Using the gamma-index analysis for inter-fractional comparison of in-beam PET images for head-and-neck treatment monitoring in proton therapy: A Monte Carlo simulation study.

GOAL: In-beam Positron Emission Tomography (PET) is a technique for in-vivo non-invasive treatment monitoring for proton therapy. To detect anatomical changes in patients with PET, various analysis methods exist, but their clinical interpretation is problematic. The goal of this work is to investigate whether the gamma-index analysis, widely used for dose comparisons, is an appropriate tool for comparing in-beam PET distributions. Focusing on a head-and-neck patient, we investigate whether the gamma-index map and the passing rate are sensitive to progressive anatomical changes. METHODS/MATERIALS: We simulated a treatment course of a proton therapy patient using FLUKA Monte Carlo simulations. Gradual emptying of the sinonasal cavity was modeled through a series of artificially modified CT scans. The in-beam PET activity distributions from three fields were evaluated, simulating a planar dual head geometry. We applied the 3D-gamma evaluation method to compare the PET images with a reference image without changes. Various tolerance criteria and parameters were tested, and results were compared to the CT-scans. RESULTS: Based on 210 MC simulations we identified appropriate parameters for the gamma-index analysis. Tolerance values of 3 mm/3% and 2 mm/2% were suited for comparison of simulated in-beam PET distributions. The gamma passing rate decreased with increasing volume change for all fields. CONCLUSION: The gamma-index analysis was found to be a useful tool for comparing simulated in-beam PET images, sensitive to sinonasal cavity emptying. Monitoring the gamma passing rate behavior over the treatment course is useful to detect anatomical changes occurring during the treatment course.

Synthetic CT imaging for PET monitoring in proton therapy: a simulation study.

Objective.This study addresses a fundamental limitation of in-beam positron emission tomography (IB-PET) in proton therapy: the lack of direct anatomical representation in the images it produces. We aim to overcome this shortcoming by pioneering the application of deep learning techniques to create synthetic control CT images (sCT) from combining IB-PET and planning CT scan data.Approach.We conducted simulations involving six patients who underwent irradiation with proton beams. Leveraging the architecture of a visual transformer (ViT) neural network, we developed a model to generate sCT images of these patients using the planning CT scans and the inter-fractional simulated PET activity maps during irradiation. To evaluate the model's performance, a comparison was conducted between the sCT images produced by the ViT model and the authentic control CT images-serving as the benchmark.Main results.The structural similarity index was computed at a mean value across all patients of 0.91, while the mean absolute error measured 22 Hounsfield Units (HU). Root mean squared error and peak signal-to-noise ratio values were 56 HU and 30 dB, respectively. The Dice similarity coefficient exhibited a value of 0.98. These values are comparable to or exceed those found in the literature. More than 70% of the synthetic morphological changes were found to be geometrically compatible with the ones reported in the real control CT scan.Significance.Our study presents an innovative approach to surface the hidden anatomical information of IB-PET in proton therapy. Our ViT-based model successfully generates sCT images from inter-fractional PET data and planning CT scans. Our model's performance stands on par with existing models relying on input from cone beam CT or magnetic resonance imaging, which contain more anatomical information than activity maps.

In-vivo range verification analysis with in-beam PET data for patients treated with proton therapy at CNAO.

Morphological changes that may arise through a treatment course are probably one of the most significant sources of range uncertainty in proton therapy. Non-invasive in-vivo treatment monitoring is useful to increase treatment quality. The INSIDE in-beam Positron Emission Tomography (PET) scanner performs in-vivo range monitoring in proton and carbon therapy treatments at the National Center of Oncological Hadrontherapy (CNAO). It is currently in a clinical trial (ID: NCT03662373) and has acquired in-beam PET data during the treatment of various patients. In this work we analyze the in-beam PET (IB-PET) data of eight patients treated with proton therapy at CNAO. The goal of the analysis is twofold. First, we assess the level of experimental fluctuations in inter-fractional range differences (sensitivity) of the INSIDE PET system by studying patients without morphological changes. Second, we use the obtained results to see whether we can observe anomalously large range variations in patients where morphological changes have occurred. The sensitivity of the INSIDE IB-PET scanner was quantified as the standard deviation of the range difference distributions observed for six patients that did not show morphological changes. Inter-fractional range variations with respect to a reference distribution were estimated using the Most-Likely-Shift (MLS) method. To establish the efficacy of this method, we made a comparison with the Beam's Eye View (BEV) method. For patients showing no morphological changes in the control CT the average range variation standard deviation was found to be 2.5 mm with the MLS method and 2.3 mm with the BEV method. On the other hand, for patients where some small anatomical changes occurred, we found larger standard deviation values. In these patients we evaluated where anomalous range differences were found and compared them with the CT. We found that the identified regions were mostly in agreement with the morphological changes seen in the CT scan.

