Performance Assessment of Cerenkov Emission Imaging

Laddade partiklar med hög energi kan ibland färdas snabbare än ljusets hastighet i det medium det för stunden befinner sig i. När detta sker, emitteras så kallat Cerenkovljus. Ljuset ligger inom det synliga spektret och kan alltså detekteras med vanlig kamerateknik. Många av de radionuklider som används för nukleärmedicinska undersökningar och terapier emitterar högenergetiska laddade partiklar när de sönderfaller. Dessa kan få tillräckligt hög hastighet för att vid passage genom kroppen emittera Cerenkovljus. Nukleärmedicinska radionuklider används även för prekliniska metoder och tidigare studier har visat att Cerenkov Luminance Imaging (CLI), en metod där man studerar det emitterade Cerenkov ljuset från försöksdjur injicerade med radionuklider, skulle kunna användas för prekliniska studier av nukleärmedicinska terapier och läkemedel. När ljus färdas genom vävnad kommer det spridas och absorberas och endast en liten del av ljuset, om något, kommer ta sig upp till ytan. Om man ska kunna kvantifiera vilken mängd radioaktivitet som gett upphov till ljuset, måste man ta reda på hur ljuset har påverkats av sin färd mot ytan. I detta arbete utfördes så kallade fantommätningar för att studera hur spridning, absorption och djup i vävnad påverkar vilken mängd ljus man kan detektera. Fantomen bestod av mus-stora epoxiharts-block med olika optiska egenskaper som fick dem att absorbera och sprida ljuset olika mycket. Genom fantomen hade kanaler borrats med varierande avstånd till ytan för att simulera aktivitetsupptag på olika djup i en muskropp. Försöken gjordes med en ljustät låda som stänger ute vanligt ljus och en så kallad CCD-kamera monterad inuti lådan som kan detektera ljuset. Fantomen fylldes med radionukliden 18F, en vanlig nuklid vid PET-undersökningar och placerades i CLI-lådan. Bilder med varierande insamlingstid togs upprepade gånger under flera timmars tid, medan aktivitetsinnehållet i fantomen sönderföll. För att jämföra CLI:s potential som nukleärmedicinsk bildverktyg utfördes Positronemissionstomografi (PET)-undersökningar av samma fantom med 18F i tre olika prekliniska PET-system, däribland det box-geometriska systemet Genisys4. Resultaten visade att radiansen sjönk som funktion av djupet och för stigande absorptionsegenskaper i fantomens material. Spridande partiklar i fantomen ökade radiansen. Upplösningen blev sämre för ökande djup och för stigande mängd spridande partiklar. Absorberande material förbättrade upplösningen något. Resultaten visade på de hinder som måste överbryggas för att CLI ska kunna användas som ett kvantitativt nukleärmedicinskt bildverktyg, eftersom ljuset som detekteras inte direkt kan översättas till ett radionuklidupptag i muskroppen. Först måste radiansen normeras mot en effektiv attenueringskoefficient som beskriver hur ljusets intensitet förändras på sin väg mot ytan. Dessutom kommer CLI bara kunna användas till ytligt belägna aktivitetsupptag, så som tumörer implanterade under huden på försöksdjur.Background: Cerenkov Luminescence Imaging detects the light emitted when a charged particle travels through a medium with a velocity greater than the phase velocity of light in that medium. The beta-particles emitted from many radionuclides used in nuclear medicine have sufficient kinetic energy to satisfy the requirement. Purpose: This thesis aimed to examine the physical and optical properties affecting the radiance of Cerenkov radiation measured in the new imaging modality Cerenkov Luminescence Imaging (CLI). In difference to established preclinical imaging modalities detecting radionuclides such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT), CLI detects Cerenkov emission. This radiation is within the optical spectral range, as opposed to high energy photons emitted as a product of the radioactive decay. Better understanding of these properties could possibly enable quantitative measurements of radionuclide uptake in animal tumor models. Materials and method: Mouse-sized phantoms of varying scattering and absorbing properties with channels drilled at different depths were filled with 18F and imaged with a laboratory-built CLI-system. Images of varying exposure times were collected repeatedly during a number of half-lives of 18F. The radiance and FWHM were analyzed with MATLAB and the custom-made MATLAB-program OptiScope. For comparison to established imaging modalities, the phantoms were imaged in three different preclinical PET-systems, including the box-geometry system Genisys4 (Sofie BioSciences). Results: The radiance of the Cerenkov radiation was found to be proportional to the activity present in the channels of the phantoms. Increasing depth of the cannels was found to decrease the radiance measured, as did increasing absorption coefficient. An increasing scattering coefficient was found to increase the radiance over the range examined. Increasing depth and scattering coefficient showed a broadening of the FWHM, while an increasing absorption coefficient narrowed the FWHM. The FWHM measured for a variety of depths down to 1 cm and varying scattering and absorption coefficients, ranged between 0.4- 3.8 cm. Conclusion: CLI is limited by its complicated relationship between activity and radiance. Due to the many factors affecting the emitted light at the surface of the phantoms, the radiance could not directly be used as a quantitative measurement of the activity uptake. For this to be possible some form of normalization for the effective attenuation coefficient would be needed and the imaging could only be done for uptakes close to the surface of the subject. The coefficient could be assessed with an external light source. CLI will never challenge PET as an equally efficient quantitative imaging modality for preclinical imaging, but could become a part of an imaging scheme where a combination of modalities is used to utilize the benefits of each system

