X-ray interferometry without analyzer for breast CT application: A simulation study

Purpose: We investigate an analyzer-less x-ray interferometer with a spatially modulated phase grating (MPG) that can deliver three modalities (attenuation image, phase image, and scatter images) in breast computed tomography (BCT). The system can provide three x-ray modalities while preserving the dose to the object and can achieve attenuation image sensitivity similar to that of a standard absorption-only BCT. The MPG system works with a source, a source-grating, a single phase grating, and a detector. No analyzer is necessary. Thus, there is an approximately 2x improvement in fluence at the detector for our system compared with the same source-detector distance Talbot-Lau x-ray interferometry (TLXI) because the TLXI has an analyzer after the object, which is not required for the MPG. Approach: We investigate the MPG BCT system in simulations and find a clinically feasible system geometry. First, the mechanism of MPG interferometry is conceptually shown via Sommerfeld-Rayleigh diffraction integral simulations. Next, we investigate source coherence requirements, fringe visibility, and phase sensitivity dependence on different system parameters and find clinically feasible system geometry. Results: The phase sensitivity of MPG interferometry is proportional to object-detector distance and inversely proportional to a period of broad fringes at the detector, which is determined by the grating spatial modulation period. In our simulations, the MPG interferometry can achieve about 27% fringe visibility with clinically realistic BCT geometry of a total source-detector distance of 950 mm and source-object distance of 500 mm. Conclusions: We simulated a promising analyzer-less x-ray interferometer, with a spatially sinusoidal MPG. Our system is expected to deliver the attenuation, phase and scatter image in a single acquisition without dose or fluence detriment, compared with conventional BCT

An investigation into the use of charge-coupled devices for digital mammography

This thesis describes the design, optimisation, construction and evaluation of a laboratory based digital mammography system which uses phosphor coated charge-coupled devices (CCDs) for x-ray detection. The size mismatch between the breast and the CCD is overcome by operating the CCD in time delay and integration (TDI) mode and scanning across the breast. Multiparameter optimisations have been carried out for a wide range of digital mammography system configurations and requirements, with the aim of optimising the image quality for a given patient dose. The influence of slot width, exposure time, focal spot size, detector resolution and noise level, dose restrictions, patient thickness and x- ray tube target on the system configuration to give optimum image quality is examined. The system is fully characterised in terms of responsivity, dark current, modulation transfer functions (MTFs), noise power spectra (NPS) and spatial frequency dependent detective quantum efficiency (DQE(f)). Direct interactions of x-rays with the CCD are shown to give a significant increase in the high frequency values of the MTF. These interactions also act as a source of noise and act to significantly reduce the DQE(f) at all frequencies. A subjective comparison of images produced with the optimised prototype system with those produced using a conventional film-screen detector shows that these interactions must be removed if the prototype system is to produce images of equal quality to those currently produced using film-screen combinations. Other improvements to the system are suggested

Optimization of a High-Energy X-Ray Inline Phase Sensitive Imaging System for Diagnosis of Breast Cancer

