Meta association of colorectal cancer confirms risk alleles at 8q24 and 18q21.

BACKGROUND: Genome-wide association studies of colorectal cancer (CRC) have identified genetic variants that reproducibly associate with CRC. Associations of 12 single nucleotide polymorphisms at 8q24, 9p24, and 18q21 (SMAD7) and CRC were investigated in a three-center collaborative study including two U.K. case-control cohorts (Sheffield and Leeds) and a U.S. case-control study of CRC cases from high-risk Utah pedigrees. METHODS: Our combined resource included 1,092 CRC case subjects and 1,060 age- and sex-matched controls. Meta statistics and Monte Carlo significance testing using Genie software provided a valid combined analysis of our mixed independent and related case-control resource. We also evaluated whether these associations differed by sex, age at diagnosis, family history, or tumor site. RESULTS: At 8q24, we observed two independent significant associations at single nucleotide polymorphisms located in two different risk regions of 8q24: rs6983267 in region 3 [P(trend) = 0.01; per allele odds ratio (OR), 1.17; 95% confidence intervals (95% CI), 1.03-1.32] and rs10090154 in region 5 (P(trend) = 0.05; per allele OR, 1.24; 95% CI, 1.01-1.51). At 18q21, associations were observed in distal colon tumors but not in proximal or rectal cancers: rs4939827 (P(trend) = 0.007; per allele OR, 0.77; 95% CI, 0.64-0.93; case-case p(diff) = 0.03) and rs12953717 (P(trend) = 0.01; per allele OR, 1.27; 95% CI, 1.06-1.52). We were unable to detect any associations at 9p24 with CRC. CONCLUSIONS: Our investigation confirms that variants across multiple risk regions of 8q24 are associated with CRC, and that associations at 18q21 differ by tumor site.

MLH1 -93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer.

Rare inherited mutations in the mutL homolog 1 (MLH1) DNA mismatch repair gene can confer an increased susceptibility to colorectal cancer (CRC) with high penetrance where disease frequently develops in the proximal colon. The core promoter of MLH1 contains a common single nucleotide polymorphism (SNP) (-93G>A, dbSNP ID:rs1800734) located in a region essential for maximum transcriptional activity. We used logistic regression analysis to examine the association between this variant and risk of CRC in patients in the United Kingdom. All statistical tests were 2 sided. In an analysis of 1,518 patients with CRC, homozygosity for the MLH1 -93A variant was associated with a significantly increased 3-fold risk of CRC negative for MLH1 protein by immunohistochemistry (odds ratio (OR): AA vs GG = 3.30, 95% CI 1.46-7.47, n = 1392, p = 0.004, MLH1 negative vs MLH1 positive CRC) and with a 68% excess of proximal CRC (OR: AA vs GG=1.68, 95% confidence interval (CI) 1.00-2.83, n = 1,518, p = 0.05, proximal vs distal CRC). These findings suggest that the MLH1 -93G>A polymorphism defines a low penetrance risk allele for CRC.

Short- and long-term outcomes following pelvic exenteration for gynae-oncological and colorectal cancers: A 9 year consecutive single-centre cohort study.

OBJECTIVES: Radical pelvic exenteration can be undertaken for locally invasive or recurrent disease in both colorectal and gynaecological malignancies. In the UK this procedure is usually undertaken by the respective surgical specialties who have undergone divergent surgical training. This study describes and compares outcomes between colorectal and gynae-oncological teams following pelvic exenteration for primary and recurrent gynaecological and colorectal cancers in a single-centre multi-disciplinary team. METHOD: A retrospective review of consecutive pelvic exenteration patients undertaken over a nine-year period in a tertiary referral centre. Analyses comparing short- and long-term morbidity and mortality outcomes were undertaken by chi-square test for categorical variables and Mann-Whitney U for continuous variables. Cumulative survival rates were calculated according to the Kaplan-Meier method and factors associated with recurrence and survival determined using a Cox regression model. RESULTS: Thirty-four exenterations were undertaken; fourteen colorectal and twenty gynae-oncological. Morbidity was seen in 50% of colorectal and 75% of gynae-oncological patients. Recurrence was seen earlier and with greater frequency in the gynaeoncology group (44.4% and median time 11 months) than the colorectal group (21.4%, median time 41 months; p > 0.05). Survival in the gynae-oncology group was also lower than the colorectal group at 1-year (69.6% vs. 92.9%) and 5-years (58.0% vs. 92.9%; p = 0.115). The majority of gynae-oncological mortality occurred within 3-years of surgery, whilst the majority of mortality in the colorectal group was after 5-years. CONCLUSION: Long-term patient outcome measures, including disease recurrence and 5-year survival, for colorectal exenteration appear better than for gynaeoncology patients, however, no statistical significant difference exists between short-term outcome measures between specialties. This is likely to be caused by different baseline pathologies and disease pattern influencing longer term prognosis but may also be a function of differing surgical thresholds and patient selection bias between specialties. Peri-operative and short-term morbidity appear equivalent despite divergent surgical backgrounds and training.

