Assessment of the additional clinical potential of X-ray dark-field imaging for breast cancer in a preclinical setup.

BACKGROUND: Mammography can identify calcifications up to 50-100 µm in size as a surrogate parameter for breast cancer or ductal carcinoma in situ (DCIS). Microcalcifications measuring <50 µm are also associated with breast cancer or DCIS and are frequently not detected on mammography, although they can be detected with dark-field imaging. This study examined whether additional breast examination using X-ray dark-field imaging can increase the detection rate of calcifications. Advances in knowledge: (1) evaluation of additional modality of breast imaging; (2) specific evaluation of breast calcifications.Implications for patient care: the addition of X-ray dark-field imaging to conventional mammography could detect additional calcifications. METHODS: Talbot-Lau X-ray phase-contrast imaging and X-ray dark-field imaging were used to acquire images of breast specimens. The radiation dosage with the technique is comparable with conventional mammography. Three X-ray gratings with periods of 5-10 µm between the X-ray tube and the flat-panel detector provide three different images in a single sequence: the conventional attenuation image, differential phase image, and dark-field image. The images were read by radiologists. Radiological findings were marked and examined pathologically. The results were described in a descriptive manner. RESULTS: A total of 81 breast specimens were investigated with the two methods; 199 significant structures were processed pathologically, consisting of 123 benign and 76 malignant lesions (DCIS or invasive breast cancer). X-ray dark-field imaging identified 15 additional histologically confirmed carcinoma lesions that were visible but not declared suspicious on digital mammography alone. Another four malignant lesions that were not visible on mammography were exclusively detected with X-ray dark-field imaging. CONCLUSIONS: Adding X-ray dark-field imaging to digital mammography increases the detection rate for breast cancer and DCIS associated lesions with micrometer-sized calcifications.The use of X-ray dark-field imaging may be able to provide more accurate and detailed radiological classification of suspicious breast lesions.Adding X-ray dark-field imaging to mammography may be able to increase the detection rate and improve preoperative planning in deciding between mastectomy or breast-conserving therapy, particularly in patients with invasive lobular breast cancer.

Discrimination analysis of breast calcifications using x-ray dark-field radiography.

BACKGROUND: X-ray dark-field radiography could enhance mammography by providing more information on imaged tissue and microcalcifications. The dark field signal is a measure of small angle scattering and can thus provide additional information on the imaged materials. This information can be useful for material distinction of calcifications and the diagnosis of breast cancer by classifying benign and malign association of these calcifications. METHODS: For this study, institutional review board approval was obtained. We present the evaluation of images acquired with interferometric grating-based x-ray imaging of 323 microcalcifications (166 malign and 157 benign associated) in freshly dissected breast tissue and compare the results to the information extracted in follow-up pathological evaluation. The number of imaged calcifications is sufficiently higher than in similar previous studies. Fourteen calcification properties were extracted from the digital images and used as predictors in three different models common in discrimination analysis namely a simple threshold model, a naive Bayes model and a linear regression model, which classify the calcifications as associated with a benign or suspicious finding. Three of these fourteen predictors have been newly defined in this work and are independent from the tissue background surrounding the microcalcifications. Using these predictors no background correction is needed, as in previous works in this field. The new predictors are the length of the first and second principle component of the absorption and dark-field data, as well as the angle between the first principle component and the dark-field axis. We called these predictors data length, data width, and data orientation. RESULTS: In fourfold cross-validation malignancy of the imaged tissue was predicted. Models that take only classical absorption predictors into account reached a sensitivity of 53.3% at a specificity of 81.1%. For a combination of predictors that also include dark field information, a sensitivity of 63.2% and specificity of 80.8% were obtained. The included dark field information consisted of the newly introduced parameters, data orientation and data width. CONCLUSIONS: While remaining at a similar specificity, the sensitivity, with which a trained model was able to distinguish malign from benign associated calcifications, was increased by 10% on including dark-field information. This suggests grating-based x-ray imaging as a promising clinical imaging method in the field of mammography.

Talbot-Lau x-ray phase-contrast setup for fast scanning of large samples.

