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Dark-field chest radiography signal intensity appeared to correlate with inflation status in a cadaveric lung., Competing Interests: Disclosures of conflicts of interest: F.T.G. No relevant relationships. M.F. No relevant relationships. F.D.M. No relevant relationships. K.W. No relevant relationships. T.U. No relevant relationships. J.H. No relevant relationships. A.A.F. No relevant relationships. A.P.S. No relevant relationships. M.R.M. No relevant relationships. F.K. No relevant relationships. F.F. No relevant relationships. C.B. No relevant relationships. F.P. No relevant relationships. D.P. No relevant relationships., (© 2022 by the Radiological Society of North America, Inc.)

Background: Currently, alternative medical imaging methods for the assessment of pulmonary involvement in patients infected with COVID-19 are sought that combine a higher sensitivity than conventional (attenuation-based) chest radiography with a lower radiation dose than CT imaging., Methods: Sixty patients with COVID-19-associated lung changes in a CT scan and 40 subjects without pathologic lung changes visible in the CT scan were included (in total, 100, 59 male, mean age 58 ± 14 years). All patients gave written informed consent. We employed a clinical setup for grating-based dark-field chest radiography, obtaining both a dark-field and a conventional attenuation image in one image acquisition. Attenuation images alone, dark-field images alone, and both displayed simultaneously were assessed for the presence of COVID-19-associated lung changes on a scale from 1 to 6 (1 = surely not, 6 = surely) by four blinded radiologists. Statistical analysis was performed by evaluation of the area under the receiver-operator-characteristics curves (AUC) using Obuchowski's method with a 0.05 level of significance., Results: We show that dark-field imaging has a higher sensitivity for COVID-19-pneumonia than attenuation-based imaging and that the combination of both is superior to one imaging modality alone. Furthermore, a quantitative image analysis shows a significant reduction of dark-field signals for COVID-19-patients., Conclusions: Dark-field imaging complements and improves conventional radiography for the visualisation and detection of COVID-19-pneumonia., (© 2022. The Author(s).)

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Background Dark-field chest radiography allows for assessment of lung alveolar structure by exploiting wave optical properties of x-rays. Purpose To evaluate the qualitative and quantitative features of dark-field chest radiography in participants with pulmonary emphysema as compared with those in healthy control subjects. Materials and Methods In this prospective study conducted from October 2018 to October 2020, participants aged at least 18 years who underwent clinically indicated chest CT were screened for participation. Inclusion criteria were an ability to consent to the procedure and stand upright without help. Exclusion criteria were pregnancy, serious medical conditions, and any lung condition besides emphysema that was visible on CT images. Participants were examined with a clinical dark-field chest radiography prototype that simultaneously acquired both attenuation-based radiographs and dark-field chest radiographs. Dark-field coefficients were tested for correlation with each participant's CT-based emphysema index using the Spearman correlation test. Dark-field coefficients of adjacent groups in the semiquantitative Fleischner Society emphysema grading system were compared using a Wilcoxon Mann-Whitney U test. The capability of the dark-field coefficient to enable detection of emphysema was evaluated with receiver operating characteristics curve analysis. Results A total of 83 participants (mean age, 65 years ± 12 [standard deviation]; 52 men) were studied. When compared with images from healthy participants, dark-field chest radiographs in participants with emphysema had a lower and inhomogeneous dark-field signal intensity. The locations of focal signal intensity loss on dark-field images corresponded well with emphysematous areas found on CT images. The dark-field coefficient was negatively correlated with the quantitative CT-based emphysema index ( r = -0.54, P < .001). Participants with Fleischner Society grades of mild, moderate, confluent, or advanced destructive emphysema exhibited a lower dark-field coefficient than those without emphysema (eg, 1.3 m -1 ± 0.6 for participants with confluent or advanced destructive emphysema vs 2.6 m -1 ± 0.4 for participants without emphysema; P < .001). The area under the receiver operating characteristic curve for detection of mild emphysema was 0.79. Conclusion Pulmonary emphysema leads to reduced signal intensity on dark-field chest radiographs, showing the technique has potential as a diagnostic tool in the assessment of lung diseases. © RSNA, 2022 See also the editorial by Hatabu and Madore in this issue.

Background: Spirometry and conventional chest x-ray have limitations in investigating early emphysema, while computed tomography, the reference imaging method in this context, is not part of routine patient care due to its higher radiation dose. In this work, we investigated a novel low-dose imaging modality, dark-field chest x-ray, for the evaluation of emphysema in patients with alpha1-antitrypsin deficiency., Methods: By exploiting wave properties of x-rays for contrast formation, dark-field chest x-ray visualises the structural integrity of the alveoli, represented by a high signal over the lungs in the dark-field image. We investigated four patients with alpha1-antitrypsin deficiency with a novel dark-field x-ray prototype and simultaneous conventional chest x-ray. The extent of pulmonary function impairment was assessed by pulmonary function measurement and regional emphysema distribution was compared with CT in one patient., Results: We show that dark-field chest x-ray visualises the extent of pulmonary emphysema displaying severity and regional differences. Areas with low dark-field signal correlate with emphysematous changes detected by computed tomography using a threshold of -950 Hounsfield units. The airway parameters obtained by whole-body plethysmography and single breath diffusing capacity of the lungs for carbon monoxide demonstrated typical changes of advanced emphysema., Conclusions: Dark-field chest x-ray directly visualised the severity and regional distribution of pulmonary emphysema compared to conventional chest x-ray in patients with alpha1-antitrypsin deficiency. Due to the ultra-low radiation dose in comparison to computed tomography, dark-field chest x-ray could be beneficial for long-term follow-up in these patients., (© 2022. The Author(s) under exclusive licence to European Society of Radiology.)

