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Zusammenfassung Ziel Im Zuge der Novellierung des Strahlenschutzrechts kam es zu einer Aktualisierung von Grenzwerten, welche Auswirkungen auf die uneingeschränkte Freigabe von Reststoffen nach nuklearmedizinischer Therapie haben können. Zudem gab es in der Vergangenheit Hinweise auf langlebige Begleitnuklide in 153Sm- und 223Ra-Präparaten. Aus diesem Grund war das Ziel dieser Arbeit, eine Analyse der Radionuklidreinheit von ausgewählten Therapiepräparaten durchzuführen. Methode Es wurden 48 Proben von insgesamt 12 verschiedenen Therapiepräparaten untersucht. Die qualitative und quantitative Bestimmung der Begleitnuklide wurde an einem Halbleiterdetektor aus hochreinem Germanium (HPGe-Detektor) durchgeführt. Ergebnis In 90Y-Citrat, 153Sm-Quadramet, 166Ho-QuiremSpheres und 169Er-Erbiumcitrat ließen sich verschiedene Europium-Isotope nachweisen, wobei der größte Anteil mit 7,0 ppm (152Eu), 8,4 ppm (154Eu) und 2,1 ppm (155Eu) in 153Sm gefunden wurde. Als deutliches Begleitnuklid in 169Er zeigte sich 169Yb (513 ppm). Im Falle von 177Lu-Präparaten zeigte sich ein deutlicher Unterschied im Gehalt von 177mLu (0,8 ppm vs. 0,0024 ppm) für zwei Hersteller. Innerhalb der Nachweisgrenzen konnten keine Begleitnuklide bei 90Y-Sphären, 223Ra und 225Ac gefunden werden. Schlussfolgerung Für die gefundenen Begleitnuklide resultiert vielfach eine Überschreitung der Grenzwerte für die uneingeschränkte Freigabe. Das hat zur Folge, das alternative Freigabeverfahren (Verlängerung der Abklingdauer, spezifische Freigabe, Freigabe im Einzelfall) oder eine Abgabe an Landessammelstellen in Erwägung gezogen werden müssen. Zusätzlich sind technische Verfahren zur Reduktion oder Vermeidung von Begleitnukliden ein möglicher Lösungsansatz. Konsequenzen für die Strahlenexposition des Patienten konnten ausgeschlossen werden.

After transarterial radioembolization (TARE) with microspheres loaded with holmium-166, radioactivity is excreted from the body. The aim of this study was to evaluate radioactive renal and intestinal excretions after TARE planning and treatment procedures with holmium-166-loaded microspheres and to correlate the findings with the intratherapeutic effective half-life. Urinary and intestinal excretions of patients who underwent TARE procedures were collected during postinterventional intervals of 24 h (TARE planning) and 48 h (TARE treatment). Whole-body effective half-life measurements were performed. Calibrations of the

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 ofA Jaszczak phantom and a NEMA PET body phantom were filled withWe found that image quality was comparable betweenThe 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

Zusammenfassung Ziel Die neue Strahlenschutz-Gesetzgebung sieht vor, dass eine Risikoanalyse neuer und bestehender Behandlungsverfahren mit offenen Radionukliden hinsichtlich der Patientensicherheit wiederkehrend durchzuführen ist, in welche der Medizinphysik-Experte maßgeblich involviert ist. Material und Methoden Als Werkzeug für die Durchführung der Risikoanalyse wurde die Fehlermöglichkeits- und Einflussanalyse (FMEA) angewendet, wie vom Bundesamt für Strahlenschutz (BfS) und den Fachgesellschaften empfohlen. Für die Radiojodtherapie, die Radiosynoviorthese, die Peptid-Radiorezeptortherapie und die selektive interne Radiotherapie wurden die Prozesse gegliedert und zunächst individuell durch die verschiedenen am Prozess beteiligten Berufsgruppen und anschließend im Konsens kategorisiert. Für Risikoprioritätszahlen > 125 wurden Gegenmaßnahmen erarbeitet. Die Risikoprioritätszahl (RPZ) ergibt sich als Produkt aus dem Schweregrad, der Auftretenswahrscheinlichkeit und der Entdeckungswahrscheinlichkeit des Fehlers oder der Folgen. Ergebnisse Neben den diversen Möglichkeiten der Verwechslung von Patienten wurden Unsicherheiten in der Aktivitäts- und Organgrößenbestimmung und eine mangelnde Compliance des Patienten als wesentliche Risiken für eine Unter- oder Übertherapie angesehen. Die ausgeprägte Streuung bei individueller Risikobetrachtung durch einzelne Berufsgruppen konnte unter Anleitung durch einen externen Moderator deutlich reduziert werden. Für die höchsten RPZ wurden Maßnahmen formuliert, deren präventive Wirkung im Verlauf noch zu überprüfen ist. Schlussfolgerung Die nuklearmedizinische Therapie wurde in der organisatorischen Durchführung als sehr sicher eingeschätzt und es wurden nur geringe Risiken bzgl. der Patientensicherheit identifiziert. Die FMEA-Analyse war ein praktikables Instrument und identifizierte Prozessschritte mit Optimierungspotenzial für die analysierten Therapieformen. Das geschilderte Vorgehen kann in anderen nuklearmedizinischen Einrichtungen adaptiert werden, wobei strukturspezifische Faktoren (technische und personelle Ausstattung, Ablauf von Prozeduren) zu berücksichtigen sind, sodass ggf. weitere Risiken identifiziert und hier aufgeführte Risiken aufgrund anderer Abläufe als abweichend eingeschätzt werden können.

Introduction Radiation-induced DNA damage occurs from direct and indirect effects. The induction is influenced by the physical characteristics of the radionuclide, especially its linear energy transfer. Hypoxia reduces the effect of irradiation treatment in tumor cells and leads to poor patient outcomes. High linear energy transfer emitters can overcome this obstacle. Our aim is to demonstrate the influence of hypoxia on the interaction of different radiation qualities with isolated DNA. Methods PuC19 Plasmid DNA was irradiated with 223Ra, 188Re, 99mTc and 99mTc-labeled pyrene with and without DMSO under hypoxia or normoxic conditions. DNA damages in form of single-(SSB) and double-strand breaks (DSB) were analyzed by gel electrophoresis. Results Radiation doses up to 200 Gy of 223Ra, 188Re and 99mTc led to maximal yields of 80% SSB and 30%, 28% and 32% DSB, respectively. Hypoxia had minor effects on damages from 223Ra, but caused a small enhancement in DSB for 188Re and 99mTc. DMSO prevented DSB completely and reduced SSB from the “free” radionuclides to comparable levels. DNA-binding 99mTc-labeled pyrene induced less SSB and DSB compared to [99mTc]TcO4−. However, the incubation with DMSO could prevent the SSB and DSB induction only to a minor extent. Conclusions Hypoxia does not limit DNA damage induced by 223Ra, 188Re, 99mTc and 99mTc-labeled pyrene. Dose-dependent radiation effects were comparable for alpha-emitters and both high- and low-energy electron emitters. The radioprotection by DMSO was not influenced by hypoxia. The results indicate the contribution of mainly indirect radiation effects for 99mTc, 188Re and 223Ra. 99mTc-labeled pyrene caused direct DNA damages and Auger-electrons from 99mTc-labeled pyrene are more effective than high-energy electrons or alpha particles. Advances in knowledge Without the consideration of DNA repair mechanisms, oxygen has no direct influence in radiation-induced DNA damages by different radiation qualities. Implications for patient care The short-time stimulation with oxygen during patient radiation could have minor influence compared to constant oxygen flooding to overcome hypoxic barriers.