Compared to conventional attenuation x-ray radiographic imaging, the x-ray Talbot-Lau technique provides further information about the scattering and the refractive properties of the object in the beam path. Hence, this additional information should improve the diagnostic process concerning medical applications and non-destructive testing. Nevertheless, until now, due to grating fabrication process, Talbot-Lau imaging suffers from small grating sizes (70 mm diameter). This leads to long acquisition times for imaging large objects. Stitching the gratings is one solution. Another one consists of scanning Talbot-Lau setups. In this publication, we present a compact and very fast scanning setup which enables imaging of large samples. With this setup a maximal scanning velocity of 71.7 mm/s is possible. A resolution of 4.1 lines/mm can be achieved. No complex alignment procedures are necessary while the field of view comprises 17.5 × 150 cm2. An improved reconstruction algorithm concerning the scanning approach, which increases robustness with respect to mechanical instabilities, has been developed and is presented. The resolution of the setup in dependence of the scanning velocity is evaluated. The setup imaging qualities are demonstrated using a human knee ex-vivo as an example for a high absorbing human sample.

Exploration of different x-ray Talbot-Lau setups for dark-field lung imaging examined in a porcine lung.

X-ray dark-field imaging is a promising technique for lung diagnosis. Due to the alveolar structure of lung tissue, a higher contrast is obtained by the dark-field image compared to the attenuation image. Animal studies indicate an enhancement regarding the detection of lung diseases in early stages. In this publication, we focus on the influence of different Talbot-Lau interferometer specifications while maintaining the x-ray source, sample magnification and detector system. By imaging the same porcine lung with three different grating sets, we analyze the contrast-to-noise ratio of the obtained dark-field images with respect to visibility and correlation length. We demonstrate that relatively large grating periods of the phase and of the analyzer grating are sufficient for high quality lung imaging at reasonable dose levels.

Simulation study on X-ray phase contrast imaging with dual-phase gratings.

PURPOSE: Two phase gratings in an X-ray grating interferometers can solve several technical challenges for clinical use of X-ray phase contrast. In this work, we adapt and evaluate this setup design to clinical X-ray sources and detectors in a simulation study. METHODS: For a given set of gratings, we optimize the remaining parameter space of a dual-phase grating setup using a numerical wave front simulation. The simulation results are validated with experimentally obtained visibility measurements on a setup with a microfocus tube and a clinical X-ray detector. We then confirm by simulation that the Lau condition for the [Formula: see text] grating also holds for two phase gratings. Furthermore, we use a [Formula: see text] grating with a fixed period to search for periods of matching phase grating configurations. RESULTS: Simulated and experimental visibilities agree very well. We show that the Lau condition for a dual-phase grating setup requires the interference patterns of the first phase grating to constructively overlay at the second phase grating. Furthermore, a total of three setup variants for given [Formula: see text] periods were designed with the simulation, resulting in visibilities between 4.5 and 9.1%. CONCLUSION: Dual-phase gratings can be used and optimized for a medical X-ray source and detector. The obtained visibilities are somewhat lower than for other Talbot-Lau interferometers and are a tradeoff between setup length and spatial resolution (or additional phase stepping, respectively). However, these disadvantage appears minor compared to the overall better photon statistics, and the fact that dual-phase grating setups can be expected to scale to higher X-ray energies.

Single-shot Talbot-Lau x-ray dark-field imaging of a porcine lung applying the moiré imaging approach.

Talbot-Lau x-ray imaging provides additionally to the conventional attenuation image, two further images: the differential phase-contrast image which is especially sensitive to differences in refractive properties and the dark-field image which is showing the x-ray scattering properties of the object. Thus, in the dark-field image sub-pixeled object information can be observed. As it has been shown in recent studies, this is of special interest for lung imaging. Changes in the alveoli structure, which are in the size of one detector pixel, can be seen in the dark-field images. A fast acquisition process is crucial to avoid motion artifacts due to heartbeat and breathing of the patient. Using moiré imaging the images can be acquired with a single-shot exposure. Nevertheless, the spatial resolution is reduced compared to the phase-stepping acquisition. We evaluate the results of both imaging techniques towards their feasibility in clinical routine. Furthermore, we analyse the influence of artificial linear object movement on the image quality, in order to simulate the heartbeat of a patient.

Implementation of a Talbot-Lau interferometer in a clinical-like c-arm setup: A feasibility study.

X-ray grating-based phase-contrast imaging has raised interest regarding a variety of potential clinical applications, whereas the method is feasible using a medical x-ray tube. Yet, the transition towards a clinical setup remains challenging due to the requirement of mechanical robustness of the interferometer and high demands applying to medical equipment in clinical use. We demonstrate the successful implementation of a Talbot-Lau interferometer in an interventional c-arm setup. The consequence of vibrations induced by the rotating anode of the tube is discussed and the prototype is shown to provide a visibility of 21.4% at a tube voltage of 60 kV despite the vibrations. Regarding clinical application, the prototype is mainly set back due to the limited size of the field of view covering an area of 17 mm × 46 mm. A c-arm offers the possibility to change the optical axis according to the requirements of the medical examination. We provide a method to correct for artifacts that result from the angulation of the c-arm. Finally, the images of a series of measurements with the c-arm in different angulated positions are shown. Thereby, it is sufficient to perform a single reference measurement in parking position that is valid for the complete series despite angulation.