The novel appearance of low rectal anastomosis on contrast enema following laparoscopic anterior resection: discriminating anastomotic leaks from "dog-ears" on water-soluble contrast enema and flexible sigmoidoscopy.

PURPOSE: Interpretation of water-soluble contrast enema following laparoscopic low anterior resection can be very challenging for both radiologists and colorectal surgeons. Discriminating the radiological appearances secondary to anastomotic configuration from those caused by actual anastomotic dehiscence is a common problem and may be made worse with the advent of laparoscopic surgery. The aim of this study is to identify potential novel appearances of the water-soluble contrast enema (WSCE) images of rectal anastomosis following laparoscopic low anterior resection to radiologists and surgeons. METHODS: We enrolled 45 patients who underwent laparoscopic low anterior resection with proximal de-functioning loop ileostomy within a specialized colorectal unit. The water-soluble contrast enema reports were reviewed. Two blinded colorectal radiologists independently reviewed the images of patients suspected of anastomotic leak. All of these patients also underwent a flexible sigmoidoscopy to confirm or exclude anastomotic leak before reversal of loop ileostomy. Inter-observer concordance was calculated. RESULTS: Seven out of eighteen patients (38.9%) were found to have true anastomotic leaks on flexible sigmoidoscopy (15% overall leak rate). In the remaining eleven patients the image appearances were attributed to the appearance of the anastomotic 'dog-ear effect', created by the anastomotic configuration due to multiple firing of the intra-corporeal laparoscopic stapling device. Radiologist inter-observer concordance was 83%. Sensitivity was 100%, specificity 71%, positive-predictive value (38.9%) and negative-predictive value (100%). CONCLUSIONS: The novel appearances of laparoscopic-stapled rectal anastomoses in WSCE can be mistaken for anastomotic leak. To avoid delay in reversal of ileostomy, a flexible sigmoidoscopy can be used to confirm or exclude a leak.

Longterm -ostomy as a quality marker: Comparison of outcomes from a six year series of laparoscopic surgery in MRI defined low rectal cancer.

AIM: We propose long-term -ostomy rate following laparoscopic rectal cancer resection must be included as an overall quality indicator of treatment in conjunction with frequently reported and readily available end points. METHOD: A database was collated prospectively of consecutive rectal cancer resections over a 6-year period. Recorded data included pre-operative MRI (tumour stage and height from the anal-verge), as well as demographics, treatment, local recurrence rate, survival and -ostomy rate as the primary outcome measure. RESULTS: 65 patients were identified and classified as low-rectal cancer if the tumour on MRI was < 6 cm from the anal verge or middle/upper-rectal cancer if between 6 and 15 cm from the anal-verge and below the peritoneal reflection. Permanent stoma rates including colostomies and non-reversed ileostomies were 31.7% for middle/upper rectal cancer; 62.5% for low-rectal cancer and an overall rate of 42.1% for all rectal cancers. For upper-rectal cancer the rates of local recurrence, predicted mortality, R0 resection and conversion were: 0%, 1.9%, 97.6% and 0% respectively. Corresponding figures for low-rectal cancer were: 4.2%, 2.7%, 95.8% and 0%. There were no significant differences for age, sex, predicted morbidity/mortality, survival, recurrence or leak rates between the groups. CONCLUSION: Laparoscopic rectal cancer surgery has a comparable permanent -ostomy rate to open rectal cancer surgery. We benchmark 31.7% as the permanent -ostomy rate for upper-rectal cancer and 62.5% for low-rectal cancer following laparoscopic resection, in the context of 96.9% R0 resection and 0% conversion rate in a consecutive series of patients.

