Realistic Total-Body J-PET Geometry Optimization--Monte Carlo Study
J. Baran, W. Krzemień, L. Raczyński, M. Bała, A. Coussat, S. Parzych, N. Chug, E. Czerwiński, C. Oana Curceanu, M. Dadgar, K. Dulski, K. Eliyan, J. Gajewski, A. Gajos, B. Hiesmayr, K. Kacprzak, Ł. Kapłon, K. Klimaszewski, G. Korcyl, T. Kozik, D. Kumar, S. Niedźwiecki, D. Panek, E. Perez del Rio, A. Ruciński, S. Sharma, Shivani, R.Y. Shopa, M. Skurzok, E. Stępień, F. Tayefiardebili, K. Tayefiardebili, W. Wiślicki, P. Moskal
abstract
Total-Body PET imaging is one of the most promising newly introduced modalities in the medical diagnostics. State-of-the-art PET scanners use inorganic scintillators such as L(Y)SO or BGO, however, those technologies are very expensive, prohibitng the broad total-body PET applications. We present the comparative studies of performance characteristics of the cost-effective Total-Body PET scanners using Jagiellonian PET (J-PET) technology that is based on plastic scintillators. Here, we investigated in silico five realistic Total-Body scanner geometries, varying the number of rings, scanner radius, and distance between the neighbouring rings. Monte Carlo simulations of two NEMA phantoms (2-meter sensitivity line source and image quality) and the anthropomorphic XCAT phantom, were used to assess the performance of the tested geometries. We compared the sensitivity profiles and we performed the quantitative analysis of the reconstructed images by using the quality metrics such as contrast recovery coefficient, background variability and root mean squared error. The optimal scanner design was selected for the first Total-Body J-PET scanner configuration.
First positronium image of the human brain in vivo
P. Moskal, J. Baran, S. Bass, J. Choiński, N. Chug, C. Curceanu, E. Czerwiński, M. Dadgar, M. Das, K. Dulski, K.V. Eliyan, K. Fronczewska, A. Gajos, K. Kacprzak, M. Kajetanowicz, T. Kaplanoglu, Ł. Kapłon, K. Klimaszewski, M. Kobylecka, G. Korcyl, T. Kozik, W. Krzemień, K. Kubat, D. Kumar, J. Kunikowska, J. Mączewska, W. Migdał, G. Moskal, W. Mryka, S. Niedźwiecki, S. Parzych, E. Perez del Rio, L. Raczyński, S. Sharma, Shivani, R.Y. Shopa, M. Silarski, M. Skurzok, F. Tayefi, K. Tayefi, P. Tanty, W. Wiślicki, L. Królicki, E. Ł. Stępień
abstract
Positronium, an unstable atom consisting of an electron and a positron, is abundantly produced within the molecular voids of a patient?s body during positron emission tomography (PET) diagnosis. Its properties, such as its average lifetime between formation and annihilation into photons, dynamically respond to the submolecular architecture of the tissue and the partial pressure of oxygen molecules. However, the diagnostic information that positronium may deliver about early molecular alterations remains unavailable in clinics with state-of-the-art PET scanners.
This study presents the first in vivo images of positronium lifetime in humans. We developed a dedicated J-PET system with multiphoton detection capability for imaging. The measurements of positronium lifetime were performed on a patient with a glioblastoma tumor in the brain. The patient was injected intratumorally with the 68Ga radionuclide attached to Substance-P, which accumulates in glioma cells, and intravenously with 68Ga attached to the PSMA-11 ligand, which is selective to glioma cells and salivary glands. The 68Ga radionuclide is routinely used in PET for detecting radiopharmaceutical accumulation and was applied for positronium imaging because it can emit an additional prompt gamma. The prompt gamma enables the determination of the time of positronium formation, while the photons from positronium annihilation were used to reconstruct the place and time of its decay. The determined positronium mean lifetime in glioblastoma cells is shorter than in salivary glands, which in turn is shorter than in healthy brain tissues, demonstrating for the first time that positronium imaging can be used to diagnose disease in vivo. This study also demonstrates that if current total-body PET systems were equipped with multiphoton detection capability and the 44Sc radionuclide was applied, it would be possible to perform positronium imaging at 6500 times greater sensitivity than achieved in this research. Therefore, it is anticipated that positronium imaging has the potential to bring a new quality of cancer diagnosis in clinics.
Feasibility of the J-PET to monitor range oftherapeutic proton beams
J. Baran, D. Borys, K. Brzeziński, J. Gajewski, M. Silarski, N. Chug, A. Coussat, E. Czerwiński, M. Dadgar, K. Dulski, K.V. Eliyan, A. Gajos, K. Kacprzak, Ł. Kapłon, K. Klimaszewski, P. Konieczka, R. Kopeć, G. Korcyl, T. Kozik, W. Krzemień, D. Kumar, A.J. Lomax, K. McNamara, S. Niedźwiecki, P. Olko, D. Panek, S. Parzych, E. Perez del Rio, L. Raczyński, M. Simbarashe, S. Sharma, Shivani, R.Y. Shopa, T. Skóra, M. Skurzok, P. Stasica, E.Ł. Stępień, K. Tayefi, F. Tayefi, D.C. Weber, C. Winterhalter, W. Wiślicki, P. Moskal, A. Ruciński
abstract
Objective: The aim of this work is to investigate the feasibility of the JagiellonianPositron Emission Tomography (J-PET) scanner for intra-treatment proton beamrange monitoring. Approach: The Monte Carlo simulation studies with GATE and PET imagereconstruction with CASToR were performed in order to compare six J-PET scannergeometries (three dual-heads and three cylindrical). We simulated proton irradiationof a PMMA phantom with a Single Pencil Beam (SPB) and Spread-Out BraggPeak (SOBP) of various ranges. The sensitivity and precision of each scanner werecalculated, and considering the setup?s cost-effectiveness, we indicated potentiallyoptimal geometries for the J-PET scanner prototype dedicated to the proton beamrange assessment. Main results: The investigations indicate that the double-layer cylindrical andtriple-layer double-head configurations are the most promising for clinical application.We found that the scanner sensitivity is of the order of 10?5coincidences per primaryproton, while the precision of the range assessment for both SPB and SOBP irradiationplans was found below 1 mm. Among the scanners with the same number of detectormodules, the best results are found for the triple-layer dual-head geometry. Significance: We performed simulation studies demonstrating that the feasibilityof the J-PET detector for PET-based proton beam therapy range monitoring ispossible with reasonable sensitivity and precision enabling its pre-clinical tests in theclinical proton therapy environment. Considering the sensitivity, precision and cost-effectiveness, the double-layer cylindrical and triple-layer dual-head J-PET geometryconfigurations seem promising for the future clinical application. Experimental testsare needed to confirm these findings.
Feasibility studies for imaging e+e- annihilation with modular multi-strip detectors
S. Sharma, L. Povolo, S. Mariazzi, G. Korcyl, K. Kacprzak, D. Kumar, S. Niedzwiecki, J. Baran, E. Beyene, R. S. Brusa, R. Caravita, N. Chug, A. Coussat, C. Curceanu, E. Czerwinski, M. Dadgar, M. Das, K. Dulski, K. Eliyan, A. Gajos, N. Gupta, B. C. Hiesmayr, L. Kaplon, T. Kaplanoglu, K. Klimaszewski, P. Konieczka, T. Kozik, M. K. Kozani, W. Krzemien, S. Moyo, W. Mryka, L. Penasa, S. Parzych, E. Perez Del Rio, L. Raczynski, R. Y. Shopa, M. Skurzok, E. L. Stepien, P. Tanty, F. Tayefi, K. Tayefi, W. Wislicki, P. Moskal
abstract
Studies based on imaging the annihilation of the electron (e-) and its antiparticle positron (e+) open up several interesting applications in nuclear medicine and fundamental research. The annihilation process involves both the direct conversion of ee into photons and the formation of their atomically bound state, the positronium atom (Ps), which can be used as a probe for fundamental studies. With the ability to produce large quantities of Ps, manipulate them in long-lived Ps states, and image their annihilations after a free fall or after passing through atomic interferometers, this purely leptonic antimatter system can be used to perform inertial sensing studies in view of a direct test of Einstein equivalence principle. It is envisioned that modular multistrip detectors can be exploited as potential detection units for this kind of studies. In this work, we report the results of the first feasibility study performed on a e beamline using two detection modules to evaluate their reconstruction performance and spatial resolution for imaging ee annihilations and thus their applicability for gravitational studies of Ps.