Breast cancer screening modalities have received constant research attention that are mainly focused on their abilities to detect cancer at an early stage while reducing the risks of harmful radiation dose delivered to the patient. As a result, numerous advancements have been made over the last two decades which include the introduction of digital mammography (DM) and digital breast tomosynthesis (DBT). Numerous clinical trials have demonstrated the decrease in mortality rates by employing these modalities. Significant research attention remains focused on investigating methods for further improving the detection capabilities and reducing the radiation dose. The conventional x-ray imaging technique relies on the attenuation characteristics of a tissue to produce imaging contrast. However, the similar attenuation characteristics of normal and malignant breast tissue present a challenge in differentiating between them using conventional x-ray imaging. The current technique for providing higher image quality involves the introduction of anti-scatter grids and operating the x-ray tubes at much lower x-ray energies as compared to the other radiography fields, both of which results in an increased radiation dose. The current method for providing higher image quality involves utilizing anti-scatter grids and operating at much lower x-ray energies than other radiography fields, both of which result in an increased radiation dose. Phase sensitive imaging is an emerging technique, which relies not only on attenuation coefficients but also the effects produced by x-ray phase shift coefficients. Within the diagnostic energy range, it has been estimated that the phase shift coefficients of a breast tissue are at least 2-3 orders of magnitude larger than their attenuation coefficients. Thus, this technique holds the potential to increase the x-ray energy and remove the grid without compromising the image quality, which could potentially reduce the patient dose. The inline phase sensitive approach involves the simplest implementation—provided that the imaging system is spatially coherent — as it does not involve the introduction of any optical element between the object and detector. Preclinical studies with the inline phase sensitive imaging technique at the same energy as conventional imaging have indicated the ability to reduce the radiation dose without negatively impacting the diagnostic capabilities. However, there are some existing challenges that have prevented this technique in its clinical implementation. Responding to the challenges, an inline phase sensitive imaging prototype has been developed in the advanced biomedical imaging laboratory. The goal of the research presented in this dissertation comprises a thorough investigation in optimizing a high energy phase sensitive imaging prototype efficiently in terms of its geometric and operating parameters. Once optimized, the imaging performance of this phase sensitive x-ray imaging prototype is going to be compared with the commercial digital mammography and digital breast tomosynthesis (DBT) imaging systems using modular breast phantoms at similar and reduced mean glandular dose (Dg) dose levels. This dissertation includes numerous original contributions, perhaps the most significant of which were the demonstration of the ability of inline phase sensitive imaging prototype to deliver higher image quality required for tumor detection and diagnosis at higher x-ray energies in comparison with low energy commercial imaging systems at similar or less radiation dose levels. These results clearly demonstrate the ability of the high energy inline phase sensitive imaging system to maintain the image quality improvement that is necessary for diagnosis at high x-ray energies without an increase in the radiation dose

Spatial Resolution Analysis of a Variable Resolution X-ray Cone-beam Computed Tomography System

A new cone-beam computed tomography (CBCT) system is designed and implemented that can adaptively provide high resolution CT images for objects of different sizes. The new system, called Variable Resolution X-ray Cone-beam CT (VRX-CBCT) uses a CsI-based amorphous silicon flat panel detector (FPD) that can tilt about its horizontal (u) axis and vertical (v) axis independently. The detector angulation improves the spatial resolution of the CT images by changing the effective size of each detector cell. Two components of spatial resolution of the system, namely the transverse and axial modulation transfer functions (MTF), are analyzed in three different situations: (1) when the FPD is tilted only about its vertical axis (v), (2) when the FPD is tilted only about its horizontal axis (u), and (3) when the FPD is tilted isotropically about both its vertical and horizontal axes. Custom calibration and MTF phantoms were designed and used to calibrate and measure the spatial resolution of the system for each case described above. A new 3D reconstruction algorithm was developed and tested for the VRX-CBCT system, which combined with a novel 3D reconstruction algorithm, has improved the overall resolution of the system compared to an FDK-based algorithm

