Perioperative GMCSF limits the proangiogenic plasma protein changes associated with colorectal cancer resection.

Aims: Colorectal resection (CR) increases plasma VEGF levels which may promote residual tumor growth. This study assessed the effect of perioperative GMCSF on plasma levels of sVEGFR1, Ang-1 and Ang-2 and also the impact of post-GMCSF plasma on in vitro endothelial cell (EC) growth and invasion. Ang-2 increases while sVEGFR1 and Ang-1 impede angiogenesis.

Insulin-like growth factor binding protein-3 inhibits colitis-induced carcinogenesis.

Purpose: Chronic inflammation in the setting of inflammatory bowel disease is thought to result in altered epithelial cell growth regulation and ultimately carcinogenesis. This loss in cell growth regulation may be partially caused by a decrease in circulating intact insulin-like growth factor binding protein-3 (IFGB-3) as a result of chronic inflammation. This study evaluates the effect of IFGB-3 on carcinogenesis in the setting of colitis.

Perioperative sargramostim (recombinant human GM-CSF) induces an increase in the level of soluble VEGFR1 in colon cancer patients undergoing minimally invasive surgery.

Introduction: Experimentally, laparotomy is associated with increased tumor growth. In humans, abdominal surgery is associated with immunosuppression and elevated plasma VEGF levels that might stimulate tumor growth early after surgery. Avoidance of these surgery-related changes and their consequences may be advantageous.

Drug evaluation: adecatumumab, an engineered human anti-EpCAM antibody.

Micromet Inc, in collaboration with Merck Serono SA, is developing adecatumumab for the potential treatment of adenocarcinomas, including breast and prostate cancer. Adecatunmumab is a fully human antibody targeting epithelial cell adhesion molecule (EpCAM). Adecatumumab is currently undergoing phase II clinical trials in breast and prostate cancer.

Major surgical trauma induces proteolysis of insulin-like growth factor binding protein-3 in transgenic mice and is associated with a rapid increase in circulating levels of matrix metalloproteinase-9.

Background: The authors previously demonstrated a significant decrease in plasma levels of intact insulin-like growth factor binding protein-3 (IGFBP-3) after major open but not after laparoscopic-assisted surgery in humans. They postulated that this decrease may have an effect on postoperative tumor growth. It also has been shown that plasma levels of matrix metalloproteinase-9 (MMP-9), a protease capable of degrading IGFBP-3, are transiently increased after open colectomy in humans.

Major abdominal surgery increases plasma levels of vascular endothelial growth factor: open more so than minimally invasive methods.

Introduction: Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis that is necessary for wound healing and also promotes tumor growth. It is anticipated that plasma levels would increase after major surgery and that such elevations may facilitate tumor growth. This study's purpose was to determine plasma VEGF levels before and early after major open and minimally invasive abdominal surgery.

Drug evaluation: IGN-101--an anti-EpCAM murine antibody vaccine for cancer.

Igeneon GmbH, a wholly owned subsidiary of Aphton Corp, is developing IGN-101, an anticancer vaccine containing the EpCAM-targeting aluminum-adsorbed munrine monoclonal antibody 17-1A (edrecolomab), for the potential subcutaneous treatment of epithelial cancers such as colorectal and rectal tumors. By February 2004, Igeneon was seeking to outlicense the drug.

Perioperative immunomodulation with Flt3 kinase ligand or a whole tumor cell vaccine is associated with a reduction in lung metastasis formation after laparotomy in mice.

Introduction: Laparotomy has been associated with temporary postoperative immunosuppression and accelerated tumor growth in experimental models. In a previous murine study, a whole cell vaccine plus the adjuvant monophosphoryl-lipid A was shown to be effective in decreasing the number of lung metastases that develop after laparotomy. This study was conducted to assess the impact of the adjuvant fetal liver tyrosine kinase 3 (Flt3) ligand on perioperative tumor growth when used alone or with a tumor cell vaccine.

Altered plasma matrix metalloproteinase-9/tissue inhibitor of matrix [corrected] metalloproteinase-1 concentration during the early postoperative period in patients with colorectal cancer.

