Characterizing the Utility and Limitations of Repurposing an Open-Field Optical Imaging Device for Fluorescence-Guided Surgery in Head and Neck Cancer Patients.

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 fluorescence-guided 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 = 15) scheduled for curative resection were enrolled in a clinical trial evaluating the safety and specificity of cetuximab-IRDye800 (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.

A ratiometric threshold for determining presence of cancer during fluorescence-guided surgery.

BACKGROUND AND OBJECTIVE: Fluorescence-guided imaging to assist in identification of malignant margins has the potential to dramatically improve oncologic surgery. However, a standardized method for quantitative assessment of disease-specific fluorescence has not been investigated. Introduced here is a ratiometric threshold derived from mean fluorescent tissue intensity that can be used to semi-quantitatively delineate tumor from normal tissue. METHODS: Open-field and a closed-field imaging devices were used to quantify fluorescence in punch biopsy tissues sampled from primary tumors collected during a phase 1 trial evaluating the safety of cetuximab-IRDye800 in patients (n = 11) undergoing surgical intervention for head and neck cancer. Fluorescence ratios were calculated using mean fluorescence intensity (MFI) from punch biopsy normalized by MFI of patient-matched tissues. Ratios were compared to pathological assessment and a ratiometric threshold was established to predict presence of cancer. RESULTS: During open-field imaging using an intraoperative device, the threshold for muscle normalized tumor fluorescence was found to be 2.7, which produced a sensitivity of 90.5% and specificity of 78.6% for delineating disease tissue. The skin-normalized threshold generated greater sensitivity (92.9%) and specificity (81.0%). CONCLUSION: Successful implementation of a semi-quantitative threshold can provide a scientific methodology for delineating disease from normal tissue during fluorescence-guided resection of cancer.

Assessment of indocyanine green-labeled cetuximab to detect xenografted head and neck cancer cell lines.

OBJECTIVE: The aim of this study is to determine the efficacy of indocyanine green (ICG) conjugated to antiepidermal growth factor receptor antibody (cetuximab) to image head and neck cancer. STUDY DESIGN: Mice (n = 3) were injected with unconjugated ICG and imaged at 100-second intervals for a total of 1000 seconds to assess imaging characteristics. Mice (n = 10) xenografted with SCC-1 cells were then systemically injected with cetuximab conjugated to indocyanine green and imaged over a 72-hour period. To assess the sensitivity and specificity, xenografted tumors underwent subtotal resections and then were assessed for residual disease by fluorescence stereomicroscopy and confirmed by histology. RESULTS: Tumors demonstrated excellent fluorescence 24 hours after injection of cetuximab-ICG. There was a direct relationship between fluorescence and the given dose of cetuximab-ICG. Following subtotal resection, we found fluorescence correlated with a sensitivity of 78.4% and specificity of 96%. CONCLUSIONS: This study provides evidence that supports further preclinical investigation of cetuximab in the evaluation of surgical margins, but linkage to ICG lacks the sensitivity for use in a clinical setting.

Free tissue transfer to manage salvage laryngectomy defects after organ preservation failure.

OBJECTIVE: Salvage laryngectomy to treat organ preservation failures results in significantly higher local wound complications. Even in the absence of extralaryngeal disease, primary closure of laryngeal defects can result in protracted wound care problems. We hypothesize that even when sufficient mucosa is present to close the defect primarily, introduction of vascularized tissue to close the defect may improve outcomes. DESIGN: Retrospective case-control study. SETTING: Two academic tertiary care centers. PATIENTS AND METHODS: Patients undergoing salvage surgery for laryngeal squamous cell carcinoma between 2000 to 2006 were considered for this study. Patients requiring total laryngopharyngectomy or partial pharyngectomy were excluded. There were 37 patients who met study criteria: 17 patients underwent free flap reconstruction (16 radial forearm flaps and 1 rectus flap), and 20 patients underwent primary closure. The median follow-up was 12 (range, 4-60) months. Previous treatment consisted of chemoradiation for 41% of the reconstruction group and 35% of the primary closure group; the remainder were treated with primary radiation alone. MAIN OUTCOME MEASURES: Pharyngocutaneous fistula, stricture, length of hospitalization, feeding tube dependence. RESULTS: The free flap reconstruction group had a lower rate of fistula (18%) compared with the primary closure group (50%). A lower rate of stricture formation (18% vs. 25%) and feeding tube dependence (23% vs. 45%) was observed in the free flap reconstruction group compared with the primary closure group. The development of a fistula in either group resulted in a prolonged hospital stay (mean, 19 vs. 7 days) and additional procedures. CONCLUSION: Planned reconstruction of salvage laryngectomy defects with vascularized tissue is associated with a lower fistula rate and may improve outcomes.

Parathyromatosis and recurrent hyperparathyroidism.

Parathyromatosis is an uncommon cause of hypercalcemia. We describe a case of parathyromatosis and hypercalcemia in a 38-year-old man with a history of end-stage renal disease and subtotal parathyroidectomy in which a previous parathyroid operation was implicated. The results of fine-needle aspiration and histologic examination demonstrated a neck mass consistent with parathyromatosis. We discuss parathyromatosis as a rare cause of recurrent hypercalcemia in patients with end-stage renal disease and in those who have undergone previous parathyroid operations. We also characterize the iatrogenic and the embryologic pathogenetic factors involved.