Superparamagnetic Iron Oxide Nanoparticles Reprogram the Tumor Microenvironment and Reduce Lung Cancer Regrowth after Crizotinib Treatment.

ALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates. Growing evidence suggests that the combination of drug and immune therapies greatly improves patient survival; however, due to the low immunogenicity of the tumors, ALK-positive patients do not respond to currently available immunotherapies. Tumor-associated macrophages (TAMs) play a crucial role in facilitating lung cancer growth by suppressing tumoricidal immune activation and absorbing chemotherapeutics. However, they can also be programmed toward a pro-inflammatory tumor suppressive phenotype, which represents a highly active area of therapy development. Iron loading of TAMs can achieve such reprogramming correlating with an improved prognosis in lung cancer patients. We previously showed that superparamagnetic iron oxide nanoparticles containing core-cross-linked polymer micelles (SPION-CCPMs) target macrophages and stimulate pro-inflammatory activation. Here, we show that SPION-CCPMs stimulate TAMs to secrete reactive nitrogen species and cytokines that exert tumoricidal activity. We further show that SPION-CCPMs reshape the immunosuppressive Eml4-Alk lung tumor microenvironment (TME) toward a cytotoxic profile hallmarked by the recruitment of CD8+ T cells, suggesting a multifactorial benefit of SPION-CCPM application. When intratracheally instilled into lung cancer-bearing mice, SPION-CCPMs delay tumor growth and, after first line therapy with a TKI, halt the regrowth of relapsing tumors. These findings identify SPIONs-CCPMs as an adjuvant therapy, which remodels the TME, resulting in a delay in the appearance of resistant tumors.

Empirical scatter correction: CBCT scatter artifact reduction without prior information.

BACKGROUND: The image quality of cone beam CT (CBCT) scans severely suffers from scattered radiation if no countermeasures are taken. Scatter artifacts may induce cupping and streak artifacts and lead to a reduced image contrast and wrong CT values of the reconstructed volumes. Established software-based approaches for a correction of scattered radiation typically rely on prior knowledge of the CT system, scan parameters, the scanned object, or all of the aforementioned. PURPOSE: This study proposes a simple and effective postprocessing software-based correction method of scatter artifacts in CBCT scans without specific prior knowledge. METHODS: We propose the empirical scatter correction (ESC), which generates scatter-like basis images from each projection image by convolution operations. A linear combination of these basis images is subtracted from the original projection image. The logarithm is taken and an FDK reconstruction is performed. The coefficients needed for the linear combination are determined automatically by a downhill simplex algorithm such that the resulting reconstructed images show no scatter artifacts. We demonstrate the potential of ESC by correcting simulated volumes with Monte Carlo scatter artifacts, a head phantom scan performed on our table-top CBCT, and a pelvis scan from a Varian Edge CBCT scanner. RESULTS: ESC is able to improve the image quality of CBCT scans, which is shown on the basis of our simulations and on measured data. For a simulated head CT, the CT value difference to the scatter-free reference image was as low as -6 HU after using ESC, whereas the uncorrected data deviated by more than -200 HU from the reference data. Simulations of thorax and abdomen CT scans show that although scatter artifacts are not fully removed, anatomical features which were hard to discover prior to the correction become clearly visible and better segmentable with ESC. Similar results are obtained in the phantom measurement, where a comparison to a slit scan of our head phantom shows only small differences. The CT values in soft tissue are improved in this measurement, as well. In soft tissue areas with severe scatter artifacts, the CT values agree well with those of the slit scan (difference to slit scan: 35 HU corrected and -289 HU uncorrected). Scatter artifacts in measured patient data can also be reduced using the proposed ESC. The results are comparable to those achieved with designated correction algorithms installed on the Varian Edge CBCT system. CONCLUSIONS: ESC allows to reduce artifacts caused by patient scatter solely based on the projection data.

Real-time scatter estimation for medical CT using the deep scatter estimation: Method and robustness analysis with respect to different anatomies, dose levels, tube voltages, and data truncation.