Relative Merits of 3D Visualization for the Detection of Subtle Lung Nodules

A new imaging modality called bi-plane correlation imaging (BCI) was examined to determine the merits of using BCI with stereoscopic visualization to detect subtle lung nodules. In the first aim of this project, the optimal geometry for conventional projection imaging applications was assessed using a theoretical model to develop generic results for MTF, NNPS, eDQE. The theoretical model was tested with a clinical system using two magnifications and two anthropomorphic chest phantoms to assess the modalities of single view CXR and stereo/BCI. Results indicated that magnification can potentially improve the signal and noise performance of digital images. Results also demonstrated that a cross over point occurs in the spatial frequency above and below which the effects of magnification differ indicating that there are task dependent tradeoffs associated with magnification. Results indicated that magnification can potentially improve the detection performance primarily due to the air gap which reduced scatter by 30-40%. For both anthropomorphic phantoms, at iso-dose, eDQE(0) for stereo/BCI was ~100 times higher than that for CXR. Magnification at iso-dose improved eDQE(0) by ~10 times for BCI. Increasing the dose did not improve results. The findings indicated that stereo/BCI with magnification may improve detection of subtle lung nodules compared to single view CXR. With quantitative results in place, a pilot clinical trial was constructed. Human subject data was acquired with a BCI acquisition system. Subjects were imaged in the PA position as well as two oblique angles. Realistic simulated lesions were added to a subset of subjects determined to be nodule free. A BCI CAD algorithm was also applied. In randomized readings, radiologists read the cases according to viewing protocol. For the radiologist trainees, the AUC of lesion detection was seen to improve by 2.8% (p < 0.05) for stereoscopic viewing after monoscopic viewing compared to monoscopic viewing only. A 13% decrease in false positives was observed. Stereo/BCI as an adjunct modality was beneficial. However, the full potential of stereo/BCI as a replacement modality for single view chest x-ray may be realized with improved observer training, clinically relevant stereoscopic displays, and more challenging detection tasks.Doctor of Philosoph

DEVELOPMENT AND CHARACTERIZATION OF A HIGH-ENERGY IN-LINE PHASE CONTRAST TOMOSYNTHESIS PROTOTYPE

Phase sensitive 3D imaging techniques have been an emerging field in x-ray imaging for two decades. Among them, in-line phase contrast tomosynthesis has been investigated with great potential for translation into clinical applications in the near future, due to combining the advantages of configuration simplicity, structural noise elimination and potentially low radiation dose delivery. The high-energy in-line phase contrast tomosynthesis technique developed and presented in this dissertation initiates this translational procedure by optimizing the imaging conditions, performing phase retrieval, offering opportunities to further reduce radiation dose delivery, improving detectability and specificity with the employment of auxiliary phase contrast agents, and potentially performing quantitative imaging. First, the high-energy in-line phase contrast tomosynthesis prototype was developed and characterized in this dissertation as the first of its kind following a number of engineering trade-off considerations. The quantitative results as well as the imaging results of tissue-simulating phantoms and biology-related phantoms demonstrate the extensive capability of this imaging prototype in improving tumor detectability. In addition, the optimization of the x-ray prime beam toward the PAD phase retrieval method proved the potential of high-energy imaging and predicated the solution toward imaging time reduction by employing photon counting based imaging techniques. In the past several years, applications of microbubbles as a phase contrast agent have shown the capability for image quality improvement in quantitative imaging. In this dissertation, a preliminary study of quantitative imaging of microbubbles using the in-line phase contrast projection mode imaging prototype, which is a system without tomosynthesis capability, provided a discussion on how the materials of the bubble shells and gas infills could impact the imaging capabilities and resulting image detectability. In addition, the results of the study provided a guideline for microbubble selections for in-line phase contrast mode imaging modalities. Based on this criterion discussed in the study, the albumin-shell microbubbles were selected as the phase contrast agent for the imaging prototype presented in this dissertation. The imaging results showed the feasibility of performing quantitative imaging by employing microbubbles as the auxiliary phase contrast agent. Clinical conditions were simulated by distributing microbubbles on the interface between two tissue-like phantom structures. The quantitative imaging results provided clinical motivation for translating phantom studies into more biology-related investigations providing radiation dose reductions in the future

Investigations into the links between the generation of X-rays in X-ray Computed Tomography and shifts in extracted areal surface texture parameters