The application of 225Ac (half-life T1/2 = 9.92 d) dramatically reduces the activity used for peptide receptor radionuclide therapy by a factor of 1000 in comparison to 90Y, 177Lu or 188Re while maintaining the therapeutic outcome. Additionally, the range of alpha particles of 225Ac and its daughter nuclides in tissue is much lower (47–85 μm for alpha energies Eα = 5.8–8.4 MeV), which results in a very precise dose deposition within the tumor. DOTA-conjugated commercially available peptides used for endoradiotherapy, which can readily be labeled with 177Lu or 90Y, can also accommodate 225Ac. The benefits are lower doses in normal tissue for the patient, dose reduction of the employees and environment and less shielding material. The low availability of 225Ac activity is preventing its application in clinical practice. Overcoming this barrier would open a broad field of 225Ac therapy. Independent which production pathway of 225Ac proves the most feasible, the use of automated synthesis and feasible and reproducible patient doses are needed. The Modular-Lab EAZY is one example of a GMP-compliant system, and the cassettes used for synthesis are small. Therefore, also the waste after the synthesis can be minimized. In this work, two different automated setups with different purification systems are presented. In its final configuration, three masterbatches were performed on the ML EAZY for DOTA-TATE and PSMA-I&T, respectively, fulfilling all quality criteria with final radiochemical yields of 80–90% for the 225Ac-labeled peptides.

The aim of this study is to assess if the number of radiation-induced double strand breaks (DSB) in lymphocytes of prostate cancer patients is affected after repeated Ra-223 therapies. In addition, we investigated the repair of ex vivo induced DSB to investigate the repair proficiency in patient's lymphocytes over the therapy course.Before each of six therapy cycles, blood samples were obtained from seventeen patients. After separation of lymphocytes, the cells were subjected to immunofluorescence staining for detection of DSB-marking γH2AX foci. The number of foci per cell per patient sample was determined for each cycle (X1-X6, baseline foci per cell). Additionally, appropriate samples were exposed ex vivo to an X-ray dose of 1 Gy. The number of γH2AX foci per cell were analyzed after 0.5 h, 2 h and 24 h of recovery.Patient-specific linear regression of the baseline foci per cell over the therapy cycles revealed no significant slopes in the regression lines. Likewise, the mean baseline foci per cell of all patients for cycles X2-X6 was not significantly elevated in comparison to the pre-therapeutic value (X1). The differences between the percentages of residual DSB and cycles were not significant, both at 2 h and 24 h repair time. Consideration of the X6/X1 ratios of both the number of lymphocytes and the amount of residual damage at 24 h indicated a significant correlation.Our findings indicate that the number of γH2AX foci per cell was not changed in dependence on the Ra-223 therapy cycles. The ability of patient's lymphocytes to repair ex vivo induced DSB remained unaffected throughout the entire therapy course.ZIEL: Das Ziel dieser Studie ist die Analyse von strahleninduzierten Doppelstrangbrüchen (DSB) in Lymphozyten von Prostatakarzinompatienten im Verlauf der sechs Ra-223 Therapiezyklen (X1-X6). Die Reparaturkapazität der Lymphozyten wurde nach Applikation einer ex vivo Bestrahlung mit 1 Gy Röntgenstrahlung evaluiert.Von 17 Patienten wurden vor jedem Therapiezyklus (X1-X6) Blutproben entnommen, die Lymphozyten isoliert und die DSB-assoziierten γH2AX Foci pro Zelle (Basiswerte) mit Immunfluoreszenzfärbung detektiert. Weiterhin wurden die entsprechenden Lymphozytenproben ex vivo mit 1 Gy Röntgenstrahlung bestrahlt und nach 0,5 h, 2 h und 24 h Reparaturzeit die γH2AX Foci pro Zelle bestimmt.Die Analyse der γH2AX Basiswerte für die einzelnen Patienten zeigte keine signifikanten Anstiege im Therapieverlauf. Die gemittelten γH2AX Basiswerte der Zyklen X2-X6 waren im Vergleich zum prätherapeutischen Wert (X1) nicht signifikant erhöht. Ein signifikanter Einfluss wiederholter Ra-223 Therapien auf die Reparatur ex vivo erzeugter DSB konnte nicht gefunden werden. Die Relation der Lymphozytenanzahl (X6/X1) korreliert mit der Relation residualer DSB (X6/X1) nach 24 h Reparaturzeit.Wiederholt applizierte Ra-223 Therapien zeigten mit dem verwendeten γH2AX Assay als DSB-Marker weder Auswirkungen auf die Basiswerte noch auf das Reparaturvermögen ex vivo induzierter DSB in Lymphozyten der Prostatakarzinom-Patienten.

Zusammenfassung Ziel Untersucht wurde, ob Propidiumiodid (PI) die DNA-schädigende Wirkung von ionisierender und nicht ionisierender Strahlung (Röntgenstrahlung, Alpha-, Beta-, Auger-Elektronen-Strahlung bzw. Licht diverser Wellenlängen) verstärken kann. Diese biophysikalische Versuchsanordnung ermöglicht es zu überprüfen, ob Cherenkov-Strahlung in relevantem Umfang via photodynamischer Effekte und erhöhter DNA-Schädigung nachweisbar ist. Material und Methoden Konformationsänderungen der Plasmid-DNA durch DNA-Schäden wurden mittels Gelelektrophorese und Fluoreszenzfärbung detektiert und quantifiziert. Wasserstoffperoxid, Zinndichlorid und Dimethylsulfoxid wurden als chemische Modulatoren, Tc-99m, Re-188, Ra-223 und Röntgenstrahlung (32 kV und 200 kV) zur Bestimmung der Radiotoxizität und Licht (λ = 254 nm, 366 nm und 530–575 nm) zur Bestimmung der Phototoxizität eingesetzt. Ergebnisse Die Radiotracer und die Röntgenstrahlung verursachten dosisabhängige DNA-Schäden. PI fungierte nicht als Radio-Sensitizer bei den Radionukliden und nur in geringem Maß bei Röntgenstrahlung. Die Phototoxizität war abhängig von der Wellenlänge. Licht im Wellenlängenbereich von 530–575 nm (VIS) resultierte in Kombination mit PI in direkten DNA-Schäden. Die Ausbeuten der Cherenkov-Strahlung lagen weit unter der Photonen-Emission der Lichtbestrahlung und konnten daher von der Radiotoxizität nicht unterschieden werden. Schlussfolgerung PI bindet an Plasmid-DNA, ist nicht chemotoxisch und steigert kaum die Radiotoxizität. Die Phototoxizität und die Wirkung von PI sind abhängig von der Wellenlänge. Keine Art der Energiezufuhr konnte via PI eine Auger-Elektronen-Kaskade induzieren. Auch eine erhöhte DNA-Schädigung durch photodynamische Effekte via Cherenkov-Strahlung war nicht nachweisbar.

