Quantification of pulmonary involvement in COVID-19 pneumonia: an upgrade of the LungQuant software for lung CT segmentation.

Computed tomography (CT) scans are used to evaluate the severity of lung involvement in patients affected by COVID-19 pneumonia. Here, we present an improved version of the LungQuant automatic segmentation software (LungQuant v2), which implements a cascade of three deep neural networks (DNNs) to segment the lungs and the lung lesions associated with COVID-19 pneumonia. The first network (BB-net) defines a bounding box enclosing the lungs, the second one (U-net 1 ) outputs the mask of the lungs, and the final one (U-net 2 ) generates the mask of the COVID-19 lesions. With respect to the previous version (LungQuant v1), three main improvements are introduced: the BB-net, a new term in the loss function in the U-net for lesion segmentation and a post-processing procedure to separate the right and left lungs. The three DNNs were optimized, trained and tested on publicly available CT scans. We evaluated the system segmentation capability on an independent test set consisting of ten fully annotated CT scans, the COVID-19-CT-Seg benchmark dataset. The test performances are reported by means of the volumetric dice similarity coefficient (vDSC) and the surface dice similarity coefficient (sDSC) between the reference and the segmented objects. LungQuant v2 achieves a vDSC (sDSC) equal to 0.96 ± 0.01 (0.97 ± 0.01) and 0.69 ± 0.08 (0.83 ± 0.07) for the lung and lesion segmentations, respectively. The output of the segmentation software was then used to assess the percentage of infected lungs, obtaining a Mean Absolute Error (MAE) equal to 2%.

A multicenter evaluation of a deep learning software (LungQuant) for lung parenchyma characterization in COVID-19 pneumonia.

BACKGROUND: The role of computed tomography (CT) in the diagnosis and characterization of coronavirus disease 2019 (COVID-19) pneumonia has been widely recognized. We evaluated the performance of a software for quantitative analysis of chest CT, the LungQuant system, by comparing its results with independent visual evaluations by a group of 14 clinical experts. The aim of this work is to evaluate the ability of the automated tool to extract quantitative information from lung CT, relevant for the design of a diagnosis support model. METHODS: LungQuant segments both the lungs and lesions associated with COVID-19 pneumonia (ground-glass opacities and consolidations) and computes derived quantities corresponding to qualitative characteristics used to clinically assess COVID-19 lesions. The comparison was carried out on 120 publicly available CT scans of patients affected by COVID-19 pneumonia. Scans were scored for four qualitative metrics: percentage of lung involvement, type of lesion, and two disease distribution scores. We evaluated the agreement between the LungQuant output and the visual assessments through receiver operating characteristics area under the curve (AUC) analysis and by fitting a nonlinear regression model. RESULTS: Despite the rather large heterogeneity in the qualitative labels assigned by the clinical experts for each metric, we found good agreement on the metrics compared to the LungQuant output. The AUC values obtained for the four qualitative metrics were 0.98, 0.85, 0.90, and 0.81. CONCLUSIONS: Visual clinical evaluation could be complemented and supported by computer-aided quantification, whose values match the average evaluation of several independent clinical experts. KEY POINTS: We conducted a multicenter evaluation of the deep learning-based LungQuant automated software. We translated qualitative assessments into quantifiable metrics to characterize coronavirus disease 2019 (COVID-19) pneumonia lesions. Comparing the software output to the clinical evaluations, results were satisfactory despite heterogeneity of the clinical evaluations. An automatic quantification tool may contribute to improve the clinical workflow of COVID-19 pneumonia.

The effect of size, shape, coating and functionalization on nuclear relaxation properties in iron oxide core-shell nanoparticles: a brief review of the situation.

In this perspective article, we present a short selection of some of the most significant case studies on magnetic nanoparticles for potential applications in nanomedicine, mainly magnetic resonance. For almost 10 years, our research activity focused on the comprehension of the physical mechanisms on the basis of the nuclear relaxation of magnetic nanoparticles in the presence of magnetic fields; taking advantage of the insights gathered over this time span, we report on the dependence of the relaxation behaviour on the chemico-physical properties of magnetic nanoparticles and discuss them in full detail. In particular, a critical review is carried out on the correlations between their efficiency as contrast agents in magnetic resonance imaging and the magnetic core of magnetic nanoparticles (mainly iron oxides), their size and shape, and the coating and solvent used for making them biocompatible and well dispersible in physiological media. Finally, the heuristic model proposed by Roch and coworkers is presented, as it was extensively adopted to describe most of the experimental data sets. The large amount of data analyzed allowed us to highlight both the advantages and limitations of the model.