The discovery of X-rays revolutionised medical imaging, never before had a technique offered a method of non-invasively imaging the human body. X-ray computed tomography (XCT) built on this, allowing not only the imaging but the reconstruction of a scanned object into a 3D volume to be realised. For both fields the primary use in the formative years was medical imaging, for which the technologies were uniquely suited. Both however were also adopted as means of non-destructive evaluation (NDE) for engineering applications. This largely occurred for the same reasons the technologies thrived in the medical field. X-rays can be used to image the internal structure of objects without line of sight, due to their penetrative capabilities. Both X-ray imaging and XCT are however not without drawback. Most obviously X-rays are a form of ionising radiation, this was unknown in the early years of using X-rays as a medical imaging tool and led to significant numbers of illness and fatality amongst the early pioneers. Another issue highlighted by early research into X-rays and XCT was the low resolution and long processing times. Whilst between the first X-ray to the first use of XCT these had both improved, the issues remain prevelant. Today XCT has been adopted into a wide range of industrial engineering disciplines, including porosity analysis and metrology. Current research in these fields works to develop specialist methods and parameters to further advance XCT’s usefulness as a tool for the non-destructive analysis. The use of XCT in fields such as metrology, has led to the need to establish traceability and an understanding of error sources in XCT. Traceability is the ability to trace measurements taken back to a pre-existing standard. For most metrology applications this standard is the meter. Current research has highlighted that extracted areal surface texture parameters show a level of variation not seen in other measurement methods.This thesis investigates how instability in several key processes of the generation of X-rays may propagate through to extracted areal surface texture parameters taken using XCT. The filament is a key component in the generation of X-rays and a consumable that requires changing on a semi-regular basis to ensure continued function of the XCT. Responsible for the emission of electrons that are used to generate X-rays it is superheated to allow for thermionic emission to occur, this causes its degradation over time. Theoretically as the cross-sectional area of a part emitting electrons is altered so with the electron beam emitted. This is investigated with several studies assessing if a pattern could be established between the filament’s age and extracted parameter results. It is shown that no pattern could be established though variation in extracted surface parameters is seen throughout the filament’s life, with larger jumps present if the filament is changed.The changing of a filament is a procedure after which the machine requires refocusing, this process is investigated, and it is shown that by refocusing the machine without changing the filament a similar variation to that noted after a filament change is achieved. To quantify this a method of measuring the focal spot of a XCT is required, several methods were considered and one selected as a base from which a novel method was developed. The novel method was developed to allow for the measurement of the focal spot alongside a surface artefact. The method proved viable returning data in line with literature and existing methods. The thesis presents work showing the development of this method and its application in measuring both the machine’s focal spot and a surface artefact simultaneously. Measured focal spot diameter is shown to shift and links to the variation noted in areal surface texture parameters are presented.The work shown in this thesis was carried out to investigate how variables inherent to XCT propagate into extracted areal surface texture parameters, the methods developed are applicable to any cone beam XCT with little alteration. Results presented show that users of cone beam XCT should take into consideration the effects of variation in the XCT process when performing non-destructive evaluation. The work also highlights the need for further work in developing XCT for surface metrology

High-resolution fluorescence endomicroscopy for rapid evaluation of breast cancer margins

