SILS colorectal resection is feasible and safe when performed by an experienced laparoscopic surgeon and theatre team. It may have advantages over conventional laparoscopic surgery in terms of reduced pain, lower cost, faster recovery and cosmesis.

No abstract

CDC4/FBXW7 is part of a ubiquitin ligase complex which targets molecules such as cyclin E, c-myc, and c-jun for destruction. CDC4 mutations occur in several cancer types and are best described in colorectal tumors. Knockout of CDC4 in vitro in colorectal cancer cells causes changes suggestive of chromosomal instability (CIN). In p53 +/À mice, radiation-induced lymphomas show deletion or mutation of one copy of CDC4 and knockdown of CDC4 leads to increased aneuploidy in mouse fibroblasts. We screened 244 colorectal tumors and 40 cell lines for CDC4 mutations and allelic loss. Six percent (18 of 284) of tumors, including near-diploid (CINÀ) lesions, harbored CDC4 mutations and there was no association between mutation and CIN (polyploidy). The CDC4 mutation spectrum in colorectal tumors was heavily biased towards C:G>T:A changes, either missense mutations at critical arginine residues or nonsense changes in the 5V half of the gene. The reasons for this odd mutation spectrum were unclear but C:G>T:A changes were not found more often than expected at APC, K-ras, or p53 in the same tumors and we found no specific defects in DNA repair to account for the observations. No colorectal tumor was found to carry two CDC4 mutations predicted to abolish protein function; partial loss of CDC4 function may therefore cause tumorigenesis. The in vitro studies, therefore, did not assess the functional effects of mutant alleles which are found in vivo. CDC4 mutations may be selected primarily to drive progression through the cell cycle although CIN might be an important secondary effect in some cancers. (Cancer Res 2005; 65(24): 11361-6)

Laparoendoscopic single-site colorectal resection using conventional instrumentation is feasible and safe when performed by an experienced team. The LESS approach may have advantages in terms of minimal pain, cosmesis, lower costs, and faster recovery. A randomized trial is required to confirm whether LESS offers a true patient benefit over standard laparoscopic resection.

The seminal 'two-hit hypothesis' implicitly assumes that bi-allelic tumour suppressor gene (TSG) mutations cause loss of protein function. All subsequent events in that tumour therefore take place on an essentially null background for that TSG protein. We have shown that the two-hit model requires modification for the APC TSG, because mutant APC proteins probably retain some function and the two hits are co-selected to produce an optimal level of Wnt activation. We wondered whether the optimal Wnt level might change during tumour progression, leading to selection for more than two hits at the APC locus. Comprehensive screening of a panel of colorectal cancer (CRC) cell lines and primary CRCs showed that some had indeed acquired third hits at APC. These third hits were mostly copy number gains or deletions, but could be protein-truncating mutations. Third hits were significantly less common when the second hit at APC had arisen by copy-neutral loss of heterozygosity. Both polyploid and near-diploid CRCs had third hits, and the third hits did not simply arise as a result of acquiring a polyploid karyotype. The third hits affected mRNA and protein levels, with potential functional consequences for Wnt signalling and tumour growth. Although some third hits were probably secondary to genomic instability, others did appear specifically to target APC. Whilst it is generally believed that tumours develop and progress through stepwise accumulation of mutations in different functional pathways, it also seems that repeated targeting of the same pathway and/or gene is selected in some cancers.

Rates of detection of dysplasia can be improved by chromoendoscopy. Molecular genetics has the potential to identify patients most at risk of cancer and can differentiate between different types of lesion.

Anastomotic leaks following colorectal surgery may be divided into those which are clinically significant and those which are not. Leakage occurs in 3.4-6% of all colorectal cases. It is most commonly associated with rectal anastomoses, being clinically significant in 2.9-15.3% of cases. Mortality following a leak may be 6.0-39.3%. There is no evidence that preoperative bowel preparation reduces the rate and consequences of leaks. There is no evidence for the use of drains when an anastomosis has been made outside the pelvis, but pelvic drainage may be important after anterior resection. The use of covering stomas has not been shown to reduce leak rate but does mitigate the clinical effects of leaks. Prompt diagnosis and further laparotomy can reduce mortality following leakage. Intra-abdominal abscesses can in most cases be treated by radiologically guided drainage. Anastomotic leaks are the most common cause of anastomotic strictures and are also associated with increased rates of local recurrence of cancer.

Major revisional surgery for symptomatic retained rectal stump after restorative proctocolectomy with stapled anastomosis was successful in 15 of 22 patients. These results are worse than the outcome following first-time restorative proctocolectomy with anastomosis constructed at the anal level. Pouch-rectal anastomosis should be avoided.