SPLIT: Statistical Positronium Lifetime Image reconstruction via time-Thresholding
B. Huang, T. Li, G, Arino-Estrada, K. Dulski, R.Y. Shopa, P. Moskal, E. Stępień, J. Qi
abstract
Positron emission tomography (PET) is a widely utilized medical imaging modality that uses positron-emitting radiotracers to visualize biochemical processes in a living body. The spatiotemporal distribution of a radiotracer is estimated by detecting the coincidence photon pairs generated through positron annihilations. In human tissue, about 40% of the positrons form positroniums prior to the annihilation. The lifetime of these positroniums is influenced by the microenvironment in the tissue and could provide valuable information for better understanding of disease progression and treatment response. Currently, there are few methods available for reconstructing high-resolution lifetime images in practical applications. This paper presents an efficient statistical image reconstruction method for positronium lifetime imaging (PLI). We also analyze the random triple-coincidence events in PLI and propose a correction methodfor random events, which is essential for real applications. Both simulation andexperimental studies demonstrate that the proposed method can produce lifetime images with high numerical accuracy, low variance, and resolution comparable to that of the activity images generated by a PET scanner with currently available time-of-flight resolution.
Discrete symmetries tested at 10^-4 precision using linear polarization of photons from positronium annihilations
P. Moskal, E. Czerwiński, J. Raj, S. D. Bass, E. Beyene, N. Chug, A. Coussat, C. Curceanu, M. Dadgar, M. Das, K. Dulski, A. Gajos, M. Gorgol, B. C. Hiesmayr, B. Jasińska, K. Kacprzak, T. Kaplanoglu, Ł. Kapłon, K. Klimaszewski, P. Konieczka, G. Korcyl, T. Kozik, W. Krzemień, D. Kumar, S. Moyo, W. Mryka, S. Niedźwiecki, S. Parzych, E. Pérez del Río, L. Raczyński, S. Sharma, S. Choudhary, R. Y. Shopa, M. Silarski, M. Skurzok, E. Ł. Stępień, P. Tanty, F. T. Ardebili, K. T. Ardebili, K. V. Eliyan, W. Wiślicki
abstract
Discrete symmetries play an important role in particle physics with violation of CP connected to the matter-antimatter imbalance in the Universe. We report the most precise test of P, T and CP invariance in decays of ortho-positronium, performed with methodology involving polarization of photons from these decays. Positronium, the simplest bound state of an electron and positron, is of recent interest with discrepancies reported between measured hyperfine energy structure and theory at the level of 10^-4 signaling a need for better understanding of the positronium system at this level. We test discrete symmetries using photon polarizations determined via Compton scattering in the dedicated J-PET tomograph on an event-by-event basis and without the need to control the spin of the positronium with an external magnetic field, in contrast to previous experiments. Our result is consistent with QED expectations at the level of 0.0007 and one standard deviation.
Estimating influence of positron range in proton-therapy-beam monitoring with PET
W. Mryka, M. Das, E.Y. Beyene, P. Moskal, E. Stępień
abstract
The application of PET scanners to proton-beam-therapy monitoring is a promising solution to obtain the range of the beam and hence the positions of a Bragg peak - maximum dose deposition point. A proton beam induces nuclear reactions in the tissue, leading to the production of isotopes that emit beta+ radiation. This enables the imaging of the density distribution of beta+ isotopes produced in the body, allowing the reconstruction of the proton beam range. Moreover, PET detectors may open the possibility for in-beam monitoring, which would offer an opportunity to verify the range during irradiation. PET detectors may also allow positronium imaging, which would be the indicator of the tissue conditions. However, the image of annihilation points does not represent the range of the proton beam. There are several factors influencing the translation from annihilation points to obtain the Bragg peak position. One of them is the kinetic energy of the positron. This energy corresponds to some range of the positron within the tissue. In this manuscript we estimate positron energy and its range and discuss its influence on proton therapy monitoring.
Exploration of simultaneous dual-isotope imaging with multi-photon modular J-PET scanner
Ermias Yitayew Beyene, Manish Das, Martyna Durak-Kozica, Grzegorz Korcyl, Wiktor Mryka, Szymon Niedźwiecki, Szymon Parzych, Keyvan Tayefi Ardebili, Rafał Walczak, Kamil Wawrowicz, Ewa Stępień, Paweł Moskal
abstract
The modular J-PET scanner, comprising 24 compact and versatile modules, each consisting of 13 plastic strips with four SiPM detectors at the ends, represents a powerful tool for clinical applications in nuclear medical imaging. This study presents preliminary results from the exploration of simultaneous dual-isotope imaging using the modular J-PET system. Our approach involved two isotopes: 68Ge, characterized by a ringlike shape, and 22Na, exhibiting a point-like shape. The imaging was based on double-coincidence and triple-coincidence events. In the double coincidence case, both isotopes contributed comparably, whereas in the triple coincidence case 22Na dominated due to the prompt gamma being emitted with 100% of positron emissions, unlike 68Ga, where the prompt gamma was emitted in only 1.3% of cases after positron emission. In this work we present direct 2? images determined for two-signal events and images for three-signal events, with two signals from annihilation photons and one from a prompt gamma. These results showcase the preliminary findings from simultaneous dual-isotope imaging of 68Ga and 22Na isotopes using the modular J-PET scanner, which will be presented and discussed.
Estimating the efficiency and purity for detecting annihilation and prompt photons for positronium imaging with J-PET using toy Monte Carlo simulation
M. Das, W. Mryka, E.Y. Beyene, S. Parzych, S. Sharma, E. Stępień, P. Moskal
abstract
The positronium imaging technique represents a potential enhancement of the PET imaging method. Its core principle involves employing a beta+ radiation source that emits additional gamma quanta referred to as prompt gamma. Our aim is to evaluate the capability to differentiate between annihilation and prompt gamma emissions, a vital aspect of positronium imaging. For this purpose, the selected isotopes should enable high efficiency and purity in detecting both prompt gamma and annihilation gamma. The assessment of the efficiency in identifying prompt and annihilation photons for various isotopes, which are potentially superior candidates for beta++ gamma emitters, is conducted through toy Monte-Carlo simulation utilizing the cross-section formula for photon-electron scattering. In this article, we have performed calculations for efficiency and purity values across different isotopes under ideal conditions and examined how these values evolve as we incorporate the fractional energy resolution into the analysis. Ultimately, the primary goal is to determine the energy threshold that optimizes both efficiency and purity, striking a balance between accurately identifying and recording events of interest while minimizing contamination from undesired events.
Application of an ultra-high dose rate (FLASH) proton beam for the 3D cancer cell model - a proof of concept
M. Durak-Kozica, E. Stępień, J. Swakoń, P. Moskal
abstract
Ultra-high dose rate (FLASH) proton radiotherapy is a promising treatment method for cancer patients. In our research, we want to compare the FLASH method with a conventional radiation method to show what effect they have on the biochemical structure of the tumour (3D model ? spheroids) and the secretion of extracellular vesicles (EVs) and their cargo. The use of a modern method of creating spheroids will enable us to create conditions that are better able to mimic the tumour microenvironment.
A new detector concept based on the prompt gamma radiation analysis for In vivo boron monitoring in BNCT
M. Silarski, K. Dziedzic-Kocurek, F. Sobczuk, A. Nykiel, P. Moskal, S. Niedźwiecki, E.Ł. Stępień, M. Szczepanek
abstract
The problem of boron concentration monitoring during the boron neutron capture therapy (BNCT) therapy is one of the main challenges of this type of radiotherapy and is directly related to the nature of the interaction of neutrons with mater. Among the available in vivo methods of boron monitoring positron emission tomography seems to be very promising but it requires a new boron carrier with a ?+ emitter, which is not yet clinically available. An alternative solution may be the prompt gamma radiation analysis (PGRA) based on the secondary radiation emitted in the interaction of neutrons with the patient's tissues. This method requires, however, compact gamma radiation detection systems sustaining high counting rates and characterized by very good energy resolution. In this contribution, we present state-of-the-art solutions for monitoring in BNCT based on PGRA. Moreover, we describe a new concept of such a system based on position-sensitive scintillator detectors equipped with an anti-Compton shield and data analysis supported with modern artificial intelligence algorithms.
Transformation of PET raw data into images for event classification using convolutional neural networks
P. Konieczka, L. Raczyński, W. Wiślicki, O. Fedoruk, K. Klimaszewski, P. Kopka, W. Krzemień, R.Y. Shopa, J. Baran, A. Coussat, N. Chug, C. Curceanu, E. Czerwiński, M. Dadgar, K. Dulski, A. Gajos, B.C. Hiesmayr, K. Kacprzak, Ł. Kapłon, G. Korcyl, T. Kozik, D. Kumar, S. Niedźwiecki, S. Parzych, E. Pérez del Río, S. Sharma, S. Shivani, M. Skurzok, E.Ł. Stępień, F. Tayefi, P. Moskal
abstract
In positron emission tomography (PET) studies, convolutional neural networks (CNNs) may be applied directly to the reconstructed distribution of radioactive tracers injected into the patient's body, as a pattern recognition tool. Nonetheless, unprocessed PET coincidence data exist in tabular format. This paper develops the transformation of tabular data into -dimensional matrices, as a preparation stage for classification based on CNNs. This method explicitly introduces a nonlinear transformation at the feature engineering stage and then uses principal component analysis to create the images. We apply the proposed methodology to the classification of simulated PET coincidence events originating from NEMA IEC and anthropomorphic XCAT phantom. Comparative studies of neural network architectures, including multilayer perceptron and convolutional networks, were conducted. The developed method increased the initial number of features from 6 to 209 and gave the best precision results (79.8) for all tested neural network architectures; it also showed the smallest decrease when changing the test data to another phantom.
