Abstract
The aim of this study is to determine the efficacy of neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) in combination with fluorescence-guided surgery (FGS) on a pancreatic cancer patient derived orthotopic xenograft (PDOX) model. A PDOX model was established from a CA19-9-positive, CEA-negative tumor from a patient who had undergone a pancreaticoduodenectomy for pancreatic adenocarcinoma. Mice were randomized to 4 groups: bright light surgery (BLS) only; BLS+NAC; FGS only; and FGS+NAC. An anti-CA19-9 or anti-CEA antibody conjugated to DyLight 650 was administered intravenously via the tail vein of mice with the pancreatic cancer PDOX 24 hours before surgery. The PDOX was brightly labeled with fluorophore-conjugated anti-CA19-9, but not with a fluorophore-conjugated anti-CEA antibody. FGS was performed using the fluorophore-conjugated anti-CA19-9 antibody. FGS had no benefit over BLS to prevent metastatic recurrence. NAC in combination with BLS did not convey an advantage over BLS to prevent metastatic recurrence. However, FGS+NAC significantly reduced the metastatic recurrence frequency to one of 8 mice, compared to FGS only after which metastasis recurred in 6 out of 8 mice, and BLS+NAC with metastatic recurrence in 7 out of 8 mice (p = 0.041). Thus NAC in combination with FGS can reduce or even eliminate metastatic recurrence of pancreatic cancer sensitive to NAC. The present study further emphasizes the power of the PDOX model which enables metastasis to occur and thereby identify the efficacy of NAC in combination with FGS on metastatic recurrence.
Highlights
Complete tumor resection improves overall survival of pancreatic cancer patients, which is presently 5% at five years [1]
The pancreatic patient derived orthotopic xenograft (PDOX) tumor was diagnosed as moderately differentiated adenocarcinoma with H&E staining (Figure 1A)
The fluorescence results were consistent with the immunohistochemical results, and based on them, it was decided to use anti-CA19-9-650 to label the PDOX for fluorescence-guided surgery (FGS)
Summary
Complete tumor resection improves overall survival of pancreatic cancer patients, which is presently 5% at five years [1]. We have previously shown that fluorescence-guided surgery (FGS) for pancreatic cancer decreased the residual tumor burden and improved overall and disease-free survival in mouse models using fluorescently-labeled human pancreatic cancer cell lines [4,5,6]. Patient-derived orthotopic xenografts (PDOX) recapitulate the biological characteristics of the disease of origin, including metastases [7,8,9,10,11] and are a clinically-relevant model for fluorescence-guided surgery [4, 12,13,14]. We determined the efficacy of CA19-9 conjugated with a fluorescent dye to illuminate pancreatic cancer PDOXs for FGS in combination with NAC
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