Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn's disease.

AIM: To study the effects of infliximab on pregnancy and foetal outcome. METHODS: We conducted a retrospective chart review of women with Crohn's disease treated intentionally with infliximab during pregnancy. The primary outcome measure was the occurrence of congenital malformations. Secondary outcome measures were the rate of premature birth, low-birth weight, small for gestational age infants, intrauterine growth retardation and caesarean section. RESULTS: Ten women were identified. Eight women received maintenance infliximab infusions throughout their pregnancy and two women received their initial infliximab infusions during pregnancy. All 10 pregnancies ended in live births. No infants had congenital malformations, intrauterine growth retardation or small for gestational age parameters. Three infants were premature and one had low-birth weight. Eight women had a caesarean section. CONCLUSIONS: This is the first reported series of intentional infliximab use throughout pregnancy. These data, combined with other studies of inadvertent use of infliximab during pregnancy, suggest that the benefits of infliximab in achieving response and maintaining remission in mothers with Crohn's disease may outweigh the risk to the foetus of exposure to the drug. Further prospective data collection will be helpful to confirm these findings.

Colonoscopic management of lower gastrointestinal hemorrhage.

Lower gastrointestinal bleeding is a common reason for hospitalization, especially among the elderly. Unlike that of upper gastrointestinal bleeding, the diagnostic and therapeutic approach to individuals with lower gastrointestinal bleeding is not well standardized. Recent reports indicate that early colonoscopy may be the best strategy to improve outcomes and reduce costs. However, good prospective, controlled data on the role of colonoscopy in the management of lower gastrointestinal bleeding are still required. Colonoscopy can establish a definite or probable diagnosis in greater than 80% of individuals with lower gastrointestinal bleeding. Based on the best available evidence, it appears that clinical and colonoscopic data may be combined in an effort to predict outcome and suggest optimal length of stay. It also appears that therapeutic colonoscopy can arrest or prevent bleeding in certain high-risk patients, offering the opportunity to change the natural history of the bleed.

Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing.

BACKGROUND & AIMS: The optimal strategy for the detection of hereditary nonpolyposis colorectal cancer (HNPCC) gene carriers remains uncertain. We evaluated whether microsatellite instability (MSI) analysis or MSH2 and MLH1 protein immunostaining of tumors will screen individuals efficiently for germline MSH2 and MLH1 testing. METHODS: We performed a case-series study of 114 eligible families enrolled in our high-risk colorectal cancer (CRC) registry. Medical history data were collected on probands and relatives. MSI analysis was performed on proband tumors, and MSH2 and MLH1 protein immunostaining was assessed. Denaturing gradient gel electrophoresis was used to identify germline MSH2 or MLH1 mutations in probands found to have tumors with high-frequency MSI. RESULTS: Tumor tissue and adequate clinical data were available in 109 of the 114 families. Amsterdam criteria and Bethesda guidelines were met by 23% and 70% of the families, respectively. High-frequency MSI was identified in the proband tumors in 47 of the 109 families (43%). Germline MSH2 and MLH1 gene testing was carried out in the probands of 32 of 47 families with MSI-H tumors. Mutations were detected in 16 families (9 in MSH2 and 7 in MLH1) and sequence variants of uncertain significance in 5 families (1 in MSH2 and 4 in MLH1). Germline mutations or sequence variants of uncertain significance were detected in 15 of 19 (79%) of our Amsterdam families and in 6 of 13 (46%) of our non-Amsterdam families with MSI-H tumors. MSH2 and MLH1 protein immunostaining was assessed in 38 of the 47 MSI-H tumors. Unequivocal loss of hMLH1 expression was found in 20 tumors and loss of MSH2 expression in 9 tumors. Corresponding loss of protein expression was seen in 17 of 18 (94%) of tumors from probands with germline mutations or variants. CONCLUSIONS: The detection of high-frequency MSI or the loss of MSH2 or MLH1 immunostaining in CRCs are both useful criteria for selecting high-risk patients who should be tested for germline mutations in MSH2 or MLH1.

Altered distribution of beta-catenin, and its binding proteins E-cadherin and APC, in ulcerative colitis-related colorectal cancers.

