Can laboratory x-ray virtual histology provide intraoperative 3D tumor resection margin assessment?

Purpose: Surgery is an essential part of the curative plan for most patients affected with solid tumors. The outcome of such surgery, e.g., recurrence rates and ultimately patient survival, depends on several factors where the resection margin is of key importance. Presently, the resection margin is assessed by classical histology, which is time-consuming (several days), destructive, and basically only gives two-dimensional information. Clearly, it would be advantageous if immediate feedback on tumor extension in all three dimensions were available to the surgeon intraoperatively. Approach: We investigate a laboratory propagation-based phase-contrast x-ray computed tomography system that provides the resolution, the contrast, and, potentially, the speed for this purpose. The system relies on a liquid-metal jet microfocus source and a scintillator-coated CMOS detector. Our study is performed on paraffin-embedded non-stained samples of human pancreatic neuroendocrine tumors, liver intrahepatic cholangiocarcinoma, and pancreatic serous cystic neoplasm (benign). Results: We observe tumors with distinct and sharp edges having cellular resolution ( ∼ 10 µ m ) as well as many assisting histological landmarks, allowing for resection margin assessment. All x-ray data are compared with classical histology. The agreement is excellent. Conclusion: We conclude that the method has potential for intraoperative three-dimensional virtual histology.

Regional variations in Sweden over time regarding the surgical treatment of acute cholecystitis: a population-based register study.

OBJECTIVE: To provide optimal health care for patients with acute cholecystitis in need of acute cholecystectomy, resource allocation has to be optimized. The aim of this study was to assess possible regional inequity regarding the treatment of acute cholecystitis and explore regional differences in the management of acute cholecystitis. METHODS: Data were retrieved from the Swedish National Register for Gallstone Surgery and Endoscopic Retrograde CholangioPancreatography. Between January 2010 and December 2019, 22,985 patients who underwent cholecystectomy for acute cholecystitis and without prior history of acute cholecystitis were included in the study. The ratio of cholecystectomies with acute cholecystitis performed within two days of admission to hospital compared to population density was studied. Furthermore, the proportion of acute performed cholecystectomies within two days of admission in regions, with or without tertiary care centers, was also examined. RESULTS: No correlation between population density and proportion of acute performed cholecystectomies was found. Regions without tertiary care centers had a higher proportion of acute cholecystectomies performed within two days (5-10%). The difference in the ratio of acute cholecystectomies within two days of admission was significant for all years investigated except 2010. CONCLUSIONS: The presence of a tertiary referral center within the region had a greater influence than the population density on the chance of undergoing acute cholecystectomy for patients with acute cholecystitis. There are several potential explanations for this, one being an interference of the needs of patients requiring tertiary referral center care with the needs of patients in need of acute care surgery.

Longitudinal In-Vivo X-Ray Fluorescence Computed Tomography With Molybdenum Nanoparticles.

X-ray fluorescence computed tomography (XFCT) with nanoparticles (NPs) as contrast agents shows potential for molecular biomedical imaging with higher spatial resolution than present methods. To date the technique has been demonstrated on phantoms and mice, however, parameters such as radiation dose, exposure times and sensitivity have not yet allowed for high-spatial-resolution in vivo longitudinal imaging, i.e., imaging of the same animal at different time points. Here we show in vivo XFCT with spatial resolution in the 200- [Formula: see text] range in a proof-of-principle longitudinal study where mice are imaged five times each during an eight-week period following tail-vein injection of NPs. We rely on a 24 keV x-ray pencil-beam-based excitation of in-house-synthesized molybdenum oxide NPs (MoO2) to provide the high signal-to-background x-ray fluorescence detection necessary for XFCT imaging with low radiation dose and short exposure times. We quantify the uptake and clearance of NPs in vivo through imaging, and monitor animal well-being over the course of the study with support from histology and DNA stability analysis to assess the impact of x-ray exposure and NPs on animal welfare. We conclude that the presented imaging arrangement has potential for in vivo longitudinal studies, putting emphasis on designing biocompatible NPs as the future focus for active-targeting preclinical XFCT.

Quantitative predictions in small-animal X-ray fluorescence tomography.

