Prospective study of the frequency and size distribution of polyps missed by colonoscopy.

An important determinant in interpreting the results of colorectal polyp chemoprevention trials is the rate of polyps missed during colonscopic examination. We prospectively examined 90 patients by tandem colonoscopy performed by two alternating examiners. In 69 (76.7%) patients, 221 neoplastic lesions were documented histologically. Of a total of 58 lesions detected in 31 patients, no neoplastic lesion greater than or equal to 10 mm in size was missed; 16% of diminutive (less than or equal to 5 mm) neoplastic polyps and 12.3% of medium-sized (6-9 mm) neoplastic polyps were missed by the first examiner. We conclude that an experienced colonoscopist will miss about 15% of colorectal neoplastic polyps less than 10 mm in size in the setting of adequate bowel preparation. Large (greater than or equal to 10 mm) polyps were rarely missed, however, with the "miss" rate in our study equal to 0, with a 95% confidence limit of 4.64%.

Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac, have cancer chemopreventive properties by a mechanism that has been suggested to involve cyclooxygenase inhibition and reduction of prostaglandin (PGE2) levels in the target tissue. To test this hypothesis, we studied the effect of dietary sulindac sulfone (500-2000 ppm), a metabolite of sulindac reported to lack cyclooxygenase inhibitory activity, on tumor formation and PGE2 levels in the azoxymethane model of colon carcinogenesis. Rats treated with sulindac at 400 ppm and piroxicam at 150 ppm were used as positive controls. Rats received two s.c. injections of azoxymethane (15 mg/kg) for 2 weeks and were fed either experimental or control diets until necropsy. After 31 weeks of sulfone treatment, a dose-related increase in sulfone levels in both serum and cecal contents was measured; there was no evidence of metabolic conversion to sulindac or other metabolites. Rats treated with sulfone at 1000 and 2000 ppm, sulindac, and piroxicam had significantly fewer colonic adenomas and carcinomas compared with rats fed control diet as measured by tumor incidence, multiplicity, and tumor burden. Sulfone-treated rats also showed a dose-response relationship for inhibiting all tumor parameters. Colons from rats treated with sulindac or piroxicam contained PGE2 levels that ranged from approximately 16-49% of control levels. PGE2 levels in rats treated with sulfone up to 2000 ppm ranged from 78-118% of control levels. Moreover, the effects of sulindac sulfone on various enzymes responsible for regulating prostaglandin levels were evaluated. No significant inhibitory effects were observed for cyclooxygenase, lipoxygenase, or phospholipase A2. These results suggest that reduction of prostaglandin levels in the target tissue may not be necessary for the chemopreventive properties of sulindac.

Prevalence of distal colonic neoplasia associated with proximal colon cancers.

BACKGROUND: The number, size, and histologic features of distal colorectal adenomatous polyps have been reported to correlate with the risk of developing proximal colon cancer. To investigate this putative relationship further, we evaluated the frequency of distal colorectal neoplastic polyps in patients with colon cancer located proximal to the splenic flexure. METHODS: All cases of colorectal adenocarcinomas treated at a tertiary referral center and Veterans Affairs hospital between 1979 and 1992 were identified by International Classification of Diseases coding and review of pathology and colonoscopy reports. The medical records of patients with documented cancers proximal to the splenic flexure were examined for the presence, location, size, and histopathologic features of synchronous neoplastic lesions found at colonoscopy. RESULTS: Among 634 patients with colorectal cancer identifiable by location, 172 had proximally located tumors. Of these, 60 patients were excluded because of lack of complete colonoscopy or because surgical resection was performed elsewhere. Forty percent of the remaining 112 patients for whom data could be evaluated demonstrated neoplastic lesions in addition to the proximal cancer. The colon was devoid of "sentinel" neoplasia distal to the splenic flexure and descending colon-sigmoid colon junction in 69% and 72% of patients, respectively. CONCLUSIONS: The majority of proximal colon cancers are not associated with distal sentinel lesions. We surmise that flexible sigmoidoscopy will fail to find evidence of neoplasia in at least 25% of patients with prevalent colon cancers.

Current trends in the pharmacotherapy for gastroesophageal reflux disease.

