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Metastatic recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model is inhibited by neoadjuvant chemotherapy in combination with fluorescence-guided surgery with an anti-CA 19-9-conjugated fluorophore.

Hiroshima Y, Maawy A, Zhang Y, Murakami T, Momiyama M, Mori R, Matsuyama R, Katz MH, Fleming JB, Chishima T, Tanaka K, Ichikawa Y, Endo I, Hoffman RM, Bouvet M - PLoS ONE (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America; Yokohama City University Graduate School of Medicine, Yokohama, Japan.

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.

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Representative images of the recurrent PDOX tumor.(A) A large local recurrent tumor (surrounded by the blue broken line) and peritoneal dissemination (yellow arrowheads) in a BLS-only treated mouse. (B) A locally recurrent tumor (surrounded by a blue dashed line) and a lymph-node metastasis in the hepatoduodenal ligament (yellow arrow heads) in a BLS+NAC-treated mouse. (C) A small local recurrent tumor (surrounded by a blue dashed line) and peritoneal dissemination (yellow arrow heads) in an FGS-only treated mouse. (D) A small local recurrent tumor (surrounded by a blue dashed line) without metastasis in an FGS+NAC-treated mouse. (E) Gross images of all excised recurrent tumors. Upper lines indicate local recurrent tumors and lower lines indicate metastatic recurrent tumors. The recurrent tumor volume in the FGS group was smaller than in the BLS group. The metastatic recurrent tumor volume in the one FGS+NAC-treated mouse that had metastatic recurrence was smaller than recurrent metastases in the FGS-only treated mice. Scale bars: 10 mm.
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pone-0114310-g005: Representative images of the recurrent PDOX tumor.(A) A large local recurrent tumor (surrounded by the blue broken line) and peritoneal dissemination (yellow arrowheads) in a BLS-only treated mouse. (B) A locally recurrent tumor (surrounded by a blue dashed line) and a lymph-node metastasis in the hepatoduodenal ligament (yellow arrow heads) in a BLS+NAC-treated mouse. (C) A small local recurrent tumor (surrounded by a blue dashed line) and peritoneal dissemination (yellow arrow heads) in an FGS-only treated mouse. (D) A small local recurrent tumor (surrounded by a blue dashed line) without metastasis in an FGS+NAC-treated mouse. (E) Gross images of all excised recurrent tumors. Upper lines indicate local recurrent tumors and lower lines indicate metastatic recurrent tumors. The recurrent tumor volume in the FGS group was smaller than in the BLS group. The metastatic recurrent tumor volume in the one FGS+NAC-treated mouse that had metastatic recurrence was smaller than recurrent metastases in the FGS-only treated mice. Scale bars: 10 mm.

Mentions: With regard to the recurrent tumor weight, the average local recurrent tumor weight was 389.2±356.6 mg in BLS-only treated mice; 369.1±251.9 mg in BLS+NAC-treated mice; 73.0±77.2 mg in FGS-only treated mice; and 78.4±90.8 mg in FGS+NAC-treated mice. The average local recurrent tumor weight in FGS-only treated mice was significantly less than in BLS-only treated mice (p = 0.041). The average metastatic recurrent tumor weight of the pancreatic cancer PDOX was 170.7±184.2 mg for BLS-only treated mice; 40.0±19.7 mg for BLS+NAC-treated mice; 31.3±37.6 mg for FGS-only mice; and 1.3±3.7 mg for FGS+NAC-treated mice. The average metastatic recurrent tumor weight in FGS+NAC was significantly less than BLS+NAC (p = 0.001). The metastatic recurrent weight in the FGS+NAC group compared to the FGS only group was marginally significant (0.059). The average total recurrent tumor weight in FGS only was significantly less than BLS only (p = 0.037), and that in FGS+NAC was also significantly less than BLS+NAC (p = 0.004) (Figures 5 and 6). The recurrence rate of FGS+NAC was also significantly less than BLS+NAC (p = 0.008). FGS+NAC significantly reduced the metastatic recurrence frequency to one of 8 mice compared to FGS only where metastasis recurred in 6 out of 8 mice and BLS+NAC where it occurred in 7 out of 8 mice (p = 0.041) (Table 1).