X-ray fluorescence (XRF) tomography from nanoparticles (NPs) shows promise for high-spatial-resolution molecular imaging in small-animals. Quantitative reconstruction algorithms aim to reconstruct the true distribution of NPs inside the small-animal, but so far there has been no feasible way to predict signal levels or evaluate the accuracy of reconstructions in realistic scenarios. Here we present a GPU-based computational model for small-animal XRF tomography. The unique combination of a highly accelerated Monte Carlo tool combined with an accurate small-animal phantom allows unprecedented realistic full-body simulations. We use this model to simulate our experimental system to evaluate the quantitative performance and accuracy of our reconstruction algorithms on large-scale organs as well as mm-sized tumors. Furthermore, we predict the detection limits for sub-mm tumors at realistic NP concentrations. The computational model will be a valuable tool for optimizing next-generation experimental arrangements and reconstruction algorithms.

Sequence and length optimization of membrane active coiled coils for triggered liposome release.

Defined and tunable peptide-lipid membrane interactions that trigger the release of liposome encapsulated drugs may offer a route to improving the efficiency and specificity of liposome-based drug delivery systems, but this require means to tailor the performance of the membrane active peptides. In this paper, the membrane activity of a de novo designed coiled coil peptide has been optimized with respect to sequence and size to improve release efficiency of liposome encapsulated cargo. The peptides were only membrane active when covalently conjugated to the liposomes. Two amino acid substitutions were made to enhance the amphipathic characteristics of the peptide, which increased the release by a factor of five at 1 µM. Moreover, the effect of peptide length was investigated by varying the number of heptad repeats from 2 to 5, yielding the peptides KVC2-KVC5. The shortest peptide (KVC2) showed the least interaction with the membrane and proved less efficient than the longer peptides in releasing the liposomal cargo. The peptide with three heptads (KVC3) caused liposome aggregation whereas KVC4 proved to effectively release the liposomal cargo without causing aggregation. The longest peptide (KVC5) demonstrated the most defined α-helical secondary structure and the highest liposome surface concentration but showed slower release kinetics than KVC4. The four heptad peptide KVC4 consequently displayed optimal properties for triggering the release and is an interesting candidate for further development of bioresponsive and tunable liposomal drug delivery systems.

High-spatial-resolution x-ray fluorescence tomography with spectrally matched nanoparticles.

Present macroscopic biomedical imaging methods provide either morphology with high spatial resolution (e.g. CT) or functional/molecular information with lower resolution (e.g. PET). X-ray fluorescence (XRF) from targeted nanoparticles allows molecular or functional imaging but sensitivity has so far been insufficient resulting in low spatial resolution, despite long exposure times and high dose. In the present paper, we show that laboratory XRF tomography with metal-core nanoparticles (NPs) provides a path to functional/molecular biomedical imaging with ~100 µm resolution in living rodents. The high sensitivity and resolution rely on the combination of a high-brightness liquid-metal-jet x-ray source, pencil-beam optics, photon-counting energy-dispersive detection, and spectrally matched NPs. The method is demonstrated on mice for 3D tumor imaging via passive targeting of in-house-fabricated molybdenum NPs. Exposure times, nanoparticle dose, and radiation dose agree well with in vivo imaging.

Focused anti-scatter grid for background reduction in x-ray fluorescence tomography.

X-ray fluorescence (XRF) tomography is an emerging imaging technology with the potential for high spatial resolution molecular imaging. One of the key limitations is the background noise due to Compton scattering since it degrades the signal and limits the sensitivity. In this Letter, we present a linear focused anti-scatter grid that reduces the Compton scattering background. An anti-scatter grid was manufactured and evaluated both experimentally and theoretically with Monte Carlo simulations. The measurements showed a 31% increase in signal-to-background ratio, and simulations of an improved grid showed that this can easily be extended up to >75%. Simulated tomographies using the improved grid show a large improvement in reconstruction quality. The anti-scatter grid will be important for in vivo XRF tomography since the background reduction allows for faster scan times, lower doses, and lower nanoparticle concentrations.

A Library of Potential Nanoparticle Contrast Agents for X-Ray Fluorescence Tomography Bioimaging.