Zusammenfassung Ziel Vor dem Hintergrund der neuen Strahlenschutzverordnung (StrlSchV) ist es sinnvoll, sich erneut einen Überblick über die Strahlenexposition des Personals bei Radiopharmakaherstellungen im radiopharmazeutischen Labor zu verschaffen. Dabei soll die Strahlenexposition im Bereich der Herstellung und Anwendung von Radiopharmaka erfasst werden, um Tätigkeiten mit hoher Exposition zu identifizieren und Arbeitsabläufe zu optimieren. In der Klinik und Poliklinik für Nuklearmedizin am Universitätsklinikum an der TU Dresden wurden dazu Messungen mit optisch stimulierten Lumineszenzdosimetern (OSL) durchgeführt. Material und Methode Es wurden lichtgeschützte OSL-Dosimeter auf die Fingerkuppen von Daumen, Zeigefinger und Mittelfinger beider Hände und auf der Stirn platziert. Jedes OSL-Dosimeter war zuvor kalibriert worden. Untersucht wurde die Teilkörperexposition der Hände im Präparationslabor bei: 99mTc-Präparationen im Routinebetrieb, Aufziehen von Spritzen zur Radiosynoviorthese und von 90Y-Sirtex-Partikeln sowie Herstellung von 177Lu- und 68Ga-Präparaten. Ergebnisse Es zeigte sich, dass die 99mTc-Präparationen zu einer relativ hohen Exposition führen aufgrund der Zahl der Präparationen und der Zahl an aufgezogenen Spritzen. Das Aufziehen der RSO-Spritzen führt in Abhängigkeit von der Zahl der zu füllenden Spritzen ebenfalls zu nennenswerter Handbelastung. Im Gegensatz dazu ist das Aufziehen der Sirtex-Partikel wenig belastend. Die Strahlenexposition bei 177Lu- und 68Ga-Präparationen hängt insbesondere vom Handling bei der Herstellung, der Verwendung von Modulen und der Art der Qualitätskontrolle ab. Bei der Ermittlung der Augenlinsenexposition wurden mit einer Ausnahme unkritische 0,02 mGy oder weniger gemessen.

Radiation-induced DNA damage occurs from direct and indirect effects. The induction is influenced by the physical characteristics of the radionuclide, especially its linear energy transfer. Hypoxia reduces the effect of irradiation treatment in tumor cells and leads to poor patient outcomes. High linear energy transfer emitters can overcome this obstacle. Our aim is to demonstrate the influence of hypoxia on the interaction of different radiation qualities with isolated DNA.PuC19 Plasmid DNA was irradiated withRadiation doses up to 200 Gy ofHypoxia does not limit DNA damage induced byWithout the consideration of DNA repair mechanisms, oxygen has no direct influence in radiation-induced DNA damages by different radiation qualities.The short-time stimulation with oxygen during patient radiation could have minor influence compared to constant oxygen flooding to overcome hypoxic barriers.

Zusammenfassung Ziel: Eine kombinierte interne-externe Radiotherapie (CIERT) erfordert eine einheitliche Betrachtung der biologischen Strahlenwirkung. Dafür sollte der Formalismus der Biologisch Effektiven Dosis (BED) am Zellmodell überprüft werden. Methoden: NIS-positive Schilddrüsenzellen FRTL-5 wurden mit Röntgenstrahlung oder/und mit Tc-99m-Pertechnetat bestrahlt. Anoder Abwesenheit von Perchlorat konnte die aktive zelluläre Aufnahme des Radiotracers während 24 h Bestrahlungsdauer verhindern oder zulassen. Die Dosisbestimmung für die Radionuklidbestrahlung erfolgte auf Basis gemessener Uptakewerte mittels Monte-Carlo-Simulation. Aus Dosiswirkungskurven mit Koloniebildungs-Assay als biologischem Endpunkt wurden zellspezifische radiobiologische Parameter abgeleitet. Für Kombinationsbestrahlungen unter Variation von Reihenfolge und Zeitabstand wurde das Zellüberleben mit Vorhersagewerten des BED-Formalismus verglichen. Ergebnisse: Die für Röntgenbestrahlung ermittelten Parameter α = (0,22 ± 0,02) Gy-1, β = (0,021 ± 0,001) Gy-2 und Reparaturhalbwertszeit (1,51 ± 0,21) h erklären auch die Dosiswirkungskurven für Tc-99m-Pertechnetat mit exponentiell fallender Dosisleistung. Die CIERT-Experimente zeigten keine signifikanten Unterschiede bezüglich Reihenfolge und Bestrahlungspause, jedoch bei Radionuklidaufnahme in die Zellen ein geringeres Überleben als durch die BED vorhergesagt. Schlussfolgerung: Am Zellmodell konnte verifiziert werden, dass die BED grundsätzlich zur Beschreibung von biologischen Strahleneffekten bei unterschiedlichen Strahlenqualitäten und Dosisleistungen anwendbar ist. Ob bei intrazellulärer Radionuklidaufnahme in Kombination mit Röntgenbestrahlung supraadditive Effekte entstehen, die auf Auger- und Konversionselektronen des Tc-99m zurückzuführen sind, bedarf weiterer Experimente.

Combination treatment of molecular targeted and external radiotherapy is a promising strategy and was shown to improve local tumor control in a HNSCC xenograft model. To enhance the therapeutic value of this approach, this study investigated the underlying molecular response. Subcutaneous HNSCC FaDuDD xenografts were treated with single or combination therapy (X-ray: 0, 2, 4 Gy; anti-EGFR antibody (Cetuximab) (un-)labeled with Yttrium-90 (90Y)). Tumors were excised 24 h post respective treatment. Residual DNA double strand breaks (DSB), mRNA expression of DNA damage response related genes, immunoblotting, tumor histology, and immunohistological staining were analyzed. An increase in number and complexity of residual DNA DSB was observed in FaDuDD tumors exposed to the combination treatment of external irradiation and90Y-Cetuximab relative to controls. The increase was observed in a low oxygenated area, suggesting the expansion of DNA DSB damages. Upregulation of genes encoding p21cip1/waf1 (CDKN1A) and GADD45? (GADD45A) was determined in the combination treatment group, and immunoblotting as well as immunohistochemistry confirmed the upregulation of p21cip1/waf1. The increase in residual H2AX foci leads to the blockage of cell cycle transition and subsequently to cell death, which could be observed in the upregulation of p21cip1/waf1 expression and an elevated number of cleaved caspase-3 positive cells. Overall, a complex interplay between DNA damage repair and programmed cell death accounts for the potential benefit of the combination therapy using90Y-Cetuximab and external radiotherapy., TU Dresden Faculty of Medicine Carl Gustav Carus; MedDrive; European Union (EU); 6th Framework; EU-Project ‘‘BioCare”; German Federal Ministry of Education and Research; German Research Foundation

Summary Aim: Ionizing radiation produces DNA lesions among which DNA double strand breaks (DSB) are the most critical events. Radiation of various energy types might differ in their biological effectiveness. Here, we compared cell survival and DNA damage induced by 188Re and X-rays using YH2AX foci as a measure of DSB. The correlation between survival and residual foci was also analyzed. Methods: PCCl3 cells were irradiated with 200 kV X-rays (1.2 Gy/min) or 0.5-25 MBq/ml 188Re (1 h irradiation) achieving doses up to 10 Gy. By blocking of sodium iodide sym- porter (NIS) essentially extracellular activity could be guaranteed. Survival fractions (SF) were detected by colony forming assay. Initial and residual YH2AX foci (15 min and 24 h after irradiation) were assessed by immunos- taining. The relationship between SF and residual radiation induced YH2AX foci (RIF) was evaluated by Spearman and Pearson correlation tests. Results: We did not find significant differences between the survival curves in terms of the radiation quality. The D37 values were 4.6 Gy and 4.2 Gy for 188Re or X-ray, respectively. The initial foci numbers were in the same range for 188Re and X-ray, but higher levels of residual foci persisted after X-rays in comparison to 188Re (1 GyX-ray 6.5 ± 0.2; 1 GyRe-188 4.8 ± 0.2 RIF). Accordingly, for 188Re a higher extent of DSB repair was found. The Spearman test revealed a significant (p < 0.01) correlation between SF and residual RIF for both radiation modalities. Conclusion: No differences in terms of radiation were found for SF and initial foci. However, residual foci were lower for 188Re than for X-rays. A prediction of SF by residual foci should consider the properties of the radiation qualities that influence foci removal and DSB repair.

