Hormone replacement therapy and colorectal adenoma recurrence among women in the Polyp Prevention Trial.

BACKGROUND: Epidemiologic studies have suggested that estrogen may protect against the development of colorectal cancers and adenomatous polyps. We conducted a prospective study to evaluate the association between hormone replacement therapy (HRT) and adenoma recurrence among perimenopausal and postmenopausal women participating in the Polyp Prevention Trial, a randomized dietary intervention study of individuals with colorectal adenomas. METHODS: We used a questionnaire and interviews to collect detailed information, at baseline and at each of four annual study visits, from 620 women regarding hormone use, menopausal status, diet, alcohol consumption, and other risk factors. Adenoma recurrence was ascertained by complete colonoscopy at baseline and after 1 and 4 years. Logistic regression models were used to evaluate the association between hormone use and adenoma recurrence after adjusting for intervention group and for age and body mass index at baseline. All statistical tests were two-sided. RESULTS: Adenomas recurred in 200 women. There was no overall association between adenoma recurrence and either overall hormone use (odds ratio [OR] = 1.01; 95% confidence interval [CI] = 0.70 to 1.45), combined estrogen and progestin use (OR = 0.94; 95% CI = 0.57 to 1.56), or unopposed estrogen use (OR = 1.04; 95% CI = 0.68 to 1.59). HRT use was associated with a reduction in risk for recurrence of distal adenomas (OR = 0.56; 95% CI = 0.32 to 1.00) and a statistically nonsignificant increase in risk for recurrence of proximal adenomas (OR = 1.39; 95% CI = 0.85 to 2.26). We observed a statistically significant interaction between the HRT-adenoma recurrence association and age (P =.02). HRT was associated with a 40% reduced risk of adenoma recurrence among women older than 62 years (OR = 0.58; 95% CI = 0.35 to 0.97) but with an increased risk among women younger than 62 years (OR = 1.99; 95% CI = 1.11 to 3.55). CONCLUSIONS: HRT was not associated with a reduced risk for overall adenoma recurrence in this trial cohort, although there was a suggestion of an age interaction. The effect of age on the association needs to be confirmed in other adenoma recurrence trials.

Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group.

BACKGROUND: We tested the hypothesis that dietary intervention can inhibit the development of recurrent colorectal adenomas, which are precursors of most large-bowel cancers. METHODS: We randomly assigned 2079 men and women who were 35 years of age or older and who had had one or more histologically confirmed colorectal adenomas removed within six months before randomization to one of two groups: an intervention group given intensive counseling and assigned to follow a diet that was low in fat (20 percent of total calories) and high in fiber (18 g of dietary fiber per 1000 kcal) and fruits and vegetables (3.5 servings per 1000 kcal), and a control group given a standard brochure on healthy eating and assigned to follow their usual diet. Subjects entered the study after undergoing complete colonoscopy and removal of adenomatous polyps; they remained in the study for approximately four years, undergoing colonoscopy one and four years after randomization. RESULTS: A total of 1905 of the randomized subjects (91.6 percent) completed the study. Of the 958 subjects in the intervention group and the 947 in the control group who completed the study, 39.7 percent and 39.5 percent, respectively, had at least one recurrent adenoma; the unadjusted risk ratio was 1.00 (95 percent confidence interval, 0.90 to 1.12). Among subjects with recurrent adenomas, the mean (+/-SE) number of such lesions was 1.85+/-0.08 in the intervention group and 1.84+/-0.07 in the control group. The rate of recurrence of large adenomas (with a maximal diameter of at least 1 cm) and advanced adenomas (defined as lesions that had a maximal diameter of at least 1 cm or at least 25 percent villous elements or evidence of high-grade dysplasia, including carcinoma) did not differ significantly between the two groups. CONCLUSIONS: Adopting a diet that is low in fat and high in fiber, fruits, and vegetables does not influence the risk of recurrence of colorectal adenomas.

Pill esophagitis.

Nine hundred seventy-nine cases of pill esophagitis due to nearly 100 different medications are reviewed. Pill-induced injuries occur when caustic medicinal pills dissolve in the esophagus rather than passing rapidly into the stomach as intended. Most patients suffer only self-limited pain, but esophageal hemorrhage, stricture, and perforation may occur, and fatal injuries have been reported. The incidence of this iatrogenic injury can be reduced but not eliminated by emphasizing the importance of taking pills while upright and with plenty of fluids.

