Faculty Bibliography

BACKGROUND & AIMS/OBJECTIVE:Asymptomatic diverticulosis is commonly attributed to constipation caused by a low-fiber diet, although evidence for this mechanism is limited. We examined the associations between constipation and low dietary fiber intake with risk of asymptomatic diverticulosis. METHODS:We performed a cross-sectional study that analyzed data from 539 individuals with diverticulosis and 1569 without (controls). Participants underwent colonoscopy and assessment of diet, physical activity, and bowel habits. Our analysis was limited to participants with no knowledge of their diverticular disease to reduce the risk of biased responses. RESULTS:Constipation was not associated with an increased risk of diverticulosis. Participants with less frequent bowel movements (<7/wk) had reduced odds of diverticulosis compared with those with regular bowel movements (7/wk) (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.40-0.80). Those reporting hard stools also had reduced odds (OR, 0.75; 95% CI, 0.55-1.02). There was no association between diverticulosis and straining (OR, 0.85; 95% CI, 0.59-1.22) or incomplete bowel movement (OR, 0.85; 95% CI, 0.61-1.20). We found no association between dietary fiber intake and diverticulosis (OR, 0.96; 95% CI, 0.71-1.30) in comparing the highest quartile with the lowest (mean intake, 25 vs 8 g/day). CONCLUSIONS:In our cross-sectional, colonoscopy-based study, neither constipation nor a low-fiber diet was associated with an increased risk of diverticulosis.

BACKGROUND:In randomized trials, fecal occult-blood testing reduces mortality from colorectal cancer. However, the duration of the benefit is unknown, as are the effects specific to age and sex. METHODS:In the Minnesota Colon Cancer Control Study, 46,551 participants, 50 to 80 years of age, were randomly assigned to usual care (control) or to annual or biennial screening with fecal occult-blood testing. Screening was performed from 1976 through 1982 and from 1986 through 1992. We used the National Death Index to obtain updated information on the vital status of participants and to determine causes of death through 2008. RESULTS:Through 30 years of follow-up, 33,020 participants (70.9%) died. A total of 732 deaths were attributed to colorectal cancer: 200 of the 11,072 deaths (1.8%) in the annual-screening group, 237 of the 11,004 deaths (2.2%) in the biennial-screening group, and 295 of the 10,944 deaths (2.7%) in the control group. Screening reduced colorectal-cancer mortality (relative risk with annual screening, 0.68; 95% confidence interval [CI], 0.56 to 0.82; relative risk with biennial screening, 0.78; 95% CI, 0.65 to 0.93) through 30 years of follow-up. No reduction was observed in all-cause mortality (relative risk with annual screening, 1.00; 95% CI, 0.99 to 1.01; relative risk with biennial screening, 0.99; 95% CI, 0.98 to 1.01). The reduction in colorectal-cancer mortality was larger for men than for women in the biennial-screening group (P=0.04 for interaction). CONCLUSIONS:The effect of screening with fecal occult-blood testing on colorectal-cancer mortality persists after 30 years but does not influence all-cause mortality. The sustained reduction in colorectal-cancer mortality supports the effect of polypectomy. (Funded by the Veterans Affairs Merit Review Award Program and others.).

The majority of the world's adult population and an estimated 80 million Americans are hypolactasic and hence malabsorb ingested lactose. Although lactose malabsorption is easily identified, less readily assessed is the clinically important question of how often does this malabsorption induce symptoms. This review summarizes: (1) knowledge concerning the etiology and diagnosis of hypolactasia and the pathophysiology of the symptoms of lactose malabsorption and (2) the results of well-controlled trials of the symptomatic response of lactose malabsorbers to varying dosages of lactose and the efficacy of therapeutic interventions to alleviate these symptoms. We conclude that the clinical significance of lactose malabsorption has been overestimated by both the lay public and physicians in that commonly ingested doses of lactose (ie, the quantity in a cup of milk) usually do not cause perceptible symptoms when ingested with a meal. Symptoms occur when the lactose dosage exceeds that in a cup of milk or when lactose is ingested without other nutrients. Simple dietary instruction, rather than the use of commercial products to reduce lactose intake, is recommended for the vast majority of lactose-malabsorbing subjects.

APC/β-catenin pathway perturbation is a common early event in colorectal carcinogenesis and is affected by calcium and vitamin D in basic science studies. To assess the effects of calcium and vitamin D on adenomatous polyposis coli (APC), β-catenin, and E-cadherin expression in the normal appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a randomized, double-blinded, placebo-controlled 2 × 2 factorial clinical trial. Pathology-confirmed colorectal adenoma cases were treated with 2 g/day elemental calcium and/or 800 IU/day vitamin D(3) versus placebo over 6 months (N = 92; 23/group). Overall APC, β-catenin, and E-cadherin expression and distributions in colon crypts in normal-appearing rectal mucosa biopsies were detected by standardized automated immunohistochemistry and quantified by image analysis. In the vitamin D(3)-supplemented group relative to placebo, the proportion of APC in the upper 40% of crypts (Φh APC) increased 21% (P = 0.01), β-catenin decreased 12% (P = 0.18), E-cadherin increased 72% (P = 0.03), and the Φh APC/β-catenin ratio (APC/β-catenin score) increased 31% (P = 0.02). In the calcium-supplemented group Φh APC increased 10% (P = 0.12), β-catenin decreased 15% (P = 0.08), and the APC/β-catenin score increased 41% (P = 0.01). In the calcium/vitamin D(3)-supplemented group, β-catenin decreased 11% (P = 0.20), E-cadherin increased 51% (P = 0.08), and the APC/β-catenin score increased 16% (P = 0.26). These results support (i) that calcium and vitamin D modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms, (ii) calcium and vitamin D as potential chemopreventive agents against colorectal neoplasms, and (iii) the potential of APC, β-catenin, and E-cadherin expression as modifiable, preneoplastic risk biomarkers for colorectal neoplasms.