Metastatic recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model is inhibited by neoadjuvant chemotherapy in combination with fluorescence-guided surgery with an anti-CA 19-9-conjugated fluorophore.

Hiroshima Y, Maawy A, Zhang Y, Murakami T, Momiyama M, Mori R, Matsuyama R, Katz MH, Fleming JB, Chishima T, Tanaka K, Ichikawa Y, Endo I, Hoffman RM, Bouvet M - PLoS ONE (2014)

Representative images of the recurrent PDOX tumor.(A) A large local recurrent tumor (surrounded by the blue broken line) and peritoneal dissemination (yellow arrowheads) in a BLS-only treated mouse. (B) A locally recurrent tumor (surrounded by a blue dashed line) and a lymph-node metastasis in the hepatoduodenal ligament (yellow arrow heads) in a BLS+NAC-treated mouse. (C) A small local recurrent tumor (surrounded by a blue dashed line) and peritoneal dissemination (yellow arrow heads) in an FGS-only treated mouse. (D) A small local recurrent tumor (surrounded by a blue dashed line) without metastasis in an FGS+NAC-treated mouse. (E) Gross images of all excised recurrent tumors. Upper lines indicate local recurrent tumors and lower lines indicate metastatic recurrent tumors. The recurrent tumor volume in the FGS group was smaller than in the BLS group. The metastatic recurrent tumor volume in the one FGS+NAC-treated mouse that had metastatic recurrence was smaller than recurrent metastases in the FGS-only treated mice. Scale bars: 10 mm.
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pone-0114310-g005: Representative images of the recurrent PDOX tumor.(A) A large local recurrent tumor (surrounded by the blue broken line) and peritoneal dissemination (yellow arrowheads) in a BLS-only treated mouse. (B) A locally recurrent tumor (surrounded by a blue dashed line) and a lymph-node metastasis in the hepatoduodenal ligament (yellow arrow heads) in a BLS+NAC-treated mouse. (C) A small local recurrent tumor (surrounded by a blue dashed line) and peritoneal dissemination (yellow arrow heads) in an FGS-only treated mouse. (D) A small local recurrent tumor (surrounded by a blue dashed line) without metastasis in an FGS+NAC-treated mouse. (E) Gross images of all excised recurrent tumors. Upper lines indicate local recurrent tumors and lower lines indicate metastatic recurrent tumors. The recurrent tumor volume in the FGS group was smaller than in the BLS group. The metastatic recurrent tumor volume in the one FGS+NAC-treated mouse that had metastatic recurrence was smaller than recurrent metastases in the FGS-only treated mice. Scale bars: 10 mm.
Mentions: With regard to the recurrent tumor weight, the average local recurrent tumor weight was 389.2±356.6 mg in BLS-only treated mice; 369.1±251.9 mg in BLS+NAC-treated mice; 73.0±77.2 mg in FGS-only treated mice; and 78.4±90.8 mg in FGS+NAC-treated mice. The average local recurrent tumor weight in FGS-only treated mice was significantly less than in BLS-only treated mice (p = 0.041). The average metastatic recurrent tumor weight of the pancreatic cancer PDOX was 170.7±184.2 mg for BLS-only treated mice; 40.0±19.7 mg for BLS+NAC-treated mice; 31.3±37.6 mg for FGS-only mice; and 1.3±3.7 mg for FGS+NAC-treated mice. The average metastatic recurrent tumor weight in FGS+NAC was significantly less than BLS+NAC (p = 0.001). The metastatic recurrent weight in the FGS+NAC group compared to the FGS only group was marginally significant (0.059). The average total recurrent tumor weight in FGS only was significantly less than BLS only (p = 0.037), and that in FGS+NAC was also significantly less than BLS+NAC (p = 0.004) (Figures 5 and 6). The recurrence rate of FGS+NAC was also significantly less than BLS+NAC (p = 0.008). FGS+NAC significantly reduced the metastatic recurrence frequency to one of 8 mice compared to FGS only where metastasis recurred in 6 out of 8 mice and BLS+NAC where it occurred in 7 out of 8 mice (p = 0.041) (Table 1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America; Yokohama City University Graduate School of Medicine, Yokohama, Japan.

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.

Show MeSH
Related in: MedlinePlus