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Annals of Surgery logoLink to Annals of Surgery
. 2006 Nov;244(5):792–798. doi: 10.1097/01.sla.0000225272.52313.e2

Major Abdominal Surgery Increases Plasma Levels of Vascular Endothelial Growth Factor

Open More So Than Minimally Invasive Methods

Avraham Belizon 1, Emre Balik 1, Daniel L Feingold 1, Marc Bessler 1, Tracey D Arnell 1, Kenneth A Forde 1, Patrick K Horst 1, Suvinit Jain 1, Vesna Cekic 1, Irena Kirman 1, Richard L Whelan 1
PMCID: PMC1856599  PMID: 17060773

Abstract

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.

Methods:

Colorectal resection for cancer (n = 139) or benign pathology (n = 48) and gastric bypass for morbid obesity (n = 40) were assessed. Similar numbers of open and laparoscopic patients were studied for each indication. Plasma samples were obtained preoperatively and on postoperative days (POD) 1 and 3. VEGF levels were determined via ELISA. The following statistical methods were used: Fisher exact test, unmatched Student t test, Wilcoxon's matched pairs test, and the Mann Whitney U Test with P < 0.05 considered significant.

Results:

The mean preoperative VEGF level of the cancer patients was significantly higher than baseline level of benign colon patients. Regardless of indication or surgical method, on POD3, significantly elevated mean VEGF levels were noted for each subgroup. In addition, on POD1, open surgery patients for all 3 indications had significantly elevated VEGF levels; no POD1 differences were noted for the closed surgery patients. At each postoperative time point for each procedure and indication, the open group's VEGF levels were significantly higher than that of the matching laparoscopic group. VEGF elevations correlated with incision length for each indication.

Conclusion:

As a group colon cancer patients prior to surgery have significantly higher mean VEGF levels than patients without tumors. Also, both open and closed colorectal resection and gastric bypass are associated with significantly elevated plasma VEGF levels early after surgery. This elevation is significantly greater and occurs earlier in open surgery patients. The duration and clinical importance of this finding is uncertain but merits further study.

Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis that is necessary for wound healing. It is logical to anticipate that plasma levels increase after major surgery. VEGF has also been shown to facilitate and promote tumor growth. A postoperative increase in plasma VEGF levels may facilitate tumor growth early after surgery. This study's purpose was to determine plasma VEGF levels before and early after major open and minimally invasive abdominal surgery.

Surgical resection remains the mainstay of definitive treatment of colon cancer patients.1 Unfortunately, after “curative” surgery, some patients develop recurrent disease either from unrecognized tissue microfoci of tumor cells or from viable cells that persist in the circulation.2,3 There are numerous variables that, together, determine whether or not a metastasis develops. The tendency of colorectal tumors to invade locally or spread via the bloodstream or lymphatics varies considerably. Also, although less often considered, there is variability among patients in regards to their ability to prevent tumor metastases from developing. Finally, the host's defenses against tumors likely vary from one time period to another. There is convincing experimental evidence that, after surgical trauma, tumor growth is accelerated and the host is at increased risk of metastases.4–14

Of note, in the majority of experimental studies that assessed both open and closed surgical methods, the latter were associated with significantly smaller increases in tumor growth or metastases formation when compared with results after open bowel resection or sham laparotomy.7,11–14 There is experimental evidence that procedure-related immunosuppression, plasma compositional changes, and tumor cell alterations account, at least in part, for the increased tumor growth noted after surgery.8,9,15 In humans, open colectomy and gastric bypass are associated with plasma depletion of the tumor inhibitor Insulin-like Growth Factor Binding Protein 3 (IGFBP-3); furthermore, postoperative plasma has been shown to stimulate in vitro tumor growth.16,17 Other plasma proteins whose levels are altered after surgery and that may impact tumor growth include Matrix Metalloproteinase 9 (MMP-9) and Tissue Inhibitor of Metalloproteinase -1 (TIMP-1).18 Undoubtedly, there are other undiscovered surgery-influenced proteins or factors that impact tumor growth and development after surgery. Of note, to date, little attention has been paid to angiogenesis in the postoperative period.

