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Significant Reduction of Laparotomy-Associated Lung Metastases and Subcutaneous Tumors After Perioperative Immunomodulation with Flt3 Ligand in Mice

Daniel L. Feingold, MD

Peer Wildbrett, BS

Anthony Oh, MD

Irena Kirman, MD, PhD

Zishan Asi, BS

George Stapleton, BS

Emina Huang, MD

Robert L. Fine, MD

Laparoscopic Physiology and Oncology Laboratory, Department of Surgery, College of Physician and Surgeons, Columbia University, New York, NY

Richard L. Whelan, MD

Laparoscopic Physiology and Oncology Laboratory, Department of Surgery, College of Physician and Surgeons, Columbia University, New York, NY; Surgical Specialties, 161 Fort Washington Avenue, Suite 819, New York, NY 10032; rlw3{at}columbia.edu

Laparotomy has been associated with increased rates of tumor establishment and metastasis formation postoperatively in animal models. The purpose of this study was to determine the impact on postoperative tumor growth of perioperative upregulation of immune function via fetal liver tyrosine kinase 3 (Flt3 ligand). Two murine studies were carried out: the first utilized a lung metastases model, and the second involved a subcutaneous tumor model. Each study included four groups: anesthesia control (AC), AC plus Flt3 ligand (ACFlt3), sham laparotomy (OP), and OP plus Flt3 ligand (OPFlt3). Flt3 ligand was administered by daily intraperitoneal injection (10 µg/dose) beginning 5 days preoperatively and continuing for 1 week postoperatively. In study 1, A/J mice were given tail vein injections of 1.5 x 105 TA3Ha cancer cells on the day of surgery. The mice were sacrificed 14 days after surgery, the lungs processed, and the surface metastases counted by a blinded observer. In study 2 C3H/He mice were given a dorsal subcutaneous injection of 104 MC-2 cancer cells on the day of surgery. The mice were sacrificed 31 days after surgery, and the injection sites were evaluated for subcutaneous tumors grossly and histologically. In study 1, the median number of surface lung metastases per mouse was 166 in the OP group and 38 in the OPFlt3 (P= .021). Mice in the AC group developed a median 50 lung metastases per animal compared with mice in the ACFlt3 group who had a median of 10 metastases per mouse (P= .001). The OP group had significantly more metastases than the AC group (P= .048). In study 2, the percentage of animals that developed tumors in the AC, OP, ACFlt3, and OPFlt3 groups was 43, 80, 0, and 20, respectively. The incidence of tumors in the OPFLt3 group and the ACFlt3 group was significantly less than their respective control groups (P< .01). The difference between the OP and AC groups was not significant (P> .05). Perioperatively administered Flt3 ligand was associated with significantly fewer lung metastases and a lower incidence of subcutaneous tumor formation after laparotomy and anesthesia alone. Perioperative immunomodulation may limit untoward surgery-related oncologic effects.

Key Words: Surgery • laparotomy • Flt3 ligand • immunomodulation • nonspecific immunotherapy

Surgical Innovation, Vol. 12, No. 4, 319-325 (2005)
DOI: 10.1177/155335060501200406


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