Meeting report from the joint IARC-NCI international cancer seminar series: a focus on colorectal cancer.

Despite significant progress in our understanding of the etiology, biology and genetics of colorectal cancer, as well as important clinical advances, it remains the third most frequently diagnosed cancer worldwide and is the second leading cause of cancer death. Based on demographic projections, the global burden of colorectal cancer would be expected to rise by 72% from 1.8 million new cases in 2018 to over 3 million in 2040 with substantial increases anticipated in low- and middle-income countries. In this meeting report, we summarize the content of a joint workshop led by the National Cancer Institute and the International Agency for Research on Cancer, which was held to summarize the important achievements that have been made in our understanding of colorectal cancer etiology, genetics, early detection and treatment and to identify key research questions that remain to be addressed.

Is Helicobacter pylori a cause of duodenal ulcer? A methodologic critique of current evidence.

INTRODUCTION: Helicobacter pylori (HP) in the gastric antrum has been strongly associated with both duodenal ulcer (DU) and chronic active gastritis (CAG). The relationship between HP and DU has been interpreted as causal by many observers. An alternate hypothesis is that HP coincidently colonizes CAG, which is independently associated with DU by some yet-unknown mechanism. PURPOSE: To assess the extent to which a causal relationship between HP and DU has been demonstrated, we performed a methodologic critique of published clinical studies. We carried out a literature search to identify clinical studies that included at least 25 subjects. Of the eight studies we identified, six used a cross-sectional design and two used a prospective cohort design. We applied methodologic criteria to assess causation: strength of association, biologic gradient, temporality, and experiment. METHODS: A strong association between HP and DU was demonstrated in all eight studies. Biologic gradient and temporality were not assessed in any study. In the two experimental studies of therapy, loss of antral HP was associated with a decreased rate of DU relapse; however, we did not interpret this as sufficient to support causality because the effect may have been due to a direct mucosal action rather than eradication of HP. CONCLUSION: We conclude that published evidence does not establish HP as a cause of DU. One approach to address causality would be an observational cohort study of ulcer relapse to assess the temporal relationships between HP, CAG, and DU.

Management of patients with symptomatic gallstones: a quantitative analysis.

Should persons with symptomatic gallstones (i.e., those that have caused biliary pain) be treated immediately? Or may they be managed expectantly until pain recurs or a biliary complication (i.e., acute cholecystitis or pancreatitis) occurs? To assess the mortality risk of different strategies, we performed a quantitative analysis. For the expectant management strategy that requires surgery only if a biliary complication occurs, the cumulative lifetime probability of gallstone disease death in a 30-year-old man is about 2%, and most deaths occur after age 65. In comparison, elective cholecystectomy has only a 0.1% rate of gallstone disease death, but all deaths occur at age 30. The average amount of life expectancy gained by immediate cholecystectomy compared with expectant management is 52 days, which is reduced to 23 days using 5% discounting. This gain could be increased only slightly by a 100% effective and risk-free therapy such as perfected lithotripsy or medical dissolution. Results are similar for women. The results suggest that, for persons with symptomatic gallstones, the life expectancy gain of immediate cholecystectomy is relatively small and that the potential incremental gain of nonsurgical therapy is also small. For patients and physicians who believe that life expectancy is of primary consideration, the decision about therapy may be made primarily on non-mortality considerations. Some patients and physicians may decide that the risk of symptomatic gallstones is low enough that a policy of expectant management may be acceptable.

Hepatitis B vaccination. Three decision strategies for the individual.

Three strategies regarding hepatitis B virus vaccination were compared by decision analysis: no vaccination, immediate vaccination, and vaccination after two years. The potential advantage of waiting two years is to learn whether serious side effects of the vaccine will become evident. For example, it was found that immediate hepatitis B vaccination of 100,000 surgical house officers with a 5 percent annual attack rate for five years would, compared with no vaccination, prevent 4,092 cases of icteric hepatitis, 335 cases of chronic active hepatitis, and 15 deaths from fulminant hepatitis. For a strategy of waiting two years, the number of cases prevented would decrease by about 40 percent. Persons in groups with an annual attack rate lower than 5 percent appear to benefit from vaccination. The known health risks of hepatitis B virus vaccination are low, and the hypothesized risks would have to be frequent to justify delay in vaccination. From an individual perspective, even persons at low risk of hepatitis B virus infection should seriously consider immediate vaccination.

Achieving quality in flexible sigmoidoscopy screening for colorectal cancer.

BACKGROUND: Sigmoidoscopy screening, which can dramatically reduce colorectal cancer mortality, is supported increasingly by physicians and payers, and is likely to be performed more frequently in the future. As more physicians and nonphysician medical personnel learn how to perform this procedure, and with attention to quality standards, the overall impact of sigmoidoscopy screening may improve. This review describes elements that characterize high-quality examinations and identifies resources for in-depth information on performing flexible sigmoidoscopy. METHODS: The domains of quality were identified from textbooks, articles, and the professional opinions of gastroenterologists and primary care physicians. Information was obtained from MEDLINE, bibliographies in recent articles, medical professional organizations, equipment manufacturers' representatives, and focus groups of primary care physicians. RESULTS: Nine domains of quality are identified and discussed: training, logistical start-up, patient interaction, bowel preparation, examination technique, lesion recognition, complications, reporting, and processing (equipment cleaning and disinfection). CONCLUSIONS: Persons learning how to perform and to implement flexible sigmoidoscopy may use this information to help ensure the quality of screening examinations.

Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications.

Assessment of epithelial dysplasia in ulcerative colitis has been hindered by inconsistencies in and disagreements about nomenclature and interpretation. To resolve these issues, pathologists from ten institutions participated in three exchanges of multiple slides and, following each exchange, in discussions of the results. A classification system for the epithelial changes that occur in ulcerative colitis was developed, which should be applicable to other forms of inflammatory bowel disease as well. The classification makes use of standardized terminology, addresses specific problem areas, and offers practical solutions. The reproducibility of the system was studied by means of examinations of both inter- and intra-observer variations. The clinical implications of the findings were incorporated into suggestions for patient management. The basis of the classification is that the term "dysplasia" is reserved for epithelial changes that are unequivocally neoplastic and may therefore give rise directly to invasive carcinoma. Specimens are categorized as negative, indefinite, or positive for dysplasia. The negative category includes all inflammatory and regenerative lesions and indicates that only continued regular surveillance is required. The indefinite category is applied to epithelial changes that appear to exceed the limits of ordinary regeneration but are insufficient for an unequivocal diagnosis of dysplasia or are associated with other features that prevent such unequivocal diagnosis. Clinically, it indicates that early repeat biopsy is often required to assess the changes more accurately. The positive category is divided into two subcategories: 1) high-grade dysplasia, for which colectomy should be strongly considered after confirmation of the diagnosis, and 2) low-grade dysplasia, which also requires confirmation and early repeat biopsy or colectomy, depending on other findings.

Exposure rates to patients' blood for surgical personnel.

BACKGROUND: Surgical personnel are at risk of contracting blood-borne diseases through exposure to patients' blood. Exposure rates for each surgical subspecialty have not been previously reported. The purpose of this study was to determine the rates of exposure to patients' blood for operating room personnel. METHODS: The study was conducted at Yale-New Haven Hospital, a level I trauma center and tertiary care hospital. During a 3-month period, exposed personnel were interviewed by a study nurse immediately after a cutaneous exposure to blood or after a sharp injury. RESULTS: During 2292 surgical procedures, 70 sharp injuries and 168 cutaneous exposures to blood were reported. The combined exposure rate (skin contact and sharp injury) was 10.4 per 100 procedures (95% confidence interval, 9.1 to 11.6) and ranged from 21.2 for general surgery to 3.3 for pediatric surgery (goodness-of-fit chi-squared, p < 0.001). The combined exposure rates were also significantly different among types of surgery and ranged from 18 for laparotomies to 4.3 for craniotomies (chi-squared, p < 0.001). The overall sharp injury rate was 3.1 per 100 procedures (95% confidence interval, 2.3 to 3.8) and ranged from 4.3 for general surgery to 1.3 for vascular surgery. CONCLUSIONS: The rate of exposure to blood for operating room personnel, which differ from prior studies, was 10.4 per 100 procedures and was highest for general surgical procedures. The differences in rates among studies might be attributable to different surgical technique, dissimilar case-mix, or different research methods relating to definition or ascertainment of exposure.

Accuracy of administrative data in trauma.

BACKGROUND: Accurate data are needed to evaluate outcomes, therapeutics, and quality of care. This study assesses the accuracy of administrative databases in recording information about trauma patients. METHODS: Patients with thoracic aorta injury were identified with a state trauma registry, and the medical records were reviewed. Data collected were compared to administrative data on patients with thoracic aorta injuries, at the same hospitals in the same time period. RESULTS: Fifteen patients (16.3%) with thoracic aorta injury were not recorded in the administrative database, and 23 patients (18.7%) were misdiagnosed. Ninety-one patients were found in both data sources. The administrative database significantly (P < .05) underrecorded abdominal injuries (50 vs 35), orthopedic injuries (117 vs 75), and chest injuries (77 vs 48). The number of aortograms (78 vs 8), type of operative procedures (use of graft; 70 vs 30), use of bypass (35 vs 16), and complications (77 vs 33) were underreported (P < .05). The Injury Severity Score was underestimated by the administrative database (38.65 +/- 12.41 vs 25.66 +/- 9.53; P < .05). CONCLUSIONS: Administrative data lack accuracy in the recording of associated injury, injury severity, diagnostic, and procedural data. Whether these data should be used to evaluate treatment or quality of care in trauma is questionable.

What can we conclude from the randomized controlled trials of fecal occult blood test screening?

The results of three published randomized controlled trials of fecal occult blood testing (FOBT) provide unequivocal proof of the principle that screening reduces mortality from colorectal cancer (CRC). However, several interesting questions remain in interpreting and applying the results of the clinical trials, including: how well does FOBT screening work (i.e. how much can CRC mortality be reduced), how does it work, when is it worthwhile and worthwhile doing, and how can technique be optimized? The answers to these questions have important practical and clinical implications.