Tools for the Advancement of Radiopharmaceutical Therapy

Radiopharmaceutical therapy is used to treat cancers and other diseases with radiolabeled pharmaceuticals. The treatment targets specific cells, and the emitted ionizing radiation cause cytotoxic damage. Dosimetry is performed to estimate the absorbed dose from the energy deposited in the body. This requires measurement of the activity in vivo and knowledge of the retention time of the activity in tumor and organs. Preclinical trials precede clinical studies and evaluate the potential of new radiopharmaceuticals for treatment. Similarly, in vitro and in vivo experiments with radiopharmaceuticals and sources of ionizing radiation are performed to increase radiobiological knowledge, which is helpful in the optimization of radiopharmaceutical therapy. Dosimetry is also necessary for these studies to correctly quantify the biological response to ionizing radiation.However, standard dosimetry only considers macroscopic volumes such as organs or solid tumors. Due to the short range of the emitted radiation, heterogeneous activity uptake can generate heterogeneous energy depositions. In a tumor, this means a large variation in particle tracks hitting the cell nuclei, where cells inundertreated areas will not receive any particle tracks through the cell nucleus. Since damage to DNA in the cell nucleus is the main cause of radiation-induced cell death, this can reduce the treatment effect. Early insight into these limitations of a new radiopharmaceutical can be achieved in preclinical studies investigatingthe intra-tumoral distribution of the radiopharmaceutical uptake. Paper 4 investigated the tumor control probability from the intra-tumoral distribution of 177Lu-PSMA-617 in LNCaP xenografts. Monte Carlo simulations can be used for small-scale and microscopic dosimetry, where small targets such as cells and cellnuclei are considered. Similarly, in paper 3, simulations of an alpha particle source and cell nuclei irradiated were used to estimate the distribution of induced γ-H2AX foci in PC3 cells irradiated with an 241Am source in vitro.In preclinical studies of therapeutic radiopharmaceuticals, xenografted animal models are followed postinjection over long periods to evaluate the treatment response. This is usually done by measuring changes in tumor size over time. In addition, molecular imaging with positron emission tomography (PET) offers anopportunity to measure biochemical changes in vivo, such as the radiation damage response. However, as investigated in paper 1, gamma emission from the therapeutic radiopharmaceutical in the animal model can cause perturbations to the image by increasing dead-time losses and causing signal pile-up. However, assuggested in paper 2, preclinical intra-therapeutic PET imaging can still be performed during 177Lu-labeled radiopharmaceutical therapy, with shielding attenuating the excess photons while still allowing coincidence detection of annihilation photons

Preserving Preclinical PET Quality During Intratherapeutic Imaging in Radionuclide Therapy with Rose Metal Shielding Reducing Photon Flux