A neural network-based algorithm for simultaneous event positioning and timestamping in monolithic scintillators.

Objective. Monolithic scintillator crystals coupled to silicon photomultiplier (SiPM) arrays are promising detectors for PET applications, offering spatial resolution around 1 mm and depth-of-interaction information. However, their timing resolution has always been inferior to that of pixellated crystals, while the best results on spatial resolution have been obtained with algorithms that cannot operate in real-time in a PET detector. In this study, we explore the capabilities of monolithic crystals with respect to spatial and timing resolution, presenting new algorithms that overcome the mentioned problems.Approach.Our algorithms were tested first using a simulation framework, then on experimentally acquired data. We tested an event timestamping algorithm based on neural networks which was then integrated into a second neural network for simultaneous estimation of the event position and timestamp. Both algorithms are implemented in a low-cost field-programmable gate array that can be integrated in the detector and can process more than 1 million events per second in real-time.Results.Testing the neural network for the simultaneous estimation of the event position and timestamp on experimental data we obtain 0.78 2D FWHM on the (x,y) plane, 1.2 depth-of-interaction FWHM and 156 coincidence time resolution on a25mm×25mm×8mm×LYSO monolith read-out by 643mm×3mmHamamatsu SiPMs.Significance.Our results show that monolithic crystals combined with artificial intelligence can rival pixellated crystals performance for time-of-flight PET applications, while having better spatial resolution and DOI resolution. Thanks to the use of very light neural networks, event characterization can be done on-line directly in the detector, solving the issues of scalability and computational complexity that up to now were preventing the use of monolithic crystals in clinical PET scanners.

Localization of anatomical changes in patients during proton therapy with in-beam PET monitoring: A voxel-based morphometry approach exploiting Monte Carlo simulations.

PURPOSE: In-beam positron emission tomography (PET) is one of the modalities that can be used for in vivo noninvasive treatment monitoring in proton therapy. Although PET monitoring has been frequently applied for this purpose, there is still no straightforward method to translate the information obtained from the PET images into easy-to-interpret information for clinical personnel. The purpose of this work is to propose a statistical method for analyzing in-beam PET monitoring images that can be used to locate, quantify, and visualize regions with possible morphological changes occurring over the course of treatment. METHODS: We selected a patient treated for squamous cell carcinoma (SCC) with proton therapy, to perform multiple Monte Carlo (MC) simulations of the expected PET signal at the start of treatment, and to study how the PET signal may change along the treatment course due to morphological changes. We performed voxel-wise two-tailed statistical tests of the simulated PET images, resembling the voxel-based morphometry (VBM) method commonly used in neuroimaging data analysis, to locate regions with significant morphological changes and to quantify the change. RESULTS: The VBM resembling method has been successfully applied to the simulated in-beam PET images, despite the fact that such images suffer from image artifacts and limited statistics. Three dimensional probability maps were obtained, that allowed to identify interfractional morphological changes and to visualize them superimposed on the computed tomography (CT) scan. In particular, the characteristic color patterns resulting from the two-tailed statistical tests lend themselves to trigger alarms in case of morphological changes along the course of treatment. CONCLUSIONS: The statistical method presented in this work is a promising method to apply to PET monitoring data to reveal interfractional morphological changes in patients, occurring over the course of treatment. Based on simulated in-beam PET treatment monitoring images, we showed that with our method it was possible to correctly identify the regions that changed. Moreover we could quantify the changes, and visualize them superimposed on the CT scan. The proposed method can possibly help clinical personnel in the replanning procedure in adaptive proton therapy treatments.

Risk assessment in different Judo techniques for children and adolescent athletes.

