Recommendations on Surveillance and Management of Biallelic Mismatch Repair Deficiency (BMMRD) Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

The US Multi-Society Task Force on Colorectal Cancer, with invited experts, developed a consensus statement and recommendations to assist health care providers with appropriate management of patients with biallelic mismatch repair deficiency (BMMRD) syndrome, also called constitutional mismatch repair deficiency syndrome. This position paper outlines what is known about BMMRD, the unique genetic and clinical aspects of the disease, and reviews the current management approaches to this disorder. This article represents a starting point from which diagnostic and management decisions can undergo rigorous testing for efficacy. There is a lack of strong evidence and a requirement for further research. Nevertheless, providers need direction on how to recognize and care for BMMRD patients today. In addition to identifying areas of research, this article provides guidance for surveillance and management. The major challenge is that BMMRD is rare, limiting the ability to accumulate unbiased data and develop controlled prospective trials. The formation of effective international consortia that collaborate and share data is proposed to accelerate our understanding of this disease.

Recommendations on Surveillance and Management of Biallelic Mismatch Repair Deficiency (BMMRD) Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

The US Multi-Society Task Force on Colorectal Cancer, with invited experts, developed a consensus statement and recommendations to assist health care providers with appropriate management of patients with biallelic mismatch repair deficiency (BMMRD) syndrome, also called constitutional mismatch repair deficiency syndrome. This position paper outlines what is known about BMMRD, the unique genetic and clinical aspects of the disease, and reviews the current management approaches to this disorder. This article represents a starting point from which diagnostic and management decisions can undergo rigorous testing for efficacy. There is a lack of strong evidence and a requirement for further research. Nevertheless, providers need direction on how to recognize and care for BMMRD patients today. In addition to identifying areas of research, this article provides guidance for surveillance and management. The major challenge is that BMMRD is rare, limiting the ability to accumulate unbiased data and develop controlled prospective trials. The formation of effective international consortia that collaborate and share data is proposed to accelerate our understanding of this disease.

Sexual transmission of hepatitis C virus among monogamous heterosexual couples: the HCV partners study.

UNLABELLED: The efficiency of hepatitis C virus (HCV) transmission by sexual activity remains controversial. We conducted a cross-sectional study of HCV-positive subjects and their partners to estimate the risk for HCV infection among monogamous heterosexual couples. A total of 500 anti-HCV-positive, human immunodeficiency virus-negative index subjects and their long-term heterosexual partners were studied. Couples were interviewed separately for lifetime risk factors for HCV infection, within-couple sexual practices, and sharing of personal grooming items. Blood samples were tested for anti-HCV, HCV RNA, and HCV genotype and serotype. Sequencing and phylogenetic analysis determined the relatedness of virus isolates among genotype-concordant couples. The majority of HCV-positive index subjects were non-Hispanic white, with a median age of 49 years (range, 26-79 years) and median of 15 years (range, 2-52 years) of sexual activity with their partners. Overall, HCV prevalence among partners was 4% (n=20), and nine couples had concordant genotype/serotype. Viral isolates in three couples (0.6%) were highly related, consistent with transmission of virus within the couple. Based on 8,377 person-years of follow-up, the maximum incidence rate of HCV transmission by sex was 0.07% per year (95% confidence interval, 0.01-0.13) or approximately one per 190,000 sexual contacts. No specific sexual practices were related to HCV positivity among couples. CONCLUSION: The results of this study provide quantifiable risk information for counseling long-term monogamous heterosexual couples in which one partner has chronic HCV infection. In addition to the extremely low estimated risk for HCV infection in sexual partners, the lack of association with specific sexual practices provides unambiguous and reassuring counseling messages.

The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on real-time endoscopic assessment of the histology of diminutive colorectal polyps.