Performing PET imaging during ongoing radionuclide therapy can be a promising method to follow tumor response in vivo. However, the high therapeutic activity can interfere with the PET camera performance and degrade both image quality and quantitative capabilities. As a solution, low-energy photon emissions from the therapeutic radionuclide can be highly attenuated, still allowing sufficient detection of annihilation photons in coincidence. Methods: Hollow Rose metal cylinders with walls 2-4 mm thick were used to shield a 22Na point source and a uniform phantom filled with 18F as they were imaged on a preclinical PET camera with increasing activities of 177Lu. A mouse with a subcutaneous tumor was injected with 18F-FDG and imaged with an additional 120 MBq of 177Lu and repeated with shields surrounding the animal. Results: The addition of 177Lu to the volume imaged continuously degraded the image quality with increasing activity. The image quality was improved when shielding was introduced. The shields showed a high ability to produce stable and reproducible results for both spatial resolution and quantification of up to 120 MBq of 177Lu activity (maximum activity tested). Conclusion: Without shielding, the activity quantification will be inaccurate for time points at which therapeutic activities are high. The suggested method shows that the shields reduce the noise induced by the 177Lu and therefore enable longitudinal quantitative intratherapeutic imaging studies

Effects of high photon fluence rate from therapeutic radionuclides on preclinical and clinical PET systems

Tumor response in radionuclide therapy can be monitored with PET/CT and/or PET/MR. A high background photon fluence from a therapy radionuclide may influence both image quality and quantification, when imaging is performed intra-therapeutically, i.e. with high activity of the therapeutic radionuclide present. Here, count losses and image distortion have been investigated for preclinical and clinical PET systems with different detector designs. The effect on the spatial resolution was studied with a point source of 22Na in a background of 99mTc, where 99mTc emulated the photon emission from a therapeutic radionuclide. An in-house made mouse phantom with silicon tubes filled with 99mTc with a centrally placed 22Na point source was used. For the clinical systems, a 70 cm long NEMA PET Scatter Phantom was used, with a 22Na point source placed at the center whereas the off-center silicon tube was filled with 99mTc. In addition, image quality was also evaluated in the presence of different levels of 99mTc with a 18F-filled NEMA image quality phantom on the preclinical systems and a 18F-filled Jaszczak phantom on the clinical system. Preclinical PET systems with different detector geometries showed that the addition of 99mTc affected the count rate capability considerably, especially those with a low number of read-out channels. The coincidence rate for was significantly reduced when high activities of 99mTc were present. The clinical PET system also showed an effect of reduced coincidence rate with increased photon fluence rate. At high 99mTc activities, the spatial resolution was degraded for both the preclinical and the clinical systems. The quantitative capability of PET systems used intra-therapeutically is significantly affected by the additional high photon fluence rate. The dead-time correction implemented on some of the investigated PET systems, was able to accurately compensate for the coincidence count losses. The reduced spatial resolution at high photon fluence rate, however, remains a potentially limiting factor

Small-scale dosimetry for alpha particle 241Am source cell irradiation and estimation of γ-H2AX foci distribution in prostate cancer cell line PC3

Background: The development of new targeted alpha therapies motivates improving alpha particle dosimetry. For alpha particles, microscopic targets must be considered to estimate dosimetric quantities that can predict the biological response. As double-strand breaks (DSB) on DNA are the main cause of cell death by ionizing radiation, cell nuclei are relevant volumes necessary to consider as targets. Since a large variance is expected of alpha particle hits in individual cell nuclei irradiated by an uncollimated alpha-emitting source, the damage induced should have a similar distribution. The induction of DSB can be measured by immunofluorescent γ-H2AX staining. The cell γ-H2AX foci distribution and alpha particle hits distribution should be comparable and thereby verify the necessity to consider the relevant dosimetric volumes. Methods: A Monte Carlo simulation model of an 241Am source alpha particle irradiation setup was combined with two versions of realistic cell nuclei phantoms. These were generated from DAPI-stained PC3 cells imaged with fluorescent microscopy, one consisting of elliptical cylinders and the other of segmented mesh volumes. PC3 cells were irradiated with the 241Am source for 4, 8 and 12 min, and after 30 min fixated and stained with immunofluorescent γ-H2AX marker. The detected radiation-induced foci (RIF) were compared to simulated RIF. Results: The mesh volume phantom detected a higher mean of alpha particle hits and energy imparted (MeV) per cell nuclei than the elliptical cylinder phantom, but the mean specific energy (Gy) was very similar. The mesh volume phantom detected a slightly larger variance between individual cells, stemming from the more extreme and less continuous distribution of cell nuclei sizes represented in this phantom. The simulated RIF distribution from both phantoms was in good agreement with the detected RIF, although the detected distribution had a zero-inflated shape not seen in the simulated distributions. An estimate of undetected foci was used to correct the detected RIF distribution and improved the agreement with the simulations. Conclusion: Two methods to generate cell nuclei phantoms for Monte Carlo dosimetry simulations were tested and generated similar results. The simulated and detected RIF distributions from alpha particle-irradiated PC3 cells were in good agreement, proposing the necessity to consider microscopic targets in alpha particle dosimetry