Judo is a combat sport that involves throwing the opponent onto the back. When being thrown, head biomechanics may be related to head injury risk. This study aimed to assess head injury risks associated with four Judo techniques in children and adolescents with different experience levels. Twenty children (<12 years) and 20 adolescents (≥ 12 years) judoka were recruited. Each group was divided into non-expert and expert. Two inertial sensors were fixed on fallers' head and torso. Two backward (o-soto-gari and o-uchi-gari) and two forward (ippon-seoi-nage and tai-otoshi) techniques were performed. Peak of linear and angular head acceleration magnitude, impact time duration, neck angle, and the Gadd Severity Index were assessed. Children did not show differences between techniques or experience levels. In contrast, adolescents showed greater linear acceleration peak in o-soto-gari than tai-otoshi (p = 0.03), greater angular acceleration peak in o-soto-gari and o-uchi-gari than ippon-seoi-nage (p < 0.05), and greater neck flexion in o-uchi-gari than ippon-seoi-nage (p = 0.004). Compared to expert adolescents, non-expert adolescents showed greater angular acceleration peak, impact duration, and the Gadd Severity Index in o-soto-gari (p < 0.05) and greater neck extension in o-uchi-gari (p = 0.02). Current results pointed out higher risks for adolescents judoka while being thrown with backward techniques, especially for non-expert participants. This study highlights the need of training athletes in controlling head and neck during back falls from a young age to become expert judoka in adulthood.

Quantification of motor abilities during the execution of judo techniques.

PURPOSE: Quantitative performance analysis is of great importance, especially to increase personalized training and to reduce injuries. The use of inertial sensors has given many possibilities and has been largely used in analysing technical capabilities of athletes. With respect to combat sports, judo has many issues resulting from the great number of variables involved in the techniques and due to the critical measurement environment. The aim of this study was to propose a method for measuring and quantifying motor abilities objectively. METHODS: Four inertial sensors were fixed to the lower limbs and one on the sternum of five male and five female elite judo athletes. Accelerations and angular velocities of the lower limbs were measured in 480 judo techniques. Regression lines of accelerations and angular velocities have been analysed to obtain 5 single technique indices and 1 overall technique index representing the motor abilities connected, respectively to force expressions and coordination capabilities. RESULTS: Correlations of motor abilities (force expression and coordination capabilities) and athletes' weight and height were found in only 6.7% of pairs. Results of force expression and coordination capabilities for most of the athletes are in line with their level of technical and combat experience. CONCLUSIONS: This method allowed to "photograph" athlete's technical level and to compare it in time through subsequent trials. With this innovative way, motor abilities could become evaluable and measurable, highlighting the importance of their objective quantification in order to evaluate effectiveness and efficiency of the sport technique.

Influence of BMI on Gait Characteristics of Young Adults: 3D Evaluation Using Inertial Sensors.

Overweight/obesity is a physical condition that affects daily activities, including walking. The main purpose of this study was to identify if there is a relationship between body mass index (BMI) and gait characteristics in young adults. 12 normal weight (NW) and 10 overweight/obese (OW) individuals walked at a self-selected speed along a 14 m indoor path. H-Gait system, combining seven inertial sensors (fixed on pelvis and lower limbs), was used to record gait data. Walking speed, spatio-temporal parameters and joint kinematics in 3D were analyzed. Differences between NW and OW and correlations between BMI and gait parameters were evaluated. Conventional spatio-temporal parameters did not show statistical differences between the two groups or correlations with the BMI. However, significant results were pointed out for the joint kinematics. OW showed greater hip joint angles in frontal and transverse planes, with respect to NW. In the transverse plane, OW showed a greater knee opening angle and a shorter length of knee and ankle trajectories. Correlations were found between BMI and kinematic parameters in the frontal and transverse planes. Despite some phenomena such as soft tissue artifact and kinematics cross-talk, which have to be more deeply assessed, current results show a relationship between BMI and gait characteristics in young adults that should be looked at in osteoarthritis prevention.

Balance Perturbations as a Measurement Tool for Trunk Impairment in Cross-Country Sit Skiing.