Medical therapy for gastroesophageal reflux disease should entail a multistep approach. After life-style changes, many patients will require histamine2 receptor antagonists in conventional doses with repeated therapeutic courses, if not continuous maintenance. Prokinetic agents are potentially useful in those patients with impaired motor function of the esophageal or gastric smooth muscle. Combination therapy with histamine2 receptor antagonists and prokinetic agents or sucralfate provides modest healing benefit, if any, over that by histamine2 receptor antagonists alone. For patients with more severe refractory disease, omeprazole has provided unequaled healing rates and accelerated symptomatic relief. High-dose (twofold or more standard dose) histamine2 receptor antagonist therapy may also heal high-grade esophagitis, but the reported experience is small. After healing is achieved, an attempt should generally be made to "step down" therapy to standard-dose histamine2 receptor antagonist as maintenance. Finding the least amount of drug to control symptoms and maintain the integrity of the esophageal mucosa would minimize cost and potential long-term risk.

Current trends in the pharmacotherapy for peptic ulcer disease.

A variety of options are available for the medical treatment of peptic ulcer disease, including antacids, histamine2 receptor antagonists, omeprazole, prostaglandin analogues, and sucralfate and bismuth formulations. Seventy percent to 90% of peptic duodenal and gastric ulcers will heal after 4 to 8 weeks of therapy. Combination regimens using these agents have not been demonstrated to be superior to single-agent therapy. Aggressive acid suppression with "high-dose" histamine2 receptor antagonists or omeprazole accelerates healing of ordinary ulcers and promotes healing of previously refractory ulcers. Although ulcer recurrence is diminished by continuous "maintenance" therapy with the aforementioned agents, recurrence seems to be dramatically suppressed after eradication of Helicobacter pylori from the gastroduodenal mucosa.

Sources of variability in estimating ornithine decarboxylase activity and polyamine contents in human colorectal mucosa.

The activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is elevated during epithelial carcinogenesis. Since this enzyme is a target for colon and other cancer chemoprevention strategies, we sought to identify sources of variability affecting the measurement of tissue ODC activities and polyamine contents. Multiple colorectal biopsies were obtained from 39 patients undergoing colonoscopy. Biopsy size affected polyamine but not ODC values. Spermidine (spd):spermine (spm) ratios varied less than the contents of the individual amines. Bowel preparation methods did not affect any of the measurements. ODC activities and spd:spm ratios did not vary with bowel location. Lab assay methods contributed to sources of error. Variability was greatest for polyamine content measurements but was reduced when polyamine contents were analyzed as spd:spm ratios. Intrapatient variability of these parameters was as great or greater than interpatient variability. When measured in apparently unaffected colorectal mucosa, none of these parameters were significantly correlated with prior polyp history, number of prevalent polyps found at current colonoscopy, or polyp size. Thus, neither ODC activity nor polyamine contents of normal mucosa appear to be discriminatory markers of colorectal carcinogenesis. However, spd:spm ratios, which show the least variability among measures of polyamine contents, should be a good marker of the consequence of polyamine synthesis inhibition in chemoprevention trials.

Gastric intestinal metaplasia in ethnic groups in the southwestern United States.

The incidence of gastric cancer has declined dramatically in the United States during this century. However, the incidence of gastric cancer among Hispanics, Blacks, and Native Americans remains 2-3-fold higher than among Whites in this country. Populations with an increased risk of gastric cancer have predominantly the "intestinal" type of gastric cancer, and intestinal metaplasia is regarded as a histological precursor lesion of this type of gastric cancer. We sought to establish the prevalence of intestinal metaplasia, identify associated epidemiological factors, and improve detection of this lesion in a patient population undergoing clinically indicated endoscopy in the Southwestern United States. Among the 440 patients studied, we observed an overall crude prevalence of intestinal metaplasia of 19%. However, the crude prevalence among Hispanics and Blacks was found to be markedly higher than among non-Hispanic Whites (50% versus 13%). Two biopsy protocols (two biopsies versus four biopsies) were used during this study, with a significantly higher rate of intestinal metaplasia detection under the four-biopsy protocol. Adjusting for protocol, we found that age and ethnicity were significantly and independently associated with the prevalence of intestinal metaplasia. The odds of intestinal metaplasia diagnosis was significantly higher in Hispanics compared to non-Hispanic Whites (P < 0.001), and the prevalence of intestinal metaplasia increased with advancing age (P = 0.01). The presence of Helicobacter pylori was also significantly associated with the presence of intestinal metaplasia (P = 0.02), although the direction of the association differed between Hispanics and non-Hispanic Whites.

Plasma selenium concentration predicts the prevalence of colorectal adenomatous polyps.

