P. J. Guillou

Randomized Trial of Laparoscopic-Assisted Resection of Colorectal Carcinoma: 3-Year Results of the UK MRC CLASICC Trial Group

PURPOSE The aim of the current study is to report the long-term outcomes after laparoscopic-assisted surgery compared with conventional open surgery within the context of the UK MRC CLASICC trial. Results from randomized trials have indicated that laparoscopic surgery for colon cancer is as effective as open surgery in the short term. Few data are available on rectal cancer, and long-term data on survival and recurrence are now required. METHODS The United Kingdom Medical Research Council Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (UK MRC CLASICC; clinical trials number ISRCTN 74883561) trial study comparing conventional versus laparoscopic-assisted surgery in patients with cancer of the colon and rectum. The randomization ratio was 2:1 in favor of laparoscopic surgery. Long-term outcomes (3-year overall survival [OS], disease-free survival [DFS], local recurrence, and quality of life [QoL]) have now been determined on an intention-to-treat basis. RESULTS Seven hundred ninety-four patients were recruited (526 laparoscopic and 268 open). Overall, there were no differences in the long-term outcomes. The differences in survival rates were OS of 1.8% (95% CI, -5.2% to 8.8%; P = .55), DFS of -1.4% (95% CI, -9.5% to 6.7%; P = .70), local recurrence of -0.8% (95% CI, -5.7% to 4.2%; P = .76), and QoL (P > .01 for all scales). Higher positivity of the circumferential resection margin was reported after laparoscopic anterior resection (AR), but it did not translate into an increased incidence of local recurrence. CONCLUSION Successful laparoscopic-assisted surgery for colon cancer is as effective as open surgery in terms of oncological outcomes and preservation of QoL. Long-term outcomes for patients with rectal cancer were similar in those undergoing abdominoperineal resection and AR, and support the continued use of laparoscopic surgery in these patients.

Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis

Background—In patients with major trauma and burns, total enteral nutrition (TEN) significantly decreases the acute phase response and incidence of septic complications when compared with total parenteral nutrition (TPN). Poor outcome in acute pancreatitis is associated with a high incidence of systemic inflammatory response syndrome (SIRS) and sepsis. Aims—To determine whether TEN can attenuate the acute phase response and improve clinical disease severity in patients with acute pancreatitis. Methods—Glasgow score, Apache II, computed tomography (CT) scan score, C reactive protein (CRP), serum IgM antiendotoxin antibodies (EndoCAb), and total antioxidant capacity (TAC) were determined on admission in 34 patients with acute pancreatitis. Patients were stratified according to disease severity and randomised to receive either TPN or TEN for seven days and then re-evaluated. Results—SIRS, sepsis, organ failure, and ITU stay, were globally improved in the enterally fed patients. The acute phase response and disease severity scores were significantly improved following enteral nutrition (CRP: 156 (117–222) to 84 (50–141), p<0.005; APACHE II scores 8 (6–10) to 6 (4–8), p<0.0001) without change in the CT scan scores. In parenterally fed patients these parameters did not change but there was an increase in EndoCAb antibody levels and a fall in TAC. Enterally fed patients showed no change in the level of EndoCAb antibodies and an increase in TAC. Conclusion—TEN moderates the acute phase response, and improves disease severity and clinical outcome despite unchanged pancreatic injury on CT scan. Reduced systemic exposure to endotoxin and reduced oxidant stress also occurred in the TEN group. Enteral feeding modulates the inflammatory and sepsis response in acute pancreatitis and is clinically beneficial.

Five‐year follow‐up of the Medical Research Council CLASICC trial of laparoscopically assisted versus open surgery for colorectal cancer

The UK Medical Research Council CLASICC trial assessed the safety and efficacy of laparoscopically assisted surgery in comparison with open surgery for colorectal cancer. The results of the 5‐year follow‐up analysis are presented.

Long‐term follow‐up of the Medical Research Council CLASICC trial of conventional versus laparoscopically assisted resection in colorectal cancer

Laparoscopic resection is used widely in the management of colorectal cancer; however, the data on long‐term outcomes, particularly those related to rectal cancer, are limited. The results of long‐term follow‐up of the UK Medical Research Council trial of laparoscopically assisted versus open surgery for colorectal cancer are presented.

Bladder and sexual function following resection for rectal cancer in a randomized clinical trial of laparoscopic versus open technique.

Bladder and sexual dysfunction are recognized complications of mesorectal resection. Their incidence following laparoscopic surgery is unknown.

Expression of the antiapoptosis gene, Survivin, predicts death from recurrent colorectal carcinoma

BACKGROUND/AIMS Inhibition of programmed cell death (apoptosis) is associated with increased tumour aggressiveness, and expression ofSurvivin, an antiapoptosis gene, in colorectal carcinomas may provide important prognostic information. PATIENTS/METHODS Expression of Survivin messenger RNA was evaluated by reverse transcription-polymerase chain reaction in 144 colorectal carcinomas and 86 adjacent histologically normal mucosa samples from patients for whom long term follow up data were available. RESULTS Survivintranscripts were detected in a significantly greater proportion of carcinomas (63.5%) than normal mucosa samples (29.1%; p<0.001). The prevalence of Survivin expression was independent of advancing pathological stage. Death due to recurrent cancer following curative resection was predicted independently by tumour expression of Survivin (hazard ratio (HR) 2.60; 95% confidence interval (95% CI) 1.17–5.75) and lymph node metastases (HR 2.38; 95% CI 1.21–4.70). On stage wise analysis, the predictive value of Survivin expression was limited to patients with stage II colorectal carcinomas; those with Survivin negative tumours had a five year survival rate of 94.4% compared with 44.8% for patients withSurvivin positive tumours (p=0.004, log rank test). CONCLUSION In patients with stage II colorectal carcinomas,Survivin expression provides prognostic information that may have important therapeutic implications.

