Faculty of Physics, Astronomy
and Applied Computer Science

Purpose: Measuring the lifetime of orthopositronium (oPs), the spin triplet of an electron and positron, has emerged as a promising approach for assessing tumor microenvironment characteristics, leveraging the susceptibility of oPs lifetime to local molecular factors such as the oxygenation level. This study investigates the feasibility of intralesional oPs lifetime measurements in patients with thyroid cancer using a commercial long axial field-of-view (LAFOV) PET/CT scanner. Methods: Three patients with thyroid cancer underwent two PET/CT scans on a Biograph Vision Quadra (Siemens Healthineers, Knoxville TN, USA) at 2 and 26 hours post-administration [124I]NaI, which included a 30 min scan in singles mode (a prototype feature for saving single crystal interactions without coincidence sorting) that allows to identify three-photon events. For regions with high 124I uptake, we determined the lifetime of oPs together with Bayesian errors estimation for a voxel-based (with a voxel size of 7×7×7 mm3), lesion based and organ based analysis. Results: The oPs lifetime of the voxel with the highest count statistics and activity concentration of 108.1 kBqmL?1 is 1.77 ? 0.26 ns. The visualization of the oPs lifetimes inside the tumor lesion was feasible, though it remains affected by statistical error. On a per-lesion basis, the lifetime could be measured (exemplary lesion:1.90 ? 0.17 ns) with mean activity concentrations ranging from 9.5 to 34.1 kBqmL?1 and volumes 1.31 to 6.27 kBqmL?1. The positronium lifetime measurement error shows a slight correlation (r=0.48 with BF10=7.88) with activity concentration of the regarded region. Besides lesions, the positronium lifetime could also be determined in several organs (average oPs lifetime in exemplary organs: liver 1.68 ? 0.08 ns, left atrium 1.83 ? 0.17 ns, right parotid gland: 2.24 ? 0.12 ns, left kidney 1.87 ? 0.12 ns). Conclusion: This is the first report human in-vivo measurement of oPs lifetime with [124I]NaI using a commercial LAFOV PET/CT scanner. The voxel-wise oPs lifetime imaging is feasible, though with a high statistical uncertainty. Lesionbased measurements can yield satisfactory statistical precision even for small volumes under clinical conditions. Future studies can leverage our approach to analyze the tumor microenvironment with regard to oPs lifetime as a surrogate marker for oxygenation.

In the state-of-the-art Positron Emission Tomography (PET), information about the polarization of annihilation photons is not available. Current PET systems track molecules labeled with positron-emitting radioisotopes by detecting the propagation direction of two photons from positron-electron annihilation. However, annihilation photons carry more information than just the site where they originated. Here we present a novel J-PET scanner built from plastic scintillators, in which annihilation photons interact predominantly via the Compton effect, providing information about photon polarization in addition to information on photon direction of propagation. Theoretically, photons from the decay of positronium in a vacuum are maximally entangled in polarization. However, in matter, when the positron from positronium annihilates with the electron bound to the atom, the question arises whether the photons from such annihilation are maximally entangled. In this work, we determine the distribution of the relative angle between polarization orientations of two photons from positron-electron annihilation in a porous polymer. Contrary to prior results for positron annihilation in aluminum and copper, where the strength of observed correlations is as expected for maximally entangled photons, our results show a significant deviation. We demonstrate that in porous polymer, photon polarization correlation is weaker than for maximally entangled photons but stronger than for separable photons. The data indicate that more than 40% of annihilations in Amberlite resin lead to a non-maximally entangled state. Our result indicates the degree of correlation depends on the annihilation mechanism and the molecular arrangement. We anticipate that the introduced Compton interaction-based PET system opens a promising perspective for exploring polarization correlations in PET as a novel diagnostic indicator.

