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

Meerkhan, Suaad LU (2014)
Abstract (Swedish)
Popular Abstract in English

111-Indium is a radioactive isotope that can be chemically linked to different molecules. When this compound is given to patients is distributed heterogeneously within the structures that build up the testicle. Different parts of the so-called germ cells are sensitive to radiation in different ways. Therefore, if a radioisotope that send out electrons with low energies and with short ranges are close to these sensitive parts then this part of the testis can receive high deposit energy and consequently a high risk for an effect as compared to if the energy are uniformly distributed over the whole testis volume. This local energy deposition may then result in temporary or permanent sterility of the... (More)
Popular Abstract in English

111-Indium is a radioactive isotope that can be chemically linked to different molecules. When this compound is given to patients is distributed heterogeneously within the structures that build up the testicle. Different parts of the so-called germ cells are sensitive to radiation in different ways. Therefore, if a radioisotope that send out electrons with low energies and with short ranges are close to these sensitive parts then this part of the testis can receive high deposit energy and consequently a high risk for an effect as compared to if the energy are uniformly distributed over the whole testis volume. This local energy deposition may then result in temporary or permanent sterility of the patient. A general calculation procedure, called the MIRD-formalism, is often used to calculate the energy deposition to an organ (the absorbed dose). If the procedure is based on an assumption of an isotope that is distributed homogenous in the testis then this assumption may lead to either under-estimation or the opposite when considering local regions within the testis. To account for this problem in the calculation a more detailed model of the tissue structures and geometry is needed. In this work, we have developed such a small-scale model of the human testis. With this model there is possibility to calculate dose factors (so-called “S” values) for several source-to-target combinations and for radioisotopes that are commonly used in both diagnostic and therapeutic applications.



This new testis model was used together with data obtained from a patient study where 111-Indium have been attached to an antibody called Zevalin® that is used to treat patients for cancer. The uptake of the isotope in the testes was estimated from images for different time points by the use of a special device called a scintillation camera. In the study, we also collected blood samples at various time points. By using a mathematical method that estimates the transport through different compartments we could separate the total amount of radioactivity in the testis into a vascular part and an extravascular part. By using a relevant distribution of the radioisotope within the testis and combine this with our calculated S values obtained from the new geometrical model, we could calculated the absorbed doses to different regions in the testis and also estimate the uncertainties associated with this calculation. With a special method called autoradiography the activity distribution in a mouse testis for both 111-InCl3 and 111-In attached to an antibody, called Rituximab, was revealed. This was made to verify our assumptions on how the activity was distributed in a human testis. In a study in rodents, we also developed a method that was able to detect double-strand breaks in the DNA of the germ cells from ionizing radiation from 111-InCl3. This was performed by use of a biomarker, called γH2AX, and with visualization equipment, called immunofluorescence laser confocal microscopy.



Our results show that the absorbed dose to the sensitive parts of the testis that is called spermatogonia depends of the localization of the radioisotope. The absorbed dose as calculated by this new geometrical model might exceed the absorbed dose that is obtained by averaging over the whole testis by a factor of 1.6-2.3. This variation comes from natural geometric variations in the diameter of the, so-called, interstitial tubules in the male testis. For radioisotopes that send out electrons of low energy, such as is the case for 111-In, the localization of the radioisotope is, thus, essential because the absorbed dose to different targets in the testis may express large difference. This may affect the estimation of possible biological effects and other side effects related to ionizing radiation especially in cases for therapy using radioisotopes that emits radiation with a high intensity. Our results also indicate that the use of the γ-H2AX biomarker can be useful to detect DNA damages in the testicular germ cells as a result of ionizing radiation. (Less)
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Bernhardt, Peter, Avd Radiofysik, Sahlgrenska universitetssjukhuset, Göteborgs universitet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Testis, 111-In, Autoradiography, Biodistribution, Small-Scale, Monte Carlo, Dosimetry, spermatogonia, gammaH2AX, immunofluorescence
pages
194 pages
publisher
Medical Radiation Physics, Lund University
defense location
Alwallhusets föreläsningssal (2 vån), Skånes universitetssjukhus, Lund
defense date
2014-10-31 09:00
ISBN
978-91-7623-108-8 (pdf)
978-91-7623-108-1 (print)
language
English
LU publication?
yes
id
b6f2d1f7-dc28-49c4-b0d3-6d5262490518 (old id 4694875)
date added to LUP
2014-10-09 16:32:35
date last changed
2016-09-19 08:45:15
@phdthesis{b6f2d1f7-dc28-49c4-b0d3-6d5262490518,
  abstract     = {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.<br/><br>
<br/><br>
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.<br/><br>
<br/><br>
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.},
  author       = {Meerkhan, Suaad},
  isbn         = {978-91-7623-108-8 (pdf)},
  keyword      = {Testis,111-In,Autoradiography,Biodistribution,Small-Scale,Monte Carlo,Dosimetry,spermatogonia,gammaH2AX,immunofluorescence},
  language     = {eng},
  pages        = {194},
  publisher    = {Medical Radiation Physics, Lund University},
  school       = {Lund University},
  title        = {Small-Scale Dosimetry for the Testis: Applications in Nuclear Medicine Diagnostics and Therapy},
  year         = {2014},
}