Background X-ray dark-field radiography takes advantage of the wave properties of x-rays, with a relatively high signal in the lungs due to the many air-tissue interfaces in the alveoli. Purpose To describe the qualitative and quantitative characteristics of x-ray dark-field images in healthy human subjects. Materials and Methods Between October 2018 and January 2020, patients of legal age who underwent chest CT as part of their diagnostic work-up were screened for study participation. Inclusion criteria were a normal chest CT scan, the ability to consent, and the ability to stand upright without help. Exclusion criteria were pregnancy, serious medical conditions, and changes in the lung tissue, such as those due to cancer, pleural effusion, atelectasis, emphysema, infiltrates, ground-glass opacities, or pneumothorax. Images of study participants were obtained by using a clinical x-ray dark-field prototype, recently constructed and commissioned at the authors' institution, to simultaneously acquire both attenuation-based and dark-field thorax radiographs. Each subject's total dark-field signal was correlated with his or her lung volume, and the dark-field coefficient was correlated with age, sex, weight, and height. Results Overall, 40 subjects were included in this study (average age, 62 years ± 13 [standard deviation]; 26 men, 14 women). Normal human lungs have high signal, while the surrounding osseous structures and soft tissue have very low and no signal, respectively. The average dark-field signal was 2.5 m -1 ± 0.4 of examined lung tissue. There was a correlation between the total dark-field signal and the lung volume ( r = 0.61, P < .001). No difference was found between men and women ( P = .78). Also, age ( r = -0.18, P = .26), weight ( r = 0.24, P = .13), and height ( r = 0.01, P = .96) did not influence dark-field signal. Conclusion This study introduces qualitative and quantitative values for x-ray dark-field imaging in healthy human subjects. The quantitative x-ray dark-field coefficient is independent from demographic subject parameters, emphasizing its potential in diagnostic assessment of the lung. ©RSNA, 2021 See also the editorial by Hatabu and Madore in this issue.

Background: Although advanced medical imaging technologies give detailed diagnostic information, a low-dose, fast, and inexpensive option for early detection of respiratory diseases and follow-ups is still lacking. The novel method of x-ray dark-field chest imaging might fill this gap but has not yet been studied in living humans. Enabling the assessment of microstructural changes in lung parenchyma, this technique presents a more sensitive alternative to conventional chest x-rays, and yet requires only a fraction of the dose applied in CT. We studied the application of this technique to assess pulmonary emphysema in patients with chronic obstructive pulmonary disease (COPD)., Methods: In this diagnostic accuracy study, we designed and built a novel dark-field chest x-ray system (Technical University of Munich, Munich, Germany)-which is also capable of simultaneously acquiring a conventional thorax radiograph (7 s, 0·035 mSv effective dose). Patients who had undergone a medically indicated chest CT were recruited from the department of Radiology and Pneumology of our site (Klinikum rechts der Isar, Technical University of Munich, Munich, Germany). Patients with pulmonary pathologies, or conditions other than COPD, that might influence lung parenchyma were excluded. For patients with different disease stages of pulmonary emphysema, x-ray dark-field images and CT images were acquired and visually assessed by five readers. Pulmonary function tests (spirometry and body plethysmography) were performed for every patient and for a subgroup of patients the measurement of diffusion capacity was performed. Individual patient datasets were statistically evaluated using correlation testing, rank-based analysis of variance, and pair-wise post-hoc comparison., Findings: Between October, 2018 and December, 2019 we enrolled 77 patients. Compared with CT-based parameters (quantitative emphysema ρ=-0·27, p=0·089 and visual emphysema ρ=-0·45, p=0·0028), the dark-field signal (ρ=0·62, p<0·0001) yields a stronger correlation with lung diffusion capacity in the evaluated cohort. Emphysema assessment based on dark-field chest x-ray features yields consistent conclusions with findings from visual CT image interpretation and shows improved diagnostic performance than conventional clinical tests characterising emphysema. Pair-wise comparison of corresponding test parameters between adjacent visual emphysema severity groups (CT-based, reference standard) showed higher effect sizes. The mean effect size over the group comparisons (absent-trace, trace-mild, mild-moderate, and moderate-confluent or advanced destructive visual emphysema grades) for the COPD assessment test score is 0·21, for forced expiratory volume in 1 s (FEV 1 )/functional vital capacity is 0·25, for FEV 1 % of predicted is 0·23, for residual volume % of predicted is 0·24, for CT emphysema index is 0·35, for dark-field signal homogeneity within lungs is 0·38, for dark-field signal texture within lungs is 0·38, and for dark-field-based emphysema severity is 0·42., Interpretation: X-ray dark-field chest imaging allows the diagnosis of pulmonary emphysema in patients with COPD because this technique provides relevant information representing the structural condition of lung parenchyma. This technique might offer a low radiation dose alternative to CT in COPD and potentially other lung disorders., Funding: European Research Council, Deutsche Forschungsgemeinschaft, Royal Philips, and Karlsruhe Nano Micro Facility., Competing Interests: Declaration of interests TK is an employee of Philips Innovative Technologies, Research Laboratories, which is part of Royal Philips. AY and TP are employees of Philips Medical System DMC, which is part of Royal Philips. GSZ receives payments for lectures from Boehringer Ingelheim, AstraZeneca, Novartis, GlaxoSmithKline, Bayer Healthcare, and Roche; and receives travel support from Novartis and Roche. FP received a European Research Council Advanced Grant and a hardware loan (x-ray source and detector) from Royal Philips. The authorship of patents related to technical implementation of the demonstrator system are KW has coauthored GB3687403B2 and US20200187893A1; FDM has coauthored GB3687403B2 and US20200187893A1; TU has coauthored PCT/EP2021/063949; TK has coauthored US10417761B2, US10945690B2, GB3687403B2, US10912532B2, PCT/EP2020/082799, PCT/EP2021/057524, PCT/EP2021/064497, PCT/EP2021/063949, and US20200187893A1; AY has coauthored GB3687403B2, US10912532B2, PCT/EP2020/082799, and US20200187893A1; TP has coauthored PCT/EP2020/082799; and FP has coauthored US10945690B2 and PCT/EP2021/063949. Royal Philips is the assignee for all patents listed. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: Radiotherapy of thoracic tumours can lead to side effects in the lung, which may benefit from early diagnosis. We investigated the potential of X-ray dark-field computed tomography by a proof-of-principle murine study in a clinically relevant radiotherapeutic setting aiming at the detection of radiation-induced lung damage., Material and Methods: Six mice were irradiated with 20 Gy to the entire right lung. Together with five unirradiated control mice, they were imaged using computed tomography with absorption and dark-field contrast before and 16 weeks post irradiation. Mean pixel values for the right and left lung were calculated for both contrasts, and the right-to-left-ratio R of these means was compared. Radiologists also assessed the tomograms acquired 16 weeks post irradiation. Sensitivity, specificity, inter- and intra-reader accuracy were evaluated., Results: In absorption contrast the group-average of R showed no increase in the control group and increased by 7% (p = 0.005) in the irradiated group. In dark-field contrast, it increased by 2% in the control group and by 14% (p = 0.005) in the irradiated group. Specificity was 100% for both contrasts but sensitivity was almost four times higher using dark-field tomography. Two cases were missed by absorption tomography but were detected by dark-field tomography., Conclusions: The applicability of X-ray dark-field computed tomography for the detection of radiation-induced lung damage was demonstrated in a pre-clinical mouse model. The presented results illustrate the differences between dark-field and absorption contrast and show that dark-field tomography could be advantageous in future clinical settings., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Grating-based X-ray dark-field imaging is a novel imaging modality with enormous technical progress during the last years. It enables the detection of microstructure impairment as in the healthy lung a strong dark-field signal is present due to the high number of air-tissue interfaces. Using the experience from setups for animal imaging, first studies with a human cadaver could be performed recently. Subsequently, the first dark-field scanner for in-vivo chest imaging of humans was developed. In the current study, the optimal tube voltage for dark-field radiography of the thorax in this setup was examined using an anthropomorphic chest phantom. Tube voltages of 50-125 kVp were used while maintaining a constant dose-area-product. The resulting dark-field and attenuation radiographs were evaluated in a reader study as well as objectively in terms of contrast-to-noise ratio and signal strength. We found that the optimum tube voltage for dark-field imaging is 70 kVp as here the most favorable combination of image quality, signal strength, and sharpness is present. At this voltage, a high image quality was perceived in the reader study also for attenuation radiographs, which should be sufficient for routine imaging. The results of this study are fundamental for upcoming patient studies with living humans.