Localization of cyclooxygenase-2 in human sporadic colorectal adenomas.

A putative target for the anti-colorectal cancer action of nonsteroidal anti-inflammatory drugs is the inducible isoform of cyclooxygenase (COX), COX-2. COX-2 is expressed within intestinal adenomas in murine polyposis models, but expression has been poorly characterized in human colorectal neoplasms. Therefore, we investigated the localization of the COX-2 protein in human sporadic colorectal adenomas. Immunohistochemistry for COX-2 and CD68 (a tissue macrophage marker) was performed on formalin-fixed, paraffin-embedded (n = 52) and frozen, acetone-fixed (n = 6) sections of human sporadic colorectal adenomas. Forty of 52 (77%) formalin-fixed adenomas expressed immunoreactive COX-2. COX-2 was localized to superficial interstitial macrophages in 39 cases (75%) and to deep interstitial macrophages in 9 cases (17%). COX-2 staining of dysplastic epithelial cells was observed in 15 cases (29%). A logistic regression analysis identified the adenoma site (P = 0.012) and histological type (P = 0.001) as independent predictors of superficial macrophage COX-2 expression. There was no relationship between the number of macrophages within an adenoma and macrophage COX-2 expression. These results indicate that COX-2 is expressed predominantly by interstitial macrophages within human sporadic colorectal adenomas. If COX-2 does indeed play a role in the early stages of colorectal carcinogenesis in man, these data suggest COX-2-mediated paracrine signaling between the macrophages and epithelial cells within adenomas.

Expression of survivin, a novel inhibitor of apoptosis and cell cycle regulatory protein, in pancreatic adenocarcinoma.

Survivin is unique for its expression in human malignancies but not in normal adult cells. It has been implicated in sensitisation to chemotherapy and as a prognostic marker in several common cancers. Immunohistochemistry for Survivin, P53 and BCL-2 expression as well as cell proliferative index (Ki-67) and apoptosis index (TUNEL) was conducted on 52 pancreatic and 12 ampullary adenocarcinomas. Survivin was detected in the cytoplasm of carcinoma cells in 46 (88%) of pancreatic tumours. P53 and BCL-2 were detected in 54% and 12% of pancreatic tumours, respectively. Proliferative index was 26.2±10.5% and apoptosis index was 1.38±0.69%. Prevalence of Survivin expression was significantly higher in P53-positive than in P53-negative cases (P=0.05) but was not associated with BCL-2 expression. Incrementally higher weighted scores of Survivin expression were associated with increased proliferative index (P=0.001). Furthermore, there was linear correlation between increased proliferative index and higher apoptosis index (P<0.001). Surprisingly, higher scores of Survivin expression were associated with increased apoptosis index (P=0.007). Survival characteristics were not influenced by Survivin, P53 or BCL-2 expression, apoptosis index or proliferative index. Ampullary carcinoma showed Survivin expression in 83% of cases. However, unlike pancreatic carcinoma, there was no correlation between Survivin and P53 expression or proliferative index. In conclusion, Survivin is expressed in the majority of pancreatic adenocarcinomas and correlates with both cellular proliferation and apoptosis. Molecular manipulation of Survivin expression may enhance chemotherapy and radiation therapy for pancreatic cancer.

Gut barrier function in malnourished patients.

Background—The integrity of the gastrointestinal mucosa is a key element in preventing systemic absorption of enteric toxins and bacteria. In the critically ill, breakdown of gut barrier function may fuel sepsis. Malnourished patients have an increased risk of postoperative sepsis; however, the effects of malnutrition on intestinal barrier function in man are unknown. Aims—To quantify intestinal barrier function, endotoxin exposure, and the acute phase cytokine response in malnourished patients. Patients—Malnourished and well nourished hospitalised patients. Methods—Gastrointestinal permeability was measured in malnourished patients and well nourished controls using the lactulose:mannitol test. Endoscopic biopsy specimens were stained and morphological and immunohistochemical features graded. The polymerase chain reaction was used to determine mucosal cytokine expression. The immunoglobulin G antibody response to endotoxin and serum interleukin 6 were measured by enzyme linked immunosorbent assay. Results—There was a significant increase in intestinal permeability in the malnourished patients in association with phenotypic and molecular evidence of activation of lamina propria mononuclear cells and enterocytes, and a heightened acute phase response. Conclusions—Intestinal barrier function is significantly compromised in malnourished patients, but the clinical significance is unclear.

Adhesions and incisional hernias following laparoscopic versus open surgery for colorectal cancer in the CLASICC trial

This study investigated adhesive intestinal obstruction (AIO) and incisional hernia (IH) in patients undergoing laparoscopically assisted and open surgery for colorectal cancer.