Objective and method: Positron annihilation lifetime spectroscopy (PALS) is a powerful technique in material science that allows the investigation of the properties and behavior of positrons in various materials. PALS can be used to investigate solid structures at the nanometer scale and enable the use of positronium properties as an additional diagnostic parameter. Here we present results from calibration of the PALS system with certificated reference materials (CRM). Materials: Source of 22Na covered with layer of Kapton film, and after that parafilm from both sides was used in all experiments. Certified materials of No_5602-a (polycarbonate) and No_5601-a (fused silica) were used to ascertain if parameters were correctly identified. Results: In an experiment three lifetime components were correctly identified. All of those components will always be present in the data in further experiments on biological samples. Lifetime components consist of: 196 ps for annihilations in AI an aluminium cover of the chamber, 386 ps for annihilations in thesource and in the Kapton foil, 463 ps for reactions with parafilm. Conclusions: These parameters will be further used to correctly identify positron lifetimes in biological samples. Recently, a new method for imaging of positronium properties was invented and the first in-vivo images of positronium lifetime in humans were demonstrated with the multi-photon J-PET scanner. In order to correlate the positronium properties in tissue with the medically useful parameters, and to translate positronium imaging to clinics, comprehensive research of positronium properties in biological samples is needed.

For in vivo dose delivery monitoring in proton therapy the positron emission tomography can be applied because the positron emitters are being produced by the nuclear reactions of protons with atomic nuclei in a human body. The estimation of cross-sections of proton-induced nuclear reactions in the body is, therefore, one of the important steps on the way to develop proton beam range monitoring with positron emission tomography. Here, we calculate cross-sections for all open nuclear reaction channels initiated by 150 MeV protons and featured with 10C and 11C formation in the output channels. Taking into account the composition of elements in the human body and the data from the literature, we estimated 10C and 11C cumulative production cross-sections for proton-induced reactions in the human body.

The presented study evaluates the spatial resolution of the Modular J-PET scanner using the National Electrical Manufacturers Association (NEMA) NU2-2018 standard. The Modular J-PET, constructed with BC-404 plastic scintillators in an axial arrangement and coupled with analogue Silicon Photomultipliers (SiPMs) at both ends, offers a 50 cm axial field of view and a bore diameter of 73.9 cm. The study compares results from GATE simulations with experimental data.

The quantum entanglement of photons used in positron emission tomography (PET) scans has been shown to be surprisingly robust, opening prospects for developing quantum-enhanced PET schemes.

Positronium is abundantly produced within the molecular voids of a patient?s body during positron emission tomography (PET). Its properties dynamically respond to the submolecular architecture of the tissue and the partial pressure of oxygen. Current PET systems record only two annihilation photons and cannot provide information about the positronium lifetime. This study presents the in vivo images of positronium lifetime in a human, for a patient with a glioblastoma brain tumor, by using the dedicated Jagiellonian PET system enabling simultaneous detection of annihilation photons and prompt gamma emitted by a radionuclide. The prompt gamma provides information on the time of positronium formation. The photons from positronium annihilation are used to reconstruct the place and time of its decay. In the presented case study, the determined positron and positronium lifetimes in glioblastoma cells are shorter than those in salivary glands and those in healthy brain tissues, indicating that positronium imaging could be used to diagnose disease in vivo.

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.

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.

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 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.

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.

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.

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.

Total-body Positron Emission Tomography (PET) scanning is a promising new method for rapidly acquiring comprehensive wide-volume metabolic data with a lower radiation dosage compared to discrete whole-body PET imaging. PET scanners are generally used with Computed Tomography (CT) scanners to precisely understand tumor location and composition with the help of anatomical images. However, PET/CT sequential imaging methods for simultaneous total-body imaging are impractical for claustrophobic patients due to the enclosed gantry design and require large examination rooms because of the need for an exceptionally long patient table. To address this challenge, the Jagiellonian--PET Tomography (J-PET) Total-body scanner employs an innovative approach: utilizing both PET and CT devices on the same patient table but from different axes. The motion system of the J-PET Total Body scanner requires custom linear stages to move both PET and CT gantries. In this study, a novel cross-staged linear guiding solution is proposed by combining scanners on intersecting separable stages. The proposed sliding system is a combination of different machine elements and will be produced for the J-PET Total-body PET/CT Scanner. Concept designs are shown, and the proposed system is described. The application of the system for the J-PET total-body PET/CT scanner is discussed. The proposed solution is still in the development phase. The system holds the potential to achieve combining CT and PET scanners from different axes and enables motion artifact-free imaging for total-body imaging.

