Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping.

BACKGROUND: Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. PATIENTS AND METHODS: We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. RESULTS: Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1-4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1-2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). CONCLUSION: Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies.

3D TOF-PET image reconstruction using total variation regularization.

In this paper we introduce a semi-analytic algorithm for 3-dimensional image reconstruction for positron emission tomography (PET). The method consists of the back-projection of the acquired data into the most likely image voxel according to time-of-flight (TOF) information, followed by the filtering step in the image space using an iterative optimization algorithm with a total variation (TV) regularization. TV regularization in image space is more computationally efficient than usual iterative optimization methods for PET reconstruction with full system matrix that use TV regularization. The efficiency comes from the one-time TOF back-projection step that might also be described as a reformatting of the acquired data. An important aspect of our work concerns the evaluation of the filter operator of the linear transform mapping an original radioactive tracer distribution into the TOF back-projected image. We obtain concise, closed-form analytical formula for the filter operator. The proposed method is validated with the Monte Carlo simulations of the NEMA IEC phantom using a one-layer, 50 cm-long cylindrical device called Jagiellonian PET scanner. The results show a better image quality compared with the reference TOF maximum likelihood expectation maximization algorithm.

Estimating relationship between the time over threshold and energy loss by photons in plastic scintillators used in the J-PET scanner.

PURPOSE: The time-over-threshold (TOT) technique is being used widely due to itsimplications in developing the multi-channel readouts, mainly when fast signal processing is required. Using the TOT technique, as a measure of energy loss instead of charge integration methods, significantly reduces the signal readout costs by combining the time and energy information. Therefore, this approach can potentially be utilized in J-PET tomograph which is built from plastic scintillators characterized by fast light signals. The drawback in adopting this technique lies 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 by the J-PET tomograph setup. METHODS: The experiment was performed using a 22Na beta emitter source placed in the center of the J-PET tomograph. This isotope produces photons of two different energies: 511 keV photons from the positron annihilation (direct annihilation or through the formation of a para-positronium atom or pick-off process of ortho-positronium atoms) and a 1275 keV prompt photon. This allows the study of the correlation between TOT values and energy loss for energy ranges up to 1000 keV. Since the photon interacts predominantly via Compton scattering inside the plastic scintillator, there is no direct information of the energy deposition. However, using the J-PET geometry, one can measure the scattering angle of the interacting photon. Since the 22Na source emits photons of two different energies, it is necessary to know unambiguously the energy of incident photons and their corresponding scattering angles in order to estimate energy deposition. In summary, this work presents a dedicated algorithm developed to tag photons of different energies and studying their scattering angles to calculate the energy deposition by the interacting photons. RESULTS: A new method was elaborated to measure the energy loss by photons interacting with plastic scintillators used in the J-PET tomograph. We find the relationship between the energy loss and TOT is non-linear and can be described by the functions TOT = A0 + A1 * ln(E dep + A2) + A3 * (ln(E dep + A2))2 and TOT = A0 - A1 * A2[Formula: see text]. In addition, we also introduced a theoretical model to calculate the TOT as a function of energy loss in plastic scintillators. CONCLUSIONS: A relationship between TOT and energy loss by photons interacting inside the plastic scintillators used in J-PET scanner is established for a deposited energy range of 100-1000 keV.

Performance assessment of the 2 γpositronium imaging with the total-body PET scanners.

PURPOSE: 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 the (i) estimation of the sensitivity of the total-body PET scanners for the ortho-positronium mean lifetime imaging using 2γ 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. METHODS: Simulations are conducted assuming that radiopharmaceutical is labeled 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 four cases were considered assuming that CRT is equal to 500 ps, 140 ps, 50 ps, and 10 ps. RESULTS: The estimated total-body PET sensitivity for the registration and selection of image forming triple coincidences (2γ+γprompt) is larger by a factor of 13.5 (for LYSO PET) and by factor of 5.2 (for plastic PET) with respect to the sensitivity for the standard 2γ imaging by LYSO PET scanners with AFOV = 20 cm. The spatial resolution of the ortho-positronium image is comparable with the resolution achievable when using TOF-FBP algorithms already for CRT = 50 ps. For the 20-min scan, the resolution better than 20 ps is expected for the mean ortho-positronium lifetime image determination. CONCLUSIONS: Ortho-positronium mean lifetime imaging based on the annihilations into two photons and prompt gamma is shown to be feasible with the advent of the high sensitivity total-body PET systems and time resolution of the order of tens of picoseconds.

