Objective: Although fluorescence imaging is being applied to a wide range of cancers, it remains unclear which disease populations will benefit greatest. Therefore, we review the potential of this technology to improve outcomes in surgical oncology with attention to the various surgical procedures while exploring trial endpoints that may be optimal for each tumor type. Background: For many tumors, primary treatment is surgical resection with negative margins, which corresponds to improved survival and a reduction in subsequent adjuvant therapies. Despite unfavorable effect on patient outcomes, margin positivity rate has not changed significantly over the years. Thus, patients often experience high rates of re-excision, radical resections, and overtreatment. However, fluorescence-guided surgery (FGS) has brought forth new light by allowing detection of subclinical disease not readily visible with the naked eye. Methods: We performed a systematic review of clinicatrials.gov using search terms ‘‘fluorescence,’’ ‘‘image-guided surgery,’’ and ‘‘near-infrared imaging’’ to identify trials utilizing FGS for those received on or before May 2016. Inclusion criteria: fluorescence surgery for tumor debulking, wide local excision, whole-organ resection, and peritoneal metastases. Exclusion criteria: fluorescence in situ hybridization, fluorescence imaging for lymph node mapping, nonmalignant lesions, nonsurgical purposes, or image guidance without fluorescence. Results: Initial search produced 844 entries, which was narrowed down to 68 trials. Review of literature and clinical trials identified 3 primary resection methods for utilizing FGS: (1) debulking, (2) wide local excision, and (3) whole organ excision. Conclusions: The use of FGS as a surgical guide enhancement has the potential to improve survival and quality of life outcomes for patients. And, as the number of clinical trials rise each year, it is apparent that FGS has great potential for a broad range of clinical applications.

Purpose Intraoperative optical imaging to guide surgeons during oncologic resections offers a unique and promising solution to the ambiguity of cancer margins to tactile and visual assessment that results in devastatingly high rates of positive margins. Sequestering of labeled antibodies by normal tissues with high expression of the antibody target, or “antigen sinks”, diminishes the efficacy of these probes to provide contrast between the tumor and background tissues by decreasing the amount of circulating probe available for uptake by the tumor and by increasing the fluorescence of non-tumor tissues. We hypothesized that administering a dose of unlabeled antibody prior to infusion of the near infrared (NIR) fluorescently-labeled antibody would improve tumor-specific uptake and contrast of the fluorescently-labeled probe by occupying extra-tumoral binding sites, thereby increasing the amount of labeled-probe available for uptake by the tumor. Procedures In this study, we explore this concept by testing two different “pre-load” doses of unlabeled cetuximab (the standard 10mg test dose, and a larger, experimental 100mg test dose) in six patients receiving cetuximab conjugated to the fluorescent dye IRDye800CW (cetuximab-IRDye800CW) in a clinical trial, and compared the amount of fluorescent antibody in tumor and background tissues, as well as the tumor-specific contrast of each. Results The patients receiving the larger preload (100 mg) of unlabeled cetuximab demonstrated significantly higher concentrations (9.5 vs. 0.1 μg) and a longer half-life (30.3 vs. 20.6 days) of the labeled cetuximab in plasma, as well as significantly greater tumor fluorescence (32.3 vs. 9.3 relative fluorescence units) and tumor to background ratios (TBRs) (5.5 vs. 1.7). Conclusions Administering a preload of unlabeled antibody prior to infusion of the fluorescently labeled drug may be a simple and effective way to improve the performance of antibody-based probes to guide surgical resection of solid malignancies.