Detection of range shifts in proton beam therapy using the J-PET scanner: a patient simulation study
K. Brzeziński, J. Baran, D. Borys, J. Gajewski, N. Chug, A. Coussat, E. Czerwiński, M. Dadgar, K. Dulski, K.V. Eliyan, A. Gajos, K. Kacprzak, Ł. Kapłon, K. Klimaszewski, P. Konieczka, R. Kopeć, G. Korcyl, T. Kozik, W. Krzemień, D. Kumar, A.J. Lomax, K. McNamara, S. Niedźwiecki, P. Olko, D. Panek, S. Parzych, E. Perez del Rio, L. Raczyński, S. Sharma, Shivani, R.Y. Shopa, T. Skóra, M. Skurzok, P. Stasica, E.Ł. Stępień, K. Tayefi, F. Tayefi, D.C. Weber, C. Winterhalter, W. Wiślicki, P. Moskal, A. Ruciński
abstract
Objective. The Jagiellonian positron emission tomography (J-PET) technology, based on plastic scintillators, has been proposed as a cost effective tool for detecting range deviations during proton therapy. This study investigates the feasibility of using J-PET for range monitoring by means of a detailed Monte Carlo simulation study of 95 patients who underwent proton therapy at the Cyclotron Centre Bronowice (CCB) in Krakow, Poland. Approach. Discrepancies between prescribed and delivered treatments were artificially introduced in the simulations by means of shifts in patient positioning and in the Hounsfield unit to the relative proton stopping power calibration curve. A dual-layer, cylindrical J-PET geometry was simulated in an in-room monitoring scenario and a triple-layer, dual-head geometry in an in-beam protocol. The distribution of range shifts in reconstructed PET activity was visualized in the beam's eye view. Linear prediction models were constructed from all patients in the cohort, using the mean shift in reconstructed PET activity as a predictor of the mean proton range deviation. Main results. Maps of deviations in the range of reconstructed PET distributions showed agreement with those of deviations in dose range in most patients. The linear prediction model showed a good fit, with coefficient of determination r2 = 0.84 (in-room) and 0.75 (in-beam). Residual standard error was below 1 mm: 0.33 mm (in-room) and 0.23 mm (in-beam). Significance. The precision of the proposed prediction models shows the sensitivity of the proposed J-PET scanners to shifts in proton range for a wide range of clinical treatment plans. Furthermore, it motivates the use of such models as a tool for predicting proton range deviations and opens up new prospects for investigations into the use of intra-treatment PET images for predicting clinical metrics that aid in the assessment of the quality of delivered treatment.
Comparative studies of plastic scintillator strips with high technical attenuation length for the total-body J-PET scanner
Ł. Kapłon, J. Baran, N. Chug, A. Coussat, C. Curceanu, E. Czerwiński, M. Dadgar, K. Dulski, J. Gajewski, A. Gajos, B. Hiesmayr, E. Kavya Valsan, K. Klimaszewski, G. Korcyl, T. Kozik, W. Krzemień, D. Kumar, G. Moskal, S. Niedźwiecki, D. Panek, S. Parzych, E. Pérez del Rio, L. Raczyński, A. Ruciński, S. Sharma, S. Shivani, R. Shopa, M. Silarski, M. Skurzok, E. Stępień, F. Tayefi Ardebili, K. Tayefi Ardebili, W. Wiślicki, P. Moskal
abstract
Plastic scintillator strips are considered as one of the promising solutions for the cost-effective construction of total-body positron emission tomography, (PET) system. The purpose of the performed measurements is to compare the transparency of long plastic scintillators with dimensions 6 mm x 24 mm x 1000 mm and with all surfaces polished. Six different types of commercial, general purpose, blue-emitting plastic scintillators with low attenuation of visible light were tested, namely: polyvinyl toluene-based BC-408, EJ-200, RP-408, and polystyrene-based Epic, SP32 and UPS-923A. For determination of the best type of plastic scintillator for total-body Jagiellonian positron emission tomograph (TB-J-PET) construction, emission and transmission spectra, and technical attenuation length (TAL) of blue light-emitting by the scintillators were measured and compared. The TAL values were determined with the use of UV lamp as excitation source, and photodiode as light detector. Emission spectra of investigated scintillators have maxima in the range from 420 nm to 429 nm. The BC-408 and EJ-200 have the highest transmittance values of about 90% at the maximum emission wavelength measured through a 6 mm thick scintillator strip and the highest technical attenuation length reaching about 2000 mm, allowing assembly of long detection modules for time-of-flight (TOF) J-PET scanners. Influence of the 6 mm × 6 mm, 12 mm × 6 mm, 24 mm × 6 mm cross-sections of the 1000 mm long EJ-200 plastic scintillator on the TAL and signal intensity was measured. The highest TAL value was determined for samples with 24 mm × 6 mm cross-section.
3D melanoma spheroid model for the development of positronium biomarker
H. Karimi, P. Moskal, E.Ł. Stępień
abstract
It was recently demonstrated that newly invented positronium imaging may be used for improving cancer diagnostics by providing additional information about tissue pathology with respect to the standardized uptake value currently available in positron emission tomography (PET). Positronium imaging utilizes properties of a positronium atoms, which are built from the electron and positron produced in the body during PET examinations.
We hypothesized whether positronium imaging would be sensitive to in vitro discrimination of tumour-like three-dimensional structures (spheroids) build of melanoma cell lines with different cancer activity and biological properties.
The lifetime of ortho-Positronium (o-Ps) was evaluated in melanoma spheroids from two cell lines (WM266-4 and WM115) differing in the stage of malignancy. Additionally, we considered such parameters: as cell size, proliferation rate and malignancy to evaluate their relationship with o-Ps lifetime. We demonstrate the pilot results for the o-Ps lifetime measurement in extracellular matrix free spheroids. With the statistical significance of two standard deviations, we demonstrated that the higher the degree of malignancy and the rate of proliferation of neoplastic cells the shorter the lifetime of ortho-positronium. In particular we observed following indications encouraging further research: (i) WM266-4 spheroids characterized with higher proliferation rate and malignancy showed shorter o-Ps lifetime compared to WM115 spheroids characterized by lower growth rate, (ii) Both cell lines showed a decrease in the lifetime of o-Ps after spheroid generation in 8th day comparing to 4th day in culture and the mean o-Ps lifetime is longer for spheroids formed from WM115 cells than these from WM266-4 cells, regardless spheroid age. The results of these study revealed that positronium is a promising biomarker that may be applied in PET diagnostics for the assessment of the degree of cancer malignancy.
Colloquium: Positronium physics and biomedical applications
S.D. Bass, S. Mariazzi, P. Moskal, E. Stępień
abstract
Positronium is the simplest bound state, built of an electron and a positron. Studies of positronium in vacuum and its decays in medium tell us about quantum electrodynamics (QED) and about the structure of matter and biological processes of living organisms at the nanoscale, respectively. Spectroscopic measurements constrain our understanding of QED bound state theory. Searches for rare decays and measurements of the effect of gravitation on positronium are used to look for new physics phenomena. In biological materials positronium decays are sensitive to the intermolecular and intramolecular structure and to the metabolism of living organisms ranging from single cells to human beings. This leads to new ideas of positronium imaging in medicine using the fact that during positron emission tomography (PET) as much as 40% of positron annihilation occurs through the production of positronium atoms inside the patient?s body. A new generation of the high sensitivity and multiphoton total-body PET systems opens perspectives for clinical applications of positronium as a biomarker of tissue pathology and the degree of tissue oxidation.
Extracellular vesicles in vascular pathophysiology: beyond their molecular content
E.Ł. Stępień, M. Durak-Kozica, P. Moskal
abstract
Extracellular vesicles (EVs) are released by all cells, both in physiological and pathological conditions. Their molecular charge and composition emerge as possible biomarkers, but EVs may also be considered for other clinical applications. This review discusses the role of other features of EVs, such as their lipid components or composition of glycans that form the EV corona and regulate EV biodistribution and uptake by target cells. The importance of EV electric charge has been discussed as a new insight into EV fate and destination.