Improved reconstruction of phase-stepping data for Talbot-Lau x-ray imaging.

Grating-based Talbot-Lau x-ray interferometry is a popular method for measuring absorption, phase shift, and small-angle scattering. The standard acquisition method for this modality is phase stepping, where the Talbot pattern is reconstructed from multiple images acquired at different grating positions. We review the implicit assumptions in phase-stepping reconstruction, and find that the assumptions of perfectly known grating positions and homoscedastic noise variance are violated in some scenarios. Additionally, we investigate a recently reported estimation bias in the visibility and dark-field signal. To adapt the phase-stepping reconstruction to these findings, we propose three improvements to the reconstruction. These improvements are (a) to use prior knowledge to compute more accurate grating positions to reduce moiré artifacts, (b) to utilize noise variance information to reduce dark-field and phase noise in high-visibility acquisitions, and (c) to perform correction of an estimation bias in the interferometer visibility, leading to more quantitative dark-field imaging in acquisitions with a low signal-to-noise ratio. We demonstrate the benefit of our methods on simulated data, as well as on images acquired with a Talbot-Lau interferometer.

Talbot-Lau X-ray phase contrast for tiling-based acquisitions without reference scanning.

PURPOSE: Grating-based Talbot-Lau interferometers are a popular choice for phase-contrast X-ray acquisitions. Here, an air reference scan has to be acquired prior to an object scan. This particularly complicates acquisition of large objects: large objects are tiled into multiple scans due to the small field of view of current gratings. However, phase reference drifts occurring between these scans may require to repeatedly move the object in and out of the X-ray beam to update the reference information. METHODS: We developed an image processing technique that completely removes the need for phase reference scans in tiled acquisitions. We estimate the reference from object scans using a tailored iterated robust regression, using a novel efficient optimizer. RESULTS: Our evaluation indicates that the estimated reference is not only close to the acquired reference but also improves the final image quality. We hypothesize that this is because we mitigate errors that are introduced when actually acquiring the reference phase. CONCLUSION: Phase-contrast imaging of larger objects may benefit from computational estimation of phase reference data due to reduced scanning complexity and improved image quality.

Designing the phase grating for Talbot-Lau phase-contrast imaging systems: a simulation and experiment study.

The performance of a Talbot-Lau interferometer depends to a great extent on its visibility. This means, to obtain high quality phase-contrast and dark-field images a high visibility is mandatory. Several parameters influence the visibility of such a system, like for example the x-ray spectrum, the inter-grating distances or the parameters of the three gratings. In this multidimensional space, wave field simulations help to find the optimal combination of the grating specifications to construct a setup with a high visibility while retaining a fixed angular sensitivity. In this work we specifically analyzed the influence of the G1 grating duty cycle in simulations and experiments. We show that there is a lot of room for improvement by varying the duty cycle of the phase-shifting grating G1. As a result, by employing a third-integer duty cycle we can increase the visibility to up to 53 % in a laboratory setup with a polychromatic spectrum. The achieved visibility is more than two times higher compared to the result with a standard-type setup. This visibility gain allows a dose reduction by a factor of 5 preserving the same image quality.

A beam hardening and dispersion correction for x-ray dark-field radiography.

PURPOSE: X-ray dark-field imaging promises information on the small angle scattering properties even of large samples. However, the dark-field image is correlated with the object's attenuation and phase-shift if a polychromatic x-ray spectrum is used. A method to remove part of these correlations is proposed. METHODS: The experimental setup for image acquisition was modeled in a wave-field simulation to quantify the dark-field signals originating solely from a material's attenuation and phase-shift. A calibration matrix was simulated for ICRU46 breast tissue. Using the simulated data, a dark-field image of a human mastectomy sample was corrected for the finger print of attenuation- and phase-image. RESULTS: Comparing the simulated, attenuation-based dark-field values to a phantom measurement, a good agreement was found. Applying the proposed method to mammographic dark-field data, a reduction of the dark-field background and anatomical noise was achieved. The contrast between microcalcifications and their surrounding background was increased. CONCLUSIONS: The authors show that the influence of and dispersion can be quantified by simulation and, thus, measured image data can be corrected. The simulation allows to determine the corresponding dark-field artifacts for a wide range of setup parameters, like tube-voltage and filtration. The application of the proposed method to mammographic dark-field data shows an increase in contrast compared to the original image, which might simplify a further image-based diagnosis.