Background: The authors have previously demonstrated that insulin-like growth factor binding protein-3 (IGFBP-3) is depleted in plasma for 1 to 3 days after major open surgery (OS), but not after laparoscopic surgery (LS). After surgery, IGFP-3 cleavage occurs rapidly and is likely attributable to altered plasma proteolytic activity. This study aimed to assess plasma proteolysis after both open and closed colorectal resection and, if possible, to identify a protease/protease inhibitor system affected by surgery.

Rapid increase in serum levels of matrix metalloproteinase-9 (MMP-9) postoperatively is associated with a decrease in the amount of intracellular MMP-9.

We have previously demonstrated a significant decrease in the serum concentration of intact insulin-like growth factor-binding protein (IGFBP-3) after laparotomy. IGFBP-3, a major IGF binding protein, inhibits the growth of tumor cells via several mechanisms. Our goal was to determine, in a murine model, whether matrix metalloproteinase-9 (MMP-9), a known protease of IGFBP-3, is responsible for the postoperative decrease in serum IGFBP-3 levels.

Significant reduction of laparotomy-associated lung metastases and subcutaneous tumors after perioperative immunomodulation with flt3 ligand in mice.

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.

Insulin-like growth factor binding protein 3 in inflammatory bowel disease.

Epithelial cell growth regulation has been reported to be altered in inflammatory bowel disease (IBD) patients. The cell growth regulatory factor, insulin-like growth factor binding protein 3 (IGFBP-3), may be partly responsible for this phenomenon. So far, IGFBP-3 levels have been assessed as values of total protein, which is a sum of bioactive intact 43- to 45-kDa protein and its inactive proteolytic cleavage fragments.

Immunological advantages of advanced laparoscopy.

Surgical trauma causes significant alterations in host immune function. Compared with open surgery, laparoscopic surgery is associated with reduced postoperative pain and more rapid return to normal activity. Experimental data have also shown more aggressive tumor establishment and growth rates following open surgery and laparoscopic surgery.

Open surgery induces a dramatic decrease in circulating intact IGFBP-3 in patients with colorectal cancer not seen with laparoscopic surgery.

Background: As shown earlier by the authors via Western blot analysis, open (OS) but not laparoscopic surgery (LS) induces a qualitative decrease in plasma insulin-like growth factor-binding protein 3 (IGFBP-3) levels on postoperative day 1 (POD 1). Intact IGFBP-3 has tumor suppressive effects, but its degradation products do not. Enzyme linked immunoassay (ELISA) inevitably measures both.

Insulin-like growth factor-binding protein 3 inhibits growth of experimental colocarcinoma.

Background: We have previously shown that an important cell growth regulatory protein, insulin-like growth factor-binding protein 3 (IGFBP-3) is depleted in peripheral blood after open--but not laparoscopic--surgery. We have also demonstrated that IGFBP-3 induces apoptosis of human colon cancer cells in vitro. We report here the effect of IGFBP-3 on the growth of colonic epithelial cells in vivo.

Infliximab: mechanism of action beyond TNF-alpha neutralization in inflammatory bowel disease.

Infliximab, a chimeric antibody to tumour necrosis factor-alpha (TNF-alpha), holds much promise for the treatment of patients with Crohn's disease. On the cellular level, infliximab affects survival and, as presented by Agnholt et al. in this issue of the journal, inhibits GM-CSF (granulocyte-macrophage colony-stimulating factor) production by intestinal T lymphocytes.

Depletion of circulating insulin-like growth factor binding protein 3 after open surgery is associated with high interleukin-6 levels.

Purpose: We have previously shown that plasma from open, but not laparoscopic-assisted, surgery patients has increased mitogenic activity for colon cancer cells. Decreased insulin-like growth factor binding protein 3 levels, most likely the result of an open surgery-induced proteolytic activity, may account for this finding. Plasma proteases are activated by interleukin-6.

B cell response to tumor antigens is associated with depletion of B progenitors in murine colocarcinoma.