Background: Grating-based x-ray dark-field and phase-contrast imaging allow extracting information about refraction and small-angle scatter, beyond conventional attenuation. A step towards clinical translation has recently been achieved, allowing further investigation on humans., Methods: After the ethics committee approval, we scanned the full body of a human cadaver in anterior-posterior orientation. Six measurements were stitched together to form the whole-body image. All radiographs were taken at a three-grating large-object x-ray dark-field scanner, each lasting about 40 s. Signal intensities of different anatomical regions were assessed. The magnitude of visibility reduction caused by beam hardening instead of small-angle scatter was analysed using different phantom materials. Maximal effective dose was 0.3 mSv for the abdomen., Results: Combined attenuation and dark-field radiography are technically possible throughout a whole human body. High signal levels were found in several bony structures, foreign materials, and the lung. Signal levels were 0.25 ± 0.13 (mean ± standard deviation) for the lungs, 0.08 ± 0.06 for the bones, 0.023 ± 0.019 for soft tissue, and 0.30 ± 0.02 for an antibiotic bead chain. We found that phantom materials, which do not produce small-angle scatter, can generate a strong visibility reduction signal., Conclusion: We acquired a whole-body x-ray dark-field radiograph of a human body in few minutes with an effective dose in a clinical acceptable range. Our findings suggest that the observed visibility reduction in the bone and metal is dominated by beam hardening and that the true dark-field signal in the lung is therefore much higher than that of the bone.

Background: Since the outbreak of the COVID-19 pandemic, a number of risk factors for a poor outcome have been identified. Thereby, cardiovascular comorbidity has a major impact on mortality. We investigated whether coronary calcification as a marker for coronary artery disease (CAD) is appropriate for risk prediction in COVID-19., Methods: Hospitalized patients with COVID-19 (n = 109) were analyzed regarding clinical outcome after native computed tomography (CT) imaging for COVID-19 screening. CAC (coronary calcium score) and clinical outcome (need for intensive care treatment or death) data were calculated following a standardized protocol. We defined three endpoints: critical COVID-19 and transfer to ICU, fatal COVID-19 and death, composite endpoint critical and fatal COVID-19, a composite of ICU treatment and death. We evaluated the association of clinical outcome with the CAC. Patients were dichotomized by the median of CAC. Hazard ratios and odds ratios were calculated for the events death or ICU or a composite of death and ICU., Results: We observed significantly more events for patients with CAC above the group's median of 31 for critical outcome (HR: 1.97[1.09,3.57], p = 0.026), for fatal outcome (HR: 4.95[1.07,22.9], p = 0.041) and the composite endpoint (HR: 2.31[1.28,4.17], p = 0.0056. Also, odds ratio was significantly increased for critical outcome (OR: 3.01 [1.37, 6.61], p = 0.01) and for fatal outcome (OR: 5.3 [1.09, 25.8], p = 0.02)., Conclusion: The results indicate a significant association between CAC and clinical outcome in COVID-19. Our data therefore suggest that CAC might be useful in risk prediction in patients with COVID-19., Competing Interests: The authors have declared that no competing interests exists.

Background: Although x-ray dark-field imaging has been intensively investigated for lung imaging in different animal models, there is very limited data about imaging features in the human lungs. Therefore, in this work, a reader study on nine post-mortem human chest x-ray dark-field radiographs was performed to evaluate dark-field signal strength in the lungs, intraobserver and interobserver agreement, and image quality and to correlate with findings of conventional x-ray and CT., Methods: In this prospective work, chest x-ray dark-field radiography with a tube voltage of 70 kVp was performed post-mortem on nine humans (3 females, 6 males, age range 52-88 years). Visual quantification of dark-field and transmission signals in the lungs was performed by three radiologists. Results were compared to findings on conventional x-rays and 256-slice computed tomography. Image quality was evaluated. For ordinal data, median, range, and dot plots with medians and 95% confidence intervals are presented; intraobserver and interobserver agreement were determined using weighted Cohen κ., Results: Dark-field signal grading showed significant differences between upper and middle (p = 0.004-0.016, readers 1-3) as well as upper and lower zones (p = 0.004-0.016, readers 1-2). Median transmission grading was indifferent between all lung regions. Intraobserver and interobserver agreements were substantial to almost perfect for grading of both dark-field (κ = 0.793-0.971 and κ = 0.828-0.893) and transmission images (κ = 0.790-0.918 and κ = 0.700-0.772). Pulmonary infiltrates correlated with areas of reduced dark-field signal. Image quality was rated good for dark-field images., Conclusions: Chest x-ray dark-field images provide information of the lungs complementary to conventional x-ray and allow reliable visual quantification of dark-field signal strength.