Purpose: In addition to gamma radiation, 99mTc emits low-energy Auger electrons with path-lengths of nanometers to micrometers that cannot be utilized for diagnostic procedures; however, they have frequently been discussed for therapeutic applications. We compared radiotoxicity of three 99mTc-labeled radiopharmaceuticals with differences in the subcellular distribution.Materials and methods: The intracellular radionuclide uptake and subcellular distribution of [99mTc]-pertechnetate (99mTc-pertechnetate), [99mTc]Tc-hexamethyl-propylene-aminoxime (99mTc-HMPAO) and [99mTc]Tc-hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) were quantified in rat thyroid FRTL-5 cells. Radiotoxicity was compared using late phosphorylated histone H2AX (γH2AX) foci as a marker for unrepaired DNA double-strand breaks (DNA-DSB) and clonogenic cell survival.Results: 99mTc-HMPAO showed a substantially higher uptake into the nucleus and the membrane/organelles than 99mTc-pertechnetate or 99mTc-MIBI. The colony-forming assay s...

Purpose: Hypoxic regions of tumors are less sensitive to radio- and chemotherapy, leading to poor prognosis of patients. One option to overcome the radioresistance is the irradiation of hypoxic tumors with high linear energy transfer (LET) α- or Auger electronemitters assuming their radiotoxicity would be less dependent on the cellular oxygenation status. Therefore, the aim of the present study was to determine whether irradiation with the intracellularly distributed Auger electron/γ-emitter 99mTc using the tracer [99mTc]TcHMPAO is a promising therapeutic option for the treatment of hypoxic tumor cells. Thus, the high LET α-particleemitter 223Ra ([223Ra]RaCl2) and the low LET β-emitter 188Re ([188Re]NaReO4) were studied in comparison to [99mTc]Tc-HMPAO. Materials and methods: A431 tumor cells were incubated with [99mTc]Tc-HMPAO (1–20 MBq/2 mL), [223Ra]RaCl2 (1.4–16.3 kBq/2 mL) or [188Re]NaReO4 (0.3–13.7 MBq/2 mL) under normoxic or hypoxic conditions. The degree of radiotoxicity was analyzed using the colony forming assay (CFA), and the intracellular radionuclide uptake of the radiotracers was quantified. Results: Hypoxic A431 cells are less radiosensitive to irradiation with [99mTc]Tc-HMPAO or [188Re]NaReO4 than normoxic ones. In contrast, the radiosensitivity of A431 cells is almost independent of the oxygen status when treated with the [223Ra]RaCl2. Conclusions: We demonstrate that the Auger electron/γ-emitter 99mTc ([99mTc]Tc-HMPAO), which does not bound directly to the DNA, is not a promising therapeutic option for hypoxic tumor cells. But the high LET α-particle-emitter 223Ra is more suitable for the treatment of hypoxic tumor cells than irradiation with [99mTc]Tc-HMPAO or the low LET bemitter 188Re. Zielsetzung: Hypoxische Tumorregionen sind bei Radio- und Chemotherapie weniger sensitiv als Tumorregionen mit ausreichender Sauerstoffversorgung. Dies verursacht eine schlechte Prognose fur Tumorpatienten. Eine Option die Radioresistenz zu uberwinden, stellt die Bestrahlung mit α-Partikel-Emittern oder Auger-Elektronen-Emittern mit einem hohen linearen Energietransfer (LET) dar. In dieser Studie soll untersucht werden, ob die Bestrahlung von hypoxischen Tumorzellen mit dem intrazellular aufgenommenen γ- sowie Auger-Elektronen-Emitter 99mTc unter Verwendung des Radiotracers [99mTc]Tc-HMPAO eine vielversprechende Therapieoption darstellen konnte. Vergleichend wurde der Hoch-LET α-Partikel-Emitter 223Ra ([223Ra]RaCl2) und der Niedrig-LET β-Emitter 188Re ([188Re]NaReO4) eingesetzt. Methoden: A431 Tumorzellen wurden unter normoxischen oder hypoxischen Kulturbedingungen mit [99mTc]Tc-HMPAO (1–20 MBq/2 ml), [223Ra]RaCl2 (1,4–16,3 kBq/2 ml) und [188Re]NaReO4 (0,3–13,7 MBq/2 ml) inkubiert. Zur Detektion der resultierenden strahlenbiologischen Wirkung wurde der Koloniebildungsassay angewendet. Zusatzlich wurde die intrazellulare Aufnahme der Radiotracer quantifiziert. Ergebnisse: Nach Inkubation von [99mTc]Tc-HMPAO sind hypoxische A431-Zellen weniger strahlensensitiv als normoxische Zellen. Im Gegensatz zur Behandlung mit [99mTc]Tc-HMPAO oder [188Re]NaReO4 wurde bei Behandlung mit [223Ra]RaCl2 ein geringerer Einfluss des Sauerstoffstatus auf die Radiosensitivitat von A431-Zellen gefunden. Schlussfolgerung: Damit konnte gezeigt werden, dass der nicht direkt an die DNA gebundene Auger-Elektronen-/ γ-Emitter 99mTc ([99mTc]Tc-HMPAO) die Radioresistenz von hypoxischen Tumorzellen nicht uberwinden kann. Jedoch stellt der Hoch-LET α-Partikel-Emitter 223Ra ([223Ra]RaCl2) eine bessere Behandlungsoption dar.

RadiomercuryA good accordance between measurements and simulations was found for planar and SPECT imaging. Simulations allowed the decomposition of the detected energy spectrum into photon origins. Measurements and simulations for the bar phantom revealed that for the LEHR collimator, the 6-mm pattern could be resolved, whereas for the HEGP collimator, the resolution is about 10 mm. Furthermore, we found that no significant image distortion results from high-energy photons when using the LEHR collimator.We demonstrated the imaging capabilities of