Background: B cells that produce antibodies to autologous tumor antigens have been found in patients with colon cancer; the significance of this phenomenon remains unknown. Normally, the elimination of autoreactive B cells occurs in the bone marrow during their maturation. We studied the production of antibodies to syngeneic tumor antigens and the maturation of bone marrow B cells in experimental colocarcinoma model.

Naturally occurring antibodies to epithelial cell adhesion molecule (EpCAM).

Epithelial cell adhesion molecule (Ep-CAM) is an epithelial tumor-associated antigen that is expressed by a number of normal tissues and has been used as a target in many immunotherapy studies. The purpose of this study was to determine the incidence of serum anti-EpCAM IgG (immunoglobulin G) antibodies in colon cancer and tumor-free patients and to assess the tumor protective value of anti-EpCAM antibodies. One third of both the cancer (16/48) and the control (9/27) patients had detectable antibodies.

Laparoscopic-assisted cecectomy is associated with decreased formation of postoperative pulmonary metastases compared with open cecectomy in a murine model.

Background: It was shown in a murine model that sham laparotomy is associated with a higher incidence of postoperative lung metastases when compared with results seen after carbon dioxide pneumoperitoneum. Using the same tumor model, the present study was undertaken to determine if the addition of bowel resection to the operative procedure would impact the results.

Methods: Sixty mice underwent anesthesia alone (anesthesia control [AC]), laparoscopic-assisted cecectomy (LC), or open cecectomy (OC).

Upregulation of interleukin-12 and -17 in active inflammatory bowel disease.

Background: Cytokines are essential mediators of the intestinal inflammation during active episodes of inflammatory bowel disease (IBD). Interleukin (IL)-12 and IL-17 are potent immunoregulatory cytokines whose roles in the pathogenesis of IBD are unknown. The aim of this study was to evaluate the colonic expression of IL-12 and IL-17 genes in IBD.

Addition of interleukin-12 to GA733 tumor protein vaccine leads to development of tumor protective immunity despite surgical stress.

Background: We have previously shown that preoperative vaccination with the GA733 protein does not inhibit tumor growth in mice undergoing open surgery or carbon dioxide insufflation. In this study we assessed the antitumor effect of a combined GA733 and interleukin-12 (IL-12) vaccine.

Methods: For this study, BALB/c mice were immunized with GA733, IL-12, or GA733 and IL-12, or they received no vaccine.

The percentage of CD31+ T cells decreases after open but not laparoscopic surgery.

Background: Efficient killing of tumor cells depends on T cells that migrate from the circulation to the peripheral tissues; these cells express CD31. This study was undertaken to determine the impact of open (OS) and laparoscopic (LS) colorectal surgery on the percentage of circulating CD3+CD31+ cells.

Methods: Peripheral blood was collected from 27 OS and 24 LS colon cancer patients preoperatively (preOP) and on postoperative days 1 (POD1) and 3 (POD3).

Isolation of native human monoclonal autoantibodies to breast cancer.

Using a unique fusion partner cell line, MFP-2, and B-lymphocytes from breast cancer patients, we developed a set of fully human monoclonal antibodies (MAbs) that bind with high specificity and sensitivity to breast cancer cells. Immunofluorescent staining of normal tissues, primary tumors, and metastatic lymph nodes demonstrates that these antibodies are specific for breast cancer of autologous and allogeneic origin. We have also determined that many of the antibodies selected based on specific binding to breast cancer cells and tissue also bind prostate cancer cells and tissue with high specificity and sensitivity.

Effect of surgical trauma on epithelial cell adhesion molecule (GA-733) vaccine-induced tumor resistance.

Background: Surgical trauma inhibits immune function. Our goal was to study the effect of surgical intervention on the development of the immune response to epithelial cell adhesion molecule (EpCAM [GA-733]), a tumor-associated protein used for vaccination in colon cancer.

Methods: Recombinant GA-733 and monophosphoryl-lipid A (MPLA) were incorporated into biodegradable beads and implanted in the following groups of mice: control, insufflation, and laparotomy.