Grating-based X-ray dark-field imaging is a novel imaging modality which has been refined during the last decade. It exploits the wave-like behaviour of X-radiation and can nowadays be implemented with existing X-ray tubes used in clinical applications. The method is based on the detection of small-angle X-ray scattering, which occurs e.g. at air-tissue-interfaces in the lung or bone-fat interfaces in spongy bone. In contrast to attenuation-based chest X-ray imaging, the optimal tube voltage for dark-field imaging of the thorax has not yet been examined. In this work, dark-field scans with tube voltages ranging from 60 to 120 kVp were performed on a deceased human body. We analyzed the resulting images with respect to subjective and objective image quality, and found that the optimum tube voltage for dark-field thorax imaging at the used setup is at rather low energies of around 60 to 70 kVp. Furthermore, we found that at these tube voltages, the transmission radiographs still exhibit sufficient image quality to correlate dark-field information. Therefore, this study may serve as an important guideline for the development of clinical dark-field chest X-ray imaging devices for future routine use.

Objectives: To evaluate the accuracy of Spectral Photon-Counting Computed Tomography (SPCCT) in the quantification of iodine concentrations and its potential for the differentiation between blood and iodine., Methods: Tubes with blood and a concentration series of iodine were scanned with a preclinical SPCCT system (both in vitro and in an ex vivo bovine brain tissue sample). Iodine density maps (IDM) and virtual non-contrast (VNC) images were generated using the multi-bin spectral information to perform material decomposition. Region-of-interest (ROI) analysis was performed within the tubes to quantitatively determine the absolute content of iodine (mg/ml)., Results: In conventional CT images, ROI analysis showed similar Hounsfield Unit (HU) values for the tubes with blood and iodine (59.9 ± 1.8 versus 59.2 ± 1.5). Iodine density maps enabled clear differentiation between blood and iodine in vitro, as well as in the bovine brain model. Quantitative measurements of the different iodine concentrations matched well with those of actual known concentrations even for very small iodine concentrations with values below 1mg/ml (RMSE = 0.19)., Conclusions: SPCCT providing iodine maps and virtual non-contrast images allows material decomposition, differentiation between blood and iodine in vitro and ex vivo in a bovine brain model and reliably quantifies the iodine concentration., Competing Interests: The authors have declared that no competing interests exist.

The purpose of this study was to investigate a preclinical spectral photon-counting CT (SPCCT) prototype compared to conventional CT for pulmonary imaging. A custom-made lung phantom, including nodules of different sizes and shapes, was scanned with a preclinical SPCCT and a conventional CT in standard and high-resolution (HR-CT) mode. Volume estimation was evaluated by linear regression. Shape similarity was evaluated with the Dice similarity coefficient. Spatial resolution was investigated via MTF for each imaging system. In-vivo rabbit lung images from the SPCCT system were subjectively reviewed. Evaluating the volume estimation, linear regression showed best results for the SPCCT compared to CT and HR-CT with a root mean squared error of 21.3 mm 3 , 28.5 mm 3 and 26.4 mm 3 for SPCCT, CT and HR-CT, respectively. The Dice similarity coefficient was superior for SPCCT throughout nodule shapes and all nodule sizes (mean, SPCCT: 0.90; CT: 0.85; HR-CT: 0.85). 10% MTF improved from 10.1 LP/cm for HR-CT to 21.7 LP/cm for SPCCT. Visual investigation of small pulmonary structures was superior for SPCCT in the animal study. In conclusion, the SPCCT prototype has the potential to improve the assessment of lung structures due to higher resolution compared to conventional CT.

Disorders of the lungs such as chronic obstructive pulmonary disease (COPD) are a major cause of chronic morbidity and mortality and the third leading cause of death in the world. The absence of sensitive diagnostic tests for early disease stages of COPD results in under-diagnosis of this treatable disease in an estimated 60-85% of the patients. In recent years a grating-based approach to X-ray dark-field contrast imaging has shown to be very sensitive for the detection and quantification of pulmonary emphysema in small animal models. However, translation of this technique to imaging systems suitable for humans remains challenging and has not yet been reported. In this manuscript, we present the first X-ray dark-field images of in-situ human lungs in a deceased body, demonstrating the feasibility of X-ray dark-field chest radiography on a human scale. Results were correlated with findings of computed tomography imaging and autopsy. The performance of the experimental radiography setup allows acquisition of multi-contrast chest X-ray images within clinical boundary conditions, including radiation dose. Upcoming clinical studies will have to demonstrate that this technology has the potential to improve early diagnosis of COPD and pulmonary diseases in general., Competing Interests: A.Y., H-I.M., T.P., H.H., R.P., T.K., N.W., and K.R. are employees of Philips Healthcare. The remaining authors have no competing interests and had complete, unrestricted access to the study data at all stages of the study. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Background: X-ray and particle radiation therapy planning requires accurate estimation of local electron density within the patient body to calculate dose delivery to tumour regions. We evaluate the feasibility and accuracy of electron density measurement using dual-layer computed tomography (DLCT), a recently introduced dual-energy CT technique., Methods: Two calibration phantoms were scanned with DLCT and virtual monoenergetic images (VMIs) at 50 keV and 200 keV were generated. We investigated two approaches to obtain relative electron densities from these VMIs: to fit an analytic interaction cross-sectional model and to empirically calibrate a conversion function with one of the phantoms. Knowledge of the emitted x-ray spectrum was not required for the presented work., Results: The results from both methods were highly correlated to the nominal values ( R  > 0.999). Except for the water and lung inserts, the error was within 1.79% (average 1.53%) for the cross-sectional model and 1.61% (average 0.87%) for the calibrated conversion. Different radiation doses did not have a significant influence on the measurement ( p  = 0.348, 0.167), suggesting that the methods are reproducible. Further, we applied these methods to routine clinical data., Conclusions: Our study shows a high validity of electron density estimation based on DLCT, which has potential to improve the procedure and accuracy of measuring electron density in clinical practice., Competing Interests: Institutional Review Board approval was obtained (Ethikkommission der Fakultät für Medizin der Technischen Universität München, Munich, Germany). Written informed consent was obtained from the patient in this study.Patient provided informed consent for the use of his/her data for research purposes.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The aim was to evaluate Virtual Non-Contrast (VNC)-CT images for the detection of acute infarcts in the brain after mechanical thrombectomy using a dual-layer spectral CT. 29 patients between September 2016 and February 2017 with unenhanced head spectral-CT after mechanical thrombectomy and available follow-up images (MRI, n:26; CT, n:3) were included. VNC-CT and conventional CT (CT) images were reconstructed using dedicated software. Based on those, contrast-to-noise ratio (CNR), and the volume of infarction were measured semi-automatically in VNC-CT, CT and MRI. Furthermore, two readers independently assessed the VNC-CT and CT images in a randomized order by using the ASPECT score, and inter-rater reliability, sensitivity and specificity were calculated. CNR was significantly higher in VNC-CT compared to CT (3.1 ± 1.5 versus 1.1 ± 1.1, p < 0.001). The mean estimated volume of infarction was significantly higher in VNC-CT compared to CT (72% versus 55% of the volume measured in MRI, p < 0.005). Inter-rater reliability was higher in VNC-CT compared to CT (0.751 versus 0.625) and sensitivity was higher in VNC-CT compared to CT (73% versus 55%). In conclusion, acute ischemic lesions after mechanical thrombectomy are better definable in VNC-CT compared to CT images using a dual-layer spectral CT system.

