Browsing by Author "Scott, Robert"
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Item Open Access Calcification microstructure reflects breast tissue microenvironment(Springer, 2019-12-05) Gosling, Sarah; Scott, Robert; Greenwood, Charlene; Bouzy, Pascaline; Nallala, Jayakrupakar; Lyburn, Iain Douglas; Stone, Nicholas; Rogers, KeithMicrocalcifications are important diagnostic indicators of disease in breast tissue. Tissue microenvironments differ in many aspects between normal and cancerous cells, notably extracellular pH and glycolytic respiration. Hydroxyapatite microcalcification microstructure is also found to differ between tissue pathologies, including differential ion substitutions and the presence of additional crystallographic phases. Distinguishing between tissue pathologies at an early stage is essential to improve patient experience and diagnostic accuracy, leading to better disease outcome. This study explores the hypothesis that microenvironment features may become immortalised within calcification crystallite characteristics thus becoming indicators of tissue pathology. In total, 55 breast calcifications incorporating 3 tissue pathologies (benign – B2, ductal carcinoma in-situ - B5a and invasive malignancy - B5b) from archive formalin-fixed paraffin-embedded core needle breast biopsies were analysed using X-ray diffraction. Crystallite size and strain were determined from 548 diffractograms using Williamson-Hall analysis. There was an increased crystallinity of hydroxyapatite with tissue malignancy compared to benign tissue. Coherence length was significantly correlated with pathology grade in all basis crystallographic directions (P < 0.01), with a greater difference between benign and in situ disease compared to in-situ disease and invasive malignancy. Crystallite size and non-uniform strain contributed to peak broadening in all three pathologies. Furthermore, crystallite size and non-uniform strain normal to the basal planes increased significantly with malignancy (P < 0.05). Our findings support the view that tissue microenvironments can influence differing formation mechanisms of hydroxyapatite through acidic precursors, leading to differential substitution of carbonate into the hydroxide and phosphate sites, causing significant changes in crystallite size and non-uniform strain.Item Open Access Elemental and phase composition of breast calcifications(2017-06-14) Scott, Robert; Rogers, Keith; Kendall, Catherine; Stone, NicholasDespite 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.Item Open Access Elemental vs. phase composition of breast calcifications(Nature Publications, 2017-03-09) Scott, Robert; Kendall, Catherine; Stone, Nicholas; Rogers, KeithDespite the importance of calcifications in early detection of breast cancer, and their suggested role in modulating breast cancer cell behaviour, very little detail is known about their chemical composition or how this relates to pathology. We measured the elemental composition of calcifications contained within histological sections of breast tissue biopsies, and related this to both crystallographic parameters measured previously in the same specimens, and to the histopathology report. The Ca:P ratio is of particular interest since this theoretically has potential as a non-invasive aid to diagnosis; this was found to lie in a narrow range similar to bone, with no significant difference between benign and malignant. The Mg:Ca ratio is also of interest due to the observed association of magnesium whitlockite with malignancy. The initially surprising inverse correlation found between whitlockite fraction and magnesium concentration can be explained by the location of the magnesium in calcified tissue. Sodium was also measured, and we discovered a substantial and significant difference in Na:Ca ratio in the apatite phase between benign and malignant specimens. This has potential for revealing malignant changes in the vicinity of a core needle biopsy.Item Open Access Exploration of utility of combined optical photothermal infrared and Raman imaging for investigating the chemical composition of microcalcifications in breast cancer(Royal Society of Chemistry, 2023-02-21) Bouzy, Pascaline; Lyburn, Iain Douglas; Pinder, Sarah E.; Scott, Robert; Mansfield, Jessica; Moger, Julian; Greenwood, Charlene; Bouybayoune, Ihssane; Cornford, Eleanor; Rogers, Keith; Stone, NickMicrocalcifications play an important role in cancer detection. They are evaluated by their radiological and histological characteristics but it is challenging to find a link between their morphology, their composition and the nature of a specific type of breast lesion. Whilst there are some mammographic features that are either typically benign or typically malignant often the appearances are indeterminate. Here, we explore a large range of vibrational spectroscopic and multiphoton imaging techniques in order to gain more information about the composition of the microcalcifications. For the first time, we validated the presence of carbonate ions in the microcalcifications by O-PTIR and Raman spectroscopy at the same time, the same location and the same high resolution (0.5 μm). Furthermore, the use of multiphoton imaging allowed us to create stimulated Raman histology (SRH) images which mimic histological images with all chemical information. In conclusion, we established a protocol for efficiently analysing the microcalcifications by iteratively refining the area of interest.Item Open Access Relationships between pathology and crystal structure in breast calcifications: an in situ X-ray diffraction study in histological sections(2016-09-28) Scott, Robert; Stone, Nicholas; Kendall, Catherine; Geraki, Kalotina; Rogers, KeithCalcifications are not only one of the most important early diagnostic markers of breast cancer, but are also increasingly believed to aggravate the proliferation of cancer cells and invasion of surrounding tissue. Moreover, this influence appears to vary with calcification composition. Despite this, remarkably little is known about the composition and crystal structure of the most common type of breast calcifications, and how this differs between benign and malignant lesions. We sought to determine how the phase composition and crystallographic parameters within calcifications varies with pathology, using synchrotron X-ray diffraction. This is the first time crystallite size and lattice parameters have been measured in breast calcifications, and we found that these both parallel closely the changes in these parameters with age observed in fetal bone. We also discovered that these calcifications contain a small proportion of magnesium whitlockite, and that this proportion increases from benign to 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.