Lectin binding to human colonocytes is predictive of colonic neoplasia.

OBJECTIVE: The aim of this study was to determine whether lectin binding to exfoliated human colonocytes could be used as a noninvasive test for colorectal polyps or cancer. METHODS: Colonocytes were harvested from 31 patients (10 controls, 10 with adenomatous polyps, and 11 with cancer), incubated with a panel of fluorescent-labeled lectins, and assayed by flow cytometry. RESULTS: The lectins jacalin (JAC) and wheat germ agglutinin (WGA) were useful in predicting the presence of a colorectal neoplasm (p = 0.0018 for JAC and p = 0.0099 for WGA). For JAC, sensitivity reached 81% with a specificity of 80%, and for WGA the sensitivity and specificity were both 75%. CONCLUSIONS: Lectin binding to human colonocytes can predict the presence of malignant and premalignant lesions of the colon, and has potential as a noninvasive screening tool for colorectal neoplasms.

Is colonoscopy needed for the nonadvanced adenoma found on sigmoidoscopy? The Polyp Prevention Trial.

BACKGROUND & AIMS: The need for colonoscopy when small tubular adenomas with low-grade dysplasia are found on sigmoidoscopy is uncertain. The aim of this study was to examine the prevalence and characteristics of proximal adenomas in patients with distal adenomas. METHODS: We studied 981 subjects with distal adenomas found on the index colonoscopy before randomization in the Polyp Prevention Trial. RESULTS: Four hundred sixty patients (46.9%) had >/=1 distal adenoma that was pathologically advanced (villous component, high-grade dysplasia, or >/=1 cm); 21.5% (211 of 981) had any proximal adenoma; and 4.3% (42 of 981) (95% confidence interval [CI], 3.0-5.5) had an advanced proximal adenoma. A greater percentage of patients with an advanced distal adenoma (5.9%) (95% CI, 3.7-8.0) had an advanced proximal adenoma compared with those with a nonadvanced distal adenoma (2.9%) (95% CI, 1.4-4.3) (OR, 2.1; 95% CI, 1.1-4.3; P = 0.03). Not performing a colonoscopy in patients with a nonadvanced distal adenoma would have missed 36% (15 of 42) of the advanced proximal adenomas. CONCLUSIONS: Patients with an advanced distal adenoma are twice as likely to have an advanced proximal adenoma as patients with a nonadvanced distal adenoma. However, eschewing a colonoscopy in patients with a nonadvanced distal adenoma would result in not detecting a sizeable percentage of the prevalent advanced proximal adenomas. These data support performance of a colonoscopy in patients with a nonadvanced distal adenoma. Confirmation of these results in asymptomatic subjects undergoing screening sigmoidoscopy is advisable.

A new probable increasing cause of esophageal ulceration: alendronate.

We present a case of esophageal ulcerations caused by alendronate (Fosamax), a recently marketed medication. The patient presented with a chief complaint of retrosternal pain and severe odynophagia of 5 days duration. She was taking prednisone 10 mg and azathioprine 100 mg p.o. q.d. for systemic lupus erythematosus. To prevent osteoporosis, she was started on alendronate 10 mg q.d. 2 wk before her symptoms started. Endoscopy of the upper GI tract revealed two deep, large ulcers at the gastroesophageal junction. Multiple biopsy specimens revealed necroinflammatory debris and acute esophagitis. However, no organisms were identified, and the result of her HIV test (ELISA) was negative. Alendronate was discontinued, and her symptoms resolved completely in 1 wk. Follow-up endoscopy performed 4 wk later revealed complete healing of the ulcers.

The polyp prevention trial I: rationale, design, recruitment, and baseline participant characteristics.