Feasibility study of the positronium imaging with the J-PET tomograph.

A detection system of the conventional PET tomograph is set-up to record data from [Formula: see text] 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 mean 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. 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 point-like sources and in a cylindrical phantom composed of a set of different materials in which the ortho-positronium lifetime varied from 2.0 ns to 3.0 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 ∼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.

Estimating the NEMA characteristics of the J-PET tomograph using the GATE package.

A novel whole-body positron emission tomography (PET) system based on plastic scintillators is developed by the J-PET Collaboration. It consists of plastic scintillator strips arranged axially in the form of a cylinder, allowing the cost-effective construction of the total-body PET system. In order to determine the properties of the scanner prototype and optimize its geometry, advanced computer simulations were performed using the GATE (Geant4 application for tomographic emission) software. The spatial resolution, sensitivity, scatter fraction and noise equivalent count rate were estimated according to the National Electrical Manufacturers Association norm, as a function of the length of the tomograph, the number of detection layers, the diameter of the tomographic chamber and for various types of applied readout. For the single-layer geometry with a diameter of 85 cm, a strip length of 100 cm, a cross-section of 4 mm × 20 mm and silicon photomultipliers with an additional layer of wavelength shifter as the readout, the spatial resolution (full width at half maximum) in the centre of the scanner is equal to 3 mm (radial, tangential) and 6 mm (axial). For the analogous double-layer geometry with the same readout, diameter and scintillator length, with a strip cross-section of 7 mm × 20 mm, a noise equivalent count rate peak of 300 kcps was reached at 40 kBq cc-1 activity concentration, the scatter fraction is estimated to be about 35% and the sensitivity at the centre amounts to 14.9 cps kBq-1. Sensitivity profiles were also determined.

Feasibility studies of the polarization of photons beyond the optical wavelength regime with the J-PET detector.

J-PET is a detector optimized for registration of photons from the electron-positron annihilation via plastic scintillators where photons interact predominantly via Compton scattering. Registration of both primary and scattered photons enables to determinate the linear polarization of the primary photon on the event by event basis with a certain probability. Here we present quantitative results on the feasibility of such polarization measurements of photons from the decay of positronium with the J-PET and explore the physical limitations for the resolution of the polarization determination of 511 keV photons via Compton scattering. For scattering angles of about 82 ∘ (where the best contrast for polarization measurement is theoretically predicted) we find that the single event resolution for the determination of the polarization is about 40 ∘ (predominantly due to properties of the Compton effect). However, for samples larger than ten thousand events the J-PET is capable of determining relative average polarization of these photons with the precision of about few degrees. The obtained results open new perspectives for studies of various physics phenomena such as quantum entanglement and tests of discrete symmetries in decays of positronium and extend the energy range of polarization measurements by five orders of magnitude beyond the optical wavelength regime.

Evaluation of Single-Chip, Real-Time Tomographic Data Processing on FPGA SoC Devices.

A novel approach to tomographic data processing has been developed and evaluated using the Jagiellonian positron emission tomography scanner as an example. We propose a system in which there is no need for powerful, local to the scanner processing facility, capable to reconstruct images on the fly. Instead, we introduce a field programmable gate array system-on-chip platform connected directly to data streams coming from the scanner, which can perform event building, filtering, coincidence search, and region-of-response reconstruction by the programmable logic and visualization by the integrated processors. The platform significantly reduces data volume converting raw data to a list-mode representation, while generating visualization on the fly.

Calculation of the time resolution of the J-PET tomograph using kernel density estimation.