Breast cancer is a major public health problem world-wide and the second leading cause of cancer-related female deaths. Breast conserving surgery (BCS), in the form of wide local excision (WLE), allows complete tumour resection while maintaining acceptable cosmesis. It is the recommended treatment for a large number of patients with early stage disease or, in more advanced cases, following neoadjuvant chemotherapy. About 30% of patients undergoing BCS require one or more re-operative interventions, mainly due to the presence of positive margins. The standard of care for surgical margin assessment is post-operative examination of histopathological tissue sections. However, this process is invasive, introduces sampling errors and does not provide real-time assessment of the tumour status of radial margins. The objective of this thesis is to improve intra-operative assessment of margin status by performing optical biopsy in breast tissue. This thesis presents several technical and clinical developments related to confocal fluorescence endomicroscopy systems for real-time characterisation of different breast morphologies. The imaging systems discussed employ flexible fibre-bundle based imaging probes coupled to high-speed line-scan confocal microscope set-up. A preliminary study on 43 unfixed breast specimens describes the development and testing of line-scan confocal laser endomicroscope (LS-CLE) to image and classify different breast pathologies. LS-CLE is also demonstrated to assess the intra-operative tumour status of whole WLE specimens and surgical excisions with high diagnostic accuracy. A third study demonstrates the development and testing of a bespoke LS-CLE system with methylene blue (MB), an US Food and Drug Administration (FDA) approved fluorescent agent, and integration with robotic scanner to enable large-area in vivo imaging of breast cancer. The work also addresses three technical issues which limit existing fibre-bundle based fluorescence endomicroscopy systems: i) Restriction to use single fluorescence agent due to low-speed, single excitation and single fluorescence spectral band imaging systems; ii) Limited Field of view (FOV) of fibre-bundle endomicroscopes due to small size of the fibre tip and iii) Limited spatial resolution of fibre-bundle endomicroscopes due to the spacing between the individual fibres leading to fibre-pixelation effects. Details of design and development of a high-speed dual-wavelength LS-CLE system suitable for high-resolution multiplexed imaging are presented. Dual-wavelength imaging is achieved by sequentially switching between 488 nm and 660 nm laser sources for alternate frames, avoiding spectral bleed-through, and providing an effective frame rate of 60 Hz. A combination of hand-held or robotic scanning with real-time video mosaicking, is demonstrated to enable large-area imaging while still maintaining microscopic resolution. Finally, a miniaturised piezoelectric transducer-based fibre-shifting endomicroscope is developed to enhance the resolution over conventional fibre-bundle based imaging systems. The fibre-shifting endomicroscope provides a two-fold improvement in resolution and coupled to a high-speed LS-CLE scanning system, provides real-time imaging of biological samples at 30 fps. These investigations furthered the utility and applications of the fibre-bundle based fluorescence systems for rapid imaging and diagnosis of cancer margins.Open Acces

Development of a Harmonic Motion Imaging guided Focused Ultrasound system for breast tumor characterization and treatment monitoring

