Intraoperative Pancreatic Cancer Detection using Tumor-Specific Multimodality Molecular Imaging

Abstract

Background: Operative management of pancreatic ductal adenocarcinoma (PDAC) is complicated by several key decisions during the procedure. Identification of metastatic disease at the outset and, when none is found, complete (R0) resection of primary tumor are key to optimizing clinical outcomes. The use of tumor-targeted molecular imaging, based on photoacoustic and fluorescence optical imaging, can provide crucial information to the surgeon. The first-in-human use of multimodality molecular imaging for intraoperative detection of pancreatic cancer is reported using cetuximab-IRDye800, a near-infrared fluorescent agent that binds to epidermal growth factor receptor.

Methods: A dose-escalation study was performed to assess safety and feasibility of targeting and identifying PDAC in a tumor-specific manner using cetuximab-IRDye800 in patients undergoing surgical resection for pancreatic cancer. Patients received a loading dose of 100 mg of unlabeled cetuximab before infusion of cetuximab-IRDye800 (50 mg or 100 mg). Multi-instrument fluorescence imaging was performed throughout the surgery in addition to fluorescence and photoacoustic imaging ex vivo.

Results: Seven patients with resectable pancreatic masses suspected to be PDAC were enrolled in this study. Fluorescence imaging successfully identified tumor with a significantly higher mean fluorescence intensity in the tumor (0.09 ± 0.06) versus surrounding normal pancreatic tissue (0.02 ± 0.01), and pancreatitis (0.04 ± 0.01; p < 0.001), with a sensitivity of 96.1% and specificity of 67.0%. The mean photoacoustic signal in the tumor site was 3.7-fold higher than surrounding tissue.

Conclusions: The safety and feasibilty of intraoperative, tumor-specific detection of PDAC using cetuximab-IRDye800 with multimodal molecular imaging of the primary tumor and metastases was demonstrated.

Conflict of interest statement

DISCLOSURE The authors declare no potential conflicts of interest.

Figures

FIG. 1

Workflow of clinical trial with imaging examples. 1. Infusion. Infusion of a loading dose cetuximab (100 mg), and cetuximab-IRDye800 (50 or 100 mg) 2-5 days before surgical resection. 2. Operating room. Intra-operative fluorescence imaging. 3. Ex vivo imaging—pathology.Ex vivo fluorescenceand photoacoustic imaging of surgical specimens. 4. Histology correlation. Histologic correlation between histologically proven tumor or normal tissue with H&E and fluorescent signal

FIG. 2

Intraoperative fluorescent imaging. Lesions could be clearly identified as shown in this figure; bright-field (A and E), overlay (B and F), grayscale (C and G), and heat-map (D and H) fluorescence imaging provided clear contrast between tumor and surrounding tissues during a Whipple procedure for both the primary tumor (A–D) and lymph nodes (E–H). PF peripancreatic fat

FIG. 3

Correlation between intraoperative fluorescence and tumor-status. Identification of primary tumor (A) and tumor-bearing lymph node using fluorescence (B), with corresponding ex vivo fluorescence (C and D). Fluorescence of the primary tumor (E) is shown, and bisected lymph node on mesoscopic scale (F), with enhancements corresponding to the tumor on H&E, outlined in red (G + H)), and increased EGFR expression, also outlined (I + J). A graphic representation is shown of the mean fluorescence intensity (MFI) in normal pancreatic tissue, pancreatitis and tumor (K), and tumor-bearing and tumor-negative nodes (L). Scale bar represents 1 cm, unless indicated differently. ***p < 0.001

FIG. 4

Photoacoustic and fluorescence imaging of tumor-bearing lymph node. Conventional ultrasound image of lymph node, surrounded by white dotted line and corresponding photoacoustic image (A). Mean photoacoustic signal in normal pancreatic tissue and tumor, and the signal-to-noise ratio (SNR) in photoacoustic signal per patient (B). Corresponding bright field (C), fluorescence overlay (D), heat-map fluorescent (E) images, and H&E section with outlined tumor (F) of tumor-bearing lymph node. ***p < 0.001. Scale bar represents 1 cm, unless indicated differently