Count rate characteristics and image distortion in preclinical PET systems during intratherapeutic radiopharmaceutical therapy imaging

Positron emission tomography (PET) may provide important information on the therapeutic response of radiopharmaceutical therapy (RPT) during therapy. The radiation emission from the RPT radionuclide may disturb the coincidence detection and impair the image resolution. In this study we tested the feasibility to perform intratherapeutic PET on three preclinical PET systems.METHODS: Using (22)Na point sources and phantoms filled with (18)F, and a phantom filled with either (99m)Tc or (177)Lu, the coincidence count rate and the spatial resolution when both a PET and a therapeutic radionuclide were present in the PET camera, were evaluated. (99m)Tc was used as a substitute for a generic therapeutic radioisotope, since it has a suitable half-life and is easy obtainable.RESULTS: High activities of (99m)Tc deteriorated the coincidence count rate from the (18)F-filled phantom with a (22)Na point source on all three systems evaluated. One of the systems could to a high degree correct the count rate with its dead time correction. The spatial resolution was degraded at high activities of (99m)Tc for all systems. On one of the systems (177)Lu increased the coincidence count rate and slightly affected the spatial resolution. The results for high activities of (177)Lu were similar to those for (99m)Tc.CONCLUSION: Intratherapeutic imaging might be a feasible method to study RPT treatment response. However, some sensitive preclinical PET systems, unable to handle high count rates, suffer count losses and may also introduce image artifacts

An attenuation method for reducing count rate losses in preclinical PET during intratherapeutic imaging

In pre-clinical imaging, tumor response to radionuclide therapy can be monitored with PET imaging. Radionuclides used for therapy such as 177Lu emit a significant amount of low energy photons. These photons may have an energy high enough to penetrate the imaged object and are the prone to be detected. Although these phtons are likely to be rejected electronically, they add dead-time to the system since they need to be processed by the electronics. This is a problem in high-sensitivity pre-clinical PET system with a low number of readout channels, such as the Genisys G8 investigated in this work. The low energy gammas may also affect image quality due to increased probability of pulse pile-up. The use of high-attenuating shields designed to absorb most of the low energy photons emitted from the therapeutic radionuclide were investigated. Cylindrical led shields were constructed with thicknesses between 1 and 3 mm. A 3mm thick cylindrical shield was also constructed out of Rose metal (50% Bi, 28% Pb, and 22% Sn). The diameter of the shield was wide enough to accommodate a NEMA IQ phantom and a mouse. The attenuation of the shields for annihilation radiation was measured with a 22Na point source placed at the center of the FOV. Measurements of the coincidence rate were performed with the lead shields in place. At a of thicknesses of 1 and 3mm, the coincidence rate was reduced by a factor or 0.70 and 0.40, respectively. To study the effect of the presence of a background of low energy gammas on the coincidence count rate and the efficacy of the lead shields, 177Lu was added to a 1 cm diameter hollow sphere. In the presence of 100 MBq of 177Lu, the coincidence count rate was reduced by a factor 0.20 due to the detector dead-time. Although the count rate was reduced by a factor of 0.40 with the 3mm shield around the source, the dead-time effects due to the 177Lu background were less than 7%. 18F imaging of a NEMA phantom and a tumor bearing mouse showed dramatic image distortions in the presence of the 177Lu background. When imaging of with the 3mm shield in place, the image distortions were eliminated and were comparable in to the images acquired without the background activity