Breast cancer is the most common cancer and the second leading cause of cancer death among women. About 1 in 8 U.S. women (about 12%) will develop invasive breast cancer over the course of their lifetime. Existing methods of early detection of breast cancer include mammography and palpation, either by patient self-examination or clinical breast exam. Palpation is the manual detection of differences in tissue stiffness between breast tumors and normal breast tissue. The success of palpation relies on the fact that the stiffness of breast tumors is often an order of magnitude greater than that of normal breast tissue, i.e., breast lesions feel ''hard'' or ''lumpy'' as compared to normal breast tissue. A mammogram is an x-ray that allows a qualified specialist to examine the breast tissue for any suspicious areas. Mammography is less likely to reveal breast tumors in women younger than 50 years with denser breast than in older women. When a suspicious site is detected in the breast through a breast self-exam or on a screening mammogram, the doctor may request an ultrasound of the breast tissue. A breast ultrasound can provide evidence about whether the lump is a solid mass, a cyst filled with fluid, or a combination of the two. An invasive needle biopsy is the only diagnostic procedure that can definitely determine if the suspicious area is cancerous. In the clinic, 80% of women who have a breast biopsy do not have breast cancer. Most women with breast cancer diagnosed will have some type of surgery to remove the tumor. Depending on the type of breast cancer and how advanced it is, the patient might need other types of treatment as well, such as chemotherapy and radiation therapy. Image-guided minimally-invasive treatment of localized breast tumor as an alternative to traditional breast surgery, such as high intensity focused ultrasound (HIFU) treatment, has become a subject of intensive research. HIFU applies extreme high temperatures to induce irreversible cell injury, tumor apoptosis and coagulative necrosis. Compared with conventional surgical procedures the main advantages of HIFU ablation lie in the fact that it is non-invasive, less scarring and less painful, allowing for shorter recovery time. HIFU can be guided by MRI (MRgFUS) or by conventional diagnostic ultrasound (USgFUS). Worldwide, thousands of patients with uterine fibroids, liver cancer, breast cancer, pancreatic cancer, bone tumors, and renal cancer have been treated by USgFUS. In this dissertation, the objective is to develop an integrated Harmonic Motion Imaging guided Focused Ultrasound (HMIgFUS) system as a clinical monitoring technique for breast HIFU with the added capability of detecting tumors for treatment planning, evaluation of tissue stiffness changes during HIFU ablation for treatment monitoring in real time, and assessment of thermal lesion sizes after treatment evaluation. A new HIFU treatment planning method was described that used oscillatory radiation force induced displacement amplitude variations to detect the HIFU focal spot before lesioning. Using this method, we were able to visualize the HMIgFUS focal region at variable depths. By comparing the estimated displacement profiles with lesion locations in pathology, we demonstrated the feasibility of using this HMI-based technique to localize the HIFU focal spot and predict lesion location during the planning phase. For HIFU monitoring, a HIFU lesion detection and ablation monitoring method was first developed using oscillatory radiation force induced displacement amplitude variations in real time. Using this method, the HMIgFUS focal region and lesion formation were visualized in real time at a feedback rate of 2.4 Hz. By comparing the estimated lesion size against gross pathology, the feasibility of using HMIgFUS to monitor treatment and lesion formation without interruption is demonstrated. In order to reduce the imaging time, it is shown in this dissertation that using the steered FUS beam, HMI can be used to image a 2.3 times larger ROI without requiring physical movement of the transducer. Using steering for HMI can be used to shorten the total imaging duration without requiring physical movement of the transducer. For the application of breast tumor, HMI and HMIgFUS were optimized and applied to ex vivo breast tissue. The results showed that HMI is experimentally capable of mapping and differentiating stiffness in normal and abnormal breast tissues. HMIgFUS can also successfully generate thermal lesions on normal and pathological breast tissues. HMI has also been applied to post-surgical breast mastectomy specimens to mimic the in vivo environment. In the end, the first HMI clinical system has been built with added capability of GUP-based parallel beamforming. A clinical trial has been approved at Columbia University to image breast tumor on patient. The HMI clinical system has shown to be able to map fibroadenoma mass on two patients with valid HMI displacement. The study in this dissertation may yield an early-detection technique for breast cancer without any age discrimination and thus, increase the survival rate

Elemental and phase composition of breast calcifications

Despite the importance of calcifications in early detection of breast cancer, and their proposed association with tumour growth, remarkably little detail is known about their chemical composition, or how this relates to pathology. One reason for this gap is the difficulty of systematically and precisely locating calcifications for analysis, particularly in sections taken from diagnostic archives. Two simple methods were developed which can achieve this in sections cut from wax embedded breast tissue. These are based on micro-CT and x-ray fluoroscopy mapping, and were used to locate calcifications for further study. The elemental composition of calcifications in histological sections was measured using energy-dispersive x-ray spectroscopy in an environmental scanning electron microscope. Variations in Ca:P ratio could in principle be detected non-invasively by dual energy absorptiometry, as demonstrated in a proof of principle experiment. However, the Ca:P ratio was found to lie in a narrow range similar to bone, with no significant difference between benign and malignant. In contrast, a substantial and significant difference in Na:Ca ratio was found between benign and malignant specimens. This has potential for revealing malignant changes in the vicinity of a core needle biopsy. The phase composition and crystallographic parameters within calcifications was measured using synchrotron x-ray diffraction. This is the first time crystallite size and lattice parameters have been measured in breast calcifications, and it was found that these both parallel closely the changes in these parameters with age observed in foetal bone. It was also discovered that these calcifications contain a small proportion of magnesium whitlockite, and that this proportion increases from benign, to carcinoma in-situ, to invasive cancer. When combined with other recent evidence on the effect of magnesium on hydroxyapatite precipitation, this suggests a mechanism explaining observations that carbonate levels within breast calcifications are lower in malignant specimens