In cancer patients, surgical removal of the primary tumor is one of the major steps within a multimodal therapy concept toward eliminating the disease and limiting further progression. In this respect, surgical trauma can have potent effects on the patient's immune system. Intraoperative blood loss associated with major surgical trauma leads to reduced blood flow, regional hypoxia, metabolic, and microenvironmental alterations stimulating an inflammatory response characterized by the release of pro-inflammatory cytokines (i.e., TNF-α, IL-6) and acute-phase proteins. The inflammatory state is accompanied by and intertwined with a counter-regulatory anti-inflammatory response reflected in the rise of anti-inflammatory cytokines (i.e., transforming growth factor-β) and prostaglandins (i.e., prostaglandin E2) which can lead to a depression of cell-mediated immunity and systemic immunosuppression. This results in a highly vulnerable state with concurrent expression of pro- and anti-inflammatory cytokines alternately predominating. The immunosuppressive state is characterized by a reduced antigen-presentation capacity of macrophages, alterations in lymphocyte proliferation, and activation as well as a shift of the Th1/Th2 (T helper cells 1 and 2) balance toward Th2 and a decrease in natural killer cell activity. The severity of the immunosuppression thereby correlates with the extent and the duration of the surgical procedure. Growing evidence suggests that the immunosuppressive state following hemorrhage and surgical trauma might not only be a risk factor for postoperative complications but also facilitate tumor proliferation, metastatic growth, and recurrence. This article provides an overview of the cascade of events and underlying mechanisms resulting in immunosuppression and describes the impact of hemorrhage and major surgical trauma on tumor growth and recurrence. Attempts to control for perioperative inflammation thereby reducing the adverse effects of postoperative immunosuppression could have positive effects on tumor growth, metastasis formation, and recurrence.

Laparoscopic surgery has been associated with many short-term benefits such as a shorter time to recovery, return of bowel function, less pain, and a decrease in wound infection rate. Several animal and human experiments have demonstrated an immunologic and oncologic benefit of minimally invasive surgery. Whether these results will translate into similar results in human settings is unclear. Although the first published prospective randomized clinical trial suggests better long-term outcomes for patients undergoing laparoscopic surgery, results from other ongoing randomized, controlled clinical trials are needed to verify this controversial result.

A total of 90 weanling female pigs (Duroc x Landrace x Yorkshire) were used in a 30-d growth experiment to investigate the effect of lactoferrin (LF) on growth performance, immune function, and serum iron concentrations. The pigs were allocated on the basis of BW and litter to 3 dietary treatments in a randomized complete block design. The dietary treatments were: control group (basal diet), antibiotics group (basal diet + 20 mg/kg of flavomycin + 110 mg/kg of aureomycin), and LF group (basal diet + 1.0 g/kg of LF). There were 3 replicate pens per treatment, and pigs were grouped with 10 pigs per pen. Six pigs, randomly selected from each treatment (2 pigs/pen), were slaughtered for serum and spleen samples on d 15 and 30. Supplementation with LF improved the phytohemagglutinin (PHA)-stimulated peripheral lymphocyte proliferation by 36% (P < 0.01), increased concanavalin A (ConA)- and PHA-induced spleen lymphocyte proliferation by 332% (P < 0.01) and 258% (P < 0.01), enhanced serum IgG by 20% (P < 0.05), IgA by 13% (P < 0.05), IgM by 15% (P < 0.05), complement 4 (C4) by 29% (P < 0.05), IL-2 by 12% (P < 0.01), and serum iron values by 22% (P < 0.05) on d 15 compared with the control. Lactoferrin supplementation increased PHA-stimulated lymphocyte proliferation (P < 0.01), serum IgG by 16% (P < 0.05), IgA by 17% (P < 0.05), C4 by 11% (P < 0.05), IL-2 by 14% (P < 0.05), and serum iron values by 23% (P < 0.01), and decreased the diarrhea ratio (P < 0.05) relative to the control on d 30. Compared with the controls, supplementation with antibiotic increased ConA- and PHA-induced spleen lymphocyte proliferation (P < 0.05) on d 15, decreased the diarrhea ratio (P < 0.05), and increased the PHA-induced spleen lymphocyte proliferation (P < 0.05) and serum iron values (P < 0.01) on d 30. These results support the possible use LF as an immunostimulant to improve immune functions and strengthen host defenses and would seem to be a good method for defending weanling piglets from infections and weanling stress.

Surgical trauma depresses cell-mediated immunity of a duration and magnitude proportional to the degree of injury. However, the cellular mechanism underlying this effect is poorly understood. Microarrays were used to survey gene expression in murine splenic T-cells after pneumoperitoneum and laparotomy.

