Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.

BACKGROUND:The objectives of this study were to evaluate the risk of local recurrence and survival after soft tissue sarcoma (STS) resection with positive margins and to evaluate the safety of sparing adjacent critical structures. METHODS: One hundred sixty-nine patients with localized STS who had positive resection margins were identified from a prospective database. Patients who had positive margins were stratified into 3 groups, each representing a specific clinical scenario: critical structure positive margin (eg major nerve, vessel, or bone), tumor bed resection positive margin, and unexpected positive margin. The rates of local recurrence-free survival (LRFS) and cause-specific survival (CSS) were calculated and compared with relevant control patients who had negative margins after STS resection. RESULTS: After planned close dissection to preserve critical structures, the 5-year LRFS and CSS rates both depended on the quality of the surgical margins (97% and 80.3%, respectively, for those with negative margins vs 85.4% and 59.4%, respectively, for those with positive margins; P 5.015 and P 5.05, respectively). Negative margins achieved through resection of critical structures because of tumor invasion or encasement only slightly improved the 5-year rates of LRFS (91.2%) and CSS (63.6%; P 5.8 and P 5.9, respectively). The lowest 5-year LRFS and CSS rates were 63.4% and 59.2%, respectively, after an unexpected positive margin during primary surgery. CONCLUSIONS: After patients undergo resection of STS with positive margins, oncologic outcomes can be predicted based on the clinical context. Sparing adjacent critical structures in this setting is safe and contributes to improved functional outcomes. Cancer 2014;120:2866-75.

Synovial chondromatosis is a rare, benign condition of unknown etiology in which the synovium undergoes metaplasia leading to cartilaginous nodules that ultimately break free, mineralize, and even ossify. The most commonly involved joint is the knee. Patients may be asymptomatic or may present with pain, swelling, and limited range of motion. Plain radiographs can be diagnostic and mineralized nodules are pathognomonic. Recommended treatment involves arthroscopic or open removal of loose bodies with or without a synovectomy to prevent further articular and periarticular destruction and to relieve symptoms.