake values measured at different times post injection

Einflussgrößen der Nephrotoxizität eines Radiotracers am Beispiel der Radioimmuntherapie mit 188Re-anti-CD66

Die Nephrotoxizität ist die wichtigste Nebenwirkung bei Applikation von Radioimmunkonjugaten zur Konditionierung des Knochenmarks bei der Leukämiebehandlung. Die Auswirkungen der Unsicherheiten bei der Dosisbestimmung der Niere, insbesondere durch individuelle Nierenmasse und regionale Aktivitätsunterschiede, wurden untersucht. Die biologische Strahlenwirkung wurde als Biologisch Effektive Dosis unter Berücksichtigung des Zeitverlaufs der Dosisapplikation quantifiziert. Berechnungen wurden neben 188Rhenium auch für andere therapierelevante Radionuklide durchgeführt

Einflussgrößen der Nephrotoxizität eines Radiotracers am Beispiel der Radioimmuntherapie mit 188Re-anti-CD66

Die Nephrotoxizität ist die wichtigste Nebenwirkung bei Applikation von Radioimmunkonjugaten zur Konditionierung des Knochenmarks bei der Leukämiebehandlung. Die Auswirkungen der Unsicherheiten bei der Dosisbestimmung der Niere, insbesondere durch individuelle Nierenmasse und regionale Aktivitätsunterschiede, wurden untersucht. Die biologische Strahlenwirkung wurde als Biologisch Effektive Dosis unter Berücksichtigung des Zeitverlaufs der Dosisapplikation quantifiziert. Berechnungen wurden neben 188Rhenium auch für andere therapierelevante Radionuklide durchgeführt

The effect of dimethyl sulfoxide on the induction of DNA strand breaks in plasmid DNA and colony formation of PC Cl3 mammalian cells by alpha-, beta-, and Auger electron emitters 223Ra, 188Re, and 99mTc

BACKGROUND: DNA damage occurs as a consequence of both direct and indirect effects of ionizing radiation. The severity of DNA damage depends on the physical characteristics of the radiation quality, e.g., the linear energy transfer (LET). There are still contrary findings regarding direct or indirect interactions of high-LET emitters with DNA. Our aim is to determine DNA damage and the effect on cellular survival induced by (223)Ra compared to (188)Re and (99m)Tc modulated by the radical scavenger dimethyl sulfoxide (DMSO). METHODS: Radioactive solutions of (223)Ra, (188)Re, or (99m)Tc were added to either plasmid DNA or to PC Cl3 cells in the absence or presence of DMSO. Following irradiation, single strand breaks (SSB) and double strand breaks (DSB) in plasmid DNA were analyzed by gel electrophoresis. To determine the radiosensitivity of the rat thyroid cell line (PC Cl3), survival curves were performed using the colony formation assay. RESULTS: Exposure to 120 Gy of (223)Ra, (188)Re, or (99m)Tc leads to maximal yields of SSB (80 %) in plasmid DNA. Irradiation with 540 Gy (223)Ra and 500 Gy (188)Re or (99m)Tc induced 40, 28, and 64 % linear plasmid conformations, respectively. DMSO prevented the SSB and DSB in a similar way for all radionuclides. However, with the α-emitter (223)Ra, a low level of DSB could not be prevented by DMSO. Irradiation of PC Cl3 cells with (223)Ra, (188)Re, and (99m)Tc pre-incubated with DMSO revealed enhanced survival fractions (SF) in comparison to treatment without DMSO. Protection factors (PF) were calculated using the fitted survival curves. These factors are 1.23 ± 0.04, 1.20 ± 0.19, and 1.34 ± 0.05 for (223)Ra, (188)Re, and (99m)Tc, respectively. CONCLUSIONS: For (223)Ra, as well as for (188)Re and (99m)Tc, dose-dependent radiation effects were found applicable for plasmid DNA and PC Cl3 cells. The radioprotection by DMSO was in the same range for high- and low-LET emitter. Overall, the results indicate the contribution of mainly indirect radiation effects for each of the radionuclides regarding DNA damage and cell survival. In summary, our findings may contribute to fundamental knowledge about the α-particle induced DNA damage

Additional file 1: of The effect of dimethyl sulfoxide on the induction of DNA strand breaks in plasmid DNA and colony formation of PC Cl3 mammalian cells by alpha-, beta-, and Auger electron emitters 223Ra, 188Re, and 99mTc

Representative agarose gels of 223Ra, 188Re, and 99mTc in the absence (lanes 1–6) and presence (lanes 7–12) of 0.2 M DMSO. Plasmid DNA was treated with 20, 40, 80, 120, 180, 540 Gy of either 223Ra (A); 40, 80, 120, 150, 200, 500 Gy 188Re (B) or 99mTc (C), respectively. Lanes C are the control plasmid DNA without irradiations. (PPTX 191 kb

99mTc-labeled HYNIC-DAPI causes plasmid DNA damage with high efficiency.