The aim of this study was to assess the diagnostic value of x-ray dark-field radiography to detect pneumothoraces in a pig model. Eight pigs were imaged with an experimental grating-based large-animal dark-field scanner before and after induction of a unilateral pneumothorax. Image contrast-to-noise ratios between lung tissue and the air-filled pleural cavity were quantified for transmission and dark-field radiograms. The projected area in the object plane of the inflated lung was measured in dark-field images to quantify the collapse of lung parenchyma due to a pneumothorax. Means and standard deviations for lung sizes and signal intensities from dark-field and transmission images were tested for statistical significance using Student's two-tailed t-test for paired samples. The contrast-to-noise ratio between the air-filled pleural space of lateral pneumothoraces and lung tissue was significantly higher in the dark-field (3.65 ± 0.9) than in the transmission images (1.13 ± 1.1; p = 0.002). In case of dorsally located pneumothoraces, a significant decrease (-20.5%; p > 0.0001) in the projected area of inflated lung parenchyma was found after a pneumothorax was induced. Therefore, the detection of pneumothoraces in x-ray dark-field radiography was facilitated compared to transmission imaging in a large animal model.

The performance of a recently introduced spectral computed tomography system based on a dual-layer detector has been investigated. A semi-anthropomorphic abdomen phantom for CT performance evaluation was imaged on the dual-layer spectral CT at different radiation exposure levels (CTDI vol of 10 mGy, 20 mGy and 30 mGy). The phantom was equipped with specific low-contrast and tissue-equivalent inserts including water-, adipose-, muscle-, liver-, bone-like materials and a variation in iodine concentrations. Additionally, the phantom size was varied using different extension rings to simulate different patient sizes. Contrast-to-noise (CNR) ratio over the range of available virtual mono-energetic images (VMI) and the quantitative accuracy of VMI Hounsfield Units (HU), effective-Z maps and iodine concentrations have been evaluated. Central and peripheral locations in the field-of-view have been examined. For all evaluated imaging tasks the results are within the calculated theoretical range of the tissue-equivalent inserts. Especially at low energies, the CNR in VMIs could be boosted by up to 330% with respect to conventional images using iDose/spectral reconstructions at level 0. The mean bias found in effective-Z maps and iodine concentrations averaged over all exposure levels and phantom sizes was 1.9% (eff. Z) and 3.4% (iodine). Only small variations were observed with increasing phantom size (+3%) while the bias was nearly independent of the exposure level (±0.2%). Therefore, dual-layer detector based CT offers high quantitative accuracy of spectral images over the complete field-of-view without any compromise in radiation dose or diagnostic image quality., (© 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

To assess whether phantomless calcium-hydroxyapatite (HA) specific bone mineral density (BMD) measurements with dual-layer spectral computed tomography are accurate in phantoms and vertebral specimens. Ex-vivo human vertebrae (n = 13) and a phantom containing different known HA concentrations were placed in a semi-anthropomorphic abdomen phantom with different extension rings simulating different degrees of obesity. Phantomless dual-layer spectral CT was performed at different tube current settings (500, 250, 125 and 50 mAs). HA-specific BMD was derived from spectral-based virtual monoenergetic images at 50 keV and 200 keV. Values were compared to the HA concentrations of the phantoms and conventional qCT measurements using a reference phantom, respectively. Above 125 mAs, errors for phantom measurements ranged between -1.3% to 4.8%, based on spectral information. In vertebral specimens, high correlations were found between BMD values assessed with spectral CT and conventional qCT (r ranging between 0.96 and 0.99; p < 0.001 for all) with different extension rings, and a high agreement was found in Bland Altman plots. Different degrees of obesity did not have a significant influence on measurements (P > 0.05 for all). These results suggest a high validity of HA-specific BMD measurements based on dual-layer spectral CT examinations in setups simulating different degrees of obesity without the need for a reference phantom, thus demonstrating their feasibility in clinical routine.

X-ray chest radiography is an inexpensive and broadly available tool for initial assessment of the lung in clinical routine, but typically lacks diagnostic sensitivity for detection of pulmonary diseases in their early stages. Recent X-ray dark-field (XDF) imaging studies on mice have shown significant improvements in imaging-based lung diagnostics. Especially in the case of early diagnosis of chronic obstructive pulmonary disease (COPD), XDF imaging clearly outperforms conventional radiography. However, a translation of this technique towards the investigation of larger mammals and finally humans has not yet been achieved. In this letter, we present the first in-vivo XDF full-field chest radiographs (32 × 35 cm 2 ) of a living pig, acquired with clinically compatible parameters (40 s scan time, approx. 80 µSv dose). For imaging, we developed a novel high-energy XDF system that overcomes the limitations of currently established setups. Our XDF radiographs yield sufficiently high image quality to enable radiographic evaluation of the lungs. We consider this a milestone in the bench-to-bedside translation of XDF imaging and expect XDF imaging to become an invaluable tool in clinical practice, both as a general chest X-ray modality and as a dedicated tool for high-risk patients affected by smoking, industrial work and indoor cooking.