Efficiency determination of J-PET: first plastic scintillators-based PET scanner
S. Sharma, J. Baran, N. Chug, C. Curceanu, E. Czerwiński, M. Dadgar, K. Dulski, K. Eliyan, A. Gajos, N. Gupta-Sharma, B. C. Hiesmayr, K. Kacprzak, Ł. Kapłon, K. Klimaszewski, P. Konieczka, G. Korcyl, T. Kozik, W. Krzemień, D. Kumar, Sz. Niedźwiecki, D. Panek, S. Parzych, E. Perez del Rio, L. Raczyński, Shivani, R. Y. Shopa, M. Skurzok, E. Ł. Stępień, F. Tayefi, K. Tayefi , W. Wiślicki and P. Moskal
abstract
Background:
The Jagiellonian Positron Emission Tomograph is the 3-layer prototype
of the first scanner based on plastic scintillators, consisting of 192 half-metre-long strips with readouts at both ends. Compared to crystal-based detectors, plastic scintillators
are several times cheaper and could be considered as a more economical alternative to crystal scintillators in future PETs. JPET is also a first multi-photon PET prototype. For the development of multi-photon detection, with photon characterized by the continuous energy spectrum, it is important to estimate the efficiency of J-PET as a function of energy deposition. The aim of this work is to determine the registration efficiency of the J-PET tomograph as a function of energy deposition by incident photons and the intrinsic efficiency of the J-PET scanner in detecting photons of different incident energies. In this study, 3-hit events are investigated, where 2-hits are caused by 511 keV
photons emitted in e+e- annihilations, while the third hit is caused by one of the scattered photons. The scattered photon is used to accurately measure the scattering angle and thus the energy deposition. Two hits by a primary and a scattered photon are sufficient to calculate the scattering angle of a photon, while the third hit ensures
the precise labeling of the 511 keV photons.
Results:
By comparing experimental and simulated energy distribution spectra, the registration efficiency of the J-PET scanner was determined in the energy deposition range of 70-270 keV, where it varies between 20 and 100%. In addition, the intrinsic efficiency of the J-PET was also determined as a function of the energy of the incident photons.
Conclusion:
A method for determining registration efficiency as a function of energy deposition and intrinsic efficiency as a function of incident photon energy of the J-PET scanner was demonstrated. This study is crucial for evaluating the performance of the scanner based on plastic scintillators and its applications as a standard and multi-photon PET systems. The method may be also used in the calibration of Compton-cameras developed for the ion-beam therapy monitoring and simultaneous multi-radionuclide imaging in nuclear medicine.
Developing a Novel Positronium Biomarker for Cardiac Myxoma Imaging
P. Moskal, E. Kubicz, G. Grudzień, E. Czerwiński, K. Dulski, B. Leszczyński, S. Niedźwiecki, E.Ł. Stępień
abstract
Purpose: Cardiac myxoma (CM), the most common cardiac tumor in adults, accounts for 50?75% of benign cardiac tumors. The diagnosis of CM is often elusive, especially in young stroke survivors and transthoracic echocardiography (TTE) is the initial technique for the differential diagnostics of CM. Less invasive cardiac computed tomography (CT) and magnetic resonance imaging (MRI) are not available for the majority of cardiac patients. Here, a robust imaging approach, ortho-Positronium (o-Ps) imaging, is presented to determine cardiac myxoma extracted from patients undergoing urgent cardiac surgery due to unexpected atrial masses. We aimed to assess if the o-Ps atom, produced copiously in intramolecular voids during the PET imaging, serves as a biomarker for CM diagnosing.
Methods: Six perioperative CM and normal (adipose) tissue samples from patients, with primary diagnosis confirmed by the histopathology examination, were examined using positron annihilation lifetime spectroscopy (PALS) and micro-CT. Additionally, cell cultures and confocal microscopy techniques were used to picture cell morphology and origin.
Results: We observed significant shortening in the mean o-Ps lifetime in tumor with compare to normal tissues: an average value of 1.92(02) ns and 2.72(05) ns for CM and the adipose tissue, respectively. Microscopic differences between tumor samples, confirmed in histopathology examination and micro-CT, did not influenced the major positronium imaging results.
Conclusions: Our findings, combined with o-Ps lifetime analysis, revealed the novel emerging positronium imaging marker (o-PS) for cardiovascular imaging. This method opens the new perspective to facilitate the quantitative in vivo assessment of intracardiac masses on a molecular (nanoscale) level.
J-PET detection modules based on plastic scintillators for performing studies with positron and positronium beams
S. Sharma, J. Baran, R.S. Brusa, R. Caravita, N. Chug, A. Coussat, C. Curceanu, E. Czerwinski, M. Dadgar, K. Dulski, K. Eliyan, A. Gajos, B.C. Hiesmayr, K. Kacprzak, L. Kaplon, K. Klimaszewski, P. Konieczka, G. Korcyl, T. Kozik, W. Krzemien D. Kumar, S. Mariazzi, S. Niedźwiecki, L. Panasa, S. Parzych, L. Povolo, E. Perez del Rio, L. Raczynski Shivani, R.Y. Shopa, M. Skurzok, E.L. Stepien, F. Tayefi, K. Tayefi, W. Wislicki and P. Moskal
abstract
The J-PET detector, which consists of inexpensive plastic scintillators, has demonstrated its potential in the study of fundamental physics. In recent years, a prototype with 192 plastic scintillators arranged in 3 layers has been optimized for the study of positronium decays. This allows performing precision tests of discrete symmetries (C, P, T) in the decays of positronium atoms. Moreover, thanks to the possibility of measuring the polarization direction of the photon based on Compton scattering, the predicted entanglement between the linear polarization of annihilation photons in positronium decays can also be studied. Recently, a new J-PET prototype was commissioned, based on a modular design of detection units. Each module consists of 13 plastic scintillators and can be used as a stand-alone, compact and portable detection unit. In this paper, the main features of the J-PET detector, the modular prototype and their applications for possible studies with positron and positronium beams are discussed. Preliminary results of the first test experiment performed on two detection units in the continuous positron beam recently developed at the Antimatter Laboratory (AML) of Trento are also reported.
Investigation of novel preclinical Total Body PET designed with J-PET technology: A simulation study
M. Dadgar, S. Parzych, F. Tayefi Ardebili, J. Baran, N. Chug, C. Curceanu, E. Czerwiński, K. Dulski, K. Eliyan, A. Gajos, B.C. Hiesmayr, K. Kacprzak, K. Klimaszewski, P. Konieczka, G. Korcyl, T. Kozik, W. Krzemień, D. Kumar, S. Niedźwiecki, D. Panek, E. Perez del Rio, L. Raczyński, S. Sharma, R.Y. Shopa, M. Skurzok, K. Tayefi Ardebili, S. Vandenberghe, W. Wiślicki, E.Ł. Stępień, P. Moskal
abstract
The growing interest in human-grade Total Body PET systems has also application in small animal research. Due to the existing limitations in human-based studies involving drug development and novel treatment monitoring, animalbased research became a necessary step for testing and protocol preparation. In this simulation-based study two unconventional, cost effective small animal Total Body PET scanners (for mouse and rat studies) have been investigated in order to inspect their feasibility for preclinical research. They were designed with the novel technology explored by the Jagiellonian PET Collaboration (J-PET). Two main PET characteristics: sensitivity and spatial resolution were mainly inspected to evaluate their performance. Moreover, the impact of the scintillator dimension and time-offlight on the latter parameter were examined in order to design the most efficient tomographs. The presented results show that for mouse TB J-PET the achievable system sensitivity is equal to 2.35% and volumetric spatial resolution to 9.46 +- 0.54 mm3, while for rat TB J-PET they are equal to 2.6% and 14.11 ? 0.80 mm3, respectively. Furthermore, it was shown that the designed tomographs are almost parallax-free systems, hence they resolve the problem of the acceptance criterion trade-off between enhancing spatial resolution and reducing sensitivity.
Transcriptomic data analysis of melanocytes and melanoma cell lines of LAT transporter genes for precise medicine
M. Szczepanek, D. Panek, M. Przybyło, P. Moskal, E. Stępień
abstract
Background: Boron Neutron Capture Therapy (BNCT) is a two-step treatment that can be used in some types of cancers. It involves administering a compound containing boron atoms to the patient and irradiating the affected area of the body with a neutron beam. The success of the therapy depends mainly on the delivery of the boron isotope (10B) to the tumor using an appropriate boron carrier. One of the boron carriers used is boronophenylalanine (BPA). Therefore, in research on the use of boron carriers, it is also important to know the mechanisms of its uptake by cells. Aim: To study the expression of LAT family genes in two melanoma (high melanotic WM115 and low melanotic WM266-4) cell lines and melanocytes (HEMa-Lp) which are responsible for the transport the BPA into cells. Methods: To normalize data from the transcriptomic analysis, the ratio of the median method was used. This allowed the samples to be compared with each other. Comparison metrics included log-fold change (LFC) values. The heatmap of LFC values and the cluster map were created. These graphs show the similarities and differences between the samples. Results: Transcriptomic data show that in melanocytes, LFC for SLC7A5 (LAT1) and SLC3A2 (4Fhc) was higher than in melanoma cell lines, which corresponded with their melanin content. Conclusion: Our results indicate overexpression of BPA transporter genes in normal cells (melanocytes), which may suggest the highest level of these proteins in melanocytes compared to less melanotic melanoma. Therefore, for BNCT, the use of BPA as the 10B carrier will require additional qualifying tests of amino acid transporter expression for patients and specific tumors to develop a personalized BNCT.