The Modular J-PET represents the latest advancement in the Jagiellonian-PET series, utilizing extended plastic scintillator strips. This prototype's modular design enables cost-effective imaging of multi-photon annihilation and positronium, allowing for easy assembly, portability, and versatility. Additionally, its lightweight construction facilitates static bed examinations with a mobile detection system that can be positioned conveniently alongside the patient, negating the requirement for spacious clinical settings. Comprising 24 modules arranged in regular 24- sided polygons circumscribing a 73.9 cm diameter circle, each module integrates 13 scintillator strips, measuring 50 cm in length and 6mm×24mm in cross-section. Scintillation light is captured at both ends through analog Silicon Photomultipliers (SiPMs). This research presents Sensitivity of the Modular J-PET tomograph, adhering to the NEMA_NU 2-2018 standards. Sensitivity measurement was performed with Ge line source inside the 5 sleeves aluminium phantom placed at center of the detector`s FOV and 10 cm offset from the center of detector. Analyzing the gathered data involved employing the specialized J-PET Framework software, developed within the C++ architecture. To validate the experimental findings, comparisons were made with GATE simulations, wherein the source and phantom were emulated in the same configuration as employed in the actual experiment. The system sensitivity of the Modular J-PET was assessed to be 1.03 ? 0.02 cps/kBq in the center of the detector`s FOV with the peak sensitivity of 2.1 cps/kBq. However, the simulations indicate that at the center of the detector's FOV, the Modular J-PET achieves a system sensitivity of 1.32 ? 0.03 cps/kBq, with a peak sensitivity of 2.9 cps/kBq.

Background: Alongside the benefits of Total-Body imaging modalities, such as higher sensitivity, single-bed position, low dose imaging, etc., their final construction cost prevents worldwide utilization. The main aim of this study is to present a simulation-based comparison of the sensitivities of existing and currently developed tomographs to introduce a cost-efficient solution for constructing a Total-Body PET scanner based on plastic scintillators. Methods: For the case of this study, eight tomographs based on the uEXPLORER configuration with different scintillator materials (BGO, LYSO), axial field-of-view (97.4 cm and 194.8 cm), and detector configuration (full and sparse) were simulated. In addition, 8 J-PET scanners with different configurations, such as various axial field-of-view (200 cm and 250 cm), the different cross-sections of plastic scintillator, and the multiple numbers of the plastic scintillator layers (2, 3, and 4), based on J-PET technology have been simulated by GATE software. Furthermore, Biograph Vision has been simulated to compare the results with standard PET scans. Two types of simulations have been performed. The first one with a centrally located source with a diameter of 1mm and a length of 250 cm, and the second one with the same source inside a water-filled cylindrical phantom with a diameter of 20 cm and a length of 183 cm. Results: With regards to sensitivity, among all the proposed scanners, the ones constructed with BGO crystals give the best performance (? 350 cps/kBq at the center). The utilization of sparse geometry or LYSO crystals significantly lowers the achievable sensitivity of such systems. The J-PET design gives a similar sensitivity to the sparse LYSO crystal-based detectors while having full detector coverage over the body. Moreover, it provides uniform sensitivity over the body with additional gain on its sides and provides the possibility for high-quality brain imaging. Conclusion: Taking into account not only the sensitivity but also the price of the Total-Body PET tomographs, which till now was one of the main obstacles in their widespread clinical availability, the J-PET tomography system based on plastic scintillators could be a cost-efficient alternative for Total-Body PET scanners.

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.

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.