In this paper we estimate the time resolution of the J-PET scanner built from plastic scintillators. We incorporate the method of signal processing using the Tikhonov regularization framework and the kernel density estimation method. We obtain simple, closed-form analytical formulae for time resolution. The proposed method is validated using signals registered by means of the single detection unit of the J-PET tomograph built from a 30 cm long plastic scintillator strip. It is shown that the experimental and theoretical results obtained for the J-PET scanner equipped with vacuum tube photomultipliers are consistent.

Time resolution of the plastic scintillator strips with matrix photomultiplier readout for J-PET tomograph.

Recent tests of a single module of the Jagiellonian Positron Emission Tomography system (J-PET) consisting of 30 cm long plastic scintillator strips have proven its applicability for the detection of annihilation quanta (0.511 MeV) with a coincidence resolving time (CRT) of 0.266 ns. The achieved resolution is almost by a factor of two better with respect to the current TOF-PET detectors and it can still be improved since, as it is shown in this article, the intrinsic limit of time resolution for the determination of time of the interaction of 0.511 MeV gamma quanta in plastic scintillators is much lower. As the major point of the article, a method allowing to record timestamps of several photons, at two ends of the scintillator strip, by means of matrix of silicon photomultipliers (SiPM) is introduced. As a result of simulations, conducted with the number of SiPM varying from 4 to 42, it is shown that the improvement of timing resolution saturates with the growing number of photomultipliers, and that the [Formula: see text] configuration at two ends allowing to read twenty timestamps, constitutes an optimal solution. The conducted simulations accounted for the emission time distribution, photon transport and absorption inside the scintillator, as well as quantum efficiency and transit time spread of photosensors, and were checked based on the experimental results. Application of the [Formula: see text] matrix of SiPM allows for achieving the coincidence resolving time in positron emission tomography of [Formula: see text]0.170 ns for 15 cm axial field-of-view (AFOV) and [Formula: see text]0.365 ns for 100 cm AFOV. The results open perspectives for construction of a cost-effective TOF-PET scanner with significantly better TOF resolution and larger AFOV with respect to the current TOF-PET modalities.

[Studies on the antiviral activity of silver sulfathiazole]. / Badania przeciwwirusowej aktywnosci soli srebrowej sulfatiazolu.

Silver sulfathiazole shows strong antibacterial activity and good tolerance after topical application. The aim of the study was to determine the antiviral activity of silver sulfathiazole in tissue culture after incubation of drug and virus. The antiviral activity was measured after various periods of exposure and at different drug concentrations. The results obtained indicate the activity of silver sulfathiazole against Herpesvirus type 1 and type 2. This drug suppresses or completely inactivates the infectivity of virus. The antiviral effect is directly related to concentration of the drug and duration of exposure. At concentration of 10 micrograms/ml it has the highest activity after 30 minutes of exposure, however at a concentration of 20 micrograms/ml it induces a similar effect after 10 minutes. Silver sulfathiazole had antiviral activity similar to that of silver nitrate, while sulfathiazole alone was ineffective.

[Physical fitness of students of various vocational schools]. / Wydolnosc fizyczna uczniów niektórych szkol zawodowych.

Average values of various anthropometric and physiologic indices have been obtained for a representative group of 485 pupils of vocational schools, aged 14-18. The mean values of height (almost 175 cm), weight (66 kg) and Vo2 max (3.25 lo2/min or 48.3 ml/kg x min. or 59.2 ml/kg FFB/min.) were somewhat higher than average product in terms of physical fitness. According to estimates for ergonomics, these investigations confirmed that Polish Anthropometric Standards could be applied to set up new workplaces using upper limits of these standards. The optimum level of average workload in the case of new workers is somewhat above 5.0 kcal/min. During pre-employment and periodical medical examinations of juveniles we can use Vitalograph spirometer because predicted values of VFC and FEV1.0 for this spirometer have been calculated.

[Lactate threshold and the physiological cost of work]. / Próg mleczanowy a koszt fizjologiczny pracy.