BACKGROUND:Chronic radiation proctopathy is associated with significant morbidity. The effectiveness of endoscopic and medical therapies has not been evaluated. OBJECTIVES/OBJECTIVE:The aim of this study was to conduct a systematic review of the effectiveness of endoscopic and comparative medical therapies for chronic radiation proctopathy. DATA SOURCES/METHODS:A comprehensive search Medline and PubMed was performed. STUDY SELECTION/METHODS:A comprehensive literature search was performed for studies of endoscopic and medical therapy for clinical and endoscopic improvement in chronic radiation proctopathy from January 1990 until December 2010. The quality of the overall evidence was rated according to the Grading of Recommendations, Assessment, Development, and Evaluation Working Group. SETTING/METHODS:Patients in both inpatient and outpatient settings were assessed. PATIENTS/METHODS:Patients experiencing chronic radiation proctopathy were included. INTERVENTIONS/METHODS:Patients had undergone medical or endoscopic treatments for chronic radiation proctopathy. MAIN OUTCOME MEASUREMENTS/METHODS:The primary outcomes measured were the resolution or improvement in symptoms. RESULTS:A total of 39 studies were found, of which 27 evaluated endoscopic therapy and 12 evaluated medical therapy chronic radiation proctopathy. Overall, there is low-level evidence for the effectiveness of endoscopic therapy with argon plasma coagulation in reducing short-term (≤6 weeks) symptoms of chronic radiation proctopathy and insufficient evidence for long-term improvement. There is moderate-level evidence for the use of sucralfate enemas and low-level evidence for use of short-chain fatty acid enemas and hyperbaric oxygen. There is insufficient evidence for other agents: topical formalin, 5-aminosalicylic acid compounds, sulfasalazine, vitamin A, and pentoxifylline. LIMITATIONS/CONCLUSIONS:Individual authors were not contacted, and the search was limited to English language journals only. CONCLUSION/CONCLUSIONS:Endoscopic treatment with argon plasma coagulation appears effective in the short-term outcome of chronic radiation proctopathy. There is a moderate level of evidence for the use of sucralfate enemas. Large, randomized, placebo-controlled studies evaluating endoscopic and medical therapies for chronic radiation proctopathy are needed.

BACKGROUND:While ulcerative colitis (UC) is a risk factor for colorectal cancer, the association of UC with survival after colorectal cancer has not been studied in an older population. AIMS/OBJECTIVE:The objective of our study was to compare the survival of colorectal cancer between persons with and without UC. METHODS:All cases of colorectal cancer (CRC) in persons 67 and older residing in a SEER catchment area and enrolled in the Medicare between 1993 and 1999 were assessed. We identified diagnosis of UC using ICD-9 codes on Medicare outpatient, office, and inpatient claims in the 2 years prior to the date of diagnosis. We used Cox proportional hazards model and Kaplan-Meier curves to compare survival between individuals with UC and CRC (UC-CRC) and sporadic CRC RESULTS: We identified 47,543 cases of colorectal cancer. Cases with UC-CRC tend to be diagnosed at earlier stages compared to sporadic CRC (42 vs. 37% local (TNM stage 1 and 2) and 11 vs. 17% distant spread (TNM stage 4), respectively; P value = 0.04). Controlling for age, gender, race and stage, diagnosis of UC did not affect the 3-year survival for CRC. CONCLUSIONS:Colorectal cancers tend to be diagnosed at earlier stages among persons with UC, but there is no difference in 3-year survival rates for colorectal cancer among individuals with and without UC.

