Utility Of Shear Wave Elastography In Breast Cancer Diagnosis: A Systematic Review And Meta-Analysis

In the United States, breast cancer is one of the most diagnosed cancers in women. Early detection, often via mammography, and intervention have been shown to reduce mortality. However, not all cancers are mammographically evident in early stages, if at all. As a result, ultrasound has been increasingly used to supplement mammography for breast cancer detection and assessment, particularly in dense breasts. Recent advancements in ultrasonography include the ability to characterize the stiffness of biological tissues. Shear Wave Elastography (SWE) is one such development used to quantify tissue stiffness within a region of interest. The resistance of soft tissue to deformation depends on the molecular makeup of the tissue components as well as elements of tissue structure, such as stromal and connective tissue. As tumor growth often involves architectural changes that cause increased stiffness compared to normal neighboring tissue, SWE has the potential to compliment mammography and B-mode ultrasound for breast lesion characterization. Studies establishing the clinical value of SWE may aid in its incorporation into diagnostic guidelines. This study aimed to quantify the performance of 2D SWE for differentiating benign and malignant breast lesions in women with abnormal mammography via a systematic review of the literature and meta-analysis. A systematic search of PubMed, Scopus, Embase, Ovid-Medline, Cochrane Library and Web of Science was performed. Studies of diagnostic accuracy published prior to June 2021 using SWE to evaluate abnormal breast tissue with at least 50 lesions that reported quantitative shear wave speed (SWS) parameters (the mean (SWSmean), maximum (SWSmax), minimum (SWSmin), or standard deviation (SWSSD) of the SWS) and thresholds and included a reference standard of either biopsy or 2-year stability were included in the analysis. The QUADAS- 2 tool was used to assess possible bias within studies as well as their applicability. 87 studies of diagnostic accuracy were included, encompassing 17,810 women (47) with 19,043 lesions (7,623 malignant). A hierarchical summary receiver operating characteristic model produced the following summary sensitivities and specificities: 0.86 [0.83, 0.88] / 0.87 [0.84, 0.88] for SWSmean, 0.83 [0.80, 0.85]/ 0.88 [0.86, 0.90] for SWSmax, 0.86 [0.74, 0.93]/ 0.81 [0.69, 0.89] for SWSmin, and 0.82 [0.77, 0.86] / 0.88 [0.85, 0.91] for SWSSD, respectively. By calculating and utilizing the resulting likelihood ratios, SWE was shown capable of downgrading BI-RADS 4a and upgrading BI-RADS 3 lesions. Thus, SWE has the potential to provide increased discriminative power in the diagnosis of breast cancer if used synergistically with mammography and B-mode ultrasound. Current society guidelines do not provide definitive recommendations about the role of SWE in screening and diagnosis, nor its counterpart strain elastography (SE). The literature suggests that a combination of SE and SWE may provide better discriminatory power than SWE alone and serve as an adjunct to current diagnostic techniques, opening an avenue for future study

Frequency Domain Ultrasound Waveform Tomography Breast Imaging

Ultrasound tomography is an emerging modality for imaging breast tissue for the detection of disease. Using the principles of full waveform inversion, high-resolution quantitative sound speed and attenuation maps of the breast can be created. In this thesis, we introduce some basic principles of imaging breast disease and the formalism of sound wave propagation. We present numerical methods to model acoustic wave propagation as well methods to solve the corresponding inverse problem. Numerical simulations of sound speed and attenuation reconstructions are used to assess the efficacy of the algorithm. A careful review of the preprocessing techniques needed for the successful inversion of acoustic data is presented. Ex vivo and in vivo sound speed reconstructions highlight the significant improvements that are made upon commonly used travel time sound speed reconstruction methods. Note that we do not present ex vivo or in vivo attenuation reconstructions in this thesis. For the sound speed images, the higher resolution and contrast of the waveform method will hopefully allow a radiologist to make a more informed diagnosis of breast disease. A comparison of full waveform sound speed imaging to MRI shows a great deal of concordant findings. Lastly, we give examples of the use of full waveform inversion sound speed imaging in a clinical setting