C3H/HeJ mice were assigned randomly to undergo anesthesia alone, sham laparotomy, or CO(2) pneumoperitoneum and sacrificed 12 or 24 hours later. RNA was isolated from purified splenic T-cells and hybridized to Affymetrix oligonucleotide microarrays.

Relative to anesthesia, 116 genes after pneumoperitoneum and 398 genes after laparotomy showed a > or =2-fold change in expression at 12 hours. One hundred thirty-two genes after pneumoperitoneum and 157 genes after laparotomy met those criteria at 24 hours. Comparing surgical modalities, 177 genes were increased and 15 decreased > or =2-fold after laparotomy relative to pneumoperitoneum at 12 hours, compared with 44 and 5 genes respectively at 24 hours. Expression changes for 8 genes were validated by quantitative real-time polymerase chain reaction.

Laparotomy and pneumoperitoneum alter splenic T-cell gene expression, with the most extensive changes occurring 12 hours after laparotomy. This study is one of the first comprehensive genomic studies of the molecular effects of surgical manipulation on immune function. The genes identified are potential targets for modulating the immune response to surgery.

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. Surgery-related immunosuppression may be partly responsible for the differences in cancer growth and outcome noted. It is clear that the choice of abdominal surgical approach has immunologic consequences. Further studies are needed to better the time course and extent of surgery-related alterations in the immune system and their clinical importance. A better understanding of the impact of surgery on the immune system may provide opportunities for pharmacologic manipulation of postoperative immune function to improve clinical results.

Several studies reporting preliminary long-term survival data after laparoscopic resections for colonic adenocarcinoma did not show any detrimental effect in comparison with historic studies of laparotomies. A previous randomized study has reported an unforeseen better long-term survival for node-positive patients treated by laparoscopic colectomy.

A single-institution prospective nonrandomized trial compared short- and long-term results of laparoscopic and open curative resection for adenocarcinoma of the left colon or rectum in 255 consecutive patients from January 1996 to December 2000.

In this study, 34 left hemicolectomy, 202 anterior resections, and 19 abdominoperineal resections were performed. A total of 74 patients underwent a laparoscopic resection (LR), and 181, an open resection (OR). The tumor site was the descending colon in 32 cases, the sigmoid colon in 98 cases, and the rectum in 125 cases, including 87 mid-low rectal cancers. Ten LR procedures (13.5%) were converted to open surgery. The hospital mortality was 0.08%, and in hospital morbidity was 16.2% for LR and 13.3% for OR (p = 0.56). The median postoperative stay was 1 day shorter for LR (9 days) than for OR (10 days) (p = 0.09). The mean number of lymph nodes retrieved were 13.8 +/- 5.7 for OR and 12.7 +/- 5; for LR (p = 0.23). Age exceeding 70 years, T stage, N stage, grading, mid-low rectal site, and laparoscopy were found by multivariate analysis to be significant prognostic factors for disease-free and cancer-related survival. When patients were stratified by stage, a trend toward a better disease-free and cancer-related survival was identified in stage III patients undergoing LR.

Laparoscopic colonic resection is a safe procedure in terms of postoperative outcome and long-term survival. Multivariate analysis showed that laparoscopy is a positive prognostic factor for disease-free and cancer-related survival. The current data agrees with the data for the only randomized study reported so far. Both suggest a better outcome for node-positive patients treated by laparoscopy.

Laparoscopic surgery is associated with reduced surgical trauma, and therefore with a less acute phase response, as compared with open surgery. Impairment of the immune system may enhance surgical infections, port-site metastases, and sepsis. The objectives of this review was to assess immunologic consequences of benign laparoscopic surgery and to highlight controversial aspects.

A literature search on stress response to nonmalignant laparoscopic and open surgery was conducted using the MEDLINE and Cochrane databases. Cross-references from the reference list of major articles on the subject were used, as well as manuscripts published between 1993 and 2002.

Local (i.e., peritoneal) immune function is affected by carbon dioxide pneumoperitoneum. The production of tumor necrosis factor and the phagocytotic capacity of peritoneal macrophages are less lowered. The systemic stress response, as determined by delayed-type hypersensitivity response and leukocyte antigen expression on lymphocytes, shows a preservation of immune function after laparoscopic surgery, as compared with conventional surgery.

Intraperitoneal carbon dioxide insufflation attenuates peritoneal immunity, but laparoscopic surgery is associated with a lower systemic stress response than open surgery.

