Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (≥3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade ≥3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.More than 50,000 people in the United States will die in 2007 from colorectal cancer. In the United States, cancer is the leading cause of death in people under age 74 years (1), and colorectal cancer is the second most common cause of cancer deaths after lung cancer (2). Colorectal cancer may be prevented by removal of precursor adenomas found during screening sigmoidoscopy or colonoscopy (3), although rates are variable and range from 30% to 90% depending highly on reimbursement policies (4, 5).Diet and inflammation have been associated with risk of colorectal cancer (6), and a series of clinical trials have been conducted to test the efficacy of individual dietary supplements or anti-inflammatory agents to prevent the incidence or recurrence of colon polyps (7-14). Unfortunately, these trials have not translated into significant changes in medical practice for prevention or management of colon cancer for a variety of reasons, including lack of efficacy, unacceptable toxicities, and the availability of competing strategies for risk reduction (15).Studies in rodent models have shown that combination chemoprevention strategies are often more effective than those using individual agents (16,17). Difluoromethylornithine (DFMO) has been identified as a potent inhibitor of intestinal and colon carcinogenesis in animal models, especially in combination with nonsteroidal anti-inflammatory drugs (18)(19)(20). DFMO and the n...
Background Stool DNA testing is a new approach to colorectal cancer detection. Few data are available from the screening setting. Objective To compare stool DNA and fecal blood testing for detection of screen-relevant neoplasia (curable-stage cancer, high-grade dysplasia, or adenomas >1 cm). Design Blinded, multicenter, cross-sectional study. Setting Communities surrounding 22 participating academic and regional health care systems in the United States. Participants 4482 average-risk adults. Measurements Fecal blood and DNA markers. Participants collected 3 stools, smeared fecal blood test cards and used same-day shipment to a central facility. Fecal blood cards (Hemoccult and HemoccultSensa, Beckman Coulter, Fullerton, California) were tested on 3 stools and DNA assays on 1 stool per patient. Stool DNA test 1 (SDT-1) was a precommercial 23-marker assay, and a novel test (SDT-2) targeted 3 broadly informative markers. The criterion standard was colonoscopy. Results Sensitivity for screen-relevant neoplasms was 20% by SDT-1, 11% by Hemoccult (P = 0.020), 21% by HemoccultSensa (P = 0.80); sensitivity for cancer plus high-grade dysplasia did not differ among tests. Specificity was 96% by SDT-1, compared with 98% by Hemoccult (P < 0.001) and 97% by HemoccultSensa (P = 0.20). Stool DNA test 2 detected 46% of screen-relevant neoplasms, compared with 16% by Hemoccult (P < 0.001) and 24% by HemoccultSensa (P < 0.001). Stool DNA test 2 detected 46% of adenomas 1 cm or larger, compared with 10% by Hemoccult (P < 0.001) and 17% by HemoccultSensa (P < 0.001). Among colonoscopically normal patients, the positivity rate was 16% with SDT-2, compared with 4% with Hemoccult (P = 0.010) and 5% with HemoccultSensa (P = 0.030). Limitations Stool DNA test 2 was not performed on all subsets of patients without screen-relevant neoplasms. Stools were collected without preservative, which reduced detection of some DNA markers. Conclusion Stool DNA test 1 provides no improvement over HemoccultSensa for detection of screen-relevant neoplasms. Stool DNA test 2 detects significantly more neoplasms than does Hemoccult or HemoccultSensa, but with more positive results in colonoscopically normal patients. Higher sensitivity of SDT-2 was particularly apparent for adenomas.