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

Personalised body counter calibration using anthropometric parameters

This book describes the development of a new method for personalisation of efficiency factors in partial body counting. Its achieved goal is the quantification of uncertainties in those factors due to variation in anatomy of the measured persons, and their reduction by correlation with anthropometric parameters. The method was applied to a detector system at the In Vivo Measurement Laboratory at Karlsruhe Institute of Technology using Monte Carlo simulation and computational phantoms

Diffusion-weighted Imaging of Lymph Node Tissue

Purpose: The study investigates the hypothesis of clinically observed decreased apparent diffusion coefficient (ADC) of cancerous lymph nodes can be attributed to increased cellularity. The study characterises the mean diffusivity (MD) of lymph node sub-structures and investigates correlation between MD and cellularity metrics. The study also investigates the theoretical information content of single and multi-biophysical models. Methods:. A 3 mm diameter core sample was extracted from a formalin fixed lymph node tissue post-surgery and imaged using 9.4T and 16.4T Bruker MRI system. Samples were sectioned and stained with haematoxylin and eosin (H&E). Diffusion tensor model was fitted voxelwise and MD values were computed using Matlab. Cellularity metrics includes measurement of nuclear count and nuclear area. Eleven models with combinations of isotropic, anisotropic, and restricted components were tested for diffusion modelling and ranked using the Akaike information criterion (AIC). Results: The findings showed distinct diffusivities of lymph node sub-structures (capsule and parenchyma). Parenchyma in normal lymph node tissues had higher MD (0.71 ± 0.17 µm2/ms) than metastatic parenchyma (0.52 ± 0.08 µm2/ms) and lymphoma (0.47 ± 0.19 µm2/ms). No correlation were observed between MD and nuclear count (r = 0.368) and nuclear area (r = 0.368) respectively at 95 % confidence intervals. The single biophysical models (ADC and DTI) were ranked lowest by AIC. Multi-biophysical models consist of anisotropic and restricted diffusion (Zeppelin-sphere, Ball-stick-sphere, and Ball-sphere) were ranked highest in the majority of voxels of the tissue samples. Conclusion: A distinct diffusivity value were found in lymph node sub-structures with no correlation to cellularity. Multi-biophysical models were ranked highest and extract more information from the measurement data than simple single biophysical models

Raman Spectroscopy Techniques for the Detection and Management of Breast Cancer

Breast cancer has recently become the most common cancer worldwide, and with increased incidence, there is increased pressure on health services to diagnose and treat many more patients. Mortality and survival rates for this particular disease are better than other cancer types, and part of this is due to the facilitation of early diagnosis provided by screening programmes, including the National Health Service breast screening programme in the UK. Despite the benefits of the programme, some patients undergo negative experiences in the form of false negative mammograms, overdiagnosis and subsequent overtreatment, and even a small number of cancers are induced by the use of ionising radiation. In addition to this, false positive mammograms cause a large number of unnecessary biopsies, which means significant costs, both financially and in terms of clinicians' time, and discourages patients from attending further screening. Improvement in areas of the treatment pathway is also needed. Surgery is usually the first line of treatment for early breast cancer, with breast conserving surgery being the preferred option compared to mastectomy. This type of operation achieves the same outcome as mastectomy - removal of the tumour - while allowing the patient to retain the majority of their normal breast tissue for improved aesthetic and psychological results. Yet, re-excision operations are often required when clear margins are not achieved, i.e. not all of the tumour is removed. This again has implications on cost and time, and increases the risk to the patient through additional surgery. Currently lacking in both the screening and surgical contexts is the ability to discern specific chemicals present in the breast tissue being assessed/removed. Specifically relevant to mammography is the presence of calcifications, the chemistry of which holds information indicative of pathology that cannot be accessed through x-rays. In addition, the chemical composition of breast tumour tissue has been shown to be different to normal tissue in a variety of ways, with one particular difference being a significant increase in water content. Raman spectroscopy is a rapid, non-ionising, non-destructive technique based on light scattering. It has been proven to discern between chemical types of calcification and subtleties within their spectra that indicate the malignancy status of the surrounding tissue, and differentiate between cancerous and normal breast tissue based on the relative water contents. Furthermore, this thesis presents work aimed at exploring deep Raman techniques to probe breast calcifications at depth within tissue, and using a high wavenumber Raman probe to discriminate tumour from normal tissue predominantly via changes in tissue water content. The ability of transmission Raman spectroscopy to detect different masses and distributions of calcified powder inclusions within tissue phantoms was tested, as well as elucidating a signal profile of a similar inclusion through a tissue phantom of clinically relevant thickness. The technique was then applied to the measurement of clinically active samples of bulk breast tissue from informed and consented patients to try to measure calcifications. Ex vivo specimens were also measured with a high wavenumber Raman probe, which found significant differences between tumour and normal tissue, largely due to water content, resulting in a classification model that achieved 77.1% sensitivity and 90.8% specificity. While calcifications were harder to detect in the ex vivo specimens, promising results were still achieved, potentially indicating a much more widespread influence of calcification in breast tissue, and to obtain useful signal from bulk human tissue is encouraging in itself. Consequently, this work demonstrates the potential value of both deep Raman techniques and high wavenumber Raman for future breast screening and tumour margin assessment methods