It has been well established that open abdominal surgery results in systemic immunosuppression postoperatively; in contrast, laparoscopic surgery is associated with significantly better preserved systemic immune function. However, when intraperitoneal (local) immune function is considered, laparoscopic procedures done under a CO2 pneumoperitoneum (pneumo) have been shown to result in greater immunosuppression compared to that of open surgery. Few studies have simultaneously assessed systemic and local immune function. The purpose of this study was to assess peripheral blood mononuclear cell (PBMC) and peritoneal macrophage tumor necrosis factor-alpha (TNF-alpha) levels, H2O2 production, and MHC class II antigen expression after open and laparoscopically assisted cecectomy in a rat model.

A total of 75 Sprague Dawley rats were used for three separate experiments. For each study, rats were randomly divided into three groups: anesthesia alone (AC), laparoscopic-assisted cecectomy (LC), and open cecectomy via full laparotomy (OP). A CO2 pneumo was used for laparoscopic operations. On postoperative day 1 the animals were sacrificed, macrophages were harvested via intraperitoneal lavage, and PBMCs were isolated from whole blood obtained by cardiac puncture. In experiment 1, macrophages and PBMC from each animal were stimulated with lipopolysaccharide, after which TNF-alpha levels of the supernatant were determined. In experiment 2, after stimulation with PMA, H2O2 release was assessed by measuring fluorescence. In experiment 3, via flow cytometry, the number of cells with surface MHC class II proteins were determined. Data from the three groups in each experiment were compared using analysis of variance Tukey-Kramer tests.

Macrophages and PBMC from rats in the OP group released significantly more TNF-alpha than cells from rats in the LC ( p < 0.05) or AC ( p < 0.05) groups. Macrophages from rats in the OP group released significantly less H2O2 than cells from the AC ( p < 0.01) and LC ( p < 0.05) groups. There was no difference between the AC and LC results. No significant differences in PBMC H2O2 release were noted among any of the groups. OP group macrophages expressed significantly less MHC class II antigen than did AC group macrophages ( p < 0.05). No differences were noted among the LC results and either the OP or AC group's outcomes. No differences were noted in PBMC MHC class II expression among any of the groups.

In all instances, the LC group's macrophage results were similar to the AC group's results. OC group macrophages produced significantly more TNF-alpha and less H2O2 than both the AC and LC groups. MHC class II protein expression was less for the OC group than for the AC group. OC group PBMCs produced more TNF-alpha. No differences in PBMC H2O2 release or MHC class II expression were noted. Laparoscopic methods better preserves the baseline values of the parameters studied.

Laparoscopic surgery is believed to lessen surgical trauma and so cause less disturbance of immune function. This may contribute to the rapid recovery noted after many laparoscopic operations. Preservation of both systemic and intraperitoneal immunity is particularly important in surgery for sepsis or cancer and so an understanding of the impact of laparoscopy on immune function is relevant.

Literature on immunological changes following laparoscopy and open surgery was identified from Medline, along with cross-referencing from the reference lists of major articles on the subject.

Despite a few contradictory reports, systemic immunity appears to be better preserved after laparoscopic surgery than after open surgery. However, the local intraperitoneal immune system behaves in a particular way when exposed to carbon dioxide pneumoperitoneum; suppression of intraperitoneal cell-mediated immunity has been demonstrated in a number of studies. This feature may be clinically important and should be acknowledged when considering laparoscopic surgery in patients with malignancy or sepsis.

The incidence of the spread of ovarian cancer after laparoscopic surgery is difficult to establish from the current literature. The prognosis incidence of a trocar site metastasis without peritoneal dissemination is not known. Data from general surgeons in prospective studies from a single institution suggested that in colon cancer the risk is low, whereas it seems to be much higher in multicentric studies of undiagnosed gallbladder cancer. Experimental studies suggested that laparoscopy has advantages and disadvantages. However, the risk of dissemination is high when a large number of malignant cells and a carbon dioxide pneumoperitoneum are present, a situation encountered when managing adnexal tumours with large vegetations. Animal studies will allow the development of a peritoneal environment adapted to the treatment of cancer. The ovary is an intraperitoneal organ and ovarian cancer a peritoneal disease, so the risk of peritoneal spread may be higher in ovarian cancer than in other gynecological cancers. A careful preoperative evaluation appears to be the best way to prevent these risks. It should also be used to choose which patient should be operated by which surgical team. The second step is a careful and cautious laparoscopic diagnosis, so that more than 98% of ovarian cancers encountered can be treated immediately and effectively. The laparoscopic management of ovarian cancer remains controversial; it should be performed only in prospective clinical trials. Until the results of such studies become available, an immediate vertical midline laparotomy remains the gold standard if a cancer is encountered.