(99m)Tc is the standard radionuclide used for nuclear medicine imaging. In addition to gamma irradiation, (99m)Tc emits low-energy Auger and conversion electrons that deposit their energy within nanometers of the decay site. To study the potential for DNA damage, direct DNA binding is required. Plasmid DNA enables the investigation of the unprotected interactions between molecules and DNA that result in single-strand breaks (SSBs) or double-strand breaks (DSBs); the resulting DNA fragments can be separated by gel electrophoresis and quantified by fluorescent staining. This study aimed to compare the plasmid DNA damage potential of a (99m)Tc-labeled HYNIC-DAPI compound with that of (99m)Tc pertechnetate ((99m)TcO4(-)). pUC19 plasmid DNA was irradiated for 2 or 24 hours. Direct and radical-induced DNA damage were evaluated in the presence or absence of the radical scavenger DMSO. For both compounds, an increase in applied activity enhanced plasmid DNA damage, which was evidenced by an increase in the open circular and linear DNA fractions and a reduction in the supercoiled DNA fraction. The number of SSBs elicited by 99mTc-HYNIC-DAPI (1.03) was twice that caused by (99m)TcO4(-) (0.51), and the number of DSBs increased fivefold in the (99m)Tc-HYNIC-DAPI-treated sample compared with the (99m)TcO4(-) treated sample (0.02 to 0.10). In the presence of DMSO, the numbers of SSBs and DSBs decreased to 0.03 and 0.00, respectively, in the (99m)TcO4(-) treated samples, whereas the numbers of SSBs and DSBs were slightly reduced to 0.95 and 0.06, respectively, in the (99m)Tc-HYNIC-DAPI-treated samples. These results indicated that (99m)Tc-HYNIC-DAPI induced SSBs and DSBs via a direct interaction of the (99m)Tc-labeled compound with DNA. In contrast to these results, (99m)TcO4(-) induced SSBs via radical formation, and DSBs were formed by two nearby SSBs. The biological effectiveness of (99m)Tc-HYNIC-DAPI increased by approximately 4-fold in terms of inducing SSBs and by approximately 10-fold in terms of inducing DSBs

Comparison of image quality and spatial resolution between ¹⁸F, ⁶⁸Ga, and ⁶⁴Cu phantom measurements using a digital Biograph Vision PET/CT

Background: PET nuclides can have a considerable influence on the spatial resolution and image quality of PET/CT scans, which can influence diagnostics in oncology, for example. The individual impact of the positron energy of ¹⁸F, ⁶⁸Ga, and ⁶⁴Cu on spatial resolution and image quality was compared for PET/CT scans acquired using a clinical, digital scanner. - Methods: A Jaszczak phantom and a NEMA PET body phantom were filled with ¹⁸F-FDG, ⁶⁸Ga-HCl, or ⁶⁴Cu-HCl, and PET/CT scans were performed on a Siemens Biograph Vision. Acquired images were analyzed regarding spatial resolution and image quality (recovery coefficients (RC), coefficient of variation within the background, contrast recovery coefficient (CRC), contrast–noise ratio (CNR), and relative count error in the lung insert). Data were compared between scans with different nuclides.- Results: We found that image quality was comparable between ¹⁸F-FDG and ⁶⁴Cu-HCl PET/CT measurements featuring similar maximal endpoint energies of the positrons. In comparison, RC, CRC, and CNR were degraded in ⁶⁸Ga-HCl data despite similar count rates. In particular, the two smallest spheres of 10 mm and 13 mm diameter revealed lower RC, CRC, and CNR values. The spatial resolution was similar between ¹⁸F-FDG and ⁶⁴Cu-HCl but up to 18% and 23% worse compared with PET/CT images of the NEMA PET body phantom filled with ⁶⁸Ga-HCl. - Conclusions: The positron energy of the PET nuclide influences the spatial resolution and image quality of a digital PET/CT scan. The image quality and spatial resolution of ⁶⁸Ga-HCl PET/CT images were worse than those of ¹⁸F-FDG or ⁶⁴Cu-HCl despite similar count rates