Diagnostic workup bias in the evaluation of a test. Serum ferritin and hereditary hemochromatosis.

Two studies report markedly divergent results about the usefulness of serum ferritin in diagnosing iron overload in relatives of patients with hereditary hemochromatosis. One study found the sensitivity of elevated serum ferritin to be 0%; another study found a sensitivity of 100%. Although different genetic abnormalities in iron or ferritin metabolism may explain the different results, our examination of these studies suggests that diagnostic workup bias also may explain the difference. In the study reporting a sensitivity of 100%, relatives with normal serum tests may have been excluded from consideration for liver biopsy, thus preventing detection of iron overload. The controversy may provide an empirical illustration of diagnostic workup bias.

To biopsy or not to biopsy in suspected herpes simplex encephalitis: a quantitative analysis.

The authors performed a decision analysis to determine whether a patient suspected to have herpes simplex encephalitis (HSE) should undergo a brain biopsy or be treated empirically with medical therapy. In most cases, empiric treatment with acyclovir would be slightly favored; brain biopsy was not essential in management. However, brain biopsy was found useful for patients who had low CSF glucose at the time of initial lumbar puncture; such patients may have a very high risk to have other treatable conditions such as tuberculosis, brain abscess, toxoplasmosis, or cryptococcosis. The results of the analysis suggest that even with the advent of safe antiviral drug therapy such as acyclovir, brain biopsy is useful in a well-defined subset of patients with possible HSE. The rationale, however, is not to confirm HSE but rather to detect other treatable conditions.

The case for colorectal cancer screening.

There is strong evidence that sigmoidoscopic screening can reduce the risk of colorectal cancer mortality by as much as 70%, but the case for extensive fecal occult blood testing is less convincing. Flexible sigmoidoscopy performed once every five to 10 years in patients aged 50 to 75 appears to be warranted; however, many practical barriers to widespread implementation still need to addressed.

Treatment of gallstones.

PURPOSE: To critically review the risks and benefits of therapy for asymptomatic and symptomatic persons with gallstones who are considering therapy to prevent future episodes of biliary pain or complications including acute cholecystitis, pancreatitis, or gallbladder cancer. DATA SOURCES: Review of English-language literature regarding the natural history of persons with gallstones and the operative mortality rates for open cholecystectomy and laparoscopic cholecystectomy. Mathematical simulation modeling was used to derive estimates of lifetime risks for gallstone-related mortality and for life expectancy, for prophylactic cholecystectomy and expectant management, for men and women of different ages. RESULTS: For persons with asymptomatic gallstones, natural history is so benign that treatment is generally not recommended. For persons with symptomatic gallstones, (that is, that have caused an episode of biliary pain), the rate for subsequent pain is high so that many persons probably choose cholecystectomy to avoid pain; however, about 30% of persons who have had pain do not have further episodes of pain. The expected loss of life for persons with symptomatic stones managed expectantly is roughly several months, on average, and may not be considered high enough in itself to warrant therapy. Although laparoscopic cholecystectomy has become popular with patients and physicians, its safety is yet unknown compared with open cholecystectomy. CONCLUSION: Prophylactic cholecystectomy should be recommended for most persons with symptomatic gallstones unless the person wants to try a period of watchful waiting to see if pain recurs. Nonsurgical therapy may be suitable for persons with high operative risk. For persons with asymptomatic gallstones, watchful waiting is the best course.

Problems of spectrum and bias in evaluating the efficacy of diagnostic tests.

To determine why many diagnostic tests have proved to be valueless after optimistic introduction into medical practice, we reviewed a series of investigations and identified two major problems that can cause erroneous statistical results for the "sensitivity" and "specificity" indexes of diagnostic efficacy. Unless an appropriately broad spectrum is chosen for the diseased and nondiseased patients who comprise the study population, the diagnostic test may receive falsely high values for its "rule-in" and "rule-out" performances. Unless the interpretation of the test and the establishment of the true diagnosis are done independently, bias may falsely elevate the test's efficacy. Avoidance of these problems might have prevented the early optimism and subsequent disillusionment with the diagnostic value of two selected examples: the carcinoembryonic antigen and nitro-blue tetrazolium tests.

Fecal occult blood screening for colorectal cancer. Is mortality reduced by chance selection for screening colonoscopy?

Annual fecal occult blood test (FOBT) screening using rehydrated Hemoccult slides has been reported in the Minnesota Colon Cancer Control Study to reduce colorectal cancer mortality by about 33%. However, some of the benefit of FOBT screening may come from "chance" selection of persons for colonoscopic examination because of the high positivity rate of FOBT (about 10%) that may occur for reasons other than a bleeding cancer or polyp. To determine how much this mechanism could account for the benefit of FOBT screening, we used a simple mathematical model to simulate the course of a cohort of screened persons, incorporating published data including those from the Minnesota study. The results suggest that one third to one half of the mortality reduction observed from FOBT screening in the Minnesota study may be attributable to chance selection for colonoscopy. We conclude that annual FOBT screening with rehydration is a haphazard method for selecting persons for colonoscopy.