BACKGROUND:Malfunctioning of the adenomatous polyposis coli (APC)/β-catenin signaling pathway is both an early and common event in sporadic colorectal cancer. To assess the potential of APC/β-catenin signaling pathway markers as treatable, preneoplastic biomarkers of risk for colorectal neoplasms, we conducted a pilot colonoscopy-based case-control study (51 cases and 154 controls) of incident, sporadic colorectal adenoma. METHODS:We evaluated APC, β-catenin, and E-cadherin expression in normal mucosa from the rectum and ascending and sigmoid colon using automated immunohistochemical and quantitative image analysis. Diet, lifestyle, and medical history were assessed with validated questionnaires. RESULTS:In the normal rectal mucosa, the ratio of the proportion of APC expression in the upper 40% of crypts with total β-catenin expression (APC/β-catenin score) was 14.3% greater in controls than in cases [P = 0.02; OR, 0.40; 95% confidence interval (CI), 0.14-1.14]. Compared with controls, in cases, APC expression was 3.2% lower, β-catenin expression was 3.0% higher, and E-cadherin expression was 0.7% lower; however, none of these differences were statistically significant. The APC/β-catenin score statistically significantly differed according to categories of plausible risk factors for colorectal cancer [e.g., it was 17.7% higher among those with 25(OH) vitamin D(3) concentrations ≥ 27 ng/mL]. CONCLUSIONS:These preliminary data suggest that the combined expression of APC and β-catenin in the normal rectal mucosa may be associated with risk for incident, sporadic colorectal neoplasms, as well as with modifiable risk factors for colorectal neoplasms. IMPACT/CONCLUSIONS:Our results may help advance the development of treatable, preneoplastic biomarkers of risk for colorectal neoplasms.

BACKGROUND:Colorectal cancers diagnosed in the interval after a complete colonoscopy may occur due to rapid tumor growth. Interval colorectal cancers are associated with microsatellite instability (MSI). AIMS/OBJECTIVE:Our aim was to study the association of KRAS mutation with interval colorectal cancers and MSI. METHODS:We searched our institution's cancer registry for interval colorectal cancers, defined as colorectal cancers that developed within 5 years of a complete colonoscopy. These were frequency matched to patients with non-interval colorectal cancers. Archived cancer specimens were evaluated for KRAS mutations in codons 12 and 13 using sequencing, and MSI by sequencing microsatellite loci. Multivariable logistic regression was used to analyze the association between KRAS mutation status, MSI status and interval colorectal cancers. RESULTS:There were 63 interval and 131 non-interval colorectal cancers. KRAS mutation was present in 12.9% of interval cancers compared to 28.9% of non-interval cancers (P = 0.03). In multivariable logistic regression model, KRAS was inversely associated with interval cancers (OR 0.36; 95% CI 0.15-0.90). In Cox proportional hazards model, adjusting for age, tumor grade, TNM Stage and MSI status, we found no association between KRAS mutation and 5-year survival compared to cancers without KRAS mutation (HR 0.84; 95% CI 0.4-1.46; P = 0.5). CONCLUSIONS:KRAS mutation is inversely associated with interval cancers and with MSI, suggesting that it is a marker of the chromosomal instability pathway associated with slow tumor growth, and distinct from MSI rapidly growing cancers. Molecular characterization of colorectal cancers is helpful in determining underlying pathway and may determine therapy.

BACKGROUND:While ulcerative colitis (UC) and Crohn's disease (CD) are thought to predispose to colorectal cancer (CRC), the association has not been well studied in an older population. AIMS/OBJECTIVE:The objective of our study was to evaluate the association of ulcerative colitis and Crohn's disease and colorectal cancer in a population-based, case-control study. We also wished to estimate the incidence rates of colorectal cancer among older individuals with UC/CD. METHODS:All cases of colorectal cancer in persons 67 and older in the SEER catchment area and in the Medicare claims database were compared with cancer-free controls residing in the same geographic area. We used multivariable logistic regression models adjusted for demographic and other factors. RESULTS:We identified 47,543 cases of CRC and 142,273 controls. We found a modest association between UC and CRC (OR 1.93; 95% CI 1.54-2.49; P-value<0.001) and a significant, albeit modest, association between CD and CRC (OR 1.45; 95% CI 1.08-1.91; P-value 0.01). We found the incidence of CRC to be 8.2 per 10,000 person-years (95% CI 6.5-10.1/10,000 person-years) among those with UC/CD, and 6.1 per 10,000 person-years (95% CI 4.6-7.8/10,000 person-years) among those without UC/CD, resulting in an incidence rate ratio of 1.34. CONCLUSIONS:Among older persons ulcerative colitis and Crohn's disease are modest risk factors for CRC, and the incidence rate ratio for CRC is modest, suggesting that risk of CRC in patients with IBD may be lower than previously thought.

BACKGROUND:Although Crohn's disease (CD) is thought to predispose to adenocarcinomas of the small bowel, the association has not been well studied in an older population. AIMS/OBJECTIVE:The objective of our study was to evaluate the association of CD with small bowel cancer in a population-based case-control study. METHODS:All cases of small bowel cancer in persons 67 and older in the Surveillance, Epidemiology and End Results catchment area and in the Medicare claims data base were compared with cancer-free controls residing in the same geographic area. We used multivariable logistic regression models adjusted for demographic and other factors. RESULTS:We identified 923 cases of small bowel cancer and 142,273 controls. Although we found a strong association between CD and small bowel cancer (OR = 12.07; 95% CI: 6.07-20.80; P < 0.001), the prevalence of CD in patients with small bowel cancer was low (1.6%). CONCLUSIONS:Although CD is a significant risk factor for small bowel cancers among individuals older than 67, the absolute risk is small. IMPACT/CONCLUSIONS:Older individuals with CD can be reassured that although there is an association between CD and small bowel cancer, the absolute risk remains small.