The purpose of this study was to assess the potential of U.S. Food and Drug Administration-cleared devices designed for indocyanine green-based perfusion imaging to identify cancer-specific bioconjugates with overlapping excitation and emission wavelengths. Recent clinical trials have demonstrated potential for fluorescenceguided surgery, but the time and cost of the approval process may impede clinical translation. To expedite this translation, we explored the feasibility of repurposing existing optical imaging devices for fluorescence-guided surgery. Methods: Consenting patients (n 5 15) scheduled for curative resection were enrolled in a clinical trial evaluating the safety and specificity of cetuximabIRDye800 (NCT01987375). Open-field fluorescence imaging was performed preoperatively and during the surgical resection. Fluorescence intensity was quantified using integrated instrument software, and the tumor-to-background ratio characterized fluorescence contrast. Results: In the preoperative clinic, the open-field device demonstrated potential to guide preoperative mapping of tumor borders, optimize the day of surgery, and identify occult lesions. Intraoperatively, the device demonstrated robust potential to guide surgical resections, as all peak tumor-to-background ratios were greater than 2 (range, 2.2-14.1). Postresection wound bed fluorescence was significantly less than preresection tumor fluorescence (P , 0.001). The repurposed device also successfully identified positive margins. Conclusion: The open-field imaging device was successfully repurposed to distinguish cancer from normal tissue in the preoperative clinic and throughout surgical resection. This study illuminated the potential for existing open-field optical imaging devices with overlapping excitation and emission spectra to be used for fluorescence-guided surgery. Sur gical resection with negative margins remains the primary treatment for many solid cancers. Unfortunately, close or positive surgical margins occur in 30%-40% of radical cancer resections (1-3) and have a direct impact on surgical outcomes (4-6). The intraoperative identification of tumor margins is inexact, as surgeons must rely on visual and manual identification of subtle tissue irregularities to discern tumor borders. Nonspecific anatomic imaging modalities can identify tumor boundaries with millimeter resolution and are being increasingly incorporated into the operating room; however, these modalities cannot provide real-time information and cannot easily be applied to the surgical field of view (7). Frozensection analysis provides guidance for intraoperative margin assessment but is time-intensive and can sample only a fraction of the wound bed (8). Optical imaging for cancer-specific surgical navigation offers a viable solution for real-time, intraoperative guidance of tumor resection and ex vivo margin analysis (9,10). Fluorescence-guided surgery has been shown to increase complete resections and improve oncologic and functional outcomes in clinical trials using 5-aminol...

Objectives Sinus hypoplasia is a hallmark characteristic in cystic fibrosis (CF). Chronic rhinosinusitis (CRS) is nearly universal from a young age, impaired sinus development could be secondary to loss of the cystic fibrosis transmembrane conductance regulator (CFTR) or consequences of chronic infection during maturation. The objective of this study is to assess sinus development relative to overall growth in a novel CF animal model. Methods Sinus development was evaluated in CFTR-/- and CFTR+/+ rats at 3 stages of development – newborns, 3 weeks, and 16 weeks. MicroCT scanning, cultures, and histology were performed. Three-dimensional sinus and skull volumes were quantified. Results At birth, sinus volumes were decreased in CFTR-/- rats compared to wild-type (in mm3 +/- SEM; 11.3 +/- 0.85 vs. 14.5 +/- 0.73; p<0.05) despite similar weights (in g +/- SEM; 8.4+/-0.46 vs. 8.3+/-0.51; p=0.86). CF rat weights declined by 16 weeks (378.4 +/- 10.6 vs. 447.4 +/- 15.9; p<0.05), sinus volume increased similar to wild-type rats (201.1 +/- 3.77 vs. 203.4 +/- 7.13; p=0.8). The ratio of sinus volume to body weight indicates hypoplasia is present at birth (1.37 +/- 0.12 vs. 1.78 +/- 0.11; p<0.05) and increases compared to CFTR+/+ animals by 16 weeks (0.53 +/- 0.02 vs. 0.46 +/- 0.02; p<0.05). Rats didn't develop histological evidence of chronic infection. Conclusion CF rat sinuses are smaller at birth, but develop volumes similar to wild-type rats with maturation. This suggests that loss of CFTR may confer sinus hypoplasia at birth, but normal development ensues without chronic sinus infection.

Background and Objectives Optical imaging to guide cancer resections is rapidly transitioning into the operating room. However, the sensitivity of this technique to detect subclinical disease is yet characterized. The purpose of this study was to determine the minimum range of cancer cells that can be detected by antibody-based fluorescence imaging. Methods 2LMP (breast), COLO-205 (colon), MiaPaca-2 (pancreas), and SCC-1 (head and neck) cells incubated in vitro with cetuximab-IRDye800CW (dose range 8.6μM to 86nM) were implanted subcutaneously in mice (n=3 mice, 5 tumors/mouse). Following incubation with 8.6×10−2μM of cetuximab-IRDye800CW in vitro, serial dilutions of each cell type (1×103–1×106) were implanted subcutaneously (n=3, 5 tumors/mouse). Tumors were imaged with Pearl Impulse and Xenogen IVIS 100 imaging systems. Scatchard analysis was performed to determine receptor density and kinetics for each cell line. Results Under conditions of minimal cetuximab-IRDye800CW exposure to low cellular quantity, closed-field fluorescence imaging theoretically detected a minimum of 4.2×104–9.5×104 2LMP cells, 1.9×105–4.5×105 MiaPaca-2 cells, and 2.4×104–6.7×104 SCC-1 cells; COLO-205 cells could not be identified. Higher EGFR-mediated uptake of cetuximab correlated with sensitivity of detection. Conclusion This study supports the clinical utility of cetuximab-IRDye800CW to sensitively localize subclinical disease in the surgical setting.