Screening X-ray mammography is limited by false positives and negatives leading to unnecessary physical and psychological morbidity. Diffuse Optical Imaging using harmless near infra red light, provides lesion detection based on functional abnormalities and represents a novel diagnostic arm that could complement traditional mammography. Reviews of optical breast imaging have not been systematic, are focused mainly on technological developments, and have become superseded by rapid technological advancement. The aim of this study is to review clinically orientated studies involving approximately 2,000 women in whom optical mammography has been used to evaluate the healthy or diseased breast. The results suggest that approximately 85% of breast lesions are detectable on optical mammography. Spectroscopic resolution of tissue haemoglobin composition and oxygen saturation may improve the detectability of breast diseases. Results suggest that breast lesions contain approximately twice the haemoglobin concentration of background tissue. Current evidence suggests that it is not possible to distinguish benign from malignant disease using optical imaging techniques in isolation. Methods to improve the performance of Diffuse Optical Imaging, such as better spectral coverage with additional wavelengths, improved modelling of light transport in tissues and the use of extrinsic dyes may augment lesion detection and characterisation. Future research should involve large clinical trials to determine the overall sensitivity and specificity of optical imaging techniques as well as to establish patient satisfaction and economic viability.

Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients.

The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumor evolution is poorly understood. Phenotypic drifts can be transmitted via inheritable transcriptional programs. Cell-type specific transcription is maintained through the activation of epigenetically defined regulatory regions including promoters and enhancers. Here we have annotated the epigenome of 47 primary and metastatic estrogen-receptor (ERα)-positive breast cancer clinical specimens and inferred phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Shared regions contain a unique set of regulatory information including the motif for transcription factor YY1. We identify YY1 as a critical determinant of ERα transcriptional activity promoting tumor growth in most luminal patients. YY1 also contributes to the expression of genes mediating resistance to endocrine treatment. Finally, we used H3K27ac levels at active enhancer elements as a surrogate of intra-tumor phenotypic heterogeneity to track the expansion and contraction of phenotypic subpopulations throughout breast cancer progression. By tracking the clonality of SLC9A3R1-positive cells, a bona fide YY1-ERα-regulated gene, we show that endocrine therapies select for phenotypic clones under-represented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.

Langerhans cell histiocytosis (LCH) is a rare disease of antigen presenting cells, with an incidence rate of 4.0-5.4 per 1 million individuals. The most common endocrinological manifestation of classical LCH is associated with the posterior pituitary, presenting as Diabetes Insipidus. However, LCH can affect multiple organs and classification is based on the body system involvement. The disease is confirmed by electron microscopy or immunohistochemical reactivity of histiocytes to CD1a and/or S100. LCH rarely involves the thyroid gland, and management of such disease is controversial. Current literature documents 65 English language reported cases of LCH involving the thyroid gland. We present an unusual case of LCH of the thyroid gland, with variable diagnoses on fine needle aspiration (FNA) cytology, and literature review of all English reported cases.