Angiogenesis, the formation of new blood vessels, is critical in wound healing because of the need to supply nutrients and oxygen to the injured area. Angiogenesis is also critical for tumor establishment, growth, and survival.19 Many tumors, including colon cancer, cannot grow more than 2 to 3 mm without new vessel development.20 Recognition of the importance of tumor angiogenesis has resulted in a determined effort to identify proangiogenic agents and, subsequently, to develop angiogenesis inhibitors.

Vascular endothelial growth factor (VEGF) is the most potent inducer of angiogenesis found, to date. It directly induces endothelial cell proliferation, migration, and tube formation.21 VEGF is also a potent tumor growth promoter.22 Preresection, cancer patients have been noted to have significantly higher mean blood VEGF levels when compared with tumor-free control populations.23–31 The extent of elevation in colon cancer patients has been shown to correlate with disease stage and/or prognosis.23,32–35

Although others have assessed preresection VEGF levels and also documented lower serum and plasma levels months later, to our knowledge, there has been no large-scale study of blood VEGF levels during the first 3 days after surgery.26,29,31 The release of VEGF after surgery could have undesirable effects on residual tumor cells and may enhance tumor growth and metastasis formation.

This study's purpose was to determine perioperative plasma VEGF levels in patients undergoing open or laparoscopic major abdominal surgery. In addition to colon cancer patients, those with benign colonic disease and a third group undergoing gastric bypass were also studied. The patients with benign disease were included to determine if surgery's impact on VEGF levels was related to surgical indication.

METHODS

Consenting patients undergoing an array of elective procedures, including colectomy and gastric bypass between 1999 and 2004 at the Presbyterian Hospital, were enrolled in an IRB-approved plasma bank and clinical database protocol. Information regarding demographics, medical history, current medications, prior surgery, surgical indication, clinical and pathologic staging (for cancer patients), length of surgery, largest incision length, intraoperative and postoperative course, length of stay, and complications was gathered for all study patients prospectively. In addition, three blood samples were taken from each patient, one immediately prior to surgery and the others on postoperative days (POD) 1, 2, or 3. The broad purpose of this IRB protocol was to determine the physiologic impact of open and minimally invasive surgical methods. Over the stated time period, more than 800 patients were enrolled. From this population, 227 patients who underwent colectomy or gastric bypass in whom adequate volumes of plasma remained for the selected time points (preoperatively, POD1, and POD3) were identified and included in this study (see Exclusion Criteria). Three different patient populations were studied. Group A consisted of 139 colorectal cancer patients, whereas Group B included 48 patients with benign colonic disease. Group C consisted of 40 morbidly obese patients undergoing gastric bypass.

Exclusion Criteria

Patients on corticosteroids and other immunosuppressive drugs were excluded as were converted laparoscopic patients and any patient transfused perioperatively.

Blood Sampling and Processing

Peripheral blood samples were collected in heparin coated tubes. Soon after being drawn, plasma was isolated from samples by centrifugation at 450g, and then stored at −80°C until the ELISA was performed.

Plasma VEGF Concentration

VEGF165 levels were determined in duplicate using an ELISA (R&D Systems Inc., Minneapolis, MN) according to the manufacturer's instructions. The ELISA was read using an automated microplate reader (ELX800NB) made by Bio-Tek Instruments, INC. (Winooski, VT). VEGF concentrations are reported as pg/mL.

Statistical Analysis

The results are reported as mean ± standard deviation unless otherwise stated. Differences in clinical parameters between the open and closed surgery groups were analyzed using Fisher exact test or an Unmatched Student t test, where appropriate. The VEGF levels at the varying time points within a group were compared using Wilcoxon's matched pairs test. The Mann Whitney U test was used to compare VEGF levels at each time point between two groups. Correlations were performed using a nonparametric (Spearman) correlation analysis. All statistical analyses were performed using Graph Pad Prism Version 4.1 software for windows. A P value of less than 0.05 was considered statistically significant.