We present the tests performed by the SIDDHARTA-2 collaboration at the DAFNE collider with a quasi-hemispherical CdZnTe detector. The very good room-temperature energy resolution and efficiency in a wide energy range show that this detector technology is ideal for studying radiative transitions in intermediate and heavy mass kaonic atoms. The CdZnTe detector was installed for the first time in an accelerator environment to perform tests on the background rejection capabilities, which were achieved by exploiting the SIDDHARTA-2 Luminosity Monitor. A spectrum with an 241Am source has been acquired, with beams circulating in the main rings, and peak resolutions of 6% at 60 keV and of 2.2% at 511 keV have been achieved. The background suppression factor, which turned out to be of the order of ~10^5?6, opens the possibility to plan for future kaonic atom measurements with CdZnTe detectors.

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.

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.

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.

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.

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.

We report a study of the original image reconstruction algorithm based on the time-of-flight maximum likelihood expectation maximisation (TOF MLEM), developed for the total-body (TB) Jagiellonian PET (J-PET) scanners. The method is applicable to generic cylindrical or modular multi-layer layouts and is extendable to multi-photon imaging. The system response matrix (SRM) is represented as a set of analytical functions, uniquely defined for each pair of plastic scintillator strips used for the detection. A realistic resolution model (RM) in detector space is derived from fitting the Monte Carlo simulated emissions and detections of annihilation photons on oblique transverse planes. Additional kernels embedded in SRM account for TOF, parallax effect and axial smearing. The algorithm was tested on datasets, simulated in GATE for the NEMA IEC and static XCAT phantoms inside a 24-module 2-layer TB J-PET. Compared to the reference TOF MLEM with none or a shift-invariant RM, an improvement was observed, as evaluated by the analysis of image quality, difference images and ground truth metrics. We also reconstructed the data with additive contributions, pre-filtered geometrically and with non-TOF scatter correction applied. Despite some deterioration, the obtained results still capitalise on the realistic RM with better edge preservation and superior ground truth metrics. The envisioned prospects of the TOF MLEM with analytical SRM include its application in multi-photon imaging and further upgrade to account for the non-collinearity, positron range and other factors.

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.

Pioneering investigations on the usage of positron-emission-tomography (PET) for the monitoring of ion beam therapy with light (protons, helium) and heavier (stable and radioactive neon, carbon and oxygen) ions started shortly after the first realization of planar and tomographic imaging systems, which were able to visualize the annihilation of positrons resulting from irradiation induced or implanted positron emitting nuclei. And while the first clinical experience was challenged by the utilization of instrumentation directly adapted from nuclear medicine applications, new detectors optimized for this unconventional application of PET imaging are currently entering the phase of (pre)clinical testing for more reliable monitoring of treatment delivery during irradiation. Moreover, recent advances in detector technologies and beam production open several new exciting opportunities which will not only improve the performance of PET imaging under the challenging conditions of in-beam applications in ion beam therapy, but will also likely expand its field of application. In particular, the combination of PET and Compton imaging can enable the most efficient utilization of all possible radiative emissions for both stable and radioactive ion beams, while positronium lifetime imaging may enable probing new features of the underlying tumour and normal tissue environment. Thereby, PET imaging will not only provide means for volumetric reconstruction of the delivered treatment and in-vivo verification of the beam range, but can also shed new insights for biological optimization of the treatment or treatment response assessment.

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.

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.

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.

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.

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.

We develop a positronium imaging method for the Jagiellonian PET (J-PET) scanners based on the time-of-flight maximum likelihood expectation maximisation (TOF MLEM). The system matrix elements are calculated on-the-fly for the coincidences comprising two annihilation and one de-excitation photons that originate from the ortho-positronium (o-Ps) decay. Using the Geant4 library, a Monte Carlo simulation was conducted for four cylindrical 22Na sources of ?+ decay with diverse o-Ps mean lifetimes, placed symmetrically inside the two JPET prototypes. The estimated time differences between the annihilation and the positron emission were aggregated into histograms (one per voxel), updated by the weights of the activities reconstructed by TOF MLEM. The simulations were restricted to include only the o-Ps decays into back-to-back photons, allowing a linear fitting model to be employed for the estimation of the mean lifetime from each histogram built in the log scale. To suppress the noise, the exclusion of voxels with activity below 2% ? 10% of the peak was studied. The estimated o-Ps mean lifetimes were consistent with the simulation and distributed quasi-uniformly at high MLEM iterations. The proposed positronium imaging technique can be further upgraded to include various correction factors, as well as be modified according to realistic o-Ps decay models.