The objective of this cross-sectional study was to determine whether plasma selenium concentration predicts the prevalence of adenomatous polyps of the colon and rectum. The source population for the study was 101 patients undergoing sequential colonoscopies at the Veterans Affairs Medical Center, Tucson, AZ. The study population was then limited to the 48 patients (all male) undergoing their initial colonoscopy who did not have a diagnosis of colorectal cancer. For each of these patients, a prediagnostic fasting plasma selenium concentration was determined. The data from this study suggest that fasting plasma selenium concentrations may be an important risk factor for colorectal adenomas. Patients with fasting plasma selenium concentrations below the median (< 128 mcg/liter) were significantly more likely to have one or more adenomatous polyps (prevalence odds ratio 4.2) and more adenomatous polyps (3.5 times) per patient. There was also a suggestion of a more proximal distribution of adenomatous polyps in the patients with a lower level of selenium. These associations were not confounded by age or smoking. The results of this study are consistent with the experimental animal studies, geographic mortality studies, and prospective cohort studies of selenium and colorectal cancer.

Ornithine decarboxylase and polyamines in colorectal neoplasia and mucosa.

Ornithine decarboxylase (ODC) and polyamines are intimately involved in normal cellular proliferation and are likely to play a role in carcinogenesis. ODC activity and polyamine content were measured in tissue samples obtained during colonoscopy from 48 benign neoplastic polyps (20 tubular adenomas; 28 villous adenomas), 18 cancers (including 5 malignant polyps), and adjacent mucosa. ODC activity in polyp and cancer tissue specimens was higher than in adjacent mucosa in 75 and 83% of pairs, respectively. Similarly, putrescine, spermidine, and spermine contents were higher in the majority of polyps and cancers compared to adjacent mucosa. ODC activity and polyamine content in colonic mucosa from 10 patients without a history of colorectal neoplasia were not different from adjacent mucosal values in the patients with neoplasia. In conclusion, ODC and polyamines are elevated in the majority of colorectal neoplasms, but amounts in normal mucosa do not differentiate between patients with cancer, benign neoplastic polyps, and normal subjects.

Comparison of proliferating cell nuclear antigen versus the more standard measures of rectal mucosal proliferation rates in subjects with a history of colorectal cancer and normal age-matched controls.

Measurement of proliferation rates by the more standard in vitro uptake techniques of [3H]thymidine and 5'-bromo-2'-deoxyuridine (BrdUrd) labeling indices (LIs) were compared to proliferating cell nuclear antigen (PCNA) in rectal mucosal biopsies from 16 subjects with resected colorectal cancer and 14 normal age-matched controls. Correlation coefficients for BrdUrd versus PCNA, [3H]thymidine versus PCNA, and BrdUrd versus [3H]thymidine were 0.691, 0.876, and 0.770, respectively. No significant differences (P > 0.05) were detected in total mean LIs between the LI methods for the normal group. In contrast, total PCNA LIs were found to be significantly different in the resected cancer patients when compared to either BrdUrd (P = 0.005) or [3H]thymidine (P < 0.001). A significant difference (P = 0.010) in total PCNA LI but not in total [3H]thymidine or BrdUrd LIs was also observed between normal controls and resected colorectal cancer subjects. Compartmental analysis of the cancer group versus the normals showed a significant difference in compartments 1 and 3 for PCNA LIs only. The reproducibility of two PCNA LI counts was excellent (r = 0.9). In addition, the reliability of mean LIs were > 0.8 with the exception of [3H]thymidine in the normal group (0.7). These study results demonstrate that PCNA LIs in human rectal mucosal biopsies are correlated highly with other more commonly used cellular proliferation measurements; however, PCNA LIs were found to be significantly higher than the other two methods in the resected colorectal cancer subjects.

Antiproliferative effect of nonsteroidal antiinflammatory drugs against human colon cancer cells.

Several lines of evidence suggest that nonsteroidal antiinflammatory drugs may be effective in preventing colorectal cancer. These include animal experiments, case-control studies, and clinical experience with sulindac in promoting the regression of adenomatous colon polyps in adenomatous polyposis coli. We determined the antiproliferative activity of various nonsteroidal antiinflammatory drugs, including two sulindac derivatives, against human colon cancer cells in vitro. Ht-29, SW480, and DLD-1 cells were continuously incubated with serial drug dilutions for 6 days prior to fixation. Cell number was determined using the sulforhodamine B assay, and drug concentrations which inhibited cell growth by 50% were estimated for each agent by interpolation. All drugs exhibited antiproliferative activity against Ht-29 and DLD-1 cells, and most inhibited SW480 cells. For Ht-29 cells, the 50% inhibitory concentration varied from 55 microM for diclofenac to 2100 microM for 5-aminosalicylic acid, with three drug groups of high, intermediate, and low potency evident. Inhibition of cell growth by sulindac sulfide was reversible following drug removal. Nonsteroidal antiinflammatory drugs exert an antiproliferative effect against human colon cancer cells with a wide range of potencies. A cytostatic response was demonstrated with sulindac sulfide. These data further support the potential role of these agents for chemoprevention of colorectal neoplasia.