Feasibility study of positronium application for blood clots structural characteristics
S. Moyo, P. Moskal, E. Stępień
abstract
Positron-electron annihilation in living organisms occurs in about 30% via the formation of a metastable ortho-positronium atom that annihilates into two 511 keV photons in tissues because of the pick-off and conversion processes. Positronium (Ps) annihilation lifetime and intensities can be used to determine the size and quantity of defects in a material's microstructure, such as voids or pores in the range of nanometers. This is particularly true for blood clots. Here we present pilot investigations of positronium properties in fibrin clots. The studies are complemented by the use of SEM Edax and micro-computed tomography (microCT) to evaluate the extracted thrombotic material's properties. microCT is a versatile characterization method offering in situ and in operando possibilities and is a qualitative diagnostic tool. With microCT the presence of pores, cracks, and structural errors can be verified, and hence the 3D inner structure of samples can be investigated.
Comparison of qNANO results from the isolation of extracellular microvesicles with the theoretical model
M. Durak-Kozica, A. Wróbel, M. Platt, E. Stępień
abstract
Objectives: Extracellular vesicles (EVs) are heterogeneous membrane vesicles in diameter of 30-5000 nm, that transport proteins, non-coding RNAs (miRNAs), lipids and metabolites. Major populations include exosomes, ectosomes and apoptotic bodies. The purpose of this study was to compare the distribution of EVs obtained under different conditions of differential centrifugation, including ultracentrifugation, with the results developed based on a theoretical model. Methods: Immortalized endothelial cell line that expresses h-TERT (human telomerase) was used to release of EVs: microvascular TIME. EVs were isolated from the culture medium at different centrifugation parameters. The size distribution of the EVs was measured using TRPS technology on a qNano instrument. Surface markers were evaluated using flow cytometry. The isolated EV subpopulations were compared with the theoretical model developed by Livshits. Results: EVs isolated from endothelial cells show strong aggregating properties, which was confirmed by TEM, TRPS imaging and flow cytometry. Conclusions: Obtaining pure EV subpopulations is difficult because of the small differences in the diameter of ectosomes and exosomes, and the strong aggregating properties of EVs.
Proteomic profiling of exosomes derived from pancreatic beta-cells cultured under hyperglycemia
C. Rząca, U. Jankowska, E. Stępień
abstract
Introduction
Cargo carried by extracellular vesicles (EVs) is considered a promising diagnostic marker, especially proteins. EVs can be divided according to their size and way of biogenesis into exosomes (diameter < 200 nm) and ectosomes (diameter > 200 nm). Exosomes are considered to be of endocytic origin, and ectosomes are produced by budding and shedding from the plasma membrane [1].
Methods
The first step of this study was a characterization of the exosome sample. Using Tunable Resistive Pulse Sensing (qNano) size distribution and concentration were measured. The mean size of exosomes was 120?9.17 nm. In the present study, a nano liquid chromatography coupled with tandem mass spectrometry (nanoLC-MS/MS) was used to compare protein profiles of exosomes secreted by pancreatic beta cells (1.1B4) grown under normal glucose (NG, 5 mM D-glucose) and high glucose (HG, 25 mM D-glucose) conditions. The EV samples were lysed, and proteins were denatured, digested, and analyzed using a Q-Exactive mass spectrometer coupled with the UltiMate 3000 RSLC nano system. The nanoLC-MS/MS data were searched against the SwissProt Homo sapiens database using MaxQuant software and protein quantitation was done by the MaxLFQ algorithm. Statistical analysis was carried out with Perseus software. Further bioinformatic analysis was performed using the FunRich 3.1.4 software with the UniProt protein database and String [2].
Results
As a result of the nanoLC-MS/MS analysis more than 1,000 proteins were identified and quantified in each sample. The average number of identified proteins in exosomes was 1,397. Label-free quantitative analysis showed that exosome composition differed significantly between those isolated under NG and HG conditions. Many pathways were down-regulated in HG, particularly the ubiquitin-proteasome pathway. In addition, a significant up-regulation of the Ras-proteins pathway was observed in HG.
Conclusion
Our description of exosomes protein content and its related functions provides the first insight into the EV interactome and its role in glucose intolerance development and diabetic complications. The results also indicate the applicability of EV proteins for further investigation regarding their potential as circulating in vivo biomarkers.
Comparison of Lugol's solution and Fe3O4 nanoparticles as contrast agents for tumor spheroid imaging using microcomputed tomography
D. Panek, M. Szczepanek, B. Leszczyński, P. Moskal, E. Stępień
abstract
Background Lugol's solution is well known for its unique contrasting properties to biological samples in in microcomputed tomography imaging. On the other hand, iron oxide nanoparticles (IONPs), which have much lower attenuation capabilities to X-ray radiation show decent cell penetration and accumulation properties, are increasingly being used as quantitative contrast agents in biology and medicine. In our research, they were used to stain 3D cell structures called spheroids. Aim In this study, the micro computed tomography (microCT) technique was used to visualize and compare the uptake and accumulation of two contrast agents, Lugol's solution and iron (II, III) oxide nanoparticles (IONPs) in the in vitro human spheroid tumour model. Methods The metastatic human melanoma cell line WM266-4 was cultured, first under standard 2D conditions, and after reaching 90% confluence cells was seeded in a low adhesive plate, which allows spheroid formation. On the 7th day of growth, the spheroids were transferred to the tubes and stained with IONPs or Lugol's solution and subjected to microCT imaging. Results Our research allows visualization of the regions of absorption at the level of single cells, with relatively short incubation times - 24h - for Lugol's solution. IONPs proved to be useful only in high concentrations (1 mg/ml) and long incubation times (96h). Conclusions When comparing the reconstructed visualizations of the distribution of these stating agents, it is worth noting that Lugol's solution spreads evenly throughout the spheroids, whereas IONPs (regardless of their size 5 and 30 nm) accumulate only in the outer layer of the spheroid structure.
ProTheRaMon - a GATE simulation framework for proton therapy range monitoring using PET imaging
D. Borys, J. Baran, K.W. Brzezinski, J. Gajewski, N. Chug, A. Coussat, E. Czerwiński, M. Dadgar, K. Dulski, K. Valsan Eliyan, A. Gajos, K. Kacprzak, Ł. Kapłon, K. Klimaszewski, P. Konieczka, R. Kopec, G. Korcyl, T. Kozik, W. Krzemień, D. Kumar, A. John Lomax, K. McNamara, S. Niedźwiecki, P. Olko, D. Panek, S. Parzych, E. Pérez del Río, L. Raczyński, S. Sharma, S. Shivani, R.Y. Shopa, T. Skóra, M. Skurzok, P. Stasica, E. Stępień, K. Tayefi Ardebili, F. Tayefi, D. Charles Weber, C. Winterhalter, W. Wiślicki, P. Moskal, A. Rucinski
abstract
Objective: This paper reports on the implementation and shows examples of the use of the ProTheRaMon framework for simulating the delivery of proton therapy treatment plans and range monitoring using positron emission tomography (PET). ProTheRaMon offers complete processing of proton therapy treatment plans, patient CT geometries, and intra-treatment PET imaging, taking into account therapy and imaging coordinate systems and activity decay during the PET imaging protocol specific to a given proton therapy facility. We present the ProTheRaMon framework and illustrate its potential use case and data processing steps for a patient treated at the Cyclotron Centre Bronowice (CCB) proton therapy center in Krakow, Poland. Approach: The ProTheRaMon framework is based on GATE Monte Carlo software, the CASToR reconstruction package and in-house developed Python and bash scripts. The framework consists of five separated simulation and data processing steps, that can be further optimized according to the user's needs and specific settings of a given proton therapy facility and PET scanner design. Main results: ProTheRaMon is presented using example data from a patient treated at CCB and the J-PET scanner to demonstrate the application of the framework for proton therapy range monitoring. The output of each simulation and data processing stage is described and visualized. Significance: We demonstrate that the ProTheRaMon simulation platform is a high-performance tool, capable of running on a computational cluster and suitable for multi-parameter studies, with databases consisting of large number of patients, as well as different PET scanner geometries and settings for range monitoring in a clinical environment. Due to its modular structure, the ProTheRaMon framework can be adjusted for different proton therapy centers and/or different PET detector geometries. It is available to the community via github.
Radiovesicolomics - new approach in medical imaging
E.Ł. Stępień, C. Rząca, P. Moskal
abstract
This review introduce extracellular vesicles (EVs) to a molecular imaging field. The idea of modern analyses based on the use of omics studies, using highthroughput methods to characterize the molecular content of a single biological system, vesicolomics seems to be the new approach to collect molecular data about EV content, to find novel biomarkers or therapeutic targets. The use of various imaging techniques, including those based on radionuclides as positron emission tomography (PET) or single photon
emission computed tomography (SPECT), combining molecular data on EVs, opens up the new space for radiovesicolomics?a new approach to be used in theranostics.
