Immunologic Aspects Of Laparoscopic Urology

Fornara et al. (86) reported a prospective, controlled, nonrandomized animal and patient study to determine the systemic response to laparoscopic and open surgical procedures. In the animal study, 26 female pigs aged six months underwent either a laparoscopic bilateral varix ligation followed by bilateral nephrectomy (group I), introduction of trocars (group II), or establishment of an open surgical approach (group III). In the patient study, 145 patients underwent various laparoscopic procedures (unilateral nephrectomy =17, bilateral laparoscopic nephrectomy = 7, renal cyst marsupialization = 29, varix ligation = 17), open surgical procedures (nephrectomy = 42, inguinal orchidectomy = 8), or extracorporeal shockwave lithotripsy = 25). A weakness of this study is the fact that the patient groups are not evenly matched. IL-6, IL-10, and C-reactive protein were measured before, during, and after the operative procedure. In animals and patients, laparoscopy resulted in significantly lower serum levels of C-reactive protein during and in the postoperative period. Animals in group I showed a five-fold elevation, in group II a three-fold elevation, and in group III a nine-fold elevation of C-reactive protein. In patients, C-reactive protein was twice as high after open unilateral nephrectomy than after laparoscopic unilateral or bilateral nephrec-tomy. Elevation of IL-6 was less pronounced during laparoscopy, extracorporeal shockwave lithotripsy, and minor procedures like laparoscopic varix ligation or inguinal orchidectomy when compared to an open unilateral nephrectomy. IL-10 was not significantly different among the patient groups (Figs. 4 and 5). The authors concluded that the acute-phase response to operative trauma correlated more to the approach than to the extent of the procedure. Larger operations like nephrectomy trigger a marked systemic acute-phase reaction, which can be reduced by laparoscopic access. In minor operative procedures like varix ligation or exploration of cryp-torchidism, laparoscopy offers technical advantages rather than minimal invasiveness as the immune response in these situations is much less.

The above findings were contradicted in a prospective study by Landman et al. (87). They compared the systemic immune and stress response of patients who underwent laparoscopic total nephrectomy and open nephrectomy for renal cell carcinoma (10,14). Unlike Fornara et al., this study concentrated on nephrectomy only for renal cancer rather than a comparison with other procedures. The open nephrectomy group comprised open radical (four), open total (two), and open partial (four) nephrectomies. Peripheral venous blood was collected preoperatively, intraoperatively, and at 24 hours, two weeks, four weeks, and three months postoperatively. Patients who had postoperative infection or illness in the three-month period following surgery were excluded

FIGURE4 ■ IL-6 levels in laparoscopic (group V) or open nephrectomy (group VII). TO = 24 hours preoperative, T1 = beginning of anesthesia, T2 = trocar insertion/skin incision, T3 = pneumoperi-toneum/peritoneal incision, T4 = ligation of renal artery, T5 = end of procedure, T6 = six hours postoperative, T7 = 12 hours postoperative, T8 = 24 hours postoperative. Abbreviation: IL, inter leukin. Source: From Ref. 86.

FIGURE5 ■ CRP serum levels of group I = ESWL, group II = lap varix ligation, group III = lap renal cyst marsupialization, group IV = open inguinal orchidectomy, group V = lap unilateral nephrectomy, group VI = lap bilateral nephrectomy, group VII = open unilateral nephrectomy from T5-8 (T5 = trocar removal/wound closure, T6 = six hours postoperative, T7 = 12 hours postoperative, T8 = 24 hours postoperative). Abbreviation: CRP, C reactive protein. Source: From Ref. 86.

FIGURE4 ■ IL-6 levels in laparoscopic (group V) or open nephrectomy (group VII). TO = 24 hours preoperative, T1 = beginning of anesthesia, T2 = trocar insertion/skin incision, T3 = pneumoperi-toneum/peritoneal incision, T4 = ligation of renal artery, T5 = end of procedure, T6 = six hours postoperative, T7 = 12 hours postoperative, T8 = 24 hours postoperative. Abbreviation: IL, inter leukin. Source: From Ref. 86.

FIGURE5 ■ CRP serum levels of group I = ESWL, group II = lap varix ligation, group III = lap renal cyst marsupialization, group IV = open inguinal orchidectomy, group V = lap unilateral nephrectomy, group VI = lap bilateral nephrectomy, group VII = open unilateral nephrectomy from T5-8 (T5 = trocar removal/wound closure, T6 = six hours postoperative, T7 = 12 hours postoperative, T8 = 24 hours postoperative). Abbreviation: CRP, C reactive protein. Source: From Ref. 86.