The Polyp Prevention Trial (PPT) is a multicenter randomized controlled trial examining the effect of a low-fat (20% of total energy intake), high-fiber (18 g/1000 kcal), high-vegetable and -fruit (5-8 daily servings) dietary pattern on the recurrence of adenomatous polyps of the large bowel, precursors of most colorectal malignancies. Eligibility criteria include one or more adenomas removed within 6 months of randomization; complete nonsurgical polyp removal and complete colonic examination to the cecum at the qualifying colonoscopy: age 35 years of more; no history of colorectal cancer, inflammatory bowel disease, or large bowel resection; and satisfactory completion of a food frequency questionnaire and 4-day food record. Of approximately 38,277 potential participants with one or more polyps recently resected, investigators at eight clinical centers randomized 2,079 (5.4%; 1,037 in the intervention and 1,042 in the control arm) between June 1991 and January 1994, making the PPT the largest adenoma recurrence trial ever conducted. Of PPT participants, 35% are women and 10% are minorities. At study entry, participants averaged 61.4 years of age; 14% of them smoked, and 22% used aspirin. At the baseline colonoscopy, 35% of participants had two or more adenomas, and 29% had at least one large (> of = 1 cm) adenoma. Demographic, behavioral, dietary, and clinical characteristics are comparable across the two study arms. Participants have repeat colonoscopies after 1 (T(1)) and 4 (T(4)) years of follow-up. The primary end point is adenoma recurrence; secondary end points include number, size, location, and histology of adenomas. All resected lesions are reviewed centrally by gastrointestinal pathologists. The trial provides 90% power to detect a reduction of 24% in the annual adenoma recurrence rate. The primary analytic period, on which sample size calculations were based is 3 years (T(1) to T(4)), which permits a 1-year lag time for the intervention to work and allows a more definitive clearing of lesions at T(1), given that at least 10-15% of polyps may be missed at baseline. The final (T(4)) colonoscopies are expected to be completed in early 1998.

Serum selenium and colonic neoplastic risk.

BACKGROUND: Selenium deficiency has been associated with cancer risk in several organs. This association was investigated in neoplasia of the colorectum. DESIGN: A case-control study is reported with two patient series, colorectal cancer and colorectal adenomatous polyps, and a control group found to be free of colorectal neoplasia. Diagnosis was determined by colonoscopy and histologic review of suspected neoplasms. Serum drawn at the time of colonoscopy was subsequently assayed for selenium content, and quartiles based on selenium were defined. Crude and adjusted odds ratios with 95 percent confidence intervals for adenoma related to selenium were calculated, controlling for known or suspected risk factors including gender, age, race, body mass index, family history, tobacco use, alcohol consumption, serum beta carotene, serum alpha tocopherol, and serum ferritin. RESULTS: There were 138 controls who had no neoplastic disease, 139 adenoma patients, and 25 cancer patients. For adenoma, comparing higher quartiles of selenium to the first (lowest selenium), the adjusted odds ratio for the second quartile was 1.7 (95 percent confidence interval, 0.8-3.7), the third quartile was 1.4 (0.7-3.2), and the fourth (highest selenium) quartile was 1.8 (0.9-4). The odds ratios for cancer patients were 0.8 for the second quartile, 1 for the third quartile, and 1.7 for the fourth quartile. CONCLUSION: No trend could be detected toward a protective effect of higher levels of serum selenium for colonic benign or malignant tumors.

Effect of cigarette smoking on gastroesophageal reflux measured by 24-h ambulatory esophageal pH monitoring.

OBJECTIVE: We reassessed the effect of cigarette smoking on gastroesophageal reflux because two previous ambulatory 24-h pH monitoring studies showed equivocal results and did not relate heartburn to changes in pH reflux events. METHODS: Our protocol design considered nicotine's pharmacokinetic half-life; 14 smokers with heartburn and esophagitis abstained from smoking for 48 h before and during an ambulatory 24-h esophageal pH monitoring study (24-h pH). After resuming their smoking habits for 48 h or more, they underwent a second 24-h pH study and smoked 20 regular, filtered Marlboro cigarettes. Acid reflux was defined as a drop in intraesophageal pH to a value < 4 at 5 cm above the lower esophageal sphincter and was measured as percent exposure and reflux events (total N, those > or = 5 min, and longest event). Heartburn episodes were noted by the patients and were correlated later to acid reflux events. RESULTS: Cigarette smoking significantly increased the percentage time that the pH was < 4 during a 24-h period from 7.35 to 11.1% (medians; p < 0.007). This increased exposure occurred predominantly during the day while in the upright posture and resulted from significant increases in both reflux events and those parameters that measure acid clearance (T events > or = 5 min and longest event). While smoking, the patients noted a 114% increase in daytime heartburn episodes that immediately followed a pH reflux event (3.5 to 7.5 episodes, medians; p < 0.009). CONCLUSIONS: Smoking 20 cigarettes has a greater effect on acid reflux and heartburn than purported.