Targeting epidermal growth factor receptor (EGFR)-overexpressing tumors with radiolabeled anti-EGFR antibodies is a promising strategy for combination with external radiotherapy. In this study, we evaluated the potential of external plus internal irradiation by [(90) Y]Y-CHX-A″-DTPA-C225 (Y-90-C225) in a 3-D environment using FaDu and SAS head and neck squamous cell carcinoma (HNSCC) spheroid models and clinically relevant endpoints such as spheroid control probability (SCP) and spheroid control dose 50% (SCD50 , external irradiation dose inducing 50% loss of spheroid regrowth). Spheroids were cultured using a standardized platform. Therapy response after treatment with C225, CHX-A"-DTPA-C225 (DTPA-C225), [(90) Y]Y-CHX-A"-DTPA (Y-90-DTPA) and Y-90-C225 alone or in combination with X-ray was evaluated by long-term monitoring (60 days) of spheroid integrity and volume growth. Penetration kinetics into spheroids and EGFR binding capacities on spheroid cells were identical for unconjugated C225 and Y-90-C225. Spheroid-associated radioactivity upon exposure to the antibody-free control conjugate Y-90-DTPA was negligible. Determination of the SCD50 demonstrated higher intrinsic radiosensitivity of FaDu as compared with SAS spheroids. Treatment with unconjugated C225 alone did not affect spheroid growth and cell viability. Also, C225 treatment after external irradiation showed no additive effect. However, the combination of external irradiation with Y-90-C225 (1 µg/ml, 24 hr) resulted in a considerable benefit as reflected by a pronounced reduction of the SCD50 from 16 Gy to 9 Gy for SAS spheroids and a complete loss of regrowth for FaDu spheroids due to the pronounced accumulation of internal dose caused by the continuous exposure to cell-bound radionuclide upon Y-90-C225-EGFR interaction.

Das Interesse am Nachweis von radioaktiven Stoffen hat nach dem jungsten Unfall im Kernkraftwerk Fukushima stark zugenommen und zu einem Engpass bei entsprechenden Messgeraten gefuhrt. Fur den Einsatz des Kamerasystems von Smartphones zum Strahlungsnachweis existiert eine kommerzielle Software, welche die Nutzung als Dosisleistungsmessgerat unter Verwendung geratespezifischer Kalibrierdaten erlaubt. Ziel: Wir untersuchten, ob die Anwendung fur in der Nuklearmedizin ubliche Nuklide und Radioaktivitatsmengen moglich ist. Methodik: Fur die Nuklide 99mTc (10–1000 MBq), 131I (3,7–1800 MBq, Therapiekapsel) und 68Ga (50–600 MBq) wurden Messungen in definierter Geometrie in verschiedenen Abstanden durchgefuhrt. Die Smartphones Milestone Droid 1 (Motorola) und HTC Desire (HTC Corporation) wurden mit den Messgeraten AD6 (automess) und DoseGUARD (AEA Technology) verglichen. Ergebnisse: Die Messwerte der Smartphones und der anderen Gerate sind gut miteinander vergleichbar: linearer Signalanstieg bei zunehmender Aktivitat und Dosisleistung. Langzeitmessungen (131I, 729 MBq, 0,5 m, 60 min) ergaben bei Smartphones Werte, die um 20% schwankten im Vergleich zu AD6. Smartphones haben im Bereich niedriger Dosisleistung (

Ionizing radiation produces DNA lesions among which DNA double strand breaks (DSB) are the most critical events. Radiation of various energy types might differ in their biological effectiveness. Here, we compared cell survival and DNA damage induced byPCCl3 cells were irradiated with 200 kV X-rays (1.2 Gy/min) or 0.5-25 MBq/mlWe did not find significant differences between the survival curves in terms of the radiation quality. The DNo differences in terms of radiation were found for SF and initial foci. However, residual foci were lower for

In addition to gamma radiation,The intracellular radionuclide uptake and subcellular distribution of [Our findings reveal that clonogenic cellular survival is not solely determined by the DNA-DSB response. This finding may suggest the involvement of extra-nuclear radiosensitive targets in cell inactivation. For example, the mitochondria or the cell membrane could be affected by

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 223Ra compared to 188Re and 99mTc modulated by the radical scavenger dimethyl sulfoxide (DMSO). Methods Radioactive solutions of 223Ra, 188Re, or 99mTc 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 223Ra, 188Re, or 99mTc leads to maximal yields of SSB (80 %) in plasmid DNA. Irradiation with 540 Gy 223Ra and 500 Gy 188Re or 99mTc 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 223Ra, a low level of DSB could not be prevented by DMSO. Irradiation of PC Cl3 cells with 223Ra, 188Re, and 99mTc 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 223Ra, 188Re, and 99mTc, respectively. Conclusions For 223Ra, as well as for 188Re and 99mTc, 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. Electronic supplementary material The online version of this article (doi:10.1186/s13550-016-0203-x) contains supplementary material, which is available to authorized users.

SummaryAim: Current reports for the radiation cataracts contained a warning for deterministic effects at 1–2 Gy radiation single exposure for lens. Recently, the German Radiation Protection Board (SSK) published a document (234. SSK-Board) in that threshold dose for radiation cataracts is claimed at 0.5 Gy. The lens of the eye is recognized as one of the most radiosensitive tissues in the human body, and the International Commission on Radiological Protection (ICRP 103) has defined a limit of 150 mSv for its exposure. Recently, the ICRP lowered this limit down to 20 mSv per year. However, this limit does not apply to patients. Therefore, the question of the lens radiation exposure for patients underwent a radioiodine therapy (RIT) is a point at issue. Patients, methods: A total of 41 patients (age: 22–92 years) underwent a radioiodine therapy were included in the study. Optical stimulated luminescence dosimeters were used to measure the radiation exposure. The dosimeters were fastened nearby the patient’s eye lens. The measurement was carried out up to 48 h after radioiodine application and the patients were divided into three groups. Group 1: patients underwent a diagnostic 131I whole body scan (mean activity: 370 MBq); group 2: thyriod carcinoma patients under RIT (mean activity: 3700 MBq); group 3: hyperthyroid patients under RIT (activity: 180–1237 MBq). Results: The cumulative exposure of the eye lens during the stay at the therapy unit (48 h) was 4.8 ± 0.7 mGy in group 1, 24.5–50.5 mGy in group 2 and 2.7–26.3 mGy in group 3, respectively. For the calculation of the expected cumulative dose, including follow-up after patient's dismissal, the effective half-lives were involved. The cumulative doses were obtained to be 6 ± 1 mGy in the first group, 63 ± 15 mGy in the second and 5–148 mGy in the third. Conclusion: The results show that there exists a low risk for radiation cataract in a nuclear medicine therapy unit. After serial radioiodine therapies radiation-induced lens opacity cannot be expected.