from study. Blood from these patients was analyzed for stress markers (adrenalin, nora-drenalin, and Cortisol), inflammatory response markers (C-reactive protein, white blood count, and leukocyte count), lymphocytic response markers (CD3, CD4, and CD8), cytokines (IL2 and IL4, INFa and tumor necrosis factora), human leucocyte antigen-DR expression, and the proliferative response to mitogen stimulation using concanavalin A, phytohemagglutinin 10, and pokeweed mitogen. Unlike in other studies IL6 levels were not measured. Tumor histopathology and Fuhrman grade were similar between the two groups although mean tumor size was nonsignificantly smaller for the laparoscopic total nephrectomy group compared to the open nephrectomy group [4.5 ± 1.6 and 5.6 ± 2.4 cm, respectively (p = 0.21)]. Inflammatory and stress response markers were statistically similar for the groups at the measured time points. A significant difference between the groups was noted for the percentage and ratio of CD4+ and CD8+ lymphocytes, which is an indicator of immune activation of helper T cells. The ratios of CD4+:CD8+ were 2.7:1 for laparoscopic total nephrectomy and 1.8:1 for open nephrectomy. However, this difference was present preoperatively and sustained at all time points, thus being unlikely to represent a surgery-specific response. The cytokine response, HLA-DR, lymphocytic stimulation index for concanavalin A, phytohemag-glutinin 10, and pokeweed mitogen were statistically similar for LRN and open nephrectomy at all time points. Age group analysis did show differences between the cohorts with respect to CD4+ and CD8+ lymphocytes in the 60 to 80-year olds. Additionally, in this age group intraoperative human leucocyte antigen-DR expression and tumor necrosis factora production were higher in those undergoing open nephrec-tomy. In the 40 to 60-year-old group, the authors found higher 24-hour cortisol for open nephrectomy, percent CD4+ lymphocytes for laparoscopic total nephrectomy, and higher three-month proliferative capacity for laparoscopic total nephrectomy, as assessed by the phytohemagglutinin 10 index. These changes are shown in Figures 6-11. This study concluded that immunological and stress responses after laparoscopic total nephrectomy and open nephrectomy for renal cell carcinoma were similar and the few changes observed were likely to reflect preoperative changes or the effects of anesthesia. Perhaps longer anesthetic times for laparoscopic total nephrectomy masked any potential differences. It would have been useful if blood samples had been taken every 30 minutes during surgery while the patients were anesthetized to substantiate this

FIGURE6 ■ Stress response after laparoscopic (lap) and open nephrectomy for localized renal cell carcinoma. Source: From Ref. 87.

FIGURE 7 ■ Inflammatory response after laparoscopic (lap) and open nephrectomy for localized renal cell carcinoma. Source: From Ref. 87.

FIGURE6 ■ Stress response after laparoscopic (lap) and open nephrectomy for localized renal cell carcinoma. Source: From Ref. 87.

FIGURE 7 ■ Inflammatory response after laparoscopic (lap) and open nephrectomy for localized renal cell carcinoma. Source: From Ref. 87.

FIGURE8 ■ Lymphocytic response after laparoscopic (lap) and open nephrectomy for localized renal cell carcinoma. Source: From Ref. 87.
FIGURE9 ■ HLA-DR response after laparoscopic (lap) and open nephrectomy for localized renal cell carcinoma. Source: From Ref. 87.

hypothesis. Preoperative immune dysfunction in renal cell carcinoma is known to be complex (88,89) and the findings of this study thus come as a surprise and do not explain the quicker short- and long-term recovery in patients undergoing laparo-scopic total nephrectomy. It is feasible that for less extensive procedures, such as laparoscopic cholecystectomy, the laparoscopic approach is immunologically superior. In contrast, ablative laparoscopic renal surgery is quite extensive and may not have a definite immunological benefit, as assessed by current techniques to measure the immune response. Another possible explanation for the discrepancy may be the biology of renal cell carcinoma. It is feasible that the malignant disease process results in a significant alteration in immune function, such that differences between laparoscopic total nephrectomy and open nephrectomy are not detectable. Similar findings have been reported in randomized trails of surgery in colonic malignancy. Tang et al. (73) observed no difference in the immune response in laparoscopic-assisted versus open sigmoidectomy for colorectal cancer and Leung et al. (27) noted differences in the stress response but no differences in the immune response.

FIGURE 10 ■ Cytokine response after laparoscopic (lap) and open nephrectomy for localized renal cell carcinoma. Source: From Ref. 87.

FIGURE 11 ■ Mitogen proliferative response after laparoscopic (lap) and open nephrectomy for localized renal cell carcinoma. Source: From Ref. 87.

FIGURE 10 ■ Cytokine response after laparoscopic (lap) and open nephrectomy for localized renal cell carcinoma. Source: From Ref. 87.

FIGURE 11 ■ Mitogen proliferative response after laparoscopic (lap) and open nephrectomy for localized renal cell carcinoma. Source: From Ref. 87.

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