Proton Therapy, Magnetic Nanoparticles and Hyperthermia as Combined Treatment for Pancreatic BxPC3 Tumor Cells.

We present an investigation of the effects on BxPC3 pancreatic cancer cells of proton therapy combined with hyperthermia, assisted by magnetic fluid hyperthermia performed with the use of magnetic nanoparticles. The cells' response to the combined treatment has been evaluated by means of the clonogenic survival assay and the estimation of DNA Double Strand Breaks (DSBs). The Reactive Oxygen Species (ROS) production, the tumor cell invasion and the cell cycle variations have also been studied. The experimental results have shown that the combination of proton therapy, MNPs administration and hyperthermia gives a clonogenic survival that is much smaller than the single irradiation treatment at all doses, thus suggesting a new effective combined therapy for the pancreatic tumor. Importantly, the effect of the therapies used here is synergistic. Moreover, after proton irradiation, the hyperthermia treatment was able to increase the number of DSBs, even though just at 6 h after the treatment. Noticeably, the magnetic nanoparticles' presence induces radiosensitization effects, and hyperthermia increases the production of ROS, which contributes to cytotoxic cellular effects and to a wide variety of lesions including DNA damage. The present study indicates a new way for clinical translation of combined therapies, also in the vision of an increasing number of hospitals that will use the proton therapy technique in the near future for different kinds of radio-resistant cancers.

1H-NMR Relaxation of Ferrite Core-Shell Nanoparticles: Evaluation of the Coating Effect.

We investigated the effect of different organic coatings on the 1H-NMR relaxation properties of ultra-small iron-oxide-based magnetic nanoparticles. The first set of nanoparticles, with a magnetic core diameter ds1 = 4.4 ± 0.7 nm, was coated with polyacrylic acid (PAA) and dimercaptosuccinic acid (DMSA), while the second set, ds2 = 8.9 ± 0.9 nm, was coated with aminopropylphosphonic acid (APPA) and DMSA. At fixed core diameters but different coatings, magnetization measurements revealed a similar behavior as a function of temperature and field. On the other hand, the 1H-NMR longitudinal r1 nuclear relaxivity in the frequency range ν = 10 kHz ÷ 300 MHz displayed, for the smallest particles (diameter ds1), an intensity and a frequency behavior dependent on the kind of coating, thus indicating different electronic spin dynamics. Conversely, no differences were found in the r1 relaxivity of the biggest particles (ds2) when the coating was changed. It is concluded that, when the surface to volume ratio, i.e., the surface to bulk spins ratio, increases (smallest nanoparticles), the spin dynamics change significantly, possibly due to the contribution of surface spin dynamics/topology.

Nanomaterials in Cancer Diagnosis and Therapy.

Currently, the most commonly used treatments for cancer are surgery, radiotherapy, and chemotherapy [...].

Tailoring the Magnetic and Structural Properties of Manganese/Zinc Doped Iron Oxide Nanoparticles through Microwaves-Assisted Polyol Synthesis.

Tuning the fundamental properties of iron oxide magnetic nanoparticles (MNPs) according to the required biomedical application is an unsolved challenge, as the MNPs' properties are affected by their composition, their size, the synthesis process, and so on. In this work, we studied the effect of zinc and manganese doping on the magnetic and structural properties of MNPs synthesized by the microwave-assisted polyol process, using diethylene glycol (DEG) and tetraethylene glycol (TEG) as polyols. The detailed morpho-structural and magnetic characterization showed a correspondence between the higher amounts of Mn and smaller crystal sizes of the MNPs. Such size reduction was compensated by an increase in the global magnetic moment so that it resulted in an increase of the saturation magnetization. Saturation magnetization MS values up to 91.5 emu/g and NMR transverse relaxivities r2 of 294 s-1mM-1 were obtained for Zn and Mn- doped ferrites having diameters around 10 nm, whereas Zn ferrites with diameters around 15 nm reached values of MS∼ 97.2 emu/g and of r2∼ 467 s-1mM-1, respectively. Both kinds of nanoparticles were synthesized by a simple, reproducible, and more sustainable method that makes them very interesting for diagnostic applications as MRI contrast agents.