Ziel: Neben der Gammastrahlung von 140 keV sendet 99mTc beim Ubergang zu 99Tc auch Elektronen geringer Energie und geringer Reichweite aus. Diese Auger-Elektronen sind diagnostisch nicht relevant, werden aber immer wieder fur den therapeutischen Einsatz diskutiert. Bislang fehlte ein Wirkungsnachweis der Auger-Elektronen von 99mTc, der jetzt in einem In-vitro-Testsystem im Vergleich zum Betastrahler 131I vorgelegt werden soll. Methoden: Die Schilddrusenzelle PCCl3, die Natriumiodid-Symporter(NIS)-positiv ist, wurde in An- bzw. Abwesenheit von Perchlorat mit 131I-Natriumiodid (131I) oder 99mTc-Pertechnetat (99mTc) inkubiert. Zum besseren Vergleich wurden die Aktivitatsmengen so adjustiert, dass bei rein extrazellularer Bestrahlung dieselbe Dosis fur beide Radionuklide resultiert. Das klonogene Zelluberleben wurde mit dem Koloniebildungs-Assay durch Bestimmung der Uberlebensfraktion ermittelt. Parallel zu allen Versuchen wurde jeweils die intrazellulare Radionuklidaufnahme bestimmt. Ergebnisse: Dosis-Wirkungskurven fur die Bestrahlung mit 131I und 99mTc unter variabler extra- und intrazellularer Verteilung der Radioaktivitat wurden erstellt. In Anwesenheit von Perchlorat war keine intrazellulare Radiotracer-Aufnahme nachweisbar. Die Uberlebenskurven waren weitgehend vergleichbar, so dass von einer korrekten Dosimetrie ausgegangen werden konnte. Ohne Perchlorat wurden zwischen 1,39% (131I) und 1,90% (99mTc) der inkubierten Aktivitat intrazellular nachgewiesen, was die Radiotoxizitat fur den Betastrahler verdoppelte, fur 99mTc jedoch mehr als verzehnfachte. Schlussfolgerung: Die intrazellulare Aufnahme des Betastrahlers 131I verursacht gegenuber der rein extrazellularen Lokalisation eine deutlich hohere DNA-Schadigung, was mittels Koloniebildungstest nachgewiesen werden kann. Die erhohte Radiotoxizitat durch intrazellulares 99mTc erklart sich am ehesten durch den grosen Dosisbeitrag in zellularen Strukturen durch die Auger- und Konversionselektronen geringer Reichweite und hoher lokaler Energiedeposition.

Ziel: Untersuchung der Biodistribution und Ermittlung von dosimetrischen Daten fur 68Ga-DOTATOC bei Patienten im Rahmen der Krankenversorgung zum Nachweis oder Ausschluss von neuroendokrinen Tumoren. Patienten, Methoden: Bei 14 Patienten (8 Manner, 6 Frauen) konnten nach Injektion von (112 ± 22)MBq 68Ga-DOTATOC dynamische Messungen am PET/CT (Biograph 16) uber 20 min gefolgt von statischen Ganzkorper-Aufnahmen uber 8 Bettpositionen in 3D-Technik 30 min p.i. und 120 min p.i. ausgewertet werden. Die Urinausscheidung wurde gemessen, die Blutaktivitat wurde bildgebend nichtinvasiv aus dem Blutpool des Herzen ermittelt. Die fur die Dosimetrie relevanten Organe waren Milz, Niere, Leber, Nebenniere, Harnblase und Hypophyse. Dosimetrische Werte wurden mit der OLINDA/EXM 1.0 Software errechnet und spezifische Organanreicherungen auch als standardisierte Uptake-Werte (SUV) angegeben. Ergebnisse: Eine schnelle physiologische Aufnahme des Radiotracers erfolgte in Leber, Milz, Nieren, Nebennieren und Hypophyse, die mittleren SUV-Werte betrugen 6, 20, 16, 10 und 4. Die Elimination erfolgte ausschlieslich renal in die Harnblase (16% der injizierten Aktivitat innerhalb von 2 h). Eine Umverteilung konnte nicht beobachtet werden. Die Organe mit der hochsten Strahlenexposition waren die Milz (0,24mSv/MBq) und die Nieren (0,22mSv/MBq), die uber die Geschlechter gemittelte effektive Dosis betrug 0,023 mSv/MBq. Schlussfolgerung: 68Ga-DOTATOC wird bereits umfangreich zur Diagnostik somatostatinrezeptor-positiver Tumore eingesetzt, weil es gegenuber 111In-Somatostatinderivaten wesentliche Vorteile aufweist. Die jetzt ermittelten dosimetrischen Werte sind niedriger als die Dosis von 111In-OctreoScan. Die Strahlenexposition der CT zur Schwachungskorrektur der PET-Daten betragt 1mSv (Niedrigdosis).

Ziel: Fur die in-vitro Exposition von Zellen mit offenen Radionukliden werden haufig zylindrische Bestrahlungsgeometrien eingesetzt. Die Dosimetrie erfolgt jedoch oftmals durch Anwendung des Kugelmodells, welches eine spharische Aktivitatsverteilung annimmt. Bei Verwendung hochenergetischer Betastrahler ist aus physikalischer Sicht jedoch im Randbereich der Aktivitatsverteilung ein Dosisabfall zu erwarten. Die Auswirkungen auf die Bestimmung von Zelldosen soll innerhalb dieser Arbeit dargestellt werden. Methoden: Die Berechnung der Dosisverteilung in verschiedenen Multiwellplatten erfolgt durch die Faltung von Dosis-Punkt-Kernen mit der vorliegenden Aktivitatsverteilung. Betrachtet werden die Radionuklide I-131, Re-188 sowie Y-90. Zum Vergleich erfolgt die Berechnung der Dosis nach dem Kugelmodell. Ergebnisse: In Abhangigkeit der Betaenergie finden sich Differenzen zwischen der berechneten mittleren Dosis und der mittleren Dosis nach dem Kugelmodell von bis zu 40%. Dabei liegen die Werte des Kugelmodells allesamt hoher als die berechneten. Zudem sind die Dosen am Boden einer Multiwellplatte nochmals niedriger als in der Gefasmitte. In Abhangigkeit der Fullhohe wurde fur drei verschiedene Welldurchmesser eine analytische Darstellung der Bodendosis gefunden. Schlussfolgerung: Die Auswirkung der Bestrahlungsgeometrie auf die Dosisverteilungen muss besonders bei in-vitro Bestrahlungen mit Betastrahlern niedriger Energie und kurzer Reichweite beachtet werden. Aufgrund der zum Teil erheblichen Abweichungen zwischen der berechneten Dosis und der Dosis nach dem Kugelmodell ist dies insbesondere im Hinblick auf die Vergleichbarkeit von Dosiswerten verschiedener Bestrahlungsexperimente erforderlich.

Summary Aim: The absorbed dose is an important parameter in experiments involving irradiation of cells in vitro with unsealed radionuclides. Typically, this is estimated with a model calculation, although the results thus obtained cannot be verified. Generally used real-time measurement methods are not applicable in this setting. A new detector material with in vitro suitability is the subject of this work. Methods: Optically-stimulated luminescence (OSL) dosimeters based on beryllium oxide (BeO) were used for dose measurement in cell cultures exposed to unsealed radionuclides. Their qualitative properties (e. g. energy-dependent count rate sensitivity, fading, contamination by radioactive liquids) were determined and compared to the results of a Monte Carlo simulation (using AMOS software). OSL dosimeters were tested in common cell culture setups with a known geometry. Results: Dose reproducibility of the OSL dosimeters was ± 1.5%. Fading at room temperature was 0.07% per day. Dose loss (optically-stimulated deletion) under ambient lighting conditions was 0.5% per minute. The Monte Carlo simulation for the relative sensitivity at different beta energies provided corresponding results to those obtained with the OSL dosimeters. Dose profile measurements using a 6 well plate and 14 ml PP tube showed that the geometry of the cell culture vessel has a marked influence on dose distribution with 188Re. Conclusion: A new dosimeter system was calibrated with β-emitters of different energy. It turned out as suitable for measuring dose in liquids. The dose profile measurements obtained are suitably precise to be used as a check against theoretical dose calculations.

