Small-Scale Dosimetry for the Testis: Applications in Nuclear Medicine Diagnostics and Therapy

Sammanfattning: It is well known that the testicles are among the most radiosensitive tissue, and constitute an important critical target for both external and internal radiation during diagnostic and therapeutic use of radionuclides. In systemic radionuclide therapy where very high activities are administered, the testis may become a dose-limiting organ; often with a complex, non-uniform activity distribution and a resulting non-uniform absorbed-dose distribution. A fundamental question in dosimetry research is then how the quantity absorbed dose links to certain biological effects in the volume of energy deposition. The main objective of the research presented in this thesis was to improve the commonly used MIRD dosimetry formalism for the testis, by the development of new methodology based on pre-clinical experiments and clinical patient data. In addition, the use of autoradiography for radioactivity distribution studies in mice, and immunohistochemistry for the detection of double-strand breaks in radiosensitive germ cells in the testis were studied. The work focused on the development of a geometrically realistic small-scale anatomical model of the human testicular tissue and by Monte Carlo modeling to determine S values for different source–target combinations. The model was applied on, and combined with pharmacokinetic modeling on individual patients that underwent pre-therapy imaging with 111-In-Zevalin®. By different autoradiography techniques the biokinetics and heterogeneity of activity distribution in the mouse testis was studied for 111-InCl3 and 111-In-Rituximab. Finally, a method using in vitro γH2AX immunofluorescence microscopy and confocal laser scanning microscope, for the determination of DNA double-strand breaks in spermatogonia and primary spermatocytes after 111-InCl3 uptake in the testis, was established. The results clearly show the importance of considering the heterogeneous distribution of radionuclides in the testis and possible hot spots of radioactivity. Autoradiography and small-scale dosimetry combined with compartment modeling may serve as a bridge between organ and tissue dosimetry. Finally, the thesis presents an efficient wide field γH2AX fluorescence quantifications method, side by side with a high specific intra-cellular confocal laser scanning microscope method to study cellular and intra-cellular radiation induced effects in the testis and might serve as powerful tool to study irradiation toxicity in the human testis.