Preliminary report on harmonization of features extraction process using the ComBat tool in the multi-center "Blue Sky Radiomics" study on stage III unresectable NSCLC.

BACKGROUND AND PURPOSE: In the retrospective-prospective multi-center "Blue Sky Radiomics" study (NCT04364776), we plan to test a pre-defined radiomic signature in a series of stage III unresectable NSCLC patients undergoing chemoradiotherapy and maintenance immunotherapy. As a necessary preliminary step, we explore the influence of different image-acquisition parameters on radiomic features' reproducibility and apply methods for harmonization. MATERIAL AND METHODS: We identified the primary lung tumor on two computed tomography (CT) series for each patient, acquired before and after chemoradiation with i.v. contrast medium and with different scanners. Tumor segmentation was performed by two oncological imaging specialists (thoracic radiologist and radio-oncologist) using the Oncentra Masterplan® software. We extracted 42 radiomic features from the specific ROIs (LIFEx). To assess the impact of different acquisition parameters on features extraction, we used the Combat tool with nonparametric adjustment and the longitudinal version (LongComBat). RESULTS: We defined 14 CT acquisition protocols for the harmonization process. Before harmonization, 76% of the features were significantly influenced by these protocols. After, all extracted features resulted in being independent of the acquisition parameters. In contrast, 5% of the LongComBat harmonized features still depended on acquisition protocols. CONCLUSIONS: We reduced the impact of different CT acquisition protocols on radiomic features extraction in a group of patients enrolled in a radiomic study on stage III NSCLC. The harmonization process appears essential for the quality of radiomic data and for their reproducibility. ClinicalTrials.gov Identifier: NCT04364776, First Posted:April 28, 2020, Actual Study Start Date: April 15, 2020, https://clinicaltrials.gov/ct2/show/NCT04364776 .

Double-Layer Fatty Acid Nanoparticles as a Multiplatform for Diagnostics and Therapy.

Today, public health is one of the most important challenges in society. Cancer is the leading cause of death, so early diagnosis and localized treatments that minimize side effects are a priority. Magnetic nanoparticles have shown great potential as magnetic resonance imaging contrast agents, detection tags for in vitro biosensing, and mediators of heating in magnetic hyperthermia. One of the critical characteristics of nanoparticles to adjust to the biomedical needs of each application is their polymeric coating. Fatty acid coatings are known to contribute to colloidal stability and good surface crystalline quality. While monolayer coatings make the particles hydrophobic, a fatty acid double-layer renders them hydrophilic, and therefore suitable for use in body fluids. In addition, they provide the particles with functional chemical groups that allow their bioconjugation. This work analyzes three types of self-assembled bilayer fatty acid coatings of superparamagnetic iron oxide nanoparticles: oleic, lauric, and myristic acids. We characterize the particles magnetically and structurally and study their potential for resonance imaging, magnetic hyperthermia, and labeling for biosensing in lateral flow immunoassays. We found that the myristic acid sample reported a large r2 relaxivity, superior to existing iron-based commercial agents. For magnetic hyperthermia, a significant specific absorption rate value was obtained for the oleic sample. Finally, the lauric acid sample showed promising results for nanolabeling.

Quantification of pulmonary involvement in COVID-19 pneumonia by means of a cascade of two U-nets: training and assessment on multiple datasets using different annotation criteria.

PURPOSE: This study aims at exploiting artificial intelligence (AI) for the identification, segmentation and quantification of COVID-19 pulmonary lesions. The limited data availability and the annotation quality are relevant factors in training AI-methods. We investigated the effects of using multiple datasets, heterogeneously populated and annotated according to different criteria. METHODS: We developed an automated analysis pipeline, the LungQuant system, based on a cascade of two U-nets. The first one (U-net[Formula: see text]) is devoted to the identification of the lung parenchyma; the second one (U-net[Formula: see text]) acts on a bounding box enclosing the segmented lungs to identify the areas affected by COVID-19 lesions. Different public datasets were used to train the U-nets and to evaluate their segmentation performances, which have been quantified in terms of the Dice Similarity Coefficients. The accuracy in predicting the CT-Severity Score (CT-SS) of the LungQuant system has been also evaluated. RESULTS: Both the volumetric DSC (vDSC) and the accuracy showed a dependency on the annotation quality of the released data samples. On an independent dataset (COVID-19-CT-Seg), both the vDSC and the surface DSC (sDSC) were measured between the masks predicted by LungQuant system and the reference ones. The vDSC (sDSC) values of 0.95±0.01 and 0.66±0.13 (0.95±0.02 and 0.76±0.18, with 5 mm tolerance) were obtained for the segmentation of lungs and COVID-19 lesions, respectively. The system achieved an accuracy of 90% in CT-SS identification on this benchmark dataset. CONCLUSION: We analysed the impact of using data samples with different annotation criteria in training an AI-based quantification system for pulmonary involvement in COVID-19 pneumonia. In terms of vDSC measures, the U-net segmentation strongly depends on the quality of the lesion annotations. Nevertheless, the CT-SS can be accurately predicted on independent test sets, demonstrating the satisfactory generalization ability of the LungQuant.