RESULTS

Group A: Colectomy for Cancer

The mean age was 69.5 years (range, 41–93) in the closed group was years and 67.2 years (range, 21–95 years) in the open group. There were more males in the open group (M:F, 37:32 vs. 31:39 for closed group, P = not significant). The mean incision size in the closed group was 5.1 ± 1.28 cm (range, 2.5–8.5 cm) compared with 19.9 ± 5.32 cm (range, 10.5–37 cm) in the open group (P < 0.0001). The mean ASA score was 2.2 for both groups. The two groups were similar in regards to the type of colectomy performed; the majority of patients in both groups underwent right or sigmoid colectomy (Table 1). The mean operative time for the laparoscopic-assisted group was 18 minutes longer; however, the difference between groups was not significant (P = 0.13) (Table 1). Although the mean number of prior abdominal operations for the open group was significantly higher than for the closed colectomy group (1.4 vs. 1.0, P = 0.04), a similar percentage in each group had at least 1 prior surgery (open, 70% vs. closed 66.6%). In regards to final pathologic stage, the stage breakdown in the open and the laparoscopic-assisted groups was also similar (data not shown).

TABLE 1. Group A: Demographic and Operative Data

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The preoperative plasma VEGF levels for the open and closed groups were similar (108.1 ± 87.90 pg/mL vs. 121 ± 131.9 pg/mL P = 0.61). In the open group, plasma VEGF levels increased significantly on POD1 (175.6 ± 113.4 pg/mL, P < 0.0001). VEGF levels continued to rise on POD3 (358.9 ± 305.2 pg/mL); the mean POD3 value was significantly higher than both the preoperative (P < 0.0001) and POD1 results (P < 0.0001) (Fig. 1).

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FIGURE 1. Concentration of plasma vascular endothelial growth factor (VEGF) in patients undergoing open and laparoscopic surgery for colorectal cancer. Sampling points were preoperatively (PO), and on postoperative days 1 (POD1) and 3 (POD3). *Open versus lap POD1 and POD3 (P < 0.0001). ∧PO open versus POD1 and POD3 open (P < 0.0001). **POD1 open versus POD3 open (P < 0.0001). +PO lap versus POD3 lap (P < 0.0001). ++POD1 lap versus POD3 lap (P < 0.0001).

In the laparoscopic-assisted group, there was no significant change in plasma VEGF levels on POD1 (103.6 ± 99.64 pg/mL) when compared with preoperative levels (121.0 ± 131.9 pg/mL, P = 0.13). In contrast, the mean POD3 VEGF level (211 ± 214.3 pg/mL) was significantly higher than both the preoperative (P < 0.0001) and the POD1 mean values (P < 0.0001) (Fig. 1). A comparison of the open and closed groups’ POD1 and POD3 VEGF levels reveals that the former were significantly greater than the latter (P < 0.0001 for both) at each time point.

A correlation analysis of the incision length and VEGF data from all open and closed cancer patients on POD1 and 3 was carried out; a positive correlation was found at both time points (Spearman r = 0.3176, P = 0.0001 on POD1; and Spearman r = 0.2063, P = 0.01 on POD3).

Group B: Colectomy for Benign Disease

A total of 48 patients were studied: 28 underwent laparoscopic-assisted and 20 had open resections. Both groups were similar with regard to age, gender, body mass index (BMI), preoperative diagnosis, operative length, and type of colectomy carried out (Table 2). The average incision size for the closed surgery group was 4.2 ± 1.26 cm (range, 2.5–7.5 cm), whereas in the open group it was 21.03 ± 4.97 cm (range, 11.5–29.5 cm) (P < 0.0001). The preoperative plasma VEGF levels were similar in both the open and closed groups (open, 63.17 ± 45.55 pg/mL; closed, 52.21 ± 36.83 pg/mL, P = 0.54).

TABLE 2. Group B Demographic and Operative Data: Benign Colectomy Patients

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Regarding the open colectomy group's postoperative VEGF results, the mean POD1 levels (151.6 ± 75.05 pg/mL) were significantly greater than the preoperative results (P = 0.0002). The levels continued to increase on POD3 (189.6 ± 132.8 pg/mL; vs. preoperative results, P < 0.0001). In the laparoscopic-assisted group, there was no significant increase in VEGF levels on POD1 (64.00 ± 72.29 pg/mL; vs. preoperative results, P = 0.97); however, levels did significantly increase on POD3 (104.8 ± 94.09 pg/mL; vs. preoperative results, P = 0.0007) (Fig. 2). When the postoperative results of the open and closed groups at each time point were compared, significantly higher levels were noted on both POD1 and POD3 in the open surgery group (POD1 comparison, P < 0.0001; POD3 comparison, P = 0.006). A significant correlation was found between the length of the largest abdominal incision and plasma VEGF levels when all 48 patients were considered together (Spearman r = 0.6524, P < 0.0001 on POD1; and Spearman r = 0.4110, P = 0.01 on POD3).