Rationale and Objectives: The study aimed to improve the detection of pulmonary embolism via an iodine contrast enhancement tool in patients who underwent suboptimal enhanced computed tomography angiography (CTA)., Materials and Methods: We evaluated the CT examinations of 41 patients who underwent CTA for evaluation of the pulmonary arteries which suffered from suboptimal contrast enhancement. The contrast enhancement of the reconstructed images was increased via a post-processing tool (vContrast). Image noise and contrast-to-noise ratio (CNR) were assessed in eight different regions: main pulmonary artery, right and left pulmonary arteries, right and left segment arteries, muscle, subcutaneous fat, and bone. For subjective image assessment, three experienced radiologists evaluated the diagnostic quality., Results: While employing the post-processing algorithm, the CNR for contrast-filled lumen and thrombus/muscle improves significantly by a factor of 1.7 (CNR without vContrast = 8.48 ± 6.79/CNR with vContrast = 14.46 ± 5.29) (P <0.01). No strengthening of artifacts occurred, and the mean Hounsfield unit values of the muscle, subcutaneous fat, and the bone showed no significant changes. Subjective image analysis illustrated a significant improvement using post-processing for clinically relevant criteria such as diagnostic confidence., Conclusions: vContrast makes CT angiograms with inadequate contrast applicable for diagnostic evaluation, offering an improved visualization of the pulmonary arteries. In addition, vContrast can help in the significant reduction of the iodine contrast material., (Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: To assess the feasibility of dual-contrast spectral photon-counting computed tomography (SPCCT) for liver imaging., Methods: We present an SPCCT in-silico study for simultaneous mapping of the complementary distribution in the liver of two contrast agents (CAs) subsequently intravenously injected: a gadolinium-based contrast agent and an iodine-based contrast agent. Four types of simulated liver lesions with a characteristic arterial and portal venous pattern (haemangioma, hepatocellular carcinoma, cyst, and metastasis) are presented. A material decomposition was performed to reconstruct quantitative iodine and gadolinium maps. Finally, a multi-dimensional classification algorithm for automatic lesion detection is presented., Results: Our simulations showed that with a single-scan SPCCT and an adapted contrast injection protocol, it was possible to reconstruct contrast-enhanced images of the liver with arterial distribution of the iodine-based CA and portal venous phase of the gadolinium-based CA. The characteristic patterns of contrast enhancement were visible in all liver lesions. The approach allowed for an automatic detection and classification of liver lesions using a multi-dimensional analysis., Conclusions: Dual-contrast SPCCT should be able to visualise the characteristic arterial and portal venous enhancement with a single scan, allowing for an automatic lesion detection and characterisation, with a reduced radiation exposure., Competing Interests: HD and RP are employees of Philips Healthcare. The remaining authors (DM, AF, FK, FD, JH, FP, ER and PN) have no financial disclosures and had complete, unrestricted access to the study data at all stages of the study.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Objective: Evaluation of a new iterative reconstruction algorithm (IMR) for detection/rule-out of pulmonary embolism (PE) in ultra-low dose computed tomography pulmonary angiography (CTPA)., Methods: Lower dose CT data sets were simulated based on CTPA examinations of 16 patients with pulmonary embolism (PE) with dose levels (DL) of 50%, 25%, 12.5%, 6.3% or 3.1% of the original tube current setting. Original CT data sets and simulated low-dose data sets were reconstructed with three reconstruction algorithms: the standard reconstruction algorithm "filtered back projection" (FBP), the first generation iterative reconstruction algorithm iDose and the next generation iterative reconstruction algorithm "Iterative Model Reconstruction" (IMR). In total, 288 CTPA data sets (16 patients, 6 tube current levels, 3 different algorithms) were evaluated by two blinded radiologists regarding image quality, diagnostic confidence, detectability of PE and contrast-to-noise ratio (CNR)., Results: iDose and IMR showed better detectability of PE than FBP. With IMR, sensitivity for detection of PE was 100% down to a dose level of 12.5%. iDose and IMR showed superiority to FBP regarding all characteristics of subjective (diagnostic confidence in detection of PE, image quality, image noise, artefacts) and objective image quality. The minimum DL providing acceptable diagnostic performance was 12.5% (= 0.45 mSv) for IMR, 25% (= 0.89 mSv) for iDose and 100% (= 3.57 mSv) for FBP. CNR was significantly (p < 0.001) improved by IMR compared to FBP and iDose at all dose levels., Conclusion: By using IMR for detection of PE, dose reduction for CTPA of up to 75% is possible while maintaining full diagnostic confidence. This would result in a mean effective dose of approximately 0.9 mSv for CTPA., Competing Interests: Competing Interests: Thomas Köhler and Bernhard Brendel are employees of Philips GmbH, Innovative Technologies. The remaining authors have no financial disclosures and had complete, unrestricted access to the study data at all stages of the study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

X-ray phase-contrast imaging is a novel technology that achieves high soft-tissue contrast. Although its clinical impact is still under investigation, the technique may potentially improve clinical diagnostics. In conventional attenuation-based X-ray computed tomography, radiological diagnostics are quantified by Hounsfield units. Corresponding Hounsfield units for phase-contrast imaging have been recently introduced, enabling a setup-independent comparison and standardized interpretation of imaging results. Thus far, the experimental values of few tissue types have been reported; these values have been determined from fixated tissue samples. This study presents phase-contrast Hounsfield units for various types of non-fixated human soft tissues. A large variety of tissue specimens ranging from adipose, muscle and connective tissues to liver, kidney and pancreas tissues were imaged by a grating interferometer with a rotating-anode X-ray tube and a photon-counting detector. Furthermore, we investigated the effects of formalin fixation on the quantitative phase-contrast imaging results.

Treatment of renal calculi is highly dependent on the chemical composition of the stone in question, which is difficult to determine using standard imaging techniques. The objective of this study is to evaluate the potential of scatter-sensitive X-ray dark-field radiography to differentiate between the most common types of kidney stones in clinical practice. Here, we examine the absorption-to-scattering ratio of 118 extracted kidney stones with a laboratory Talbot-Lau Interferometer. Depending on their chemical composition, microscopic growth structure and morphology the various types of kidney stones show strongly varying, partially opposite contrasts in absorption and dark-field imaging. By assessing the microscopic calculi morphology with high resolution micro-computed tomography measurements, we illustrate the dependence of dark-field signal strength on the respective stone type. Finally, we utilize X-ray dark-field radiography as a non-invasive, highly sensitive (100%) and specific (97%) tool for the differentiation of calcium oxalate, uric acid and mixed types of stones, while additionally improving the detectability of radio-lucent calculi. We prove clinical feasibility of the here proposed method by accurately classifying renal stones, embedded within a fresh pig kidney, using dose-compatible measurements and a quick and simple visual inspection.