Benign colonic ulcers associated with nonsteroidal antiinflammatory drug ingestion.

Nonsteroidal antiinflammatory drugs can be associated with benign colonic ulcers. The ulcers are easily diagnosed by colonoscopy, and, if uncomplicated, they are best treated by cessation of the nonsteroidal antiinflammatory drugs. Benign colonic ulcers should be included in the differential diagnosis of any patient who presents with gastrointestinal complaints and is taking nonsteroidal antiinflammatory drugs.

Body iron stores and risk of colonic neoplasia.

BACKGROUND: Body iron stores and dietary iron intake have both been shown to be positively associated with subsequent risk of colon cancer. This finding comes from a cohort study involving 14,000 men, but the positive association occurred in only 12 cases. PURPOSE: We performed a case-control study of 264 men and 98 women to test for an association between serum ferritin levels and the presence of adenoma of the colon that would be independent of other known risk factors. METHODS: Serum ferritin levels were determined in this study from sera, frozen at -80 degrees C for 5-8 years, that had been originally obtained between 1984-1987 at the Walter Reed Army Medical Center from adult male and postmenopausal female patients undergoing routine colonoscopic examination and previously enrolled in a case-control study that assessed the potential dietary and environmental risk factors for colonic neoplasia. The presence of fecal occult blood in the stool or the suggestion of colonic polyps seen on barium enema defined eligibility for the study. Patients with known preexisting colonic disease were excluded. Eligible patients had their blood drawn and serum prepared. Following colonoscopy and histologic review, the patients were classified into three groups: normal (without neoplastic disease), 159 subjects; adenoma, 145 subjects; and colon cancer, 29 subjects. Body iron stores were determined by measuring serum ferritin levels by a competitive-binding radiometric immunoassay. Ferritin levels categorized into quintiles for adenoma were defined. Crude and adjusted odds ratios (ORadj) with 95% confidence intervals (CIs) for cancer and adenoma related to ferritin were calculated, controlling for known or suspected risk factors including sex, age, race, body mass index, family history, tobacco use, and alcohol consumption. RESULTS: Statistically significant associations of adenoma risk were seen in the third ([ORadj] = 3.8; 95% CI = 1.5-9.5) and fourth (ORadj = 5.1; 95% CI = 2.0-12.7) quintiles of ferritin relative to the first quintile, for smoking history (ORadj = 2.4; 95% CI = 1.3-4.3), for male sex (ORadj = 1.9; 95% CI = 1.0-3.7), and for family history of polyps or cancer (ORadj = 1.8; 95% CI = 1.0-3.4). From a second set of analyses that excluded 36 patients with serum ferritin of greater than or equal to 399 ng/mL, the greatest effect of ferritin on adenoma risk by anatomic subsite was seen in the right colon. CONCLUSION: The apparent dose-response for serum ferritin level and adenoma risk suggest that exposure to iron may be related to adenoma formation.

beta-Carotene inhibits rectal mucosal ornithine decarboxylase activity in colon cancer patients.

Colonic adenocarcinoma affects approximately 6% of adults in many Western countries. beta-Carotene (BC), a safe, inexpensive, and widely available compound, has been proposed as a cancer chemopreventive agent. To evaluate whether BC shows promise as an inhibitor of colonic carcinogenesis, we studied 20 male subjects who had previously undergone resection of colonic adenocarcinoma. Each subject received beta-carotene, 30 mg orally, daily for 6 months. Rectal mucosa was sampled at multiple intervals prior to, during, and following BC administration. Mucosal ornithine decarboxylase (ODC) activity and serum and mucosal BC concentrations were determined at each interval. ODC activity was inhibited by 44% (P < 0.05) and 57% (P < 0.01) after 2 and 9 weeks, respectively, of BC administration and remained low compared with baseline even 6 months following discontinuation of BC. Serum and mucosal BC concentrations increased as expected during BC administration and remained elevated for 6 months following BC discontinuation. The demonstrated inhibition of rectal mucosal ODC activity in these patients with resected colon cancer suggests that BC may prove useful as a cancer chemopreventive agent.

