Abstract
.Intraoperative margin assessment is imperative to cancer cure but is a continued challenge to successful surgery. Breast conserving surgery is a relevant example, where a cosmetically improved outcome is gained over mastectomy, but re-excision is required in of cases due to positive or closely involved margins. Clinical translation of margin assessment modalities that must directly contact the patient or required administered contrast agents are time consuming and costly to move from bench to bedside. Tumor resections provide a unique surgical opportunity to deploy margin assessment technologies including contrast agents on the resected tissues, substantially shortening the path to the clinic. However, staining of resected tissues is plagued by nonspecific uptake. A ratiometric imaging approach where matched targeted and untargeted probes are used for staining has demonstrated substantially improved biomarker quantification over staining with conventional targeted contrast agents alone. Our group has developed an antibody-based ratiometric imaging technology using fluorescently labeled, spectrally distinct targeted and untargeted antibody probes termed dual-stain difference specimen imaging (DDSI). Herein, the targeted biomarker expression level and pattern are evaluated for their effects on DDSI diagnostic potential. Epidermal growth factor receptor expression level was correlated to DDSI diagnostic potential, which was found to be robust to spatial pattern expression variation. These results highlight the utility of DDSI for accurate margin assessment of freshly resected tumor specimens.
Highlights
Through implementation of widespread mammography screening programs in the United States, a substantial number of early stage breast cancers are detected.[1,2] One of the most common treatments for early stage breast cancer is breast conserving surgery (BCS) or lumpectomy.[3]
Qualitative assessment of calculated dual-stain difference specimen imaging (DDSI) as compared to the targeted and untargeted fluorescence images showed an improved match between signal intensity and biomarker expression as determined by gold standard hematoxylin and eosin (H&E) and IHC
DDSI for the lower EGFRexpressing AsPC-1 and MDA-MB-231 xenografts were plotted on the same scale as the highly epidermal growth factor receptor (EGFR)-expressing A431 tumors, where DDSI intensity was not as obvious for the lower EGFRexpressing tumors (Fig. 2)
Summary
Through implementation of widespread mammography screening programs in the United States, a substantial number of early stage breast cancers are detected.[1,2] One of the most common treatments for early stage breast cancer is breast conserving surgery (BCS) or lumpectomy.[3] While cosmetically improved over mastectomy, BCS can have re-excision rates ranging from 23% to 38% due to close or involved tumor margins as determined through comprehensive histopathological analysis following surgery.[4,5] Any findings of close or involved margins require immediate follow-up surgery, which increases patient stress and risk of morbidity, reducing the likelihood of a positive outcome.[6,7,8,9] it is important that the entire tumor is removed during the primary surgery to minimize re-excision rates as well as risk for local recurrence.[10] A number of intraoperative margin analysis technologies have been developed to reduce re-excision rates, including frozen section analysis and touch prep cytology, which have been deployed clinically.[11,12] none of the current intraoperative margin assessment techniques have been able to counter the current re-excision rate due to lack of sensitivity and specificity and/or challenges in adopting these procedures into the standard surgical
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