Common variants in human CRC genes as low-risk alleles.

The genetic susceptibility to colorectal cancer (CRC) has been estimated to be around 35% and yet high-penetrance germline mutations found so far explain less than 5% of all cases. Much of the remaining variations could be due to the co-inheritance of multiple low penetrant variants. The identification of all the susceptibility alleles could have public health relevance in the near future. To test the hypothesis that what are considered polymorphisms in human CRC genes could constitute low-risk alleles, we selected eight common SNPs for a pilot association study in 1785 cases and 1722 controls. One SNP, rs3219489:G>C (MUTYH Q324H) seemed to confer an increased risk of rectal cancer in homozygous status (OR=1.52; CI=1.06-2.17). When the analysis was restricted to our 'super-controls', healthy individuals with no family history for cancer, also rs1799977:A>G (MLH1 I219V) was associated with an increased risk in both colon and rectum patients with an odds ratio of 1.28 (CI=1.02-1.60) and 1.34 (CI=1.05-1.72), respectively (under the dominant model); while 2 SNPs, rs1800932:A>G (MSH6 P92P) and rs459552:T>A (APC D1822V) seemed to confer a protective effect. The latter, in particular showed an odds ratio of 0.76 (CI=0.60-0.97) among colon patients and 0.73 (CI=0.56-0.95) among rectal patients. In conclusion, our study suggests that common variants in human CRC genes could constitute low-risk alleles.

The correlation between a family history of colorectal cancer and survival of patients with colorectal cancer.

The purpose was to analyze survival of patients with colorectal cancer and a positive family history for colorectal cancer in first degree relatives compared with those with no such family history and to determine whether differences in survival could be explained by known clinico-pathological factors. During 2000-2003, 318 consecutive patients with colorectal cancer answered a written questionnaire about their family history for colorectal cancer. During a 6-year follow-up, recurrences and survival were registered. Thirty-one (10%) patients had a first-degree relative with colorectal cancer, moreover two patients fulfilled the criteria of hereditary non-polyposis colorectal cancer and were excluded. Patients with a first-degree relative with colorectal cancer had better survival and lower risk for recurrences compared to those with no relatives with colorectal cancer. In a multivariate analysis including age, gender, stage of disease, tumor differentiation, vascular invasion and family history, patients with first-degree relatives with colorectal cancer had lower risks for death (RR 0.37; 95% CI 0.17-0.78) and death from cancer (RR 0.25; 95% CI 0.08-0.80), compared to those with a no relative with colorectal cancer. The differences were seen in patients with colon cancer but not rectal cancer. Family history for colorectal cancer in a first-degree relative is an individual prognostic factor in patients with colon cancer and could not be explained by known clinico-pathological factors. The value of family history taking in patients with colon cancer is therefore not only to identify families with hereditary colorectal cancer, but also to add information to the prognosis of the patients.

Effects of centralization of colorectal surgery on the outcome of patients with distal sigmoid colonic cancer.

BACKGROUND: In 1996, all colorectal surgery in the county of Vastmanland, Sweden, was centralized to the central District Hospital in Vasterås. A Colorectal Unit was established and modern surgical procedures were introduced. The aim of this study was to analyze the outcome for patients treated surgically for distal sigmoid colonic cancer before and after the centralization. METHODS: Hospital records of all patients with distal sigmoid colonic cancer, treated between 1991-1995, group 1 (n = 64), and 1996-2000, group 2 (n = 82), were studied retrospectively. RESULTS: In group 2, there were fewer reoperations (n = 0) than in group 1 (n = 6; p = 0.005) and the postoperative mortality was lower; one in group 2 compared with five in group 1 (p = 0.047). The amount of lymph nodes examined were higher and the length of distal surgical margin longer in group 2. Curatively treated patients in group 2 had better overall survival compared to group 1 (RR 0.56; 95% CI 0.34-0.93). CONCLUSION: Centralization of colorectal surgery resulted in an improvement of pathologic specimens and a decrease in postoperative reoperations and mortality in patients treated surgically for distal sigmoid colonic cancer. Moreover, the overall survival of curatively treated patients was improved.

Lack of an association between the TGFBR1*6A variant and colorectal cancer risk.