The PIVI (Preservation and Incorporation of Valuable endoscopic Innovations) initiative is an ASGE program whose objectives are to identify important clinical questions related to endoscopy and to establish a priori diagnostic and/or therapeutic thresholds for endoscopic technologies designed to resolve these clinical questions. Additionally, PIVIs may also outline the data and or the research study design required for proving an established threshold is met. Once endoscopic technologies meet an established PIVI threshold, those technologies are appropriate to incorporate into clinical practice presuming the appropriate training in that endoscopic technology has been achieved. The ASGE encourages and supports the appropriate use of technologies that meet its established PIVI thresholds. The PIVI initiative was developed primarily to direct endoscopic technology development toward resolving important clinical issues in endoscopy. The PIVI initiative is also designed to minimize the possibility that potentially valuable innovations are prematurely abandoned due to lack of utilization and to avoid widespread use of an endoscopic technology before clinical studies documenting their effectiveness have been performed. The following document, or PIVI, is one of a series of statements defining the diagnostic or therapeutic threshold that must be met for a technique or device to become considered appropriate for incorporation into clinical practice. It is also meant to serve as a guide for researchers or those seeking to develop technologies that are designed to improve digestive health outcomes. An ad hoc committee under the auspices of the existing ASGE Technology and Standards of Practice Committees Chairs develops PIVIs. An expert in the subject area chairs the PIVI, with additional committee members chosen for their individual expertise. In preparing this document, evidence-based methodology was employed, using a MEDLINE and PubMed literature search to identify pertinent clinical studies on the topic. PIVIs are ultimately submitted to the ASGE Governing Board for approval, as is done for all Technology and Standards of Practice documents. This document is provided solely for educational and informational purposes and to support incorporating these endoscopic technologies into clinical practice. It should not be construed as establishing a legal standard of care.

Race, ethnicity, sex and temporal differences in Barrett's oesophagus diagnosis: a large community-based study, 1994-2006.

OBJECTIVE: To evaluate the demographics and incidence of Barrett's oesophagus diagnosis using community-based data. DESIGN: Observational study. SETTING: Kaiser Permanente, Northern California healthcare membership, 1994-2006. PATIENTS: Members with an electronic diagnosis of Barrett's oesophagus. MAIN OUTCOME MEASURES: Incidence and prevalence of a new Barrett's oesophagus diagnosis by race, sex, age and calendar year. RESULTS: 4205 persons met the study definition for a diagnosis of Barrett's oesophagus. The annual incidence in 2006 was highest among non-Hispanic whites (39/100,000 race-specific member-years, 95% confidence interval (95% CI) 35 to 43), with lower rates among Hispanics (22/100,000, 95% CI 16 to 29), Asians (16/100,000, 95% CI 11 to 22), and blacks (6/100,000, 95% CI 2 to 12). The annual incidence was higher among men than women (31 vs 17/100,000, respectively, year 2006; p<0.01). The incidence increased with age from 2 per 100,000 for persons aged 21-30 years, to a peak of 31 per 100,000 member-years for persons aged 61-70 years (year 2006). There was no increase in the incidence of new diagnoses until the last two observation years, which coincided with changes in data collection methods and may be due to bias. The overall prevalence among active members increased almost linearly to 131/100,000 member-years by 2006. CONCLUSIONS: The demographic distributions of Barrett's oesophagus differ markedly by race, age and sex and were comparable to those for oesophageal adenocarcinoma. Thus, demographic disparities in oesophageal adenocarcinoma risk may arise partly from the risk of having Barrett's oesophagus, rather than from differing risks of progression from Barrett's oesophagus to cancer. There has been an almost linear increase in the prevalence of diagnosed disease.

Cigarette smoking and the risk of Barrett's esophagus.

INTRODUCTION: We examined the association between smoking and the risk of Barrett's esophagus (BE), a metaplastic precursor to esophageal adenocarcinoma. METHODS: We conducted a case-control study within the Kaiser Permanente Northern California population. Patients with a new diagnosis of BE (n = 320) were matched to persons with gastroesophageal reflux disease (GERD) (n = 316) and to population controls (n = 317). Information was collected using validated questionnaires from direct in-person interviews and electronic databases. Analyses used multivariate unconditional logistic regression that controlled for age, gender, race, and education. RESULTS: Ever smoking status, smoking intensity (pack-years), and smoking cessation were not associated with the risk of BE. Stratified analyses suggested that ever smoking may be associated with an increased risk of BE among some groups (compared to population controls): persons with long-segment Barrett's esophagus (odds ratio [OR] = 1.72, 95% confidence interval [CI] 1.12-2.63); subjects without GERD symptoms (OR = 3.98, 95% CI 1.58-10.0); obese subjects (OR = 3.38, 95% CI 1.46-7.82); and persons with a large abdominal circumference (OR = 3.02, 95% CI (1.18-2.75)). CONCLUSION: Smoking was not a strong or consistent risk factor for BE in a large community-based study, although associations may be present in some population subgroups.

