Accepted for publication 9 February 1989. tumour. These findings were then analysed in relation to operative and eventual outcome.
MethodsAll endoscopically removed neoplastic colorectal polyps greater than 1 cm diameter were retrieved from three hospitals in the West Midlands for the five year period 1981 to 1985. A total of 367 neoplastic polyps were examined. All slides and reports were reviewed by two pathologists (SM and JN). The majority of polyps, 297, were completely removed small adenomas showing only mild or moderate dysplasia. A further 36 showed severe dysplasia, and the remaining 34 showed invasive carcinoma.The 34 polyps with invasive carcinoma were subjected to further study. Excluded from this study were polyps arising in patients with a known colorectal carcinoma (past or synchronous), familial adenomatous polyposis, and cases without full follow up details.The adenomatous element was classified as either tubular, tubulovillous, or villous according to standard histopathologic criteria. Other factors noted were the degree of epithelial dysplasia, the degree of differentiation of the carcinoma (well, moderately, 1385 on 10 May 2018 by guest. Protected by copyright.
Purpose: Fluorescence-guided surgery using tumor-targeted contrast agents has been developed to improve the completeness of oncologic resections. Quenched activity-based probes that fluoresce after covalently binding to tumor-specific enzymes have been proposed to improve specificity, but none have been tested in humans. Here, we report the successful clinical translation of a cathepsin activity-based probe (VGT-309) for fluorescence-guided surgery. Experimental Design: We optimized the specificity, dosing, and timing of VGT-309 in preclinical models of lung cancer. To evaluate clinical feasibility, we conducted a canine study of VGT-309 during pulmonary tumor resection. We then conducted a randomized, double-blind, dose-escalation study in healthy human volunteers receiving VGT-309 to evaluate safety. Finally, we tested VGT-309 in humans undergoing lung cancer surgery. Results: In preclinical models, we found highly specific tumor cell labeling that was blocked by a broad spectrum cathepsin inhibitor. When evaluating VGT-309 for guidance during resection of canine tumors, we found that the probe selectively labeled tumors and demonstrated high tumor-to-background ratio (TBR range: 2.15-3.71). In the Phase 1 human study, we found that VGT-309 was safe at all doses studied. In the ongoing Phase 2 trial, we report two cases in which VGT-309 localized visually occult, non-palpable tumors (TBRs= 2.83 & 7.18) in real-time to illustrate its successful clinical translation and potential to improve surgical management. Conclusions: This first-in-human study demonstrates the safety and feasibility of VGT-309 to label human pulmonary tumors during resection. These results may be generalizable to other cancers due to cathepsin overexpression in many solid tumors.
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