PURPOSE: X-ray scattering leads to CT images with a reduced contrast, inaccurate CT values as well as streak and cupping artifacts. Therefore, scatter correction is crucial to maintain the diagnostic value of CT and CBCT examinations. However, existing approaches are not able to combine both high accuracy and high computational performance. Therefore, we propose the deep scatter estimation (DSE): a deep convolutional neural network to derive highly accurate scatter estimates in real time. METHODS: Gold standard scatter estimation approaches rely on dedicated Monte Carlo (MC) photon transport codes. However, being computationally expensive, MC methods cannot be used routinely. To enable real-time scatter correction with similar accuracy, DSE uses a deep convolutional neural network that is trained to predict MC scatter estimates based on the acquired projection data. Here, the potential of DSE is demonstrated using simulations of CBCT head, thorax, and abdomen scans as well as measurements at an experimental table-top CBCT. Two conventional computationally efficient scatter estimation approaches were implemented as reference: a kernel-based scatter estimation (KSE) and the hybrid scatter estimation (HSE). RESULTS: The simulation study demonstrates that DSE generalizes well to varying tube voltages, varying noise levels as well as varying anatomical regions as long as they are appropriately represented within the training data. In any case the deviation of the scatter estimates from the ground truth MC scatter distribution is less than 1.8% while it is between 6.2% and 293.3% for HSE and between 11.2% and 20.5% for KSE. To evaluate the performance for real data, measurements of an anthropomorphic head phantom were performed. Errors were quantified by a comparison to a slit scan reconstruction. Here, the deviation is 278 HU (no correction), 123 HU (KSE), 65 HU (HSE), and 6 HU (DSE), respectively. CONCLUSIONS: The DSE clearly outperforms conventional scatter estimation approaches in terms of accuracy. DSE is nearly as accurate as Monte Carlo simulations but is superior in terms of speed (≈10 ms/projection) by orders of magnitude.

Effect of detruncation on the accuracy of Monte Carlo-based scatter estimation in truncated CBCT.

PURPOSE: The purpose of this study is to investigate the necessity of detruncation for scatter estimation of truncated cone-beam CT (CBCT) data and to evaluate different detruncation algorithms. Scattered radiation results in some of the most severe artifacts in CT and depends strongly on the size and the shape of the scanned object. Especially in CBCT systems the large cone-angle and the small detector-to-isocenter distance lead to a large amount of scatter detected, resulting in cupping artifacts, streak artifacts, and inaccurate CT-values. If a small field of measurement (FOM) is used, as it is often the case in CBCT systems, data are truncated in longitudinal and lateral direction. Since only truncated data are available as input for the scatter estimation, the already challenging correction of scatter artifacts becomes even more difficult. METHODS: The following detruncation methods are compared and evaluated with respect to scatter estimation: constant detruncation, cosine detruncation, adaptive detruncation, and prior-based detruncation using anatomical data from a similar phantom or patient, also compared to the case where no detruncation was performed. Each of the resulting, detruncated reconstructions serve as input volume for a Monte Carlo (MC) scatter estimation and subsequent scatter correction. An evaluation is performed on a head simulation, measurements of a head phantom and a patient using a dental CBCT geometry with a FOM diameter of 11 cm. Additionally, a thorax phantom is measured to assess performance in a C-Arm geometry with a FOM of up to 20 cm. RESULTS: If scatter estimation is based on simple detruncation algorithms like a constant or a cosine detruncation scatter is estimated inaccurately, resulting in incorrect CT-values as well as streak artifacts in the corrected volume. For the dental CBCT phantom measurement CT-values for soft tissue were corrected from -204 HU (no scatter correction) to -87 HU (no detruncation), -218 HU (constant detruncation), -141 HU (cosine detruncation), -91 HU (adaptive detruncation), -34 HU (prior-based detruncation using a different prior) and -24 HU (prior-based detruncation using the identical prior) for a reference value of -26 HU measured in slit scan mode. In all cases the prior-based detruncation results in the best scatter correction, followed by the adaptive detruncation, as these algorithms provide a rather accurate model of high-density structures outside the FOM, compared to a simple constant or a cosine detruncation. CONCLUSIONS: Our contribution is twofold: first we give a comprehensive comparison of various detruncation methods for the purpose of scatter estimation. We find that the choice of the detruncation method has a significant influence on the quality of MC-based scatter correction. Simple or no detruncation is often insufficient for artifact removal and results in inaccurate CT-values. On the contrary, prior-based detruncation can achieve a high CT-value accuracy and nearly artifact-free volumes from truncated CBCT data when combined with other state-of-the-art artifact corrections. Secondly, we show that prior-based detruncation is effective even with data from a different patient or phantom. The fact that data completion does not require data from the same patient dramatically increases the applicability and usability of this scatter estimation.