Longitudinal and transverse NMR relaxivities of Ln(III)-DOTA complexes: A comprehensive investigation.

Longitudinal and transverse 1H nuclear magnetic resonance relaxivities of Ln(III)-DOTA complexes (with Ln = Gd, Tb, Dy, Er; DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid) and Mn(II) aqueous solutions were measured in a wide range of frequencies, 10 kHz to 700 MHz. The experimental data were interpreted by means of models derived from the Solomon-Bloembergen-Morgan theory. The data analysis was performed assuming the orbital angular momentum L = 0 for Gd-DOTA and the aqua ion [Mn(H2O)6]2+ and L ≠ 0 for Dy-, Tb-, and Er-DOTA. A refined estimation of the zero-field-splitting barrier Δ and of the modulation correlation time τv was obtained for [Mn(H2O)6]2+ by extending the fitting of nuclear magnetic relaxation dispersion profiles to the low-field regime. The Gd-DOTA fitting parameters resulted in good agreement with the literature, and the fit of transverse relaxivity data confirmed the negligibility of the scalar interaction in the nuclear relaxation mechanism. Larger transverse relaxivities of Dy-DOTA and Tb-DOTA (∼10 mM-1 s-1) with respect to Er-DOTA (∼1 mM-1 s-1) were observed at 16 T. Such higher values are suggested to be due to a shorter residence time τm that is possibly linked to the fluctuations of the hyperfine interaction and the different shape of the magnetic anisotropy. The possible employment of Dy-DOTA, Tb-DOTA, and Er-DOTA as negative magnetic resonance imaging contrast agents for high-field applications was envisaged by collecting spin-echo images at 7 T. Particularly in Dy- and Tb-derivatives, the transverse relaxivity at 16 T is of the order of the Gd-one at 1.5 T.

Hadron Therapy, Magnetic Nanoparticles and Hyperthermia: A Promising Combined Tool for Pancreatic Cancer Treatment.

A combination of carbon ions/photons irradiation and hyperthermia as a novel therapeutic approach for the in-vitro treatment of pancreatic cancer BxPC3 cells is presented. The radiation doses used are 0-2 Gy for carbon ions and 0-7 Gy for 6 MV photons. Hyperthermia is realized via a standard heating bath, assisted by magnetic fluid hyperthermia (MFH) that utilizes magnetic nanoparticles (MNPs) exposed to an alternating magnetic field of amplitude 19.5 mTesla and frequency 109.8 kHz. Starting from 37 °C, the temperature is gradually increased and the sample is kept at 42 °C for 30 min. For MFH, MNPs with a mean diameter of 19 nm and specific absorption rate of 110 ± 30 W/gFe3o4 coated with a biocompatible ligand to ensure stability in physiological media are used. Irradiation diminishes the clonogenic survival at an extent that depends on the radiation type, and its decrease is amplified both by the MNPs cellular uptake and the hyperthermia protocol. Significant increases in DNA double-strand breaks at 6 h are observed in samples exposed to MNP uptake, treated with 0.75 Gy carbon-ion irradiation and hyperthermia. The proposed experimental protocol, based on the combination of hadron irradiation and hyperthermia, represents a first step towards an innovative clinical option for pancreatic cancer.

Coating Effect on the 1H-NMR Relaxation Properties of Iron Oxide Magnetic Nanoparticles.