Serum gastrin is not higher in subjects with colonic neoplasia.

Two previous studies have shown higher circulating gastrin levels in subjects with colonic neoplasia than in colonoscopy-negative controls. In this much larger study, sera were collected from fasting subjects undergoing colonoscopy. Colonoscopy with biopsy classified participants as having colonic adenomas (N = 139), colon carcinoma (N = 29), or controls without colonic neoplasia (N = 150). Frozen, stored sera were later analyzed for gastrin by radioimmunoassay. Serum gastrin values were no higher in subjects with colonic adenomas or carcinoma than in colonoscopy-negative controls. We conclude that elevated serum gastrin levels play little, if any, role in the initiation of colonic neoplasia.

Pill-induced esophageal injury.

Delay in esophageal transit of caustic medicinal pills may precipitate esophageal ulceration. The injury is usually mild, producing only self-limited pain. More serious injury may result in esophageal hemorrhage, perforation, or stricture. Injury is more likely if pills are taken without water or while lying down. Patients with esophageal compression from left atrial enlargement are at increased risk, especially if they have had cardiac surgery.

Caustic ingestion injuries.

Ingestion of caustic agents causes more than 5000 injuries yearly. There is little that the physician can do acutely to attenuate the severity of the internal injuries, but the physician must intensively monitor the patient and react quickly to treat laryngeal burns or transmural penetration of esophageal or gastric burns. Esophageal strictures may appear at any time after the second week. No therapy has been shown to reduce the incidence of strictures. A policy of vigilant anticipation and early dilatation of developing strictures is recommended.

Small bile duct abnormalities in sarcoidosis.

We report four patients with hepatic involvement of sarcoidosis manifested primarily by bile duct depletion. The patients developed fever, weight loss, anorexia, a markedly elevated alkaline phosphatase, and mildly abnormal serum levels of aspartate aminotransferase. Endoscopic retrograde cholangiopancreatography showed slight intrahepatic irregularities but were not diagnostic of sclerosing cholangitis. Liver biopsy showed predominantly bile duct depletion, ranging from an estimated 10-100% absence of bile ducts in portal areas, which correlated with the degree of fibrosis. The degree of bile duct depletion is useful as a histological marker in patients with sarcoid liver disease. Steroids improve symptoms, but do not inhibit the development of "ductopenia."

Chronic beta-carotene supplementation does not alter the gastric mucosal response to acute aspirin ingestion.

Carotenoids and retinoids have been reported to reduce gastrointestinal mucosa damage from a variety of irritants. We performed double-blind, placebo-controlled endoscopic trial to evaluate the effect of chronic beta-carotene supplementation upon the gastric mucosal response to acute aspirin injury. Six subjects taking chronic beta-carotene and six taking placebo each ingested 650 mg of aspirin after an endoscopy confirmed normal gastric mucosa. Three hours later, mucosal lesions were counted at repeat endoscopy. beta-Carotene did not prevent acute mucosal injury better than placebo.

Cigarettes and alcohol as independent risk factors for colonic adenomas.

Healthy adults completed smoking and alcohol consumption questionnaires before colonoscopies, which were performed because of occult blood in the stool or prior barium enema suggesting polyps. Subjects with adenomas at colonoscopy (n = 102) were compared with colonoscopy-negative controls (n = 89). In univariate analyses, age (p less than 0.05), male sex (p less than 0.005), cumulative smoking (p less than 0.0001), and cumulative beer consumption (p less than 0.005) were associated with adenomas. The association of smoking with adenomas was stronger in younger subjects. The association of beer with adenomas was stronger in older subjects. Logistic regression confirmed statistically significant associations of smoking (odds ratio for greater than 40 pack-years = 3.31; confidence intervals 1.41, 7.81) and beer consumption (odds ratio for greater than 40 beer-years = 2.64; confidence intervals 1.10, 6.32) with adenomas. These results suggest that smoking and beer consumption are independent risk factors for colonic adenomas.