Study of the influence of hyperglycemia on the abundance of amino acids, fatty acids, and selected lipids in extracellular vesicles using TOF-SIMS
M. E. Marzec, C. Rząca, P. Moskal, E. Ł. Stępień
abstract
Time-of-flight secondary ion mass spectrometry (TOF-SIMS) with the Bi3+ liquid metal ion gun was used to investigate the content of lipids and amino acids (AAs) in extracellular vesicles (EVs). We induced metabolic changes in human pancreatic beta-cells by stimulation with high glucose concentrations (35 mM) and tested the hypothesis of hyperglycemia (HG) has a detrimental effect on lipids and AAs in released EV subpopulations: ectosomes and exosomes. As a result of HG treatment, selected fatty acids (FAs) such as arachidonic, myristic and palmitic acids, changed their abundance in ectosomes and exosomes. Also, intensities of the characteristic peaks for cholesterol (m/z 95.09; 147.07; 161.11; 369.45) along with the molecular ion m/z 386.37 [C27H46O+] under HG conditions, both for ectosomes and exosomes, have changed significantly. Comparative analysis of HG EVs and normoglycemic (NG) ones showed statistically significant differences in the signal intensities of four AAs: valine (m/z 72.08 and 83.05), isoleucine (m/z 86.10), phenylalanine (m/z 120.08 and 132.05) and tyrosine (m/z 107.05 and 136.09). We confirmed that ToF-SIMS is a useful technique to study selected AAs and lipid profiles in various EV subpopulations. Our study is the first demonstration of changes in FAs and AAs in exosomes and ectosomes derived from ?-cells under the influence of HG.
Perspectives on translation of positronium imaging into clinics
P. Moskal, E.Ł. Stępień
abstract
The image of positronium properties created in the patient?s body during PET examination tells about the inter- and intra-molecular structure of the tissue and the concentration of bio-active molecules in the tissue [2?4]. In this article, we advocate the opinion that total-body PET systems, thanks to their high imaging sensitivity and high time resolution, open up the prospect of translating
positronium imaging into clinics.
Positronium as a biomarker of hypoxia
P. Moskal and E.Ł. Stępień
abstract
In this review article, we present arguments demonstrating that the advent of high sensitivity total-body PET systems and the invention of the method of positronium imaging, open realistic perspectives for the application of positronium as a biomarker forin-vivo assessment of the degree of hypoxia. Hypoxia is a state or condition, in which the availability of oxygen is not sufficient to support physiological processes in tissue and organs. Positronium is a meta-stable atom formed from electron and positron which is copiously produced in the intramolecular spaces in the living organisms undergoing positron emission tomography (PET). Properties of positronium, such as e.g., lifetime, depend on the size of intramolecular spaces and the concentration in them of oxygen molecules. Therefore, information on the partial pressure of oxygen (pO2) in the tissue may be derived from the positronium lifetime measurement. The partial pressure of oxygen differs between healthy and cancer tissues in the range from 10 to 50 mmHg. Such differences of pO2 result in the change of ortho-positronium lifetime e.g., in water by about 2?7 ps. Thus, the application of positronium as a biomarker of hypoxia requires the determination of the mean positronium lifetime with the resolution in the order of2 ps. We argue that such resolution is in principle achievable for organ-wise positronium imaging with the total-body PET systems.
New trends in theranostics
P. Moskal, E.Ł. Stępień
abstract
Novel biomarker and drug delivery systems for theranostics-extracellular vesicles
E.Ł. Stępień, C. Rząca, P. Moskal
abstract
Extracellular vesicles (EVs) are nano- and micro-sized double-layered membrane entities derivedfrom most cell types and released into biological fluids. Biological properties (cell-uptake, biocompatibility), and chemical (composition, structure) or physical (size, density) characteristics make EVs a good candidate for drug delivery systems (DDS). Recent advances in the field of EVs (e.g., scaling-up production, purification) and developments of new imaging methods (total-body positron emission tomography [PET]) revealed benefits ofradio labeled EVs in diagnostic and interventional medicine as a potential DDs in theranostics.
Unparalleled and revolutionary impact of PET imaging on research and day to day practice of medicine
A. Alavi, T.J. Werner, E.Ł. Stępień, P. Moskal
abstract
Positron emission tomography (PET) imaging is the most quantitative modality for assessing diseaseactivity at the molecular and cellular levels, and therefore, it allows monitoring its course and determining the efficacy of various therapeutic interventions. In this scientific communication, we describe the unparalleled and revolutionary impact of PET imaging on researchand day to day practice of medicine. We emphasize thecritical importance of the development and synthesis of novel radiotracers (starting from the enormous impactof F-Fluorodeouxyglucose (FDG) introduced by investigators at the University of Pennsylvania (PENN)) and PET instrumentation. These innovations have led to the total-body PET systems enabling dynamic and parametric molecular imaging of all organs in the body simultaneously. We also present our perspectives for future development of molecular imaging by multiphoton PET systems that will enable users to extract substantial information (owing to the evolving role of positronium imaging) about the related molecular and biological bases of various disorders, which are unachievable by the current PET imaging techniques.
Positronium imaging with the novel multiphoton PET scanner
P. Moskal, K. Dulski, N. Chug, C. Curceanu, E. Czerwiński, M. Dadgar, J. Gajewski, A. Gajos, G. Grudzień, B.C. Hiesmayr, K. Kacprzak, Ł. Kapłon, H. Karimi, K. Klimaszewski, G. Korcyl, P. Kowalski, T. Kozik, N. Krawczyk, W. Krzemień, E. Kubicz, P. Małczak, S. Niedźwiecki, M. Pawlik-Niedźwiecka, M. Pędziwiatr, L. Raczyński, J. Raj, A. Ruciński, S. Sharma, Shivani, R.Y. Shopa, M. Silarski, M. Skurzok, E.Ł. Stępień, M. Szczepanek, F. Tayefi, W. Wiślicki
abstract
In vivo assessment of cancer and precise location of altered tissues at initial stages of molecular disorders are important diagnostic challenges. Positronium is copiously formed in the free molecular spaces in the patient?s body during positron emission tomography (PET). The positronium properties vary according to the size of inter- and intramolecular voids and the concentration of molecules in them such as, e.g., molecular oxygen, O2; therefore, positronium imaging may provide information about disease progression during the initial stages of molecular alterations. Current PET systems do not allow acquisition of positronium images. This study presents a new method that enables positronium imaging by simultaneous registration of annihilation photons and deexcitation photons from pharmaceuticals labeled with radionuclides. The first positronium imaging of a phantom built from cardiac myxoma and adipose tissue is demonstrated. It is anticipated that positronium imaging will substantially
enhance the specificity of PET diagnostics.
Optimisation of the event-based TOF filtered back-projection for online imaging in total-body J-PET
R.Y. Shopa, K. Klimaszewski, P. Kopka, P. Kowalski, W. Krzemień, L. Raczyński, W. Wiślicki, N. Chug, C. Curceanu, E. Czerwiński, M. Dadgar, K. Dulski, A. Gajos, B.C. Hiesmayr, K. Kacprzak, Ł. Kapłon, D. Kisielewska, G. Korcyl, N. Krawczyk, E. Kubicz, Sz. Niedźwiecki, J. Raj, S. Sharma, Shivani, E.Ł. Stępień, F. Tayefi, P. Moskal
abstract
We perform a parametric study of the newly developed time-of-flight (TOF) image reconstruction algorithm, proposed for the real-time imaging in total-body Jagiellonian PET (J-PET) scanners. The asymmetric 3D filtering kernel is applied at each most likely position of electron-positron annihilation, estimated from the emissions of back-to-back gamma-photons. The optimisation of its parameters is studied using Monte Carlo simulations of a 1-mm spherical source, NEMA IEC and XCAT phantoms inside the ideal J-PET scan- ner. The combination of high-pass filters which included the TOF filtered back-projection (FBP), resulted in spatial resolution, 1.5 times higher in the axial direction than for the conventional 3D FBP. For real- istic 10-minute scans of NEMA IEC and XCAT, which require a trade-offbetween the noise and spatial resolution, the need for Gaussian TOF kernel components, coupled with median post-filtering, is demon- strated. The best sets of 3D filter parameters were obtained by the Nelder-Mead minimisation of the mean squared error between the resulting and reference images. The approach allows training the recon- struction algorithm for custom scans, using the IEC phantom, when the temporal resolution is below 50 ps. The image quality parameters, estimated for the best outcomes, were systematically better than for the non-TOF FBP.
Testing CPT symmetry in ortho-positronium decays with positronium annihilation tomography
P. Moskal, A. Gajos, M. Mohammed, J. Chhokar, N. Chug, C. Curceanu, E. Czerwiński, M. Dadgar, K. Dulski, M. Gorgol, J. Goworek, B. Hiesmayr, B. Jasińska, K. Kacprzak, Ł. Kapłon, H. Karimi, D. Kisielewska, K. Klimaszewski, G. Korcyl, P. Kowalski, N. Krawczyk, W. Krzemień, T. Kozik, E. Kubicz, S. Niedźwiecki, S. Parzych, M. Pawlik-Niedźwiecka, L. Raczyński, J. Raj, S. Sharma, S. Choudhary, R. Shopa, A. Sienkiewicz, M. Silarski, M. Skurzok, E. Stepien, F. Tayefi, W. Wiślicki
abstract
Charged lepton system symmetry under combined charge, parity, and time-reversal transformation (CPT) remain scarcely tested. Despite stringent quantum-electrodynamic limits, discrepancies in predictions for the electron-positron bound state (positronium atom) motivate further investigation, including fundamental symmetry tests. While CPT noninvariance effects could be manifested in non-vanishing angular correlations between final-state photons and spin of annihilating positronium, measurements were previously limited by the knowledge of the latter. Here, we demonstrate tomographic reconstruction techniques applied to three-photon annihilations of ortho-positronium atoms to estimate their spin polarisation without a magnetic field or polarised positronium source. We use a plastic-scintillator-based positron-emission-tomography scanner to record ortho-positronium (o-Ps) annihilations with a single-event estimation of o-Ps spin and determine the complete spectrum of an angular correlation operator sensitive to CPT-violating effects. We find no violation at the precision level of 10^{-4}, with an over threefold improvement on the previous measurement.