Helicobacter pylori infection and the risk of Barrett's oesophagus: a community-based study.

OBJECTIVE: Gastric colonisation with the Helicobacter pylori bacterium is a proposed protective factor against oesophageal adenocarcinoma, but its point of action is unknown. Its associations with Barrett's oesophagus, a metaplastic change that is a probable early event in the carcinogenesis of oesophageal adenocarcinoma, were evaluated METHODS: A case-control study was carried out in the Kaiser Permanente Northern California population, a large health services delivery organisation. Persons with a new Barrett's oesophagus diagnosis (cases) were matched to subjects with gastro-oesophageal reflux disease (GORD) without Barrett's oesophagus and to population controls. Subjects completed direct in-person interviews and antibody testing for H pylori and its CagA (cytotoxin-associated gene product A) protein. RESULTS: Serological data were available on 318 Barrett's oesophagus cases, 312 GORD patients and 299 population controls. Patients with Barrett's oesophagus were substantially less likely to have antibodies for H pylori (OR = 0.42, 95% CI 0.26 to 0.70) than population controls; this inverse association was stronger among those with lower body mass indexes (BMIs < 25, OR = 0.03, 95% CI 0.00 to 0.20) and those with CagA+ strains (OR = 0.08, 95% CI 0.02 to 0.35). The associations were diminished after adjustment for GORD symptoms. The H pylori status was not an independent risk factor for Barrett's oesophagus compared with the GORD controls. CONCLUSIONS: Helicobacter pylori infection and CagA+ status were inversely associated with a new diagnosis of Barrett's oesophagus. The findings are consistent with the hypothesis that H pylori colonisation protects against Barrett's oesophagus and that the association may be at least partially mediated through GORD.

Dietary patterns and the risk of Barrett's esophagus.

The objective of this study was to examine the associations between dietary patterns and the risk of Barrett's esophagus, a precursor to esophageal adenocarcinoma. The authors conducted a case-control study within the Kaiser Permanente Northern California population between 2002 and 2005. Patients with a new diagnosis of Barrett's esophagus (n = 296 cases) were matched to persons with gastroesophageal reflux disease (n = 308) without Barrett's esophagus and to population controls (n = 309). Dietary information was obtained from a validated, 110-item food frequency questionnaire. A principal component analysis was used to identify major dietary patterns. Two major dietary patterns were "Western" (high in fast food and meat) and "health-conscious" (high in fruits, vegetables, and nonfried fish). When cases and population controls were compared, strong adherence to the health-conscious dietary pattern was inversely associated with Barrett's esophagus (odds ratio = 0.35, 95% confidence interval: 0.20, 0.64; fourth vs. first quartile comparison). In contrast, data suggested an adverse effect of the Western dietary pattern on the risk of Barrett's esophagus, although no dose-effect relation was found. Results suggest strong associations between a diet rich in fruits and vegetables and the risk of Barrett's esophagus.

Helicobacter pylori and gastroesophageal reflux disease: a case-control study.