Limitations of combined flexible sigmoidoscopy and double contrast barium enema in patients with rectal bleeding.

Eighty-seven outpatients with non-massive rectal bleeding or asymptomatic positive fecal occult blood were evaluated with 35 cm flexible sigmoidoscopy, double contrast barium enema (DBCE) and colonoscopy. 82% had hemorrhoids and 35% harbored colorectal neoplasia. The combination of flexible sigmoidoscopy and DCBE missed none of 7 malignant lesions. However, 36% of benign polyps greater than or equal to 1 cm and 60.25% of those less than 1 cm were not detected by this combination. The presence of hemorrhoids should not prevent a search for colon neoplasia and colonoscopy is the preferred method.

Biliary obstruction. Nonsurgical treatment with endoscopic and radiologic techniques.

Several methods and combinations of techniques are available to treat biliary obstruction. The approach to treatment should be determined by the patient's situation and the expertise available in the various treatment options rather than by adherence to a standard plan. Clinical outcomes reported in the literature reflect results achieved by experts, and traditional surgical approaches may be most appropriate if experience with endoscopic and radiologic techniques is lacking in the patient's community. Various methods can often be used in a complementary or sequential fashion to provide optimal patient care.

Fatal hyperphosphatemia following Fleet Phospo-Soda in a patient with colonic ileus.

A fatal case of hyperphosphatemia secondary to enteral administration of Fleet Phospo-Soda is presented. A 64-yr-old male admitted for theophylline toxicity was treated with activated charcoal and sorbitol, but subsequently developed colonic ileus. Two sequential doses of Phospo-Soda were administered to facilitate clearance of the charcoal; however, this resulted in marked hyperphosphatemia, hypocalcemia, acidemia, and other electrolyte abnormalities, followed by the patient's demise. This case is added to several other reports about the risks of injudicious use of sodium phosphate cathartics.

Piroxicam and other cyclooxygenase inhibitors: potential for cancer chemoprevention.

Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) widely used for treatment of inflammatory arthritis. Recent experimental and clinical studies suggest that piroxicam, as well as other NSAIDs, may be useful for chemoprevention of colon cancer. While there is less information regarding NSAIDs for chemoprevention of urinary bladder malignancy, there are compelling data which suggest that this should be evaluated. A major effect of NSAIDs is inhibition of cyclooxygenase, the rate-limiting enzyme for conversion of arachidonic acid to important signal molecules, including prostaglandins, which profoundly affect cellular functions in many tissues. The initial enzyme reaction leading to formation of prostaglandin H can be accompanied by cooxidation of xenobiotics resulting in extrahepatic and local tissue production of reactive products which are carcinogenic. The end product prostaglandins, especially prostaglandin E2 (PGE2), are biological modifiers which can significantly affect cell proliferation and tumor growth. High levels of PGE2 stimulate growth of certain tumor cell lines while inhibition of prostaglandin synthesis with indomethacin or piroxicam can cause suppression. The mechanisms for this effect are unclear. Studies in cultured cells exposed to indomethacin show inhibition of G1-to-S phase progression of the cell cycle and a reduction in overall DNA synthesis. It is unclear whether this effect on cell growth results from some direct action of the NSAID or a reduction in prostaglandins or indirectly from modulation of important control signals, such as calcium flux. In addition to cyclooxygenase, NSAIDs can inhibit activity of other enzymes, including phosphodiesterases and cyclic GMP-AMP protein kinases, which may be central to cancer initiation and promotion. NSAIDs can also interfere with transmembrane ion fluxes and with cell-to-cell binding. Prostaglandins can modulate a variety of immunological responses and thereby play an important role in host antitumor immunity. For example, high levels of tissue PGE2 are frequently associated with suppression of immune surveillance and killing of malignant cells. Conversely, immune responses are generally enhanced by drugs that inhibit prostaglandin synthesis. PGE2 can act as a feedback inhibitor for cellular immune processes, such as T-cell proliferation, lymphokine production, and cytotoxicity. This effect is also seen for macrophage activity and natural killer cell toxicity. In general, either increased production of PGE2 or increased sensitivity to normal amounts of PGE2 results in depressed cellular immunity. Cyclooxygenase inhibitors (NSAIDs) such as piroxicam which decrease PGE2 production can stimulate cellular immune function both in vitro and in vivo. A variety of tumor cell lines and human malignancies produce large quantities of prostaglandins.(ABSTRACT TRUNCATED AT 400 WORDS)

False-positive secretin-KABI provocation test associated with achlorhydria.