Report of improved performance in Talbot-Lau phase-contrast computed tomography.

PURPOSE: Many expectations have been raised since the use of conventional x-ray tubes on grating-based x-ray phase-contrast imaging. Despite a reported increase in contrast-to-noise ratio (CNR) in many publications, there is doubt on whether phase-contrast computed tomography (CT) is advantageous in clinical CT scanners in vivo. The aim of this paper is to contribute to this discussion by analyzing the performance of a phase-contrast CT laboratory setup. METHODS: A phase-contrast CT performance analysis was done. Projection images of a phantom were recorded, and image slices were reconstructed using standard filtered back projection methods. The resulting image slices were analyzed by determining the CNRs in the attenuation and phase image. These results were compared to analytically calculated expectations according to the already published phase-contrast CT performance analysis by Raupach and Flohr [Med. Phys. 39, 4761-4774 (2012)]. There, a severe mistake was found leading to wrong predictions of the performance of phase-contrast CT. The error was corrected and with the new formulae, the experimentally obtained results matched the analytical calculations. RESULTS: The squared ratios of the phase-contrast CNR and the attenuation CNR obtained in the authors' experiment are five- to ten-fold higher than predicted by Raupach and Flohr [Med. Phys. 39, 4761-4774 (2012)]. The effective lateral spatial coherence length deduced outnumbers the already optimistic assumption of Raupach and Flohr [Med. Phys. 39, 4761-4774 (2012)] by a factor of 3. CONCLUSIONS: The authors' results indicate that the assumptions made in former performance analyses are pessimistic. The break-even point, when phase-contrast CT outperforms attenuation CT, is within reach even with realistic, nonperfect gratings. Further improvements to state-of-the-art clinical CT scanners, like increasing the spatial resolution, could change the balance in favor of phase-contrast computed tomography even more. This could be done by, e.g., quantum-counting pixel detectors with four-fold smaller pixel pitches.

Simulation framework for coherent and incoherent X-ray imaging and its application in Talbot-Lau dark-field imaging.

A simulation framework for coherent X-ray imaging, based on scalar diffraction theory, is presented. It contains a core C++ library and an additional Python interface. A workflow is presented to include contributions of inelastic scattering obtained with Monte-Carlo methods. X-ray Talbot-Lau interferometry is the primary focus of the framework. Simulations are in agreement with measurements obtained with such an interferometer. Especially, the dark-field signal of densely packed PMMA microspheres is predicted. A realistic modeling of the microsphere distribution, which is necessary for correct results, is presented. The framework can be used for both setup design and optimization but also to test and improve reconstruction methods.

Energy weighted x-ray dark-field imaging.

The dark-field image obtained in grating-based x-ray phase-contrast imaging can provide information about the objects' microstructures on a scale smaller than the pixel size even with low geometric magnification. In this publication we demonstrate that the dark-field image quality can be enhanced with an energy-resolving pixel detector. Energy-resolved x-ray dark-field images were acquired with a 16-energy-channel photon-counting pixel detector with a 1 mm thick CdTe sensor in a Talbot-Lau x-ray interferometer. A method for contrast-noise-ratio (CNR) enhancement is proposed and validated experimentally. In measurements, a CNR improvement by a factor of 1.14 was obtained. This is equivalent to a possible radiation dose reduction of 23%.

Signal decomposition for X-ray dark-field imaging.

Grating-based X-ray dark-field imaging is a new imaging modality. It allows the visualization of structures at micrometer scale due to small-angle scattering of the X-ray beam. However, reading darkfield images is challenging as absorption and edge-diffraction effects also contribute to the dark-field signal, without adding diagnostic value. In this paper, we present a novel--and to our knowledge the first--algorithm for isolating small-angle scattering in dark-field images, which greatly improves their interpretability. To this end, our algorithm utilizes the information available from the absorption and differential phase images to identify clinically irrelevant contributions to the dark-field image. Experimental results on phantom and ex-vivo breast data promise a greatly enhanced diagnostic value of dark-field images.

Grating-based x-ray phase-contrast imaging with a multi energy-channel photon-counting pixel detector.