The objective of this study was to investigate the improvement in diagnostic quality of an iterative model-based reconstruction (IMBR) algorithm for low-tube-voltage (80-kVp) and low-tube-current in abdominal computed tomography angiography (CTA). A total of 11 patients were imaged on a 256-slice multidetector computed tomography for visualization of the aorta. For all patients, three different reconstructions from the low-tube-voltage data are generated: filtered backprojection (FBP), IMBR, and a mixture of both [Formula: see text]. To determine the diagnostic value of IMBR-based reconstructions, the image quality was assessed. With IMBR-based reconstructions, image noise could be significantly reduced, which was confirmed by a highly improved contrast-to-noise ratio. In the image quality assessment, radiologists were able to reliably detect more third-order and higher aortic branches in the IMBR reconstructions compared to FBP reconstructions. The effective dose level was, on average, 3.0 mSv for 80-kVp acquisitions. Low-tube-voltage CTAs significantly improve vascular contrast as presented by others; however, this effect in combination with IMBR enabled yet another substantial improvement of diagnostic quality. For IMBR, a significant improvement of image quality and a decreased radiation dose at low-tube-voltage can be reported.

Purpose: Evaluation of a new software tool for generation of simulated low-dose computed tomography (CT) images from an original higher dose scan., Materials and Methods: Original CT scan data (100 mAs, 80 mAs, 60 mAs, 40 mAs, 20 mAs, 10 mAs; 100 kV) of a swine were acquired (approved by the regional governmental commission for animal protection). Simulations of CT acquisition with a lower dose (simulated 10-80 mAs) were calculated using a low-dose simulation algorithm. The simulations were compared to the originals of the same dose level with regard to density values and image noise. Four radiologists assessed the realistic visual appearance of the simulated images., Results: Image characteristics of simulated low dose scans were similar to the originals. Mean overall discrepancy of image noise and CT values was -1.2% (range -9% to 3.2%) and -0.2% (range -8.2% to 3.2%), respectively, p>0.05. Confidence intervals of discrepancies ranged between 0.9-10.2 HU (noise) and 1.9-13.4 HU (CT values), without significant differences (p>0.05). Subjective observer evaluation of image appearance showed no visually detectable difference., Conclusion: Simulated low dose images showed excellent agreement with the originals concerning image noise, CT density values, and subjective assessment of the visual appearance of the simulated images. An authentic low-dose simulation opens up opportunity with regard to staff education, protocol optimization and introduction of new techniques.

The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ)-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC) therapy., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

X-ray phase-contrast imaging shows improved soft-tissue contrast compared to standard absorption-based X-ray imaging. Especially the grating-based method seems to be one promising candidate for clinical implementation due to its extendibility to standard laboratory X-ray sources. Therefore the purpose of our study was to evaluate the potential of grating-based phase-contrast computed tomography in combination with a novel bi-lateral denoising method for imaging of focal liver lesions in an ex vivo feasibility study. Our study shows that grating-based phase-contrast CT (PCCT) significantly increases the soft-tissue contrast in the ex vivo liver specimens. Combining the information of both signals--absorption and phase-contrast--the bi-lateral filtering leads to an improvement of lesion detectability and higher contrast-to-noise ratios. The normal and the pathological tissue can be clearly delineated and even internal structures of the pathological tissue can be visualized, being invisible in the absorption-based CT alone. Histopathology confirmed the presence of the corresponding findings in the analyzed tissue. The results give strong evidence for a sufficiently high contrast for different liver lesions using non-contrast-enhanced PCCT. Thus, ex vivo imaging of liver lesions is possible with a polychromatic X-ray source and at a spatial resolution of ∼100 µm. The post-processing with the novel bi-lateral denoising method improves the image quality by combining the information from the absorption and the phase-contrast images.

Purpose: Evaluation of 15,000 computed tomography (CT) examinations to investigate if iterative reconstruction (IR) reduces sustainably radiation exposure., Method and Materials: Information from 15,000 CT examinations was collected, including all aspects of the exams such as scan parameter, patient information, and reconstruction instructions. The examinations were acquired between January 2010 and December 2012, while after 15 months a first generation IR algorithm was installed. To collect the necessary information from PACS, RIS, MPPS and structured reports a Dose Monitoring System was developed. To harvest all possible information an optical character recognition system was integrated, for example to collect information from the screenshot CT-dose report. The tool transfers all data to a database for further processing such as the calculation of effective dose and organ doses. To evaluate if IR provides a sustainable dose reduction, the effective dose values were statistically analyzed with respect to protocol type, diagnostic indication, and patient population., Results: IR has the potential to reduce radiation dose significantly. Before clinical introduction of IR the average effective dose was 10.1±7.8mSv and with IR 8.9±7.1mSv (p*=0.01). Especially in CTA, with the possibility to use kV reduction protocols, such as in aortic CTAs (before IR: average14.2±7.8mSv; median11.4mSv /with IR:average9.9±7.4mSv; median7.4mSv), or pulmonary CTAs (before IR: average9.7±6.2mSV; median7.7mSv /with IR: average6.4±4.7mSv; median4.8mSv) the dose reduction effect is significant(p*=0.01). On the contrary for unenhanced low-dose scans of the cranial (for example sinuses) the reduction is not significant (before IR:average6.6±5.8mSv; median3.9mSv/with IR:average6.0±3.1mSV; median3.2mSv)., Conclusion: The dose aspect remains a priority in CT research. Iterative reconstruction algorithms reduce sustainably and significantly radiation dose in the clinical routine. Our results illustrate that not only in studies with a limited number of patients but also in the clinical routine, IRs provide long-term dose saving.