Simulating NEMA characteristics of the modular total-body J-PET scanner - an economic total-body PET from plastic scintillators
P. Moskal, P. Kowalski, R.Y. Shopa, L. Raczyński, J. Baran, N. Chug, C. Curceanu, E. Czerwiński, M. Dadgar, K. Dulski, A. Gajos, B.C. Hiesmayr, K. Kacprzak, Ł. Kapłon, D. Kisielewska, K. Klimaszewski, P. Kopka, G. Korcyl, N. Krawczyk, W. Krzemień, E. Kubicz, Sz. Niedźwiecki, Sz. Parzych, J. Raj, S. Sharma, S. Shivani, E. Stępień, F. Tayefi, W. Wiślicki
abstract
The purpose of the presented research is the estimation of the performance characteristics of the economic total-body Jagiellonian-PET system (TB-J-PET) constructed from plastic scintillators. The characteristics are estimated according to the NEMANU-2-2018 standards utilizing the GATE package. The simulated detector consists of 24 modules, each built out of 32 plastic scintillator strips
(each with a cross-section of 6 mm times 30 mm and length of 140 or 200 cm) arranged in two layers in regular 24-sided polygon circumscribing a circle with a diameter of 78.6 cm. For the TB-J-PET with an axial field-of-view (AFOV) of 200 cm, a spatial resolution (SRs) of 3.7mm (transversal) and 4.9mm (axial) are achieved. The noise equivalent count rate (NECR) peak of 630 kcps is expected at 30 kBq cc^-1. Activity concentration and the sensitivity at the center amount to 38 cps kBq^-1. The scatter fraction (SF) is estimated to 36.2 %. The values of SF and SR are comparable to those obtained for the state-of-the-art clinical PET scanners and the first total-body tomographs: uExplorer and PennPET.With respect to the standard PET systemswithAFOVin the range from16 to 26 cm, the TBJ-PET is characterized by an increase inNECRapproximately by a factor of 4 and by the increase of the whole-body sensitivity by a factor of 12.6 to 38. The time-of-flight resolution for the TB-J-PETis expected to be at the level ofCRT=240 ps fullwidth at half-maximum. For the TB-J-PETwith an AFOVof 140 cm, an image quality of the reconstructed images of a NEMAIEC phantom was presented with a contrast recovery coefficient and a background variability parameters. The increase of the whole-body sensitivity andNECRestimated for the TB-J-PET with respect to current commercial PETsystems makes the TB-J-PET a promising cost-effective solution for the broad clinical applications of total-body PET scanners. TB-J-PETmay constitutes an economic alternative for the crystal TB-PET scanners, since plastic scintillators are much cheaper than BGO or LYSO crystals and the axial arrangement of the strips significantly reduces the costs of readout electronics and SiPMs.
The J-PET detector - a tool for precision studies of ortho-positronium decays
K. Dulski, S.D. Bass, J. Chhokar, N. Chug, C. Curceanu, E. Czerwiński, M. Dadgar, J. Gajewski, A. Gajos, M. Gorgol, R. Del Grande, B.C. Hiesmayr, B. Jasińska, K. Kacprzak, Ł. Kapłon, H. Karimi, D. Kisielewska, K. Klimaszewski, P. Kopka, G. Korcyl, P. Kowalski, T. Kozik, N. Krawczyk, W. Krzemień, E. Kubicz, P. Małczak, M. Mohammed, Sz. Niedźwiecki, M. Pałka, M. Pawlik-Niedźwiecka, M. Pędziwiatr, L. Raczyński7, J. Raj, A. Ruciński, S. Sharma, Shivani, R.Y. Shopa, M. Silarski, M. Skurzok, E. Ł. Stępień, F. Tayefi, W. Wiślicki, B. Zgardzińska, P. Moskal
abstract
The J-PET tomograph is constructed from plastic scintillator strips arranged axially in concentric cylindrical layers. It enables investigations of positronium decays by measurement of the time, position, polarization and energy deposited by photons in the scintillators, in contrast to studies conducted so far with crystal and semiconductor based detection systems where the key selection of events is based on the measurement of the photons energies. In this article we show that the J-PET tomography system constructed solely from plastic scintillator detectors is capable of exclusive measurements of the decays of ortho-positronium atoms. We present the first positronium production results and its lifetime distribution measurements. The obtained results prove the capability of the J-PET tomograph for (i) fundamental studies of positronium decays (in particular test of discrete symmetries in purely leptonic systems), (ii) positron annihilation lifetime spectroscopy, as well as (iii) molecular imaging diagnostics and (iv) observation of entanglement
Synchronisation and calibration of the 24-modules J-PET prototype with 300 mm axial field of view
P. Moskal, T. Bednarski, Sz. Niedźwiecki, M. Silarski, E. Czerwiński, T. Kozik, J. Chhokar, M. Bała, C. Curceanu, R. Del Grande, M. Dadgar, K. Dulski, A. Gajos, M. Gorgol, N. Gupta-Sharma, B. C. Hiesmayr, B. Jasińska, K. Kacprzak, Ł. Kapłon, H. Karimi, D. Kisielewska, K.Klimaszewski, G. Korcyl, P. Kowalski, N. Krawczyk, W. Krzemień, E. Kubicz, M. Mohammed, M. Pawlik-Niedźwiecka, L. Raczyński, S. Sharma, Shivani, R. Y. Shopa, M. Skurzok, E. Stępień, W. Wiślicki, B. Zgardzińska
abstract
Research conducted in the framework of the J-PET project aims to develop a cost-effective total-body positron emission tomography scanner. As a first step on the way to construct a full-scale J-PET tomograph from long strips of plastic scintillators, a 24-strip prototype was built and tested. The prototype consists of detection modules arranged axially forming a cylindrical diagnostic chamber with an inner diameter of 360 mm and an axial field-of-view of 300 mm. Promising perspectives for a low-cost construction of a total-body PET scanner are opened due to an axial arrangement of strips of plastic scintillators, which have a small light attenuation, superior timing properties, and the possibility of cost-effective increase of the axial field-of-view. The presented prototype comprises dedicated solely digital front-end electronic circuits and a triggerless data acquisition system which required development of new calibration methods including time, thresholds and gain synchronization. The system and elaborated calibration methods including first results of the 24-module J-PET prototype are presented and discussed. The achieved coincidence resolving time equals to CRT = 490 +- 9 ps. This value can be translated to the position reconstruction accuracy s(Dl) = 18 mm which is fairly position-independent Keywords: positron emission tomography, plastic scintillators, J-PET.
Prospects and clinical perspectives of total-body PET imaging using plastic scintillators
P. Moskal, E. Ł. Stępień
abstract
Total-body PET opens new diagnostic paradigm with prospects for personalized disease treatment, yet the high cost of the current crystal-based PET technology limits dissemination of total-body PET in hospitals and even in the research
clinics.
The J-PET tomography system is based on axially arranged low-cost plastic scintillator strips. It constitutes a realistic cost-effective solution of a total-body PET for broad clinical applications.
High sensitivity of total-body J-PET and trigger-less data acquisition enable multi-photon imaging, opening possibilities for multi-tracer and positronium imaging, thus promising quantitative enhancement of specificity in cancer and inflammatory diseases assessment.
An example of dual tracer analysis, becoming possible with total-body J-PET system, could be a concurrent application of FDA-approved 82Rb-Chloride and [18F]FDG, allowing simultaneous assessment of myocardium metabolic rate and perfusion of the cardiovascular system.
X-ray microtomography as a new approach for imaging and analysis of tumor spheroids
H. Karimi, B. Leszczyński, T. Kołodziej, E. Kubicz, M. Przybyło, E. Stępień
abstract
Three-dimensional (3D) spheroids mimic important properties of tumors and may soon become a reasonable
substitute for animal models and human tissue, eliminating numerous problems related to in vivo and ex vivo
experiments and pre-clinical drug trials. Currently, various imaging methods including X-ray microtomography
(micro-CT), exist but their spatial resolution is limited. Here, we visualized and provided a morphological
analysis of spheroid cell cultures using micro-CT and compared it to that of confocal microscopy. An approach is
proposed that can potentially open new diagnostic opportunities to determine the morphology of cancer cells
cultured in 3D structures instead of using actual tumors.