We have carried out grating-based x-ray differential phase-contrast measurements with a hybrid pixel detector in 16 energy channels simultaneously. A method for combining the energy resolved phase-contrast images based on energy weighting is presented. An improvement in contrast-to-noise ratio by 58.2% with respect to an emulated integrating detector could be observed in the final image. The same image quality could thus be achieved with this detector and with energy weighting at 60.0% reduced dose compared to an integrating detector. The benefit of the method depends on the object, spectrum, interferometer design and the detector efficiency.

Projection angle dependence in grating-based X-ray dark-field imaging of ordered structures.

Over the recent years X-ray differential phase-contrast imaging was developed for the hard X-ray regime as produced from laboratory X-ray sources. The technique uses a grating-based Talbot-Lau interferometer and was shown to yield image contrast gain, which makes it very interesting to the fields of medical imaging and non-destructive testing, respectively. In addition to X-ray attenuation contrast, the differential phase-contrast and dark-field images provide different structural information about a specimen. For the dark-field even at length scales much smaller than the spatial resolution of the imaging system. Physical interpretation of the dark-field information as present in radiographic and tomographic (CT) images requires a detailed look onto the geometric orientation between specimen and the setup. During phase-stepping the drop in intensity modulation, due to local scattering effects within the specimen is reproduced in the dark-field signal. This signal shows strong dependencies on micro-porosity and micro-fibers if these are numerous enough in the object. Since a grating-interferometer using a common unidirectional line grating is sensitive to X-ray scattering in one plane only, the dark-field image is influenced by the fiber orientations with respect to the grating bars, which can be exploited to obtain anisotropic structural information. With this contribution, we attempt to extend existing models for 2D projections to 3D data by analyzing dark-field contrast tomography of anisotropically structured materials such as carbon fiber reinforced carbon (CFRC).

Increasing the darkfield contrast-to-noise ratio using a deconvolution-based information retrieval algorithm in X-ray grating-based phase-contrast imaging.

A novel information retrieval algorithm for X-ray grating-based phase-contrast imaging based on the deconvolution of the object and the reference phase stepping curve (PSC) as proposed by Modregger et al. was investigated in this paper. We applied the method for the first time on data obtained with a polychromatic spectrum and compared the results to those, received by applying the commonly used method, based on a Fourier analysis. We confirmed the expectation, that both methods deliver the same results for the absorption and the differential phase image. For the darkfield image, a mean contrast-to-noise ratio (CNR) increase by a factor of 1.17 using the new method was found. Furthermore, the dose saving potential was estimated for the deconvolution method experimentally. It is found, that for the conventional method a dose which is higher by a factor of 1.66 is needed to obtain a similar CNR value compared to the novel method. A further analysis of the data revealed, that the improvement in CNR and dose efficiency is due to the superior background noise properties of the deconvolution method, but at the cost of comparability between measurements at different applied dose values, as the mean value becomes dependent on the photon statistics used.

On a dark-field signal generated by micrometer-sized calcifications in phase-contrast mammography.

We show that a distribution of micrometer-sized calcifications in the human breast which are not visible in clinical x-ray mammography at diagnostic dose levels can produce a significant dark-field signal in a grating-based x-ray phase-contrast imaging setup with a tungsten anode x-ray tube operated at 40 kVp. A breast specimen with invasive ductal carcinoma was investigated immediately after surgery by Talbot-Lau x-ray interferometry with a design energy of 25 keV. The sample contained two tumors which were visible in ultrasound and contrast-agent enhanced MRI but invisible in clinical x-ray mammography, in specimen radiography and in the attenuation images obtained with the Talbot-Lau interferometer. One of the tumors produced significant dark-field contrast with an exposure of 0.85 mGy air-kerma. Staining of histological slices revealed sparsely distributed grains of calcium phosphate with sizes varying between 1 and 40 µm in the region of this tumor. By combining the histological investigations with an x-ray wave-field simulation we demonstrate that a corresponding distribution of grains of calcium phosphate in the form of hydroxylapatite has the ability to produce a dark-field signal which would-to a substantial degree-explain the measured dark-field image. Thus we have found the appearance of new information (compared to attenuation and differential phase images) in the dark-field image. The second tumor in the same sample did not contain a significant fraction of these very fine calcification grains and was invisible in the dark-field image. We conclude that some tumors which are invisible in x-ray absorption mammography might be detected in the x-ray dark-field image at tolerable dose levels.

Grating-based darkfield imaging of human breast tissue.

Mastectomy specimens were investigated using a Talbot-Lau X-ray imaging set-up. Significant structures in the darkfield were observed, which revealed considerably higher contrast than those observed in digital mammography. Comparison with the histomorphometric image proofs that the darkfield signal correlates with a tumor region containing small calcification grains of 3 to 30µm size.