PURPOSE: Recently a common variant of the TGFBR1 gene, TGFBR1*6A, has been proposed to act as a low-penetrance tumor susceptibility allele for colorectal cancer, but data from published studies with individually low statistical power are conflicting. To further evaluate the relationship between TGFBR1*6A and colorectal cancer risk, we have conducted a large case-control study and a meta-analysis of previously published studies. EXPERIMENTAL DESIGN: A total of 1,042 colorectal cancer cases and 856 population controls were genotyped for the TGFBR1*6A polymorphism. Previously published case-control studies of the relationship between TGFBR1*6A and colorectal cancer were identified, and a meta-analysis was conducted. RESULTS: We found no evidence that homozygosity, heterozygosity or carrier status for the TGFBR1*6A allele confers an increased risk of colorectal cancer; respective odds ratios (OR) were 1.05 [95% confidence interval (95% CI), 0.83-1.32], 0.82 (95% CI, 0.34-1.99), and 0.92 (95% CI, 0.74-1.15), respectively. A meta-analysis of our case-control study and seven other studies that provided data on 2,627 colorectal cancer cases and 3,387 controls also yielded no evidence that possession of the TGFBR1*6A allele is associated with an elevated risk of colorectal cancer; pooled estimate of the OR were 1.20 (95% CI, 0.64-2.24) for homozygosity, 1.11 (95% CI, 0.96-1.29) for heterozygosity, and 1.13 (95% CI, 0.98-1.30) for carriers of TGFBR1*6A. CONCLUSION: Current data provide limited support for the hypothesis that sequence variation in TGFBR1 defined by the TGFBR1*6A allele confers an elevated risk of colorectal cancer.

Leukocyte scintigraphy compared to intraoperative small bowel enteroscopy and laparotomy findings in Crohn's disease.

BACKGROUND: Leukocyte scintigraphy is a noninvasive investigation to assess inflammation. We evaluated the utility of labeled leukocytes to detect small bowel inflammation and disease complications in Crohn's disease and compared it to whole small bowel enteroscopy and laparotomy findings. METHODS: Scintigraphy with technetium-99m exametazime-labeled leukocytes was prospectively performed in 48 patients with Crohn's disease a few days before laparotomy; 41 also had an intraoperative small bowel enteroscopy. The same procedures were performed in 8 control patients. Independent grading of scans was compared with the results of enteroscopy and with surgical, histopathologic, and clinical data. RESULTS: In the 8 control patients leukocyte scan, endoscopy, and histopathology were all negative for the small bowel. In patients with Crohn's disease and small bowel inflammation seen at enteroscopy and/or laparotomy (n = 39) the scan was positive in 33. In 8 patients without macroscopic small bowel inflammation, the scan was positive for the small bowel in 3 patients; at histology, 2 of 3 had inflammation. When combining results for patients and controls, the sensitivity of leukocyte scan for macroscopically evident small bowel inflammation was 0.85, specificity 0.81, accuracy 0.84, positive predictive value 0.92, and negative predictive value 0.68. Scintigraphy detected inflammatory lesions not known before laparotomy in 16 of 47 (34%) Crohn's disease patients and showed uptake in 25 of 35 (71%) bowel strictures. It was diagnostic regarding 4 of 8 abscesses and 9 of 15 fistulas. In 6 patients (13%) lesions first demonstrated by leukocyte scintigraphy were treated during the surgery performed. CONCLUSIONS: Leukocyte scintigraphy reliably detects small bowel inflammation in Crohn's disease. It gives additional information on the presence of inflammatory lesions in a fraction of patients planned for surgery.

Abdominoperineal excision with partial anterior en bloc resection in multimodal management of low rectal cancer: a strategy to reduce local recurrence.

PURPOSE: Total mesorectal excision is the gold standard in the performance of an abdominoperineal resection but little has changed in the way the perineal operation is performed. A frequent problem is anterior dissection. The aim of this study was to present the results of abdominoperineal resection using selected partial anterior en bloc resection to reduce recurrence. METHODS: The data were population-based and prospectively registered. Two experienced surgeons performed the operations. In selected cases, depending on clinical and magnetic resonance imaging findings, parts of the vagina or prostate close to the tumor were resected. All specimens were examined according to Quirke. RESULTS: Sixty-three patients underwent abdominoperineal resection with total mesorectal excision; 56 received preoperative radiotherapy. The tumors involved the anterior bowel wall in 40 cases and in 23 (58 percent) of them, en bloc resections were performed. The distance from the tumor to the conventional resection margin (without en bloc resection) was 0 mm in ten cases. The median follow-up period was 37 months. So far, one (1.7 percent) local recurrence has been detected in 58 (92 percent) curative and indeterminate cases. The cancer-specific five-year survival in these cases was 87 percent (Kaplan-Meier). CONCLUSION: A multimodal management regimen in patients with low rectal cancer, including preoperative radiotherapy and abdominoperineal resection with a high frequency of partial en bloc resection of the vagina or prostate, resulted in excellent local control and survival. In some male patients, excenteration with urinary stoma can be avoided.