The optical sensitivity of BeO-based luminophors is well known for many years. A simple OSL treatment, the equipment and resulting dosimetric properties of BeO will be described. In contrast to most OSL measurement techniques, detector stimulation and luminescence light recording are performed from opposite sides of the detector. This gives rise to a very short distance between detector surface and light sensor, and consequently an optimum of light yield. Dosimetric properties of various available forms of BeO sinter pellets were examined for a broad range of conditions. The dosimeters show linear dose response between less than 5 μ Gy and 5 Gy. Long time fading of the signal is negligible. It amounts to less than 1% over six months. Other environmental factors like humidity neither influence the response. The greatest advantage of BeO is its very low photon energy dependence. Because of its effective atomic number the luminophor is nearly tissue equivalent. This fact and all other excellent dosimetric properties make BeO of interest for all applications in medicine, personal and environmental dosimetry.

The no carrier added (NCA) radionuclide 197(m)Hg is accessible through proton induced nuclear reactions on gold. The decay properties of both simultaneous produced nuclear isomers 197mHg and 197Hg like convenient half life, low energy gamma radiations for imaging, Auger and conversion electrons for therapy are combined with unique chemical and physical properties of mercury and its compounds. Gold as a monoisotopic element has a natural abundance of 100% 197Au superseding expensive enrichment for the target material. Additionally, the high thermal conductivity of gold enables high beam current irradiations. For separation of target material a liquid–liquid extraction method was applied.

SummaryPurpose: 68Ga-labelled compounds are increasingly used for somatostatin-receptor scintigraphy because of their favourable biokinetic properties, a higher tumour-to- background contrast and higher diagnostic accuracy compared to the gamma-emitting tracer 111In-DTPA-octreotide. Recently, we have introduced the new tracer 68Ga-DOTA- 3-iodo-Tyr3-Thr8-octreotide (68Ga-HA-DOTA- TATE). The present study demonstrates the biodistribution and radiation dosimetry of this tracer in humans. Patients, methods: Seven men were enrolled in this analysis. Every patient underwent a 20 min dynamic PET scan after intravenous injection of about 114 ± 9 MBq of 68Ga-HA-DOTATATE. This was followed by two whole-body scans at 30 min p. i. and 120 min p. i. Blood radioactivity concentration was determined non-invasively from a ROI drawn over the aorta. Urine was collected until the time of the last scan. Liver, spleen, kidneys and urinary bladder wall were included in the dosimetric estimation that was carried out with the software package OLINDA 1.0. Results: Physiological 68Ga- HA-DOTATATE uptake was observed in the pituitary gland, thyroid, salivary glands, liver, spleen, kidneys, urinary bladder, adrenals and intestine. Organs with the highest absorbed dose were spleen (0.26 ± 0.11 mSv/MBq), kidneys (0.14 ± 0.03 mSv/MBq) and liver (0.12 ± 0.02 mSv/MBq).The estimated effective dose was 0.024 ± 0.001 mSv/MBq. Conclusion: Our study demonstrates biokinetics and radiation exposure of the 68Ga-labelled tracer HA-DOTATATE to be comparable to other 68Ga-labelled SSR analogues in clinical use.

Purpose: Epidermal growth factor receptor (EGFR) is critically involved in progression and therapy resistance of squamous cell carcinoma (SCC). Albeit EGFR targeting could improve the effect of radiotherapy on patients' outcome, the clinical results failed to meet expectations from preclinical studies. In this work, we evaluated the potential of the radionuclide Yttrium-90 (90Y) bound to Cetuximab (90Y-Cetuximab) as novel targeting approach for SCC cells in vitro. Materials and methods: FaDu and A431 cell lines were used. EGFR subcellular localization, clonogenic survival, radiation-induced γH2AX foci and EGFR signaling were examined. Cells were treated with DTPA, DTPA-Cetuximab, 90Y and 90Y-Cetuximab alone or in combination with external X-ray irradiation. Results: Dose- and cell line-dependently, 90Y-Cetuximab mediated a significant reduction in clonogenicity relative to unbound 90Y. Combined 2-Gy external radiation plus 2-Gy equivalent dose of 90Y-Cetuximab was more effective than equivalent doses of 90Y and X-ray radiation. Analogous effects were observed in the number of residual radiation-induced foci. Additionally, EGFR, ERK1/2 and AKT phosphorylation showed alterations upon different treatments. Conclusions: Our findings show that Cetuximab-conjugated 90Y has a significant potential to eradicate human SCC cells. A combination of radioimmunotherapeutic compounds and external radiotherapy might be a promising treatment strategy for clinical application.

Cellular radionuclide uptake increases the heterogeneity of absorbed dose to biological structures. Dose increase depends on uptake yield and emission characteristics of radioisotopes. We used an in vitro model to compare the impact of cellular uptake of (188)Re-perrhenate and (99m)Tc-pertechnetate on cellular survival.Rat thyroid PC Cl3 cells in culture were incubated with (188)Re or (99m)Tc in the presence or absence of perchlorate for 1 hour. Clonogenic cell survival was measured by colony formation. In addition, intracellular radionuclide uptake was quantified.Dose effect curves were established for (188)Re and (99m)Tc for various extra- and intracellular distributions of the radioactivity. In the presence of perchlorate, no uptake of radionuclides was detected and (188)Re reduced cell survival more efficiently than (99m)Tc. A(37), the activity that is necessary to yield 37% cell survival was 14 MBq/ml for (188)Re and 480 MBq/ml for (99m)Tc. In the absence of perchlorate, both radionuclides showed similar uptakes; however, A(37) was reduced by 30% for the beta-emitter and by 95% for (99m)Tc. The dose D(37) that yields 37% cell survival was between 2.3 and 2.8 Gy for both radionuclides.Uptake of (188)Re and (99m)Tc decreased cell survival. Intracellular (99m)Tc yielded a dose increase that was higher compared to (188)Re due to emitted Auger and internal conversion-electrons. Up to 5 Gy there was no difference in radiotoxicity of (188)Re and (99m)Tc. At doses higher than 5 Gy intracellular (99m)Tc became less radiotoxic than (188)Re, probably due to a non-uniform lognormal radionuclide uptake.

SummaryPurpose: We evaluated the DNA damaging potential of Auger electrons emitted in the decay of 99mTc compared to α-particles of 211At. Material and methods: The impact of 99mTc and 211At was monitored in a NIS-expressing rat thyroid cell model PC Cl3 with varying, yet defined intra- and extracellular radionuclide distribution (using ± perchlorate). The radiotoxicity of 99mTc and 211At was studied by the comet assay under neutral and alkaline conditions and colony formation. Results: In the presence of perchlorate, the radioactivity yielding 37 % cellular survival, A37, was estimated to be (0.27 ± 0.02) MBq/ml and (450 ± 30) MBq/ml for 211At and 99mTc, respectively. In absence of perchlorate, cellular radiotracer uptake was similar for both radionuclides (2.2 %, 2.7 %), yet the A37 was reduced by 82% for the α-emitter and by 95 % for 99mTc. Cellular dose increased by a factor of 5 (211At) and 38 (99mTc). Comet assays revealed an increased DNA damage after intracellular uptake of both radiotracers. Conclusions: The data indicate damage to the cell to occur from absorbed dose without recognizable contribution from intracellular heterogeneity of radionuclide distribution. Comet assay under alkaline and neutral conditions did not reveal any shift to more complex DNA damage after radionuclide uptake. Cellular uptake of 99mTc and 211At increased cellular dose and reduced clonogenic survival.