In Vivo Quantification of Myocardial Infarction in Mice Using Micro-CT and a Novel Blood Pool Agent.

We herein developed a micro-CT method using the innovative contrast agent ExiTron™ MyoC 8000 to longitudinally monitor cardiac processes in vivo in small animals. Experiments were performed on healthy mice and mice with myocardial infarction inflicted by ligation of the left anterior descending artery. Time-dependent signal enhancement in different tissues of healthy mice was measured and various contrast agent doses were investigated so as to determine the minimum required dose for imaging of the myocardium. Due to its ability to be taken up by healthy myocardium but not by infarct tissue, ExiTron MyoC 8000 enables detection of myocardial infarction even at a very low dose. The signal enhancement in the myocardium of infarcted mice after contrast agent injection was exploited for quantification of infarct size. The values of infarct size obtained from the imaging method were compared with those obtained from histology and showed a significant correlation (R2 = 0.98). Thus, the developed micro-CT method allows for monitoring of a variety of processes such as cardiac remodeling in longitudinal studies.

Segmentation-free empirical beam hardening correction for CT.

PURPOSE: The polychromatic nature of the x-ray beams and their effects on the reconstructed image are often disregarded during standard image reconstruction. This leads to cupping and beam hardening artifacts inside the reconstructed volume. To correct for a general cupping, methods like water precorrection exist. They correct the hardening of the spectrum during the penetration of the measured object only for the major tissue class. In contrast, more complex artifacts like streaks between dense objects need other techniques of correction. If using only the information of one single energy scan, there are two types of corrections. The first one is a physical approach. Thereby, artifacts can be reproduced and corrected within the original reconstruction by using assumptions in a polychromatic forward projector. These assumptions could be the used spectrum, the detector response, the physical attenuation and scatter properties of the intersected materials. A second method is an empirical approach, which does not rely on much prior knowledge. This so-called empirical beam hardening correction (EBHC) and the previously mentioned physical-based technique are both relying on a segmentation of the present tissues inside the patient. The difficulty thereby is that beam hardening by itself, scatter, and other effects, which diminish the image quality also disturb the correct tissue classification and thereby reduce the accuracy of the two known classes of correction techniques. The herein proposed method works similar to the empirical beam hardening correction but does not require a tissue segmentation and therefore shows improvements on image data, which are highly degraded by noise and artifacts. Furthermore, the new algorithm is designed in a way that no additional calibration or parameter fitting is needed. METHODS: To overcome the segmentation of tissues, the authors propose a histogram deformation of their primary reconstructed CT image. This step is essential for the proposed algorithm to be segmentation-free (sf). This deformation leads to a nonlinear accentuation of higher CT-values. The original volume and the gray value deformed volume are monochromatically forward projected. The two projection sets are then monomially combined and reconstructed to generate sets of basis volumes which are used for correction. This is done by maximization of the image flatness due to adding additionally a weighted sum of these basis images. sfEBHC is evaluated on polychromatic simulations, phantom measurements, and patient data. The raw data sets were acquired by a dual source spiral CT scanner, a digital volume tomograph, and a dual source micro CT. Different phantom and patient data were used to illustrate the performance and wide range of usability of sfEBHC across different scanning scenarios. The artifact correction capabilities are compared to EBHC. RESULTS: All investigated cases show equal or improved image quality compared to the standard EBHC approach. The artifact correction is capable of correcting beam hardening artifacts for different scan parameters and scan scenarios. CONCLUSIONS: sfEBHC generates beam hardening-reduced images and is furthermore capable of dealing with images which are affected by high noise and strong artifacts. The algorithm can be used to recover structures which are hardly visible inside the beam hardening-affected regions.