Two patients with chronic abdominal pain and fasting hypergastrinemia had increases in serum gastrin of 440 and 300 pg/ml after injection of 2 U/kg Secretin-KABI. Both subsequently proved to have pentagastrin-fast achlorhydria. Intragastric instillation of 0.1 N HCl suppressed serum gastrin concentration by greater than 60%. In both, the pancreas was normal by sonography or computed tomography (CT) scan and at laparotomy in one. Both are currently asymptomatic 12 and 18 months later. We conclude that achlorhydria may be associated after injection of Secretin-KABI with a false-positive rise in fasting serum gastrin concentration of greater than 200 pg/ml and that gastric analysis for hypochlorhydria should be performed before secretin provocation testing.

Design and analysis of studies to reduce the incidence of colon polyps.

Decisions regarding the design and analysis of a phase III study to reduce the incidence of colorectal polyps must take into account two complicating factors: the possibility that polyps are missed during screening exams, and variable lengths of follow-up. In this paper we investigate the effects due to misclassification on the power of statistical tests to detect a change in polyp recurrence rates. We also use Monte Carlo studies to examine the relative efficiency of different methods of adjusting for variable times of follow-up.

NSAID effect on sporadic colon polyps.

UNLABELLED: In this study, our objective was to determine whether 6 months of open-label therapy with sulindac 400 mg/daily or piroxicam 20 mg/daily promote regression of adenomatous colonic polyps left in situ. Left-sided colonic polyps (size 3-12 mm) detected at colonoscopy were measured and left without being biopsied. The bowel wall opposite to the polyps was marked with India ink submucosally. Patients were assigned to drug therapy, and compliance was determined by pill count. Polyps were measured during sigmoidoscopy after 3 and 6 months of treatment; polyps were removed at the 6-month examination. Examiners were not blinded to drug therapy or previous polyp measurements. Seven patients completed 6 months of therapy (five sulindac and two piroxicam). Two additional patients treated with piroxicam were withdrawn secondary to adverse events (bleeding gastric ulcer and rash). In one patient treated with sulindac, a 6-mm polyp disappeared, and two other polyps seemed to regress partially. One polyp regressed partially in a piroxicam-treated patient. All other polyps remained unchanged. CONCLUSIONS: We did not observe dramatic regression of sporadic colon adenomatous polyps to either sulindac or piroxicam after 6 months of therapy in this small uncontrolled pilot study.

Referral patterns and the results of antireflux operations in patients more than sixty years of age.

The role of antireflux operations in the elderly is ill-defined. Often, these patients are managed medically despite refractory symptoms for fear of surgical morbidity and mortality by referring physicians. This investigation was done to review the referral patterns and results of antireflux operations for patients more than 60 years old. The charts of all patients undergoing operation for reflux were reviewed during an eight year period from 1981 to 1989. One hundred and three patients underwent Nissen fundoplication. All patients had been treated with H2 blockers or antacids, or both, prior to referral for operation. Group 1 (N = 43) consisted of all patients who were 60 years of age and group 2 (N = 60), all patients less than 60 years of age. The mean age of those in group 1 was 70.6 years versus 43.7 years for those in group 2. The mean duration of symptoms was far greater in the elderly group versus the younger group (14.4 versus 4.1 years) (p less than 0.001). Twenty-eight patients in group 1 were referred for surgical treatment because of complications of reflux versus only four in group 2 (p less than 0.01) in whom intractability was the main indication for surgical treatment. The specific complications of gastroesophageal reflux disease that led to the referral of elderly patients for operation were stricture, bleeding, aspiration and Barrett's esophagus. There was one death and this occurred in a 46 year old woman who had a massive pulmonary embolism postoperatively. The mean duration of follow-up study was 5.1 years. Improvement in symptoms was noted by 37 patients in group 1 versus 56 in group 2. We conclude that elderly patients are most often referred for antireflux operations for complications of reflux versus younger patients in whom intractability is the most common indication. Earlier referral is warranted if reflux symptoms persist despite adequate medical therapy. Despite advanced esophageal disease, the results of antireflux operations are good, and surgical morbidity and mortality rates are low enough to warrant intervention in this group of patients, provided no medical contraindications exist.

Prospective blinded trial of the colonoscopic miss-rate of large colorectal polyps.

We prospectively studied the colonoscopic miss-rate of large colorectal polyps in a blinded trial featuring tandem colonoscopy. Sixty-three lesions greater than or equal to 1 cm in size were discovered and none were missed. Confidence intervals of 95% are a miss-rate of 0 to 4.6%. We conclude that less than 5% of large colorectal polyps are missed during the index colonoscopic examination in a well-prepared colon.