SummaryTechnetium radiopharmaceuticals are well established in nuclear medicine. Besides its well-known gamma radiation, 99mTc emits an average of five Auger and internal conversion electrons per decay. The biological toxicity of these low-energy, high-LET (linear energy transfer) emissions is a controversial subject. One aim of this study was to estimate in a cell model how much 99mTc can be present in exposed cells and which radiobiological effects could be estimated in 99mTc-overloaded cells. Methods: Sodium iodine symporter (NIS)- positive thyroid cells were used. 99mTc-uptake studies were performed after preincubation with a non-radioactive (cold) stannous pyro - phosphate kit solution or as a standard 99mTc pyrophosphate kit preparation or with pure pertechnetate solution. Survival curves were analyzed from colony-forming assays. Results: Preincubation with stannous complexes causes irreversible intracellular radioactivity retention of 99mTc and is followed by further pertechnetate influx to an unexpectedly high 99mTc level. The uptake of 99mTc pertechnetate in NIS-positive cells can be modified using stannous pyrophosphate from 3–5% to >80%. The maximum possible cellular uptake of 99mTc was 90 Bq/cell. Compared with nearly pure extracellular irradiation from routine 99mTc complexes, cell survival was reduced by 3–4 orders of magnitude after preincubation with stannous pyrophosphate. Conclusions: Intra cellular 99mTc retention is related to reduced survival, which is most likely mediated by the emission of low-energy electrons. Our findings show that the described experiments constitute a simple and useful in vitro model for radiobiological investigations in a cell model.

The application of unsealed radionuclides in radiobiological experiments can lead to intracellular radionuclide uptake and an increased absorbed dose. Accurate dose quantification is essential to assess observed radiobiological effects. Due to small cellular dimensions direct dose measurement is impossible. We will demonstrate the application of Monte Carlo simulations for dose calculation. Dose calculations were performed using the Geant4 Monte Carlo toolkit, wherefore typical experimental situations were designed. Dose distributions inside wells were simulated for different radionuclides. S values were simulated for spherical cells and cell monolayers of different diameter. Concomitantly experiments were performed using the PC Cl3 cell line with mediated radionuclide uptake. For various activity distributions cellular survival was measured. We yielded S values for dose distribution inside the wells. Calculated S values for a single cell are in good agreement to S values provided in the literature (ratio 0.87 to 1.07). Cross-dose is up to ten times higher for Y-90. Concomitantly performed cellular experiments confirm the dose calculation. Furthermore the necessity of correct dose calculation was shown for assessment of radiobiological effects after application of unsealed radionuclides. Thereby the feasibility of using Geant4 was demonstrated.

The radioprotective effect of antithyroid drugs on radioiodine treatment is a controversial issue. However, it is of clinical relevance whether antithyroid medication has to be interrupted for therapy and when antithyroid medication can be continued after radioiodine treatment. We investigated DNA damage caused by internal or external radiation using thyroid cells (sodium iodine symporter [NIS] positive).Adherent thyroid cells were irradiated following incubation with the mediators methimazole and perchlorate using either X-ray tube or Re-188-perrhenate. DNA damage was quantified by OTM (Olive's tail moment) of the alkaline comet assay.Following external irradiation of 15 Gy OTM was 4.3 ± 4.2 compared to 0.5 ± 1.4 in controls. DNA damage was reduced by methimazole to 70%. Incubation with Re-188 showed effects depending on presence of the mediators. Non-irradiated controls had a mean OTM1, internal irradiation increased OTM to 25.5 ± 9.1 in cells without mediators. OTM decreased to 60% after pre-incubation with methimazole and to 15% with perchlorate. Re-188 uptake was modified by both perchlorate and, to a lesser extent, methimazole.Methimazole was shown to have a radioprotective effect not only by its scavenger capacity but also by interaction with NIS. Perchlorate acted by competitive inhibition of NIS mediated Re-188 uptake.

1817 Objectives The prevalence of left ventricular mechanical dyssynchrony (LVMD) in stable angina pectoris (AP) has not been fully clarified. The aim of this study was to assess the presence and severity of LVMD in stable AP. Methods A total of 201 patients (age 69 ± 11, 137 males) with suspected ischemic heart disease underwent stress/rest gated myocardial perfusion SPECT (GMPS). For the evaluation of LVMD, histogram bandwidth (HBW) and phase standard deviation (PSD) were determined by GMPS using phase analysis. LVMD at stress and rest were compared among three groups: 103 normal patients (NG) [summed stress score (SSS) 50 %], 54 patients with ischemia (IG) [SSS > 3, summed difference score (SDS) > 1, and summed rest score (SRS) 3 and SDS Results The measured LVMD parameters (HBW and PSD) in NG, IG, and pMIG are summarized in the figure. At stress, both HBW and PSD in IG were significantly greater than those in NG (p Conclusions In patients with stable AP, LVMD was demonstrated to be enhancement at stress, and was found to be detectable equally well with prior MI

Purpose: Based on the authors’ previous findings concerning the radiotoxicity of99mTc, the authors compared the cellular survival under the influence of this nuclide with that following exposure to the Auger electron emitter 123I. To evaluate the relative biological effectiveness (RBE) of both radionuclides, knowledge of the absorbed dose is essential. Thus, the authors present the dose calculations and discuss the results based on different models of the radionuclide distribution. Both different target volumes and the influence of the uptake kinetics were considered. Methods: Rat thyroid PC Cl3 cells in culture were incubated with either99mTc or 123I or were irradiated using 200 kV x-rays in the presence or absence of perchlorate. The clonogenic cell survival was measured via colony formation. In addition, the intracellular radionuclide uptake was quantified. Single-cell dose calculations were based on Monte Carlo simulations performed using Geant4. Results: Compared with external radiation using x-rays (D37 = 2.6 Gy), the radionuclides 99mTc (D37 = 3.5 Gy), and 123I (D37 = 3.8 Gy) were less toxic in the presence of perchlorate. In the absence of perchlorate, the amount of activity a37 that was necessary to reduce the surviving fraction (SF) to 0.37 was 22.8 times lower for 99mTc and 12.4 times lower for 123I because of the dose increase caused by intracellular radionuclide accumulation. When the cell nucleus was considered as the target for the dose calculation, the authors found a RBE of 2.18 for 99mTc and RBE = 3.43 for 123I. Meanwhile, regarding the dose to the entire cell, RBE = 0.75 for 99mTc and RBE = 1.87 for 123I. The dose to the entire cell was chosen as the dose criterion because of the intracellular radionuclide accumulation, which was found to occur solely in the cytoplasm. The calculated number of intracellular decays per cell was (975 ± 109) decays/MBq for 99mTc and (221 ± 82) decays/MBq for 123I. Conclusions: The authors’ data indicate that extra-nuclear targets to Auger electrons exist, which is obvious from our dose calculations. When considering the dose to the cell nucleus, the authors found an enhanced RBE for99mTc and 123I relative to acute x-ray irradiation and pure extracellular irradiation with both radionuclides. Surprisingly, the authors did not find any radionuclide accumulation in the cell nucleus, indicating that there are additional radiosensitive targets besides the DNA. In addition, the authors demonstrated the necessity of cellular dose calculations in radiobiological experiments using unsealed radionuclides and identified the relevant parameters.

TO THE EDITOR: Cai et al. ([1][1]) reported Monte Carlo calculations to estimate cellular doses using 111In in different cell configurations. Therefore, the authors used the Monte Carlo N-particle (MCNP) code and compared their results with values provided by Goddu et al. ([2][2],[3][3]) for a