Spheroids were formed from human melanoma cell lines WM266-4 and WM115 seeded at different cell
densities using the hanging drop method. Micro-CT analysis of spheroid showed that spheroid size and shape
differed depending on the cell line, initial cell number, and duration of culture.
The melanoma cell lines used in this study can successfully be cultured as 3D spheroids and used to substitute
human and animal models in pre-clinical studies. The micro-CT allows for high-resolution visualization of the
spheroids structure.
Performance assessment of the 2gamma positronium imaging with the total-body PET scanners
P. Moskal, D. Kisielewska, Z. Bura, C. Chhokar, C. Curceanu, E. Czerwiński, M. Dadgar, K. Dulski, J. Gajewski, A. Gajos, M. Gorgol, R. Del Grande, B. C. Hiesmayr, B. Jasińska, K. Kacprzak, A. Kamińska, Ł. Kapłon, H. Karimi, G. Korcyl, P. Kowalski, N. Krawczyk, W. Krzemień, T. Kozik, E. Kubicz, P. Małczak, M. Mohammed, Sz. Niedźwiecki, M. Pałka, M. Pawlik-Niedźwiecka, M. Pędziwiatr, L. Raczyński, J. Raj, A. Ruciński, S. Sharma, Shivani, R. Y. Shopa, M. Silarski, M. Skurzok, E. Ł. Stępień, S. Vandenberghe, W. Wiślicki, B. Zgardzińska
abstract
In living organisms the positron-electron annihilation (occurring during the PET imaging) proceeds in about 30% via creation of a metastable ortho-positronium atom. In the tissue, due to the pick-off and conversion processes, over 98% of ortho-positronia annihilate into two 511~keV photons. In this article we assess the feasibility for reconstruction of the mean ortho-positronium lifetime image based on annihilations into two photons. The main objectives of this work include: (i) estimation of the sensitivity of the total-body PET scanners for the ortho-positronium mean lifetime imaging using 2gamma annihilations, and (ii) estimation of the spatial and time resolution of the ortho-positronium image as a function of the coincidence resolving time (CRT) of the scanner. Simulations are conducted assuming that radiopharmaceutical is labelled with 44Sc isotope emitting one positron and one prompt gamma. The image is reconstructed on the basis of triple coincidence events. The ortho-positronium lifetime spectrum is determined for each voxel of the image. Calculations were performed for cases of total-body detectors build of (i) LYSO scintillators as used in the EXPLORER PET, and (ii) plastic scintillators as anticipated for the cost-effective total-body J-PET scanner. To assess the spatial and time resolution the three cases were considered assuming that CRT is equal to 140ps, 50ps and 10ps. The estimated total-body PET sensitivity for the registration and selection of image forming triple coincidences is larger by a factor of 12.2 (for LYSO PET) and by factor of 4.7 (for plastic PET) with respect to the sensitivity for the standard 2gamma imaging by LYSO PET scanners with AFOV=20cm.
Estimating relationship between the Time Over Threshold and energy loss by photons in plastic scintillators used in the J-PET scanner
S. Sharma, J. Chhokar, C. Curceanu, E. Czerwinski, M. Dadgar, K. Dulski, J. Gajewski, A. Gajos, M. Gorgol, N. Gupta-Sharma, R. Del Grande, B. C. Hiesmayr, B. Jasinska, K. Kacprzak, L. Kaplon, H. Karimi, D. Kisielewska, K. Klimaszewski, G. Korcyl, P. Kowalski, T. Kozik, N. Krawczyk, W. Krzemien, E. Kubicz, M. Mohammed, Sz. Niedzwiecki, M. Palka, M. Pawlik-Niedzwiecka, L. Raczynski, J. Raj, A. Rucinski, Shivani, R. Y. Shopa, M. Silarski, M. Skurzok, E. L. Stepien, W. Wislicki, B. Zgardzinska, P. Moskal
abstract
Time-Over-Threshold (TOT) technique is being used widely due to its implications in developing the multi channel readouts mainly when fast signal processing is required. Using TOT technique as a measure of energy loss instead of charge integration methods significantly reduces the signals readout cost by combining the time and energy information. Therefore, this approach can potentially be used in J-PET tomograph which is build from plastic scintillators characterized by fast light signals. The drawback in adopting this technique is lying in the non-linear correlation between input energy loss and TOT of the signal. The main motivation behind this work is to develop the relationship between TOT and energy loss and validate it with the J-PET tomograph.
The experiment was performed using the 22Na beta emitter source placed in the center of the J-PET tomograph. One can obtain primary photons of two different energies: 511 keV photon from the annihilation of positron (direct annihilation or through the formation of para-Positronim atom or pick-off process of ortho-Positronium atoms), and 1275 keV prompt photon. This allows to study the correlation between TOT values and energy loss for energy range up to 1000 keV. As the photon interacts dominantly via Compton scattering inside the plastic scintillator, there is no direct information of primary photon energy. However, using the J-PET geometry one can measure the scattering angle of the interacting photon. Since, 22Na source emits photons of two different energies, it is required to know unambiguously the energy of incident photons and its corresponding scattering angle for the estimation of energy deposition. In this work, the relationship between Time Over Threshold and energy loss by interacting photons inside the plastic scintillators used in J-PET scanner is established for a energy deposited range 100-1000 keV.
Studies of the ortho-Positronium lifetime for cancer diagnostics
Z. Bura, K. Dulski, E. Kubicz, P. Małczak, M. Pędziwiatr, M. Szczepanek, E.Ł. Stępień, P. Moskal
abstract
Positron Annihilation Lifetime Spectroscopy (PALS) is a technique based on the analysis of the lifetime of positronium emitted from implanted or delivered positronium donors. This technique employs the lifetime and intensity dependence on the structure of analyzed material. Due to this specific features, PALS might be used in further research protocols and clinical studies for cancer diagnostic purposes. This article reports the progress in the study design, main objectives of the study, protocols of measurement sand data analysis and further perspective of this study. The main goal of this work was to show the effectiveness of this method and progress in its development. For this purpose, colorectal cancer was examined.
Melanoma spheroids as a model for cancer imaging study
E. Ł. Stępień, H. Karimi, B. Leszczyński, M. Szczepanek
abstract
In contrast to standard 2D cell cultures, spheroids are three-dimensional (3D) models which can mimic natural conditions of cancer growth and metabolism. Their complex structure can be investigated and analyzed using fluorescence microscopy and micro-tomographic imaging (micro-CT) as a new technique. In this study, we show application of two different melanoma cell lines (WM115 and WM266) with different biological characteristics to form spheroids by a hanging drop method.
Feasibility study of the positronium imaging with the J-PET tomograph
P. Moskal, D. Kisielewska, C. Curceanu, E. Czerwiński, K. Dulski, A. Gajos, M. Gorgol, B. Hiesmayr, B. Jasińska, K. Kacprzak, Ł. Kapłon, G. Korcyl, P. Kowalski, W. Krzemień, T. Kozik, E. Kubicz, M. Mohammed, Sz. Niedźwiecki, M. Pałka, M. Pawlik-Niedźwiecka, L. Raczyński, J. Raj, S. Sharma, Shivani, R.Y. Shopa, M. Silarski, M. Skurzok, E. Stępień, W. Wiślicki, B. Zgardzińska
abstract
A detection system of the conventional PET tomograph is set-up to record data from e+ e- annihilation into two photons with energy of 511 keV, and it gives information on the density distribution of a radiopharmaceutical in the body of the object. In this paper we explore the possibility of performing the three gamma photons imaging based on ortho- positronium annihilation, as well as the possibility of positronium average lifetime imaging with the J-PET tomograph constructed from plastic scintillators. For this purposes simulations of the ortho-positronium formation and its annihilation into three photons were performed taking into account distributions of photons' momenta as predicted by the theory of quantum electrodynamics and the response of the J-PET tomograph. In order to test the proposed ortho-positronium lifetime image reconstruction method, we concentrate on the decay of the ortho-positronium into three photons and applications of radiopharmaceuticals labeled with isotopes emitting a prompt gamma quantum. The proposed method of imaging is based on the determination of hit-times and hit-positions of registered photons which enables the reconstruction of the time and position of the annihilation point as well as the lifetime of the ortho-positronium on an event-by-event basis. We have simulated the production of the positronium in a cylindrical phantom composed of a set of different materials in which the ortho-positronium lifetime varied from 2 ns to ~2.9 ns, as expected for ortho-positronium created in the human body. The presented reconstruction method for total-body J-PET like detector allows to achieve a mean lifetime resolution of about 40 ps. Recent Positron Annihilation Lifetime Spectroscopy measurements of cancerous and healthy uterine tissues show that this sensitivity may allow to study the morphological changes in cell structures.
Positronium in medicine and biology
P. Moskal, B. Jasińska, E. Ł. Stępień, S. D. Bass
abstract
In positron emission tomography, as much as 40% of positron annihilation occurs through the production of positronium atoms inside the patient's body. The decay of these positronium atoms is sensitive to metabolism and could provide information about disease progression. New research is needed to take full advantage of what positronium decays reveal.