Covered metallic stents for the palliation of colovesical fistula.

Colovesical fistula is a distressing condition that is usually managed surgically. For some patients in whom surgery is not feasible, covered colonic stents offer palliation. We present two challenging cases with contrasting outcomes. The first case is a colovesical fistula secondary to malignancy with a successful outcome after stenting and the second a complex diverticular fistula with a poor outcome. From our limited experience, it is a useful technique but careful patient selection is essential to its safe application. There is little published experience of the use of these stents for colovesical fistula.

Genetic variants in XRCC2: new insights into colorectal cancer tumorigenesis.

Polymorphisms in DNA double-strand break repair gene XRCC2 may play an important role in colorectal cancer etiology, specifically in disease subtypes. Associations of XRCC2 variants and colorectal cancer were investigated by tumor site and tumor instability status in a four-center collaboration including three U.K. case-control studies (Sheffield, Leeds, and Dundee) and a U.S. case-control study of cases from high-risk Utah pedigrees (total: 1,252 cases and 1,422 controls). The 14 variants studied were tagging single nucleotide polymorphisms (SNP) selected from National Institute of Environmental Health Sciences/HapMap data supplemented with SNPs identified from sequencing of 125 cases chosen to represent multiple colorectal cancer groups (familial, metastatic disease, and tumor subsite). Monte Carlo significance testing using Genie software provided valid meta-analyses of the total resource that includes family-based data. Similar to reports of colorectal cancer and other cancer sites, the rs3218536 R188H allele was not associated with increased risk. However, we observed a novel, highly significant association of a common SNP, rs3218499G>C, with increased risk of rectal tumors (odds ratio, 2.1; 95% confidence interval, 1.3-3.3; P(chi2) = 0.0006) versus controls, with the largest risk found for female rectal cases (odds ratio, 3.1; 95% confidence interval, 1.6-6.1; P(chi2) = 0.0006). This difference was significantly different to that for proximal and distal colon cancers (P(chi2) = 0.02). Our investigation supports a role for XRCC2 in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors.

Intermittent torsion of a megapouch: report of a case.

We report an unusual presentation of pouch dysfunction because of excessive pouch enlargement or "mega pouch" and probable torsion. The patient presented with abdominal pain that was positional. Contrast-enhanced computerized tomography showed pouch anastomotic staples extending into the right upper quadrant. At operation, gross pouch enlargement with dilation of the afferent ileum was confirmed. Reduction pouch-plasty resulted in pain resolution and maintenance of satisfactory function.

Nicorandil and idiopathic anal ulceration.

PURPOSE: Several reports have implicated nicorandil as a reversible cause of anal ulceration. We have recently commenced a specialist clinic for patients presenting with severe anal ulceration to assess treatment in this difficult group. Recognition of this association may avoid unnecessary surgery. METHODS: Twenty-six patients treated with nicorandil had severe painful anal ulceration. Examination under anesthesia was required to biopsy the lesions to exclude neoplasia or inflammatory bowel disease. In total, three patients had proximal diverting stomas without subsequent ulcer resolution, two had perineal debridement with one requiring subsequent skin grafting, and one had an abdominoperineal excision for unremitting pain. RESULTS: The association of perianal ulceration with nicorandil became apparent only in the latter part of this series. Ten ulcers successfully re-epithelialized when nicorandil was stopped. Nine patients reported anal pain relief and partial healing on clinical examination at two months but failed to show subsequent complete resolution. One patient agreed to nicorandil cessation and reported symptomatic anal pain relief at two weeks but subsequently developed unstable angina requiring hospital admission. Nicorandil was recommenced with anal pain relapse. CONCLUSIONS: Failure to recognize nicorandil as an etiologic factor in the development of anal ulceration, when other potential underlying well-recognized inflammatory or neoplastic processes have been excluded, may lead to unnecessary surgical intervention in a group of high-risk patients. One of our patients had a potentially avoidable abdominoperineal resection. Pharmaceutical manipulation with alternative antiangina medication may induce healing. Pharmacologic manipulation should be coordinated with a physician to minimize precipitation of unstable angina.