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FIGURE 2. Concentration of plasma vascular endothelial growth factor (VEGF) in patients undergoing open and laparoscopic colectomy for benign disease. Sampling points were preoperatively (PO), and on postoperative days 1 (POD1) and 3 (POD3). *Open versus Lap POD1 P < 0.0001). **Open versus lap POD3 (P < 0.0134). ∧PO open versus POD1 open (P = 0.0002). ∧∧PO open versus POD3 open (P < 0.0001). +PO Lap versus POD3 lap (P = 0.0003). ++POD1Lap versus POD3 lap (P = 0.0016).

Of note, when the baseline presurgery VEGF levels of the benign and malignant colon patients were compared, the former were found to be significantly lower than the latter (P ≤ 0.03). Also, the mean POD1 and POD3 laparoscopic benign VEGF results were significantly lower than the minimally invasive cancer patients’ values at the same time points (POD1, P = 0.04; POD3, P = 0. 003). When a similar comparison was made between the open benign and cancer patients, the mean VEGF levels of the former were noted to be significantly lower on POD3 (P = 0.01) but not on POD1.

Group C: Gastric Bypass for Obesity

Forty morbidly obese patients who underwent gastric bypass were studied: 20 had an open and 20 a laparoscopic procedure. Both groups were similar with regard to age and the predominance of females. The laparoscopic bypass, on average, was significantly longer than the open bypass, and the average incision size was significantly longer for the open group (Table 3). Of note, the mean BMI for the open group was 53.1, whereas it was 48.0 for the laparoscopic group (P < 0.05).

TABLE 3. Group C: Demographic and Operative Data (Gastric Bypass)

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The mean preoperative VEGF levels in the two groups were similar (open, 75.04 ± 107.5 pg/mL; closed, 80.41 ± 84.09 pg/mL; P = 0.26) and consistent with the levels seen in the benign colon patients. VEGF levels in the open group were significantly higher on POD1 (182.3 ± 108.1 pg/mL; vs. preoperative, P = 0.0001) and POD3 (480.7 ± 346.7 pg/mL; vs. preoperative, P = 0.0001; vs. POD1, P = 0.0003) (Fig. 3). In regards to the laparoscopic group, the POD1 mean level (73.75 ± 61.53 pg/mL) was similar to the preoperative result (80.41 ± 84.09 pg/mL), whereas the POD3 mean value (263.3 ± 199.7 pg/mL) was significantly greater than both the preoperative and the POD1 results (P = 0.0001 for both comparisons) (Figure 3).

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FIGURE 3. Concentration of plasma vascular endothelial growth factor (VEGF) in patients undergoing open and laparoscopic surgery for obesity. Sampling points were preoperatively (PO), and on postoperative days 1 (POD1) and 3 (POD3). *Open versus lap POD1 (P = 0.0009). **Open versus Lap POD3 (P = 0.0155). ∧PO open versus POD1 open (P = 0.0001); PO open versus POD3 open (P < 0.0001). ∧∧POD1 open versus POD3 open (P = 0.0003). +PO Lap versus POD3 lap (P = 0.0001). ++POD1 lap versus POD3 lap (P < 0.0001).

Of note, the open group's VEGF results on POD1 and POD3 were significantly greater than the laparoscopic group's results at the same time points (POD1, P = 0.0009; POD3, P = 0.02). A correlation analysis of incision length and postoperative VEGF levels revealed a significant correlation between these two parameters on POD1 (Spearman r = 0.4653, P = 0.003) but not POD3 (Spearman r = 0.2879, P = 0.07).

To determine if the higher mean BMI of the open group had an impact on VEGF levels, the gastric bypass data was reexamined after excluding patients with BMI higher than 52 kg/m2. This left 14 closed patients (mean BMI, 44.7 kg/m2) and 9 open patients (mean BMI, 46.9 kg/m2, P = not significant). Similar VEGF levels were noted postsurgery for both groups; the open group's levels were still significantly higher than those of the laparoscopic group on both POD1 and POD3, suggesting that the higher BMI of the open group did not impact VEGF levels.