Nanoparticles (NPs) have been used as contrast agents for several bioimaging modalities. X-ray fluorescence (XRF) tomography can provide sensitive and quantitative 3D detection of NPs. With spectrally matched NPs as contrast agents, we demonstrated earlier in a laboratory system that XRF tomography could achieve high-spatial-resolution tumor imaging in mice. Here, we present the synthesis, characterization, and evaluation of a library of NPs containing Y, Zr, Nb, Rh, and Ru that have spectrally matched K-shell absorption for the laboratory scale X-ray source. The K-shell emissions of these NPs are spectrally well separated from the X-ray probe and the Compton background, making them suitable for the lab-scale XRF tomography system. Their potential as XRF contrast agents is demonstrated successfully in a small-animal equivalent phantom, confirming the simulation results. The diversity in the NP composition provides a flexible platform for a better design and biological optimization of XRF tomography nanoprobes.

Removal of ring artifacts in microtomography by characterization of scintillator variations.

Ring artifacts reduce image quality in tomography, and arise from faulty detector calibration. In microtomography, we have identified that ring artifacts can arise due to high-spatial frequency variations in the scintillator thickness. Such variations are normally removed by a flat-field correction. However, as the spectrum changes, e.g. due to beam hardening, the detector response varies non-uniformly introducing ring artifacts that persist after flat-field correction. In this paper, we present a method to correct for ring artifacts from variations in scintillator thickness by using a simple method to characterize the local scintillator response. The method addresses the actual physical cause of the ring artifacts, in contrary to many other ring artifact removal methods which rely only on image post-processing. By applying the technique to an experimental phantom tomography, we show that ring artifacts are strongly reduced compared to only making a flat-field correction.

Characterization of scintillator-based detectors for few-ten-keV high-spatial-resolution x-ray imaging.

PURPOSE: High-spatial-resolution x-ray imaging in the few-ten-keV range is becoming increasingly important in several applications, such as small-animal imaging and phase-contrast imaging. The detector properties critically influence the quality of such imaging. Here the authors present a quantitative comparison of scintillator-based detectors for this energy range and at high spatial frequencies. METHODS: The authors determine the modulation transfer function, noise power spectrum (NPS), and detective quantum efficiency for Gadox, needle CsI, and structured CsI scintillators of different thicknesses and at different photon energies. An extended analysis of the NPS allows for direct measurements of the scintillator effective absorption efficiency and effective light yield as well as providing an alternative method to assess the underlying factors behind the detector properties. RESULTS: There is a substantial difference in performance between the scintillators depending on the imaging task but in general, the CsI based scintillators perform better than the Gadox scintillators. At low energies (16 keV), a thin needle CsI scintillator has the best performance at all frequencies. At higher energies (28-38 keV), the thicker needle CsI scintillators and the structured CsI scintillator all have very good performance. The needle CsI scintillators have higher absorption efficiencies but the structured CsI scintillator has higher resolution. CONCLUSIONS: The choice of scintillator is greatly dependent on the imaging task. The presented comparison and methodology will assist the imaging scientist in optimizing their high-resolution few-ten-keV imaging system for best performance.

Laboratory x-ray fluorescence tomography for high-resolution nanoparticle bio-imaging.

We demonstrate that nanoparticle x-ray fluorescence computed tomography in mouse-sized objects can be performed with very high spatial resolution at acceptable dose and exposure times with a compact laboratory system. The method relies on the combination of the 24 keV line-emission from a high-brightness liquid-metal-jet x-ray source, pencil-beam-forming x-ray optics, photon-counting energy-dispersive detection, and carefully matched (Mo) nanoparticles. Phantom experiments and simulations show that the arrangement significantly reduces Compton background and allows 100 µm detail imaging at dose and exposure times compatible with small-animal experiments. The method provides a possible path to in vivo molecular x-ray imaging at sub-100 µm resolution in mice.

Polarization-controlled circular second-harmonic generation from metal hole arrays with threefold rotational symmetry.

The discrete rotational symmetry of nanostructures provides a powerful and simple guiding principle for designing the second-harmonic generation process in nonlinear metamaterials. We demonstrate that, in achiral nanostructures with threefold rotational symmetries, a circularly polarized fundamental beam produces a countercircularly polarized second-harmonic beam. In this case, the polarization state of the second harmonic is determined in a very simple manner. We also demonstrate how rotational symmetries in nonlinear metamaterials manifest themselves in SHG selection rules.