Significance of extranodal tumour deposits in colorectal cancer: A systematic review and meta-analysis.

AIMS: The presence and significance of extranodal tumour deposits (ENTDs) in colorectal cancer (CRC) continue to cause controversy in terms of origin, classification and prognostic significance. This review aims to assess current evidence on the origin of ENTDs in CRC and their effect on overall and disease-free survival. METHODS: A systematic review and meta-analysis were carried out in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. End-points included prevalence of ENTDs, relationship with extramural venous invasion (EMVI), overall survival (OS) and disease-free survival (DFS). Pooled hazard ratios (HRs) and odds ratios (ORs) were calculated using Stata software. RESULTS: Twenty-six studies comprising 19,980 patients were included. The prevalence of ENTDs ranged from 10.2% to 44.2% (median 21.3%). There was a significantly increased odds of having ENTD if EMVI was present with a pooled OR of 2.51 (95% CI 2.27-2.77) p ≤ 0.001. The pooled HR for adverse OS in patients with ENTD was 1.63 (95% CI 1.44-1.61), p ≤ 0.001. For adverse DFS the pooled HR was 1.77 (95% CI 1.37-2.11), p ≤ 0.001. CONCLUSION: This meta-analysis confirms the negative impact of ENTDs on OS and DFS despite variations in classification and prevalence. ENTDs are significantly associated with EMVI. The prognostic implications of ENTDs are not sufficiently recognised in current staging systems. TNM 8 has failed to address this and has not made use of the available evidence to determine the correct position of ENTDs according to their prognostic effect. The prognostic hierarchy should be N0, N1, N2 with N1c being the most severe. Additionally the exclusion of lesions of vascular, lymphatic and perineural origin by TNM 8 has no evidence base.

Loss of expression and promoter methylation of SLIT2 are associated with sessile serrated adenoma formation.

Serrated adenomas form a distinct subtype of colorectal pre-malignant lesions that may progress to malignancy along a different molecular pathway than the conventional adenoma-carcinoma pathway. Previous studies have hypothesised that BRAF mutation and promoter hypermethylation plays a role, but the evidence for this is not robust. We aimed to carry out a whole-genome loss of heterozygosity analysis, followed by targeted promoter methylation and expression analysis to identify potential pathways in serrated adenomas. An initial panel of 9 sessile serrated adenomas (SSA) and one TSA were analysed using Illumina Goldengate HumanLinkage panel arrays to ascertain regions of loss of heterozygosity. This was verified via molecular inversion probe analysis and microsatellite analysis of a further 32 samples. Methylation analysis of genes of interest was carried out using methylation specific PCR (verified by pyrosequencing) and immunohistochemistry used to correlate loss of expression of genes of interest. All experiments used adenoma samples and normal tissue samples as control. SSA samples were found on whole-genome analysis to have consistent loss of heterozygosity at 4p15.1-4p15.31, which was not found in the sole TSA, adenomas, or normal tissues. Genes of interest in this region were PDCH7 and SLIT2, and combined MSP/IHC analysis of these genes revealed significant loss of SLIT2 expression associated with promoter methylation of SLIT2. Loss of expression of SLIT2 by promoter hypermethylation and loss of heterozygosity events is significantly associated with serrated adenoma development, and SLIT2 may represent a epimutated tumour suppressor gene according to the Knudson "two hit" hypothesis.

Straight to colonoscopy: the ideal patient pathway for the 2-week suspected cancer referrals?

INTRODUCTION: The UK has a higher mortality for colon cancer than the European average. The UK Government introduced a 2-week referral target for patients with colorectal symptoms meeting certain criteria and 62-day target for the delivery of treatment from the date of referral for those patients diagnosed with cancer. Hospitals are expected to meet 100% and 95% of these targets, respectively; therefore, an efficient and effective patient pathway is required to deliver diagnosis and treatment within this period. It is suggested that 'straight-to-test' will help this process and we have examined our implementation of 'straight-to-colonoscopy' as a method of achieving this aim. PATIENTS AND METHODS: We carried out a retrospective audit of 317 patients referred under the 2-week rule over a 1-year period between October 2004 and September 2005 and were eligible for 'straight-to-colonoscopy'. Demographic data, appropriateness of referral and colonoscopy findings were obtained. The cost effectiveness and impact on waiting period were also analysed. RESULTS: A total of 317 patients were seen within 2 weeks. Cancer was found in 23 patients and all were treated within 62 days. Forty-four patients were determined by the specialist to have been referred inappropriately because they did not meet NICE referral guidelines. No cancer was found in any of the inappropriate referrals. The use of straight-to-test colonoscopy lead to cost savings of £26,176 (£82.57/patient) in this group compared to standard practice. There was no increase in waiting times. CONCLUSIONS: Straight-to-colonoscopy for urgent suspected cancer referrals is a safe, feasible and cost-effective method for delivery of the 62-day target and did not lead to increase in the endoscopy waiting list.

Use of plasma MMP-2 and MMP-9 levels as a surrogate for tumour expression in colorectal cancer patients.

Matrix metalloproteinases, and notably the gelatinases MMP-2 and MMP-9, have important roles in tumour invasion, metastasis and angiogenesis. Our study investigates the distribution of MMP-2 and MMP-9 in colorectal cancer, the correlation with plasma levels, changes following surgical resection and whether plasma levels reflect clinical staging and disease course. MMP-2 and MMP-9 expression in 48 colorectal tumours and 13 adenomatous polyps was analysed by RT-PCR, immunohistochemistry, and quantified by ELISA of tumour lysates. Concentrations of MMP-2 and MMP-9 in plasma samples from these patients and 36 other patients who underwent curative resections were measured by ELISA prior to and 6-12 months after surgery. MMP-2 expression was significantly increased in colorectal cancer tissues compared to matched normal colon as measured by ELISA. Active MMP-2 was localised by immunohistochemistry to regions where tumour cells invaded the muscularis with little staining in more superficial areas. Plasma MMP-2 levels were also significantly elevated in patients with colorectal cancer, with significant reductions following curative resections at all stages. Similarly, MMP-9 expression was significantly increased in colorectal cancer tissues, predominantly in the tumour stroma. Plasma levels of MMP-9 were significantly elevated at all stages in colorectal cancer patients and a significant reduction was seen following curative resections. With both MMP-2 and MMP-9, the strongest correlation with clinical staging in colorectal cancer was represented by the total plasma concentration of the enzymes, both falling to within the normal range following curative surgery. Plasma levels of these enzymes may therefore have potential as a noninvasive indicator of invasion or metastasis in colorectal cancer or as a marker of disease status during follow-up.