In cross-country sit-skiing, the trunk plays a crucial role in propulsion generation and balance maintenance. Trunk stability is evaluated by automatic responses to unpredictable perturbations; however, electromyography is challenging. The aim of this study was to identify a measure to group sit-skiers according to their ability to control the trunk. Seated in their competitive sit-ski, 10 male and 5 female Paralympic sit-skiers received 6 forward and 6 backward unpredictable perturbations in random order. k-means clustered trunk position at rest, delay to invert the trunk motion, and trunk range of motion significantly into 2 groups. In conclusion, unpredictable perturbations might quantify trunk impairment and may become an important tool in the development of an evidence-based classification system for cross-country sit-skiers.

Online proton therapy monitoring: clinical test of a Silicon-photodetector-based in-beam PET.

Particle therapy exploits the energy deposition pattern of hadron beams. The narrow Bragg Peak at the end of range is a major advantage but range uncertainties can cause severe damage and require online verification to maximise the effectiveness in clinics. In-beam Positron Emission Tomography (PET) is a non-invasive, promising in-vivo technique, which consists in the measurement of the ß+ activity induced by beam-tissue interactions during treatment, and presents the highest correlation of the measured activity distribution with the deposited dose, since it is not much influenced by biological washout. Here we report the first clinical results obtained with a state-of-the-art in-beam PET scanner, with on-the-fly reconstruction of the activity distribution during irradiation. An automated time-resolved quantitative analysis was tested on a lacrimal gland carcinoma case, monitored during two consecutive treatment sessions. The 3D activity map was reconstructed every 10 s, with an average delay between beam delivery and image availability of about 6 s. The correlation coefficient of 3D activity maps for the two sessions (above 0.9 after 120 s) and the range agreement (within 1 mm) prove the suitability of in-beam PET for online range verification during treatment, a crucial step towards adaptive strategies in particle therapy.

A Wearable Magneto-Inertial System for Gait Analysis (H-Gait): Validation on Normal Weight and Overweight/Obese Young Healthy Adults.

Background: Wearable magneto-inertial sensors are being increasingly used to obtain human motion measurements out of the lab, although their performance in applications requiring high accuracy, such as gait analysis, are still a subject of debate. The aim of this work was to validate a gait analysis system (H-Gait) based on magneto-inertial sensors, both in normal weight (NW) and overweight/obese (OW) subjects. The validation is performed against a reference multichannel recording system (STEP32), providing direct measurements of gait timings (through foot-switches) and joint angles in the sagittal plane (through electrogoniometers). Methods: Twenty-two young male subjects were recruited for the study (12 NW, 10 OW). After positioning body-fixed sensors of both systems, each subject was asked to walk, at a self-selected speed, over a 14-m straight path for 12 trials. Gait signals were recorded, at the same time, with the two systems. Spatio-temporal parameters, ankle, knee, and hip joint kinematics were extracted analyzing an average of 89 ± 13 gait cycles from each lower limb. Intraclass correlation coefficient and Bland-Altmann plots were used to compare H-Gait and STEP32 measurements. Changes in gait parameters and joint kinematics of OW with respect NW were also evaluated. Results: The two systems were highly consistent for cadence, while a lower agreement was found for the other spatio-temporal parameters. Ankle and knee joint kinematics is overall comparable. Joint ROMs values were slightly lower for H-Gait with respect to STEP32 for the ankle (by 1.9° for NW, and 1.6° for OW) and for the knee (by 4.1° for NW, and 1.8° for OW). More evident differences were found for hip joint, with ROMs values higher for H-Gait (by 6.8° for NW, and 9.5° for OW). NW and OW showed significant differences considering STEP32 (p = 0.0004), but not H-Gait (p = 0.06). In particular, overweight/obese subjects showed a higher cadence (55.0 vs. 52.3 strides/min) and a lower hip ROM (23.0° vs. 27.3°) than normal weight subjects. Conclusions: The two systems can be considered interchangeable for what concerns joint kinematics, except for the hip, where discrepancies were evidenced. Differences between normal and overweight/obese subjects were statistically significant using STEP32. The same tendency was observed using H-Gait.

Decrease of muscle fiber conduction velocity correlates with strength loss after an endurance run.