BACKGROUND: Gastric colonization with Helicobacter pylori is a proposed protective factor against gastroesophageal reflux disease (GERD), but little population-based data exist and other data conflict. METHODS: We conducted a case-control study within the membership of a large integrated health-care system that compared GERD-free subjects with two groups: subjects with a physician-assigned GERD diagnosis and randomly selected members with self-described weekly GERD symptoms. Subjects completed interviews, GERD questionnaires, and antibody testing for H. pylori and its cagA protein. RESULTS: Serologic data were available for 301 physician-assigned GERD patients, 81 general membership subjects with GERD symptoms, and 175 general membership subjects without GERD symptoms. Physician-assigned GERD patients were less likely to have H. pylori antibodies than GERD-free member controls (odds ratio (OR) = 0.27, 95% confidence interval (CI) 0.15-0.47); there was also an inverse association between H. pylori and GERD symptom severity (OR = 0.18, 95% CI 0.08-0.41; severe or very severe symptoms) and GERD frequency (OR = 0.18, 95% CI 0.09-0.38; for symptoms at least weekly). The association was stronger among persons with erosive GERD and was similar between H. pylori-positive subjects with and without cagA. There was no association among persons who were cagA positive, but H. pylori negative. Similar findings were found in analyses of the general membership with self-described GERD symptoms. CONCLUSIONS: H. pylori antibody status was inversely associated with a GERD diagnosis and GERD symptoms compared with a general membership population.

Gastric and duodenal safety of daily alendronate.

BACKGROUND: Isolated case reports of gastric ulcers after alendronate sodium use raised concern about the gastroduodenal safety of daily alendronate. This study was conducted to estimate the excess risk of hospitalizations for gastric or duodenal perforations, ulcers, and bleeding associated with alendronate use. PARTICIPANTS AND METHODS: Study subjects were 6432 men and women, 35 years or older. The subjects were members of 8 health maintenance organizations who were dispensed alendronate from October 1995 through September 1997. There was also a group of 33 176 age-, sex-, and health maintenance organization-matched unexposed persons. Because of concerns that osteoporosis might confound the association between alendronate use and perforation, ulcer, or bleeding, a second comparison group of 9776 women, 60 years or older, who had osteoporotic fractures was assembled. Hospitalizations for gastroduodenal events were identified by discharge diagnosis codes in automated claims records, and confirmed by manual record review. RESULTS: Based on the 14 confirmed events in the alendronate group and 35 in the unexposed group, the crude incidence rate ratio of gastroduodenal perforation, ulcer, or bleeding for the alendronate cohort was 3.0. The incidence rate ratio was 1.8 (95% confidence interval, 0.8-3.9) after control for prior hospitalizations, comorbidity, and recent exposure to prescription nonsteroidal anti-inflammatory drugs and oral corticosteroids. The crude incidence ratio rate for the age, sex, and health maintenance organizations-restricted cohort of alendronate users relative to the fracture cohort was 1.1 and the adjusted incidence rate ratio was 1.1 (95% confidence interval, 0.6-2.2). CONCLUSIONS: Osteoporosis and related factors appear to play an important role in the relationship between alendronate use and confirmed gastroduodenal perforation, ulcer, or bleeding; a substantial fraction of the increased risk we observed for alendronate users in the unadjusted analysis was the result of confounding.

Costs of acid-related disorders to a health maintenance organization.

BACKGROUND: Little is known about the economic impact of the acid-related disorders (ARDs), which include dyspepsia, gastritis, gastroesophageal reflux disease (GERD), and peptic ulcer disease (PUD), in managed care patient populations. OBJECTIVES: To describe the prevalence of medically attended ARDs, and their direct medical costs from the perspective of a large health maintenance organization (HMO). METHODS: A total of 1,550 ARDs subjects (age > or = 18 years), were randomly sampled from outpatient diagnosis and pharmacy databases of the Kaiser Permanente Medical Care Program of Northern California and verified by chart review. Five age- and gender-matched controls were identified per subject. One-year prevalence, excess annual costs, and initial 6-month costs for incident cases were estimated using the HMO cost accounting system. RESULTS: Total ARDs prevalence (5.8%) increases with advancing age. GERD is the most common ARD (2.9% overall prevalence). Annual per person attributable costs were $1,183, $471, and $431 respectively for PUD, GERD, and gastritis/dyspepsia. Excess inpatient costs for PUD explain its higher costs. Outpatient costs were somewhat higher for GERD ($279) than for PUD or gastritis/dyspepsia. Pharmacy costs were relatively low for each condition, in part because many patients were treated with generic cimetidine. Total annual HMO expenditures for ARDs were $59.4 million, with 40.6%, 36.8%, and 22.6% respectively for GERD, PUD, and gastritis/dyspepsia. CONCLUSIONS: Acid-related disorders, particularly GERD and PUD, contribute substantially to the direct costs of medical care in this managed care population.