Colorectal cancer accounts for more than 10% of all cancer deaths but is curable, if detected early. We reported previously on a stool-based screening test in which DNA from stool samples is subjected to genome analysis; sensitivity of the test has been limited in part by inefficiency of retrieving DNA from stool. Our aim was to test the impact of a new purification method that would increase the yield of human DNA from stool. DNA from 86 cancer and 100 non-cancer subjects (diagnosed by colonoscopy) were purified from stool with a new method for DNA recovery based on sequence-specific capture with acrylamide gel immobilized capture probes as well as with a previously developed magnetic bead-capture procedure. The new purification method gives an average 5.4-fold increase in the quantity of human DNA that can routinely be retrieved from fecal samples. The increased recovery of DNA corresponds with an increase in assay sensitivity from 53% (CI: 42 to 64%) to 70% (CI: 59 to 79%); P ؍ Colorectal cancer (CRC) is curable in more than 90% of cases when caught in the earliest stages. Current colorectal cancer screening guidelines include a variety of options. Colonoscopy may be the most sensitive screening test, 1 however its invasiveness (including bowel preparation and the procedure itself) present major barriers to its implementation for large-scale, nationwide screening.2 An improved non-invasive screening option could address many of the issues associated with colonoscopy. Non-invasive screening is available today through assessment of occult blood in fecal samples, but this test has relatively low sensitivity, especially for early stage cancer, limiting its impact on cancer mortality. However, analysis of DNA from stool provides an attractive, alternative, non-invasive means for CRC screening if scalable, sensitive, and specific tests can be developed.We have previously described 3 a stool-based screening test for early detection of colorectal cancers. The multi-target nucleic acid assay consists of a panel of 21 specific mutations in adenomatous polyposis coli (APC), 4 p53 5,6 , and K-ras 7 genes, a microsatellite instability marker (BAT-26), 8 and a marker for genomic integrity (DNA Integrity assay; DIA). 9 As reported in separate studies, 3,10,11,12 the multi-target assay has an aggregate sensitivity of 67% (95% CI: 60.3 to 73.9%) and specificity of 97% (95% CI: 92.9 to 99.2%), a major improvement to the current screening methods of the fecal occult blood test (25 to 40% sensitivity). 13,14 In the multi-target assay studies human DNA was recovered and purified using streptavidin-bound magnetic beads. 3,15 We have reported on the use of separate components of this multi-target test elsewhere. 9,11,16,17,18 The mutation panel portion of the multi-target assay relies on detecting mutations in several well-documented colorectal cancer-associated genes. 19,20 The DNA integrity portion of the test consists of a set of markers that serve as surrogate markers for the presence of long DNA fragments. The principles and...
Sulindac, atorvastatin, or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects 40 years or older, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required five or more rectal ACFs at baseline. Intervention assignments were as follows: (a) atorvastatin 20 mg qd; (b) sulindac 150 mg bid; (c) oligofructose-enriched inulin (as ORAFTI Ò Synergy1) 6 gm bid; or (d) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%DACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5-34) and 8 (0-37) at baseline and postintervention, respectively. The median (SD) for %DACF was 5.6 (À69% to 143%), À18.6 (À83% to 160%), À3.6 (À88% to 83%), and À10.0 (À100% to 117%) in the atorvastatin, sulindac, ORAFTI Ò Synergy1 and control arms, respectively.Neither within-arm (P ¼ 0.12-0.59) nor between-arm (P ¼ 0.30-0.92) comparisons of %DACF were statistically significant. The active and control interventions also seemed to have similar effects on mucosal proliferation and apoptosis (P > 0.05 for each comparison). Data from this multicenter, phase II trial do not provide convincing evidence of CRC risk reduction from 6-month interventions with atorvastatin, sulindac, or ORAFTI Ò Synergy1, although statistical power was limited by the relatively small sample size.
In the healthy colon, sodium nitrite stimulates mucosal metabolism of short-chain fatty acids and absorption of ions, both functions that are impaired in the mucosa of patients with ulcerative colitis (UC). To assess the role of nitrite in colonic inflammatory disease, sodium nitrite was measured in rectal dialysate of 49 subjects (18 controls, 23 UC and 8 other colitis). None of the control or quiescent UC patients had measurable levels of nitrite while 78% of patients with acute UC and 38% of patients with other colitis had measurable nitrite levels (acute UC vs. other colitis eχ2 = 5.555, p < 0.02). Functional acitivity of the colonic mucosa, judged by bicarbonate output, was impaired in all subjects with measurable nitrite levels in UC. Detection of nitrite in acute colitis suggests impaired oxidation of nitrite to nitrate in the colonic mucosa or impaired luminal reduction of nitrite to NH4 by bacteria.
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