Abstract. Breast cancer management could be improved by developing real-time imaging tools to assess tissue architecture without extensive processing. We sought to determine whether confocal fluorescence microscopy (CFM) provides sufficient information to identify neoplasia in breast tissue. Breast tissue specimens were imaged following proflavine application. Regions of interest (ROIs) were selected in histologic slides and in the corresponding region on confocal images, and then divided into sets for training and validation. Readers reviewed images in the training set and evaluated images in the validation set for the presence of neoplasia. Accuracy was assessed using histologic diagnosis as the gold standard. Seventy tissue specimens from 31 patients were imaged; 235 ROIs were identified and diagnosed as neoplastic or non-neoplastic. A training set was assembled using 23 matched ROIs; 49 matched ROIs were assembled into a validation set. Neoplasia was identified in histologic images: 93% sensitivity, 97% specificity [area under the curve (AUC ¼ 0.987)] and in confocal images: 93% sensitivity 93% specificity (AUC ¼ 0.957). CFM produced images of architectural features in breast tissue comparable with conventional histology, while requiring little processing. Potential applications include assessment of excised tissue margins and evaluation of tissue adequacy for bio-banking and genomic studies. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.
Tissue sampling is a problematic issue for inflammatory breast carcinoma, and immediate evaluation following core needle biopsy is needed to evaluate specimen adequacy. We sought to determine if confocal fluorescence microscopy provides sufficient resolution to evaluate specimen adequacy by comparing invasive tumor cellularity estimated from standard histologic images to invasive tumor cellularity estimated from confocal images of breast core needle biopsy specimens. Grayscale confocal fluorescence images of breast core needle biopsy specimens were acquired following proflavine application. A breast-dedicated pathologist evaluated invasive tumor cellularity in histologic images with hematoxylin and eosin staining and in grayscale and false-colored confocal images of cores. Agreement between cellularity estimates was quantified using a kappa coefficient. 23 cores from 23 patients with suspected inflammatory breast carcinoma were imaged. Confocal images were acquired in an average of less than 2 min per core. Invasive tumor cellularity estimated from histologic and grayscale confocal images showed moderate agreement by kappa coefficient: κ = 0.48 ± 0.09 (p < 0.001). Grayscale confocal images require less than 2 min for acquisition and allow for evaluation of invasive tumor cellularity in breast core needle biopsy specimens with moderate agreement to histologic images. We show that confocal fluorescence microscopy can be performed immediately following specimen acquisition and could indicate the need for additional biopsies at the initial visit.
Preventing breast cancer will require the development of targeted strategies that can effectively block disease progression. Tamoxifen and aromatase inhibitors are effective in addressing estrogen receptor-positive (ER+) breast cancer development, but estrogen receptor-negative (ER−) breast cancer remains an unmet challenge due to gaps in pathobiological understanding. In this study, we used reverse phase protein array (RPPA) to identify activation of Src kinase as an early signaling alteration in premalignant breast lesions of women who did not respond to tamoxifen, a widely used ER antagonist for hormonal therapy of breast cancer. Src kinase blockade with the small molecule inhibitor saracatinib prevented the disorganized 3D growth of ER− mammary epithelial cells in vitro and delayed the development of pre-malignant lesions and tumors in vivo in mouse models developing HER2+ and ER− mammary tumors, extending tumor-free and overall survival. Mechanistic investigations revealed that Src blockade reduced glucose metabolism as a result of an inhibition in ERK1/2-MNK1-eIF4E-mediated cap-dependent translation of c-Myc and transcription of the glucose transporter GLUT1, thereby limiting energy available for cell growth. Taken together, our results provide a sound rationale to target Src pathways in premalignant breast lesions to limit the development of breast cancers.
Abstract. In order to diagnose cancer, a sample must be removed, prepared, and examined under a microscope, which is expensive, invasive, and time consuming. Fiber optic fluorescence endomicroscopy, where an image guide is used to obtain high-resolution images of tissue in vivo, has shown promise as an alternative to conventional biopsies. However, the resolution of standard endomicroscopy is limited by the fiber bundle sampling frequency and out-of-focus light. A system is presented which incorporates a plastic, achromatic objective to increase the sampling and which provides optical sectioning via structured illumination to reject background light. An image is relayed from the sample by a fiber bundle with the custom 2.1-mm outer diameter objective lens integrated to the distal tip. The objective is corrected for the excitation and the emission wavelengths of proflavine (452 and 515 nm). It magnifies the object onto the fiber bundle to improve the system's lateral resolution by increasing the sampling. The plastic lenses were fabricated via single-point diamond turning and assembled using a zero alignment technique. Ex vivo images of normal and neoplastic murine mammary tissues stained with proflavine are captured. The system achieves higher contrast and resolves smaller features than standard fluorescence endomicroscopy.
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