Objective: To improve image and diagnostic quality in dynamic CT myocardial perfusion imaging (MPI) by using motion compensation and a spatio-temporal filter., Methods: Dynamic CT MPI was performed using a 256-slice multidetector computed tomography scanner (MDCT). Data from two different patients-with and without myocardial perfusion defects-were evaluated to illustrate potential improvements for MPI (institutional review board approved). Three datasets for each patient were generated: (i) original data (ii) motion compensated data and (iii) motion compensated data with spatio-temporal filtering performed. In addition to the visual assessment of the tomographic slices, noise and contrast-to-noise-ratio (CNR) were measured for all data. Perfusion analysis was performed using time-density curves with regions-of-interest (ROI) placed in normal and hypoperfused myocardium. Precision in definition of normal and hypoperfused areas was determined in corresponding coloured perfusion maps., Results: The use of motion compensation followed by spatio-temporal filtering resulted in better alignment of the cardiac volumes over time leading to a more consistent perfusion quantification and improved detection of the extend of perfusion defects. Additionally image noise was reduced by 78.5%, with CNR improvements by a factor of 4.7. The average effective radiation dose estimate was 7.1±1.1 mSv., Conclusion: The use of motion compensation and spatio-temporal smoothing will result in improved quantification of dynamic CT MPI using a latest generation CT scanner.

Purpose: Phase-contrast X-ray computed tomography (PCCT) is currently investigated and developed as a potentially very interesting extension of conventional CT, and can offer several advantages for specific indications in diagnostic imaging. Current absorption-based computed tomography (CT) without the application of contrast material is limited in the detection of minor density differences in soft-tissue. The purpose of this study is to test whether PCCT can improve soft tissue contrast in healthy and tumorous human liver specimens., Materials and Methods: Two specimens of human liver (one healthy and one metastasized liver sample) were imaged with brilliant X-ray beam at the synchrotron radiation source ESRF in Grenoble, France. For correlation the same specimens were imaged with a magnetic resonance imaging system at 1.5 T. The histopathology confirmed our findings in the corresponding sections of the specimens., Results: In the phase-contrast CT images we observed a significantly enhanced soft-tissue contrast when compared to simultaneously recorded standard absorption CT measurements. Further, we found that the pathological and morphological information in the PCCT reconstructions show significant improvement when compared to those performed on MRI. Based on matching of prominent features, a good correlation between PCCT and the histological section is demonstrated; especially the tumor capsule and the surrounding vascular structures are visible in PCCT. In addition, our study revealed the ability of PCCT to visualize the blood vessels structure in the tumorous liver without the need of any contrast agents., Conclusion: Grating-based PCCT significantly improves the soft-tissue contrast in ex-vivo liver specimens and holds the potential to overcome the need of contrast materials for visualization of the tumor vascularization., (Copyright © 2013. Published by Elsevier GmbH.)

Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-κB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-κB's function in tumor-initiating cells has not been examined yet. Using a genetic model of intestinal epithelial cell (IEC)-restricted constitutive Wnt-activation, which comprises the most common event in the initiation of colon cancer, we demonstrate that NF-κB modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-κB signaling enhances Wnt activation and induces dedifferentiation of nonstem cells that acquire tumor-initiating capacity. Thus, our data support the concept of bidirectional conversion and highlight the importance of inflammatory signaling for dedifferentiation and generation of tumor-initiating cells in vivo., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Our understanding of pancreatic ductal adenocarcinoma (PDAC) is shifting away from a disease of malignant ductal cells-only, toward a complex system where tumor evolution is a result of interaction of cancer cells with their microenvironment. This change has led to intensification of research focusing on the fibrotic stroma of PDAC. Pancreatic stellate cells (PSCs) are the main fibroblastic cells of the pancreas which are responsible for producing the desmoplasia in chronic pancreatitis (CP) and PDAC. Clinically, the effect of desmoplasia is two-sided; on the negative side it is a hurdle in the diagnosis of PDAC because the fibrosis in cancer resembles that of CP. It is also believed that PSCs and pancreatic fibrosis are partially responsible for the therapy resistance in pancreatic cancer. On the positive side, a fibrotic pancreas is safer to operate on compared to a fatty and soft pancreas which is prone for postoperative pancreatic fistula. In this review the impact of pancreatic fibrosis on diagnosis of pancreatic cancer and surgical decisions are discussed from a clinical point of view.

NF-kappaB is a key transcriptional regulator of inflammatory responses, but also controls expression of prosurvival genes, whose products protect tissues from damage and may thus act indirectly in an antiinflammatory fashion. The variable importance of these two distinct NF-kappaB-controlled responses impacts the potential utility of NF-kappaB inhibition as a treatment strategy for intractable inflammatory conditions, such as inflammatory bowel disease. Here, we show in murine models that inhibition of IKKbeta-dependent NF-kappaB activation exacerbates acute inflammation, but attenuates chronic inflammatory disease in the intestinal tract. Acute ulcerating inflammation is aggravated because of diminished NF-kappaB-mediated protection against epithelial cell apoptosis and delayed mucosal regeneration secondary to reduced NF-kappaB-dependent recruitment of inflammatory cells that secrete cytoprotective factors. In contrast, in IL-10-deficient mice, which serve as a model of chronic T cell-dependent colitis, ablation of IKKbeta in the intestinal epithelium has no impact, yet IKKbeta deficiency in myeloid cells attenuates inflammation and prolongs survival. These results highlight the striking context and tissue dependence of the proinflammatory and antiapoptotic functions of NF-kappaB. Our findings caution against the therapeutic use of IKKbeta/NF-kappaB inhibitors in acute inflammatory settings dominated by cell loss and ulceration.

TGFalpha/p53(+/-) transgenic mice represent a genetically engineered mouse model for pancreatic adenocarcinoma. The tumors develop a characteristic pattern of secondary genetic changes. From one of these tumors, the permanent cell line TD2 was established. Here, we describe in detail the genetic changes by molecular-cytogenetic techniques. The original tumor-specific CGH profile has been retained unchanged. The most characteristic aberration pattern bears chromosome 11. Egfr, localized on proximal chromosome 11, is amplified two to three times and leads to an easily identifiable, stable marker chromosome with a large amplification unit, which is present in each metaphase. The wild-type p53 gene on distal chromosome 11 is lost. The p16Ink4a locus on chromosome 4 is hypermethylated. For c-Myc a 15-fold amplification, present in a 1.65 Mb amplification unit, is detected on chromosome 15. Transition between presence in the form of several double minutes, DMs, or a single homogeneously staining region, HSR, was observed for c-Myc. Molecular-cytogenetic analysis of both amplification units show that Egfr amplification and c-Myc amplification represent two alternative modes by which genes get amplified in tumor cells. The expression level of the respective genes was proven by Northern blot analysis. The cell line TD2 represents a valuable in vitro model for pancreatic adenocarcinoma.