DISCUSSION

As noted, there is experimental evidence that surgical trauma is associated with a period of increased tumor growth and establishment.4–18 In both the experimental and human arenas, several potential mechanisms by which surgical trauma might impact tumor growth have been discovered. None, however, has been linked to tumor recurrence or outcome, thus far, in the human setting. Of note, little clinical research has been done regarding surgery and angiogenesis.

It is logical to assume that the body should be primed for angiogenesis postoperatively because of the surgical wounds. This may be problematic for cancer patients since the conditions conducive to wound healing may also promote tumor growth. The goal of this study was to determine surgery's impact on plasma levels of VEGF, a potent promoter of angiogenesis. We assessed whether VEGF levels rise early after surgery and if the increase is dependent on the indication for surgery.

In the present study, the cancer patients’ mean VEGF level before surgery was significantly higher than in the benign colon patients; others have noted similar increases in regards to colon, gastric, renal cell, lung, and other cancers (vs. controls).23–31,36–43 In some studies, preoperative VEGF elevations correlate with cancer stage, resectability, depth of invasion, and tumor-related mortality.23,26,29,31 Thus far, VEGF levels have not been closely studied early after surgery nor has the impact of open and closed surgical methods been determined.

In the present study, regardless of indication or surgical method, major abdominal surgery was associated with significant plasma VEGF elevations on POD3. With one exception, the open and closed cancer groups’ mean postoperative VEGF levels were significantly higher than the values of the corresponding benign colon group. Of note, the choice of surgical method (ie, open vs. minimally invasive) had an impact on the timing and extent of the VEGF elevation.

All three open surgery subgroups (cancer, benign colon, morbid obesity) demonstrated a progressive and significant increase in VEGF levels from before surgery to POD1 and from POD1 to POD3 (Figs. 1, 2, 3). On the contrary, for the three laparoscopic subgroups, there was no POD1 VEGF increase; on POD3, however, VEGF levels were significantly higher in all three groups. Further, for all three indications, the open surgery VEGF increases were significantly greater on POD1 and POD3 when compared with the matching laparoscopic group's results. The reason(s) for the open and closed groups’ differences and for the delay in the VEGF rise in the closed group is unclear. Possible contributing factors include: incision length, tissue ischemia, air exposure and peritoneal desiccation, CO2 pneumo, bowel handling, etc.

VEGF plays a key role in wound healing.21 It is logical to assume that plasma VEGF levels after surgery reflect the extent of wounding (abdominal wall + internal trauma) and that most of the VEGF increase is due to local production at the wound(s). Since, for a given operation, the intraabdominal trauma should be comparable regardless of surgical approach, the abdominal incision length might be a factor. Of note, a significant correlation between incision length and postoperative plasma VEGF levels was found for all three indications in this study. Most likely, multiple factors influence VEGF levels.

Does BMI affect plasma VEGF levels? Silha et al found higher VEGF levels in moderately obese as opposed to “lean” patients; however, no difference was noted between the moderately and morbidly obese.44 In the current study, VEGF levels prior to bypass were higher than before colectomy for benign disease but not significantly so. Of note, the mean BMI of the open bypass group was significantly higher than that of the closed group. Did this impact postoperative VEGF levels? Not likely, because, with the heaviest patients excluded, the VEGF results of the remaining open and closed bypass patients (with similar mean BMIs) were essentially unchanged.

Most tumors can produce VEGF, which probably accounts for the elevated mean levels noted in cancer populations. However, many other cell types can produce both VEGF mRNA or protein, including endothelial cells, fibroblasts, adipocytes, omental and peritoneal mesothelial cells, and alveolar epithelial cells.45–47 Hypoxia also stimulates numerous cell types, including adipocytes, to generate VEGF.47 Morbidly obese patients may develop hypoxia to a greater extent during surgery, which may account for the very high VEGF levels seen after open surgery in this group. Undoubtedly, there are other stimuli to VEGF production.