The CHEK2 1100delC variant in Swedish colorectal cancer.

BACKGROUND: The cell cycle checkpoint kinase 2 (CHEK2) 1100delC variant has recently been identified at high frequency in families with both breast and colorectal cancer, suggesting the possible role of this variant in colorectal cancer predisposition. PATIENTS AND METHODS: To evaluate the role of CHEK2 ll00delC among Swedish colorectal cancer patients, the variant frequency was determined in 174 selected familial cases, 644 unselected cases and 760 controls, as well as in l8 families used in the genome-wide linkage analysis, where weak linkage was seen for the region harboring the CHEK2 gene. RESULTS: CHEK2 l100delC was found in 1.15% of familial and in 0.93% of unselected cases, compared to 0.66% of controls, showing no significant difference between groups. One out of 45 familial cases with a family history of breast cancer was shown to be a carrier. The variant was not identified in the 18 families included in the linkage analysis. CONCLUSION: The CHEK2 1100delC was not significantly increased in Swedish colorectal cancer patients, however, in order to determine the role of the variant in colorectal cancer families with the history of breast cancer a larger sample size is needed.

[Self-expanding stent in obstructing colorectal cancer. A new technique to avoid abdominal surgery]. / Vinster med självexpanderande stent vid obstruerande kolorektal cancer. Ny teknik för att undvika bukoperation.

Emergency operations for obstructing colorectal cancer are associated with high morbidity and mortality rates and often result in a temporary or permanent colostomy. A colorectal stent can be used both for palliation and as a "bridge to surgery". Twenty-three patients with obstructive sigmoid or rectal cancer were selected for stenting. Self-expanding metal mesh stents were placed under endoscopic and flouroscopic guidance. Stent placement was technically successful in 19 patients and clinical success was seen in 18. There were only three minor complications, no major and no procedure related mortality. Four patients were later resected without a diverting stoma, two with rectal cancer had preoperative MRI and radiotherapy. In 15 patients the procedure was regarded as palliative. Stent migration was noted in four patients but symptomatic reobstruction did not occur, no patient needed later surgery. Colorectal stenting procedure is effective and safe and can be used in obstructing cancers both as a temporary relief before elective resection and as a definitive treatment in palliative cases.

[Time to institute more active follow up after curative surgery for colorectal cancer? Wide variation of follow up and diagnostic routines]. / Dags för aktiv uppföljning efter kurativ kirurgi för kolorektal cancer? Stora variationer i rutiner för uppföljning och diagnostik.

There are still no large controlled studies that have proved any survival benefit with intensive follow-up after curative surgery for colorectal cancer. There is a wide variation in follow-up. Three meta-analysis have shown that intensive follow-up can improve survival, the most recent based on five previously published small controlled trials that compared intensive with control follow-up. Since the randomised studies were initiated, there have been a strong development of rectal cancer surgery and surgery for livermetastasis as well as for adjuvant and palliative oncologic treatments. This development gives support to a more active attitude towards intensive regular follow-up. An active follow-up should be selective and only include patients who tolerate oncologic or surgical treatment. Diagnostic tests to find intraluminal recurrence are ineffective. Large multicenter studies are still warranted.

Preoperative management is more important than choice of sutured or stapled anastomosis in Crohn's disease.

OBJECTIVE: To find out if there were any differences in postoperative complications and anastomotic leak rate between sutured and stapled anastomoses after bowel resection in patients exposed to the same preoperative management programme. DESIGN: Prospective observational non-randomised study. SETTING: Colorectal unit, Sweden. PATIENTS: Between 1996 and 2000 bowel resections with anastomosis were done for 42 consecutive patients with Crohn's disease. 20 patients had their anastomoses sutured (sutured group) and 22 had their anastomosis stapled (stapled group) over two successive periods. MAIN OUTCOME MEASURES: Postoperative complications and anastomotic leak rate. RESULTS: None of the patients were on immunosuppressive treatment and about half in each group had had several weeks of preoperative enteral nutrition. No anastomotic-related complications and few other postoperative complications were noted, irrespective of the anastomotic technique used. CONCLUSION: A strategy to operate on Crohn patients without steroids and, if indicated, treated preoperatively with enteral nutrition and percutaneous drainage of abscesses resulted in no anastomotic leaks and few postoperative complications. These results were independent of the anastomotic technique used.