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.

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.

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.

The entanglement of photons originating from electron-positron annihilation has not been experimentally proven. owever, the independent experiments performed so far unanimously confirm that the correlation between the linear polarizations of back-to-back photons from electron?positron annihilation is consistent with the assumption that these photons are entangled in the polarization. Yet, unexpectedly, recent experiments differ as regards the correlation of polarization direction of back-to-back photons after the decoherence induced by the scattering of one of these photons on the electron in the scattering material. In one of the experiments, the correlation before and after the decoherence of the photon state is the same, and in the other experiment, the scattering of one photon leads to a significant decrease in this correlation. Here we discuss this puzzle. Decoherent states were ensured provided by forcing one of the annihilation photons to scatter earlier before measuring the polarization correlation based on Compton kinematics. The comparison is made between the experimental setups used for the different measurements, and the results obtained are briefly discussed, highlighting the parameters that are important in performing such measurements. Finally, the main features of the J-PET detector are presented, along with the schemes for performing similar studies, so that the conclusive results can be used as remarks to solve the puzzle in question. Solving the decoherence puzzle will have crucial consequences for basic studies of entanglement, as well as for the proposed application of the photon polarization in positron emission tomography. If the correlation of the polarization of back-to-back photons from the electron?positron annihilation is the same before and after the scattering of these photons, then it will not be useful for the reduction of scatter fraction in positron emission tomography diagnostics.

The positronium system ? a bound state of an electron and a positron ? is suitable for testing the predictions of quantum electrodynamics, since its properties can be perturbatively calculated to high accuracy and, unlike the hydrogen system, it is not affected by the finite size or quantum chromodynamics effects at the current level of experimental precision. Experiments searching for invisible decays of the positronium triplet state ? the ortho-positronium ? which mainly decays to three photons, are being conducted since they are sensitive to new physics scenarios, e.g., mirror matter, milli-charged particles, and extra space-time dimensions. The particular case of mirror matter and its search with the novel total-body positron emission tomography scanner at the Jagiellonian University is presented. This J-PET is a large, high precision medical imaging tool based on plastic scintillators.

J-PET is a photon detector built of plastic scintillators, which already has been commissioned for CPT studies in the decays of positronium. In the first experiment, J-PET has achieved a sensitivity to CPT violation at a level of 10^{-4}, and now it aims to reach a level of 10^{-5}. This will be done by enhancing the three-photon registration efficiency for ortho-positronium decays using a new layer of densely packed plastic scintillators termed Modular J-PET. We present the simulation studies performed for different experimental detection setups to be used for the next CPT test with the Modular J-PET detector.

The positronium atom, a bound state of electron and positron, is a suitable leptonic test site for Charge-Parity (CP) discrete symmetry research. According to the Standard Model, the photon?photon interaction in the final state due to the vacuum polarization may mimic CP violation of the order of 10^-9, while weak interaction effects lead to a violation of the order of 10^-14. So far, the experimental limits on CP symmetry violation in the decay of o-Ps are set at the level of 10^-3. The J-PET detector can be used to explore discrete symmetries by looking for probable non-zero expectation values of the symmetry-odd operators, constructed from spin of ortho-Positronium (o-Ps) and momentum, and polarization vectors of gamma quanta resulting from o-Ps annihilation. The upgraded version of the J-PET detector, with an additional fourth layer of detection modules increases signal acceptance, which allows to triple the efficiency of quanta detection for CP discrete symmetry studies.