The evolution to stool DNA testing for colorectal cancer.

Despite a variety of screening strategies and recent trends showing death rate stabilization, colorectal cancer still remains the second leading cause of overall cancer death. Current screening tools suffer from performance limitations, low patient acceptability, and marginal reliable access within the health care system. Noninvasive strategies present the lowest risk with the highest potential for patient satisfaction. However, serious implementation barriers exist requiring consistent programmatic screening, strict patient adherence, and poor sensitivity for adenomas. Colonoscopy remains an invasive screening test with the best sensitivity and specificity, but faces large financial costs, manpower requirements, patient access and adherence. Development of advanced molecular techniques identifying altered DNA markers in exfoliated colonocytes signify early or precancerous growth. Stool-based DNA testing provides an entirely noninvasive population-based screening strategy which patients can perform easier than faecal occult blood testing (FOBT). Large-scale prospective randomized control trials currently pending should help characterize accurate test performance, screening intervals, cost-effectiveness, direct comparison to FOBT and analysis of patient adherence. As tumour development pathways and potential target genes are further elucidated, refinements in multi-assay stool-based DNA testing portend enhanced test characteristics to detect and treat this genetically heterogeneous disease.

Validation of diagnoses of peptic ulcers and bleeding from administrative databases: a multi-health maintenance organization study.

The automated health plan data and data from medical chart abstractions from eight large health maintenance organizations were used to evaluate the positive predictive values (PPVs) of the International Classification of Diseases, 9th revision (ICD-9) codes for cases of peptic ulcers and upper gastrointestinal bleeding. Overall, 207 of 884 cases of peptic ulcers and upper gastrointestinal bleeding (23%) were confirmed by surgery, endoscopy, X-ray, or autopsy. The PPVs were 66% for hospitalizations with codes for duodenal ulcer (ICD-9-CM 532), 61% for gastric/gastrojejunal ulcer (ICD-9-CM 531, 534), 1% for peptic ulcer (ICD-9-CM 533), and 9% for gastrointestinal hemorrhage (ICD-9-CM578). The overall and diagnostic category-specific PPVs were generally similar for the various HMOs. This study, using data from a large number of health plans located in different geographical regions, underscores the importance of evaluating the accuracy of the diagnoses from automated health plan databases.

Cimetidine use and risk of breast, prostate, and other cancers.

Purpose - The study was conducted to examine whether use of cimetidine is associated with the risk of cancer, with special attention to cancers of the breast and prostate because cimetidine increases estradiol levels and interferes with androgen binding. Methods - Individuals who received a prescription of cimetidine were identified from two computerized pharmacy databases of medications dispensed at Northern California Kaiser Permanente between 1982 and 1987. Users of ranitidine, a histamine-2 receptor antagonist that does not appear to influence estrogen levels or androgen binding, and non-users of either cimetidine or ranitidine, were also identified from these databases. Study subjects were followed through December 1995 for new diagnoses of cancer. Cox regression was used to estimate relative risks of cancer associated with use of cimetidine and ranitidine. Non-users of cimetidine and ranitidine were the referent group for all analyses. Result - While there were very modest increases and decreases in risk for some cancer sites among cimetidine users, most were within the limits of chance given no true association. Furthermore, similar risks of these cancers were also observed among ranitidine users. Conclusions - Although our results do not support an association between cancer risk and cimetidine use, it is one of the most widely prescribed drugs in the US and may now be purchased over-the-counter. The potential effect of cimetidine on risk of cancer, especially those that are hormone-related, should continue to be monitored, preferably in larger study populations. Copyright (c) 2000 John Wiley & Sons, Ltd.

Colorectal cancer screening: new opportunities.