Mean values for body size, fitness and endurance performance indices have been obtained from 20 industrial workers. Then the pulse rate from ECG using the Holter method during the worktime was registered and from the regression line PF on load energy expenditure was calculated. The "somatic" and "fitness" indices of subjects were not statistically significantly different from average workers population in Poland. The mean AT demonstrated that the subjects were able to perform hard work without metabolic acidosis developing, though those exhibiting lower AT worked with higher physiological cost of work. The study confirmed that the Holter method is extremely good for energy expenditure investigation during the worktime. Furthermore it was demonstrated that the physiological cost of moderate-heavy work was lower in subjects with higher AT. The authors suggested that the level of AT for medium-fit workers should come to about 2 dm3(02) X min.-1 (60%v02 max.

The management of common gastrointestinal disorders in general practice A survey by the European Society for Primary Care Gastroenterology (ESPCG) in six European countries.

BACKGROUND: Gastrointestinal (GI) disorders account for 10% of all consultations in primary care. Little is known about the management of GI disorders by general practitioners (GP) across different European countries. AIM AND METHODS: We undertook a postal survey of randomly selected samples of GPs in six European countries (UK, Holland, Spain, Greece, Poland, Czech Republic) to determine patterns of diagnosis, management and service use in GI disorders. RESULTS: We received 939 responses, response rate 32%. Over 80% of GPs were aware of at least three national guidelines for gastrointestinal disease. The availability of open access endoscopy ranged from 28% (Poland) to over 80% (Holland, Czech and UK). For uninvestigated dyspepsia the preferred first line management was proton pump inhibitor therapy (33-82%), Helicobacter pylori test and treat (19-47%), early endoscopy (5-32%), specialist referral (2-21%). Regarding irritable bowel syndrome, 23% of respondents were familiar with one or more diagnostic criteria, but between 7% (Netherlands) and 32% (Poland) would ask for a specialist opinion before making the diagnosis. CONCLUSION: The wide variation between GPs both between and within countries partly reflects variations in health care systems but also differing levels of knowledge and awareness, factors which are relevant to educational and research policy.

Spirometric predicted values for teenage boys: relation to body composition and exercise performance.

Forced expiratory volume and vital capacity of 428 healthy adolescent boys have been related to the age, body size, body composition, athletic prowess and maximal oxygen uptake. After allowing for age and height the lung function is related to the fat free mass and index of muscularity (fat free mass/height 2) but not to the other indices. This finding contributes to the derivation of reference values and to understanding the factors which promote the development of the lungs during adolescence.

Standards and predicted values of anaerobic threshold.

Mean values for body size, body composition and endurance indices have been obtained from a homogeneous group of 125 physically active men to find predicted values of AT (age 23.4 +/- 4.3 years; height 175.9 +/- 6.5 cm; weight 72.2 +/- 8.9 kg; body fat 17.9 +/- 4.7% body weight, muscularity index 19.0 +/- 1.5 kg fat-free mass/cm2 X 10(-4) height; forced vital lung capacity 5667 +/- 815 cm3; VO2max 48.5 +/- 6.0 cm3 X kg-1 X min-1; anaerobic threshold 61.0 +/- 7.8% VO2max). Endurance performance and fitness indices were a little higher than average, but about 10% lower than in endurance-trained athletes. The authors suggest that standards of anaerobic threshold (AT) for ergonomics and endurance training should be about 55-65% VO2max, but not lower than 1800 cm3 O2 X min-1. The coefficients of correlation of AT relating to VO2max, PFO2 and submaximal load were significant at the 0.01 level. Using regression analysis, predicted values of AT were developed. A predicted value of AT can be obtained from the regression line of AT on Lsubmax used as a nomogram, during a simple PWC170 exercise test without blood or gas analysis.

Kallikrein-kinin system in patients with neoplastic diseases.

The concentrations of kininogens, prokallikrein, fibrinogen, plasma protein, proteinase inhibitor antigens, and the kininase, fibrinolytic and antipapain activities in plasma of 29 patients with various tumours (lung cancers, lymphomas, and others) during chemotherapy were measured. The same studies were performed on blood plasma of female patients operated on because of cervical or endometrial carcinoma (37 subjects) and submitted to subsequent local radiotherapy (before and after radiotherapy). A weak activation of kallikrein-kinin system and significant decrease in kininase and fibrinolytic activities were found in those patients. It may suggest a role of bradykinin in prevention of therapy-induced hypercoagulability in patients with neoplastic diseases.