How long are VEGF levels elevated after surgery? The current study provides data for 3 days; however, a literature review reveals more data. A colorectal and a gastric cancer study found that on POD7 mean serum VEGF levels were 1.3 to 1.5 times the mean preoperative levels.26,31 Another colorectal cancer study noted a 1.8-fold increase on POD1 (P = not significant) and a 2.8-fold elevation on POD6 (P < 0.05).28 One study noted lower levels 7 days after open colectomy for cancer.29 Thus, 3 of 4 human studies suggest that blood VEGF levels remain elevated for at least 1 week. Three studies noted that 30 days after surgery the mean VEGF level was below the preoperative cancer patient baseline although still 1.3 to 2 times higher than the mean control levels.26,29,31

Some think that plasma38,48 rather than serum25,27 VEGF assays are more appropriate. Centrifugation of clotted blood yields serum, whereas spinning nonclotted samples (anticoagulant added) provides plasma. VEGF stored in WBCs and platelets39,40 are released when blood clots, which explains why serum levels are notably higher than plasma values.41 Most studies have shown similar VEGF trends in cancer and control populations regardless of whether plasma or serum was used.25,27,38–41 The present study used plasma. It has also been noted that platelet rich, as opposed to platelet poor, plasma has considerably higher VEGF levels.48 Double centrifugation of samples at high speeds yields platelet poor plasma. In the current study, blood samples were centrifuged once at moderate speed, which likely resulted in platelet rich plasma. This probably accounts for our high mean VEGF values, which are among the highest in the literature.

Exposure of postresection cancer patients to high VEGF levels for a period when no chemotherapy is given may stimulate the development and growth of metastases. Major surgery has also been associated with immunosuppression, IGFBP-3 depletion, and increased plasma MMP-9 levels, which appear to make the early postresection period a dangerous time for patients with residual tumor cells or microfoci.15,16–18 Antiangiogenesis therapy early postsurgery is an option that would bridge the patient to the start of standard chemotherapy usually 4 to 6 weeks postoperatively. It is not clear that such therapy would be safe in this timeframe (ie, wound and anastomotic healing) or effective. Alternately, select conventional chemotherapy or one of the agents directed against EGF (monoclonal Ab or tyrosine kinase inhibitors) might be given early after surgery. Realization that the early postoperative period is dangerous from the oncologic perspective will hopefully lead to a search for safe and effective antitumor agents for this previously ignored window of time.

What is the importance, if any, of the earlier and significantly greater VEGF increase noted after open surgery when compared with minimally invasive results? If VEGF levels remain elevated for several weeks, as suspected, then a 1- or 2-day lag in the VEGF increase may be of limited importance. However, it needs to be determined whether the closed patients’ VEGF levels eventually catch up to open group values. If peak values remain significantly below the open results, then it is possible that these differences may confer an oncologic advantage to the minimally invasive patient.49

Laparoscopic surgery in humans is associated with better preserved plasma IGFBP-3 and MMP-9 levels. Increased VEGF levels in tumor bearing mice are associated with higher MMP-9 values.37 MMP-9 is associated with tumor metastases and IGFBP3 proteolysis.18 Thus, higher VEGF levels after open surgery may account for the MMP-9 increase and the greater IGFBP-3 decrease noted in these patients.17,18 There is a growing body of evidence, not substantiated in regards to oncologic outcome, that laparoscopic methods may be advantageous for cancer patients.

Presently, VEGF levels 1 to 4 weeks after major abdominal surgery are being measured to determine the duration of the VEGF increase. Further, in an effort to use the perioperative period for anticancer therapy, our group is performing a perioperative phase 1 immunotherapy study.

CONCLUSION

Major abdominal surgery is associated with significantly increased plasma VEGF levels postoperatively in both the cancer and noncancer setting regardless of the surgical method. As previously shown, the cancer group had higher baseline levels. This study documented VEGF elevations up to POD3; however, it is likely that levels remain increased for at least 1 week. The highest elevations were observed in the open gastric bypass patients reasons that are unclear. Laparoscopic methods were associated with delayed and significantly smaller VEGF level increases on POD1 and POD3 in all patient groups. Although unproven, it is possible that elevated VEGF levels after tumor resection may encourage the development or establishment of tumor metastases. The duration of the plasma VEGF elevation after surgery needs to be determined. Finally, it appears logical to develop and assess early adjuvant and/or neoadjuvant therapeutic approaches that would hopefully defend the patient against metastases during the immediate postsurgery time window.

Footnotes

Supported by a grant from the Department of Surgery at Columbia University Medical Center.

Reprints: Richard L. Whelan, MD, 630 W. 168th Street, Department of Surgery, BB1702, New York, NY 10032. E-mail: rlw3@columbia.edu.

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