Functional Magnetic Resonance Imaging of Breast Cancer

This thesis examines the use of magnetic resonance imaging (MRI) techniques in the detection of breast cancer and the prediction of pathological complete response (pCR) to neoadjuvant chemotherapy (NACT). This thesis compares the diagnostic performance of diffusion-weighted imaging (DWI) models in the breast using a systematic review and meta-analysis. Advanced diffusion models have been proposed that may improve the performance of standard DWI using the apparent diffusion coefficient (ADC) to discriminate between malignant and benign breast lesions. Pooling the results from 73 studies, comparable diagnostic accuracy is shown using the ADC and parameters from the intra-voxel incoherent motion (IVIM) and diffusion tensor imaging (DTI) models. This work highlights a lack of standardisation in DWI protocols and methodology. Conventional acquisition techniques used in DWI often suffer from image artefacts and low spatial resolution. A multi-shot DWI technique, multiplexed sensitivity encoding (MUSE), can improve the image quality of DWI. A MUSE protocol has been optimised through a series of phantom experiments and validated in 20 patients. Comparing MUSE to conventional DWI, statistically significant improvements are shown in distortion and blurring metrics and qualitative image quality metrics such as lesion conspicuity and diagnostic confidence, increasing the clinical utility of DWI. This thesis investigates the use of dynamic contrast-enhanced MRI (DCE-MRI) in the detection of breast cancer and the prediction of pCR. Abbreviated MRI (ABB-MRI) protocols have gained increasing attention for the detection of breast cancer, acquiring a shortened version of a full diagnostic protocol (FDP-MRI) in a fraction of the time, reducing the cost of the examination. The diagnostic performance of abbreviated and full diagnostic protocols is systematically compared using a meta-analysis. Pooling 13 studies, equivalent diagnostic accuracy is shown for ABB-MRI in cohorts enriched with cancers, and lower but not significantly different diagnostic performance is shown in screening cohorts. Higher order imaging features derived from pre-treatment DCE-MRI could be used to predict pCR and inform decisions regarding targeted treatment, avoiding unnecessary toxicity. Using data from 152 patients undergoing NACT, radiomics features are extracted from baseline DCE-MRI and machine learning models trained to predict pCR with moderate accuracy. The stability of feature selection using logistic regression classification is demonstrated and a comparison of models trained using features from different time points in the dynamic series demonstrates that a full dynamic series enables the most accurate prediction of pCR.GE Healthcare funded PhD Studentshi

Proceedings of the International Workshop on Medical Ultrasound Tomography: 1.- 3. Nov. 2017, Speyer, Germany

Ultrasound Tomography is an emerging technology for medical imaging that is quickly approaching its clinical utility. Research groups around the globe are engaged in research spanning from theory to practical applications. The International Workshop on Medical Ultrasound Tomography (1.-3. November 2017, Speyer, Germany) brought together scientists to exchange their knowledge and discuss new ideas and results in order to boost the research in Ultrasound Tomography