We present a 1H Nuclear Magnetic Resonance (NMR) relaxometry experimental investigation of two series of magnetic nanoparticles, constituted of a maghemite core with a mean diameter dTEM = 17 ± 2.5 nm and 8 ± 0.4 nm, respectively, and coated with four different negative polyelectrolytes. A full structural, morpho-dimensional and magnetic characterization was performed by means of Transmission Electron Microscopy, Atomic Force Microscopy and DC magnetometry. The magnetization curves showed that the investigated nanoparticles displayed a different approach to the saturation depending on the coatings, the less steep ones being those of the two samples coated with P(MAA-stat-MAPEG), suggesting the possibility of slightly different local magnetic disorders induced by the presence of the various polyelectrolytes on the particles' surface. For each series, 1H NMR relaxivities were found to depend very slightly on the surface coating. We observed a higher transverse nuclear relaxivity, r2, at all investigated frequencies (10 kHz ≤ νL ≤ 60 MHz) for the larger diameter series, and a very different frequency behavior for the longitudinal nuclear relaxivity, r1, between the two series. In particular, the first one (dTEM = 17 nm) displayed an anomalous increase of r1 toward the lowest frequencies, possibly due to high magnetic anisotropy together with spin disorder effects. The other series (dTEM = 8 nm) displayed a r1 vs. νL behavior that can be described by the Roch's heuristic model. The fitting procedure provided the distance of the minimum approach and the value of the Néel reversal time (τ ≈ 3.5 ÷ 3.9·10-9 s) at room temperature, confirming the superparamagnetic nature of these compounds.

Cell Membrane-Coated Magnetic Nanocubes with a Homotypic Targeting Ability Increase Intracellular Temperature due to ROS Scavenging and Act as a Versatile Theranostic System for Glioblastoma Multiforme.

In this study, hybrid nanocubes composed of magnetite (Fe3 O4 ) and manganese dioxide (MnO2 ), coated with U-251 MG cell-derived membranes (CM-NCubes) are synthesized. The CM-NCubes demonstrate a concentration-dependent oxygen generation (up to 15%), and, for the first time in the literature, an intracellular increase of temperature (6 °C) due to the exothermic scavenging reaction of hydrogen peroxide (H2 O2 ) is showed. Internalization studies demonstrate that the CM-NCubes are internalized much faster and at a higher extent by the homotypic U-251 MG cell line compared to other cerebral cell lines. The ability of the CM-NCubes to cross an in vitro model of the blood-brain barrier is also assessed. The CM-NCubes show the ability to respond to a static magnet and to accumulate in cells even under flowing conditions. Moreover, it is demonstrated that 500 µg mL-1 of sorafenib-loaded or unloaded CM-NCubes are able to induce cell death by apoptosis in U-251 MG spheroids that are used as a tumor model, after their exposure to an alternating magnetic field (AMF). Finally, it is shown that the combination of sorafenib and AMF induces a higher enzymatic activity of caspase 3 and caspase 9, probably due to an increment in reactive oxygen species by means of hyperthermia.

Elongated magnetic nanoparticles with high-aspect ratio: a nuclear relaxation and specific absorption rate investigation.

Medical application of nanotechnology implies the development of nanomaterials capable of being functional in different biological environments. In this sense, elongated nanoparticles (e-MNPs) with high-aspect ratio have demonstrated more effective particle cellular internalization, which is favoured by the increased surface area. This paper makes use of an environmentally friendly hydrothermal method to produce magnetic iron oxide e-MNPs, starting from goethite precursors. At high temperatures (Td) goethite transforms into hematite, which subsequently reduces to magnetite when exposed to a hydrogen atmosphere for a certain time. It is shown that by adjusting Td it is possible to obtain Fe3O4 e-MNPs with partially controlled specific surface area and magnetic properties, attributed to different porosity of the samples. The particles' efficiencies for diagnostic and therapeutic purposes (in magnetic resonance imaging and magnetic fluid hyperthermia, respectively) are very good in terms of clinical standards, some samples showing transversal proton nuclear relaxivity r2 (B0 = 1.33 T) = 340 s-1 mM-1 and specific absorption rate SAR > 370 W g-1 at high field amplitudes (B0 = 55 mT). Direct correlations between the SAR, relaxivity, magnetic properties and porosity of the samples are found, and the physico-chemical processes underneath these correlations are investigated. Our results open the possibility of using very efficient high-aspect ratio elongated nanoparticles with optimized chemico-physical properties for biomedical applications.