Monitoring surface electromyographic (EMG) signals can provide useful insights for characterizing muscle fatigue, which is defined as an exercise-induced strength loss. This experiment investigated the muscle fiber conduction velocity (CV) changes induced by an endurance run. The day before and immediately after a half-marathon run (21.097 km) 11 amateur runners performed maximum voluntary contractions (MVCs) of knee extensor muscles. During the MVC, multichannel EMG was recorded from the vastus lateralis and EMG amplitude and CV were calculated. After the run, knee extensors showed a decreased strength (-13 ± 9%, p = 0.001) together with a reduction in EMG amplitude (-13 ± 10%, p = 0.003) and in CV (-6 ± 8%, p = 0.032). Knee extensor strength loss positively correlated with vastus lateralis CV differences (r = 0.76, p = 0.006). Thus, the exercises-induced muscle fatigue was associated not only with a decrease in EMG amplitude, but also with a reduction in CV. This finding suggests that muscle fibers with higher CV (i.e. those with greater fiber size) were the most impaired during strength production after an endurance run.

INSIDE in-beam positron emission tomography system for particle range monitoring in hadrontherapy.

The quality assurance of particle therapy treatment is a fundamental issue that can be addressed by developing reliable monitoring techniques and indicators of the treatment plan correctness. Among the available imaging techniques, positron emission tomography (PET) has long been investigated and then clinically applied to proton and carbon beams. In 2013, the Innovative Solutions for Dosimetry in Hadrontherapy (INSIDE) collaboration proposed an innovative bimodal imaging concept that combines an in-beam PET scanner with a tracking system for charged particle imaging. This paper presents the general architecture of the INSIDE project but focuses on the in-beam PET scanner that has been designed to reconstruct the particles range with millimetric resolution within a fraction of the dose delivered in a treatment of head and neck tumors. The in-beam PET scanner has been recently installed at the Italian National Center of Oncologic Hadrontherapy (CNAO) in Pavia, Italy, and the commissioning phase has just started. The results of the first beam test with clinical proton beams on phantoms clearly show the capability of the in-beam PET to operate during the irradiation delivery and to reconstruct on-line the beam-induced activity map. The accuracy in the activity distal fall-off determination is millimetric for therapeutic doses.

1-(Fluoroalkylidene)-1,1-bisphosphonic acids are potent and selective inhibitors of the enzymatic activity of Toxoplasma gondii farnesyl pyrophosphate synthase.

α-Fluorinated-1,1-bisphosphonic acids derived from fatty acids were designed, synthesized and biologically evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and against Toxoplasma gondii, the agent responsible for toxoplasmosis, and also towards the target parasitic enzymes farnesyl pyrophosphate synthase of T. cruzi (TcFPPS) and T. gondii (TgFPPS). Interestingly, 1-fluorononylidene-1,1-bisphosphonic acid (compound 43) proved to be an extremely potent inhibitor of the enzymatic activity of TgFPPS at the low nanomolar range, exhibiting an IC(50) of 30 nM. This compound was two-fold more potent than risedronate (IC(50) = 74 nM) that was taken as a positive control. This enzymatic activity was associated with a strong cell growth inhibition against tachyzoites of T. gondii, with an IC(50) value of 2.7 µM.

Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase.

The effect of long-chain 2-alkylaminoethyl-1,1-bisphosphonates against proliferation of the clinically more relevant form of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis (Chagas' disease), and against tachyzoites of Toxoplasma gondii was investigated. Particularly, compound 26 proved to be an extremely potent inhibitor against the intracellular form of T. cruzi, exhibiting IC(50) values at the nanomolar range. This cellular activity was associated with a strong inhibition of the enzymatic activity of T. cruzi farnesyl diphosphate synthase (TcFPPS), which constitutes a valid target for Chagas' disease chemotherapy. Compound 26 was an effective agent against T. cruzi (amastigotes) exhibiting an IC(50) value of 0.67 µM, while this compound showed an IC(50) value of 0.81 µM against the target enzyme TcFPPS. This drug was less effective against the enzymatic activity of T. cruzi solanesyl diphosphate synthase TcSPPS showing an IC(50) value of 3.2 µM. Interestingly, compound 26 was also very effective against T. gondii (tachyzoites) exhibiting IC(50) values of 6.23 µM. This cellular activity was also related to the inhibition of the enzymatic activity towards the target enzyme TgFPPS (IC(50)=0.093 µM) As bisphosphonate-containing compounds are FDA-approved drugs for the treatment of bone resorption disorders, their potential low toxicity makes them good candidates to control different tropical diseases.