Colorectal cancer is the third most common cancer among men and women in the United States, and the third leading cause of cancer death. Strategies currently available to screen for colorectal cancer include fecal occult blood tests, sigmoidoscopy, or both tests used in combination. Colonoscopy and double contrast barium enema are potentially preferable options because they offer improved sensitivity over currently available tests, but the feasibility of these tests for population screening remains in doubt. Future opportunities for screening include focusing special efforts to deliver screening to higher risk individuals based on family history or age and the use of molecular or computer-aided radiographic techniques as alternatives to colonoscopy.

Hemochromatosis gene status as a risk factor for Barrett's esophagus.

Conditions causing high iron levels, such as hemochromatosis, are proposed risk factors for esophageal adenocarcinoma. Although this hypothesis is supported by animal models, no human data currently exist. We conducted a case-control study of persons with a new Barrett's esophagus diagnosis (cases), persons with gastroesophageal reflux disease (GERD) (without Barrett's esophagus), and population controls. Subjects completed detailed examinations and assays for hemochromatosis mutations and serum iron stores. We evaluated 317 cases, 306 GERD patients, and 308 population controls. There was no significant association between Barrett's esophagus and any hemochromatosis gene defect (odds ratio [OR] = 1.32, 95% confidence interval [CI]: 0.95-1.84), a moderate or severe mutation (OR = 1.54, 95% CI: 0.94-2.52), or a severe mutation (C282Y homozygote or C282Y/H63D heterozygote; OR = 0.77, 95% CI: 0.24-2.48) compared with the population controls. As expected, gene defects were associated with increased iron stores. We can conclude from our findings that Barrett's esophagus was not associated with hemochromatosis gene defects, although we cannot exclude small effects.

Incomplete screening flexible sigmoidoscopy associated with female sex, age, and increased risk of colorectal cancer.

BACKGROUND: Several previous studies have found that females and older individuals are at greater risk of having incomplete flexible sigmoidoscopy. However, no prior study has reported the subsequent risk of colorectal cancer (CRC) following incomplete sigmoidoscopy. METHODS: Using data from 55 791 individuals screened as part of the Colon Cancer Prevention (CoCaP) programme of Kaiser Permanente of Northern California, we evaluated the likelihood of having an inadequate (<40 cm) examination by age and sex, and estimated the risk of distal CRC according to depth of sigmoidoscope insertion at the baseline screening examination. Multivariate estimation of risks was performed using Poisson regression. RESULTS: Older individuals were at a much greater risk of having an inadequate examination (relative risk (RR) for age 80+ years compared with 50-59 years 2.6 (95% confidence interval (CI) 2.3-3.0)), as were females (RR 2.3 (95% CI 2.2-2.5)); these associations were attenuated but remained strong if Poisson models were further adjusted for examination limitations (pain, stool, and angulation). There was an approximate threefold increase in the risk of distal CRC if the baseline sigmoidoscopy did not reach a depth of at least 40 cm; a smaller increase in risk was observed for examinations that reached 40-59 cm. CONCLUSIONS: Older individuals and women are at an increased risk of having inadequate sigmoidoscopy. Because inadequate sigmoidoscopy results in an increased risk of subsequent CRC, physicians should consider steps to maximise the depth of insertion of the sigmoidoscope or, failing this, should consider an alternative screening test.

Quality in the technical performance of screening flexible sigmoidoscopy: recommendations of an international multi-society task group.

BACKGROUND: Flexible sigmoidoscopy (FS) is a complex technical procedure performed in a variety of settings, by examiners with diverse professional backgrounds, training, and experience. Potential variation in technical quality may have a profound impact on the effectiveness of FS on the early detection and prevention of colorectal cancer. AIM: We propose a set of consensus and evidence based recommendations to assist the development of continuous quality improvement programmes around the delivery of FS for colorectal cancer screening. RECOMMENDATIONS: These recommendations address the intervals between FS examinations, documentation of results, training of endoscopists, decision making around referral for colonoscopy, policies for antibiotic prophylaxis and management of anticoagulation, insertion of the FS endoscope, bowel preparation, complications, the use of non-physicians as FS endoscopists, and FS endoscope reprocessing. For each of these areas, continuous quality improvement targets are recommended, and research questions are proposed.