The beta-catenin pathway plays a central role in transcriptional signaling and cell-cell interactions in colonic epithelium. Alterations of the expression of beta-catenin, and its binding partners E-cadherin and the adenomatous polyposis coli protein (APC), are frequent events in sporadic colorectal cancer. Ulcerative colitis (UC)-related cancers originate in a field of chronic inflammation and therefore may have different alterations in the beta-catenin pathway than sporadic cancers. To test this hypothesis, expression and subcellular localization of beta-catenin, E-cadherin, and APC were detected by immunohistochemistry in paraffin sections from 33 UC-related and 42 sporadic colorectal cancers. Although beta-catenin and E-cadherin expression were predominantly limited to the lateral cell membrane in normal colonic epithelium, both tumor groups showed an overall shift from membranous to cytoplasmic expression for these proteins. An increase in nuclear localization of beta-catenin and a decrease in cytoplasmic APC expression also were seen in both cancer groups compared with normal epithelium. Abnormal beta-catenin expression was more closely linked to E-cadherin alterations in UC-related cancers than in sporadic cancers. In contrast, abnormal beta-catenin expression was more closely linked to APC alterations in sporadic cancers than in UC-related cancers. These data suggest that alterations of the beta-catenin pathway are important in both UC-related and sporadic colorectal cancers. However, differences in the expression patterns of beta-catenin, E-cadherin, and APC between UC-related and sporadic colorectal cancers suggest that the specific alterations in this pathway may differ in these two cancer groups.

Genomic events in the adenoma to carcinoma sequence.

Owing to its high incidence and anatomical accessibility, colorectal cancer has become the most extensively studied human neoplasm with respect to molecular pathogenesis. Many of the genomic alterations that occur when a normal colonic epithelial cell gradually is transformed into a malignant cell have been well characterized. An understanding of the molecular basis of colorectal cancer will lead to better cancer control through novel and scientifically based cancer risk assessment, diagnostics, prognostics, and therapeutics. It is imperative that clinicians possess a basic understanding of the molecular pathogenesis of colorectal cancer so that they are poised to embrace new, molecularly based, preventive and treatment measures. This task is formidable given the rapidly expanding body of scientific knowledge on the genomics of colorectal cancer.

Chromosomal alterations in ulcerative colitis-related and sporadic colorectal cancers by comparative genomic hybridization.

Both ulcerative colitis (UC)-related and sporadic colorectal cancers are thought to evolve through a multistep process of genomic instability, accumulation of genomic alterations, and clonal expansion. This process may involve different genomic changes in UC-related cancers than in sporadic cancers because of the origin of UC-related cancers in an inflammatory field. This study was designed to define the specific genomic events occurring in UC-related cancers. Comparative genomic hybridization (CGH) was performed on 32 UC-related and 42 stage-matched sporadic colorectal cancers. The mean number of chromosomal alterations per case was similar in the UC-related and sporadic tumor groups (8.6 in UC, 8.1 in sporadic). The 2 tumor groups shared many chromosomal alterations: losses on 18q (78% UC v69% sporadic), 8p (53% v50%), 17p (44% v57%), and gains on 8q (63% v45%), 20q (44% UC v67%), and 13q (44% UC v38%). However, differences in the frequency and timing of specific alterations were observed. Chromosome 5q was lost in 56% of UC-related but in only 26% of sporadic cancers. Alterations of chromosome 8 were associated with stage progression in UC-related, but not in sporadic cancers. In contrast, 18q loss was associated with stage progression in sporadic cancers only. Thus, differences in the frequency and timing of individual chromosomal alterations suggest that genetic progression in these 2 tumor groups may follow multiple pathways.

Genetic testing in hereditary colorectal cancer: indications and procedures.

Approximately 25% of colorectal cancers occur in younger individuals or those with a personal or family history of the disease, suggesting a heritable susceptibility. The minority of these cases are accounted for by one of the well-described hereditary colorectal cancer syndromes, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). The recent identification and cloning of the genes responsible for FAP and HNPCC, along with other colon cancer susceptibility genes, has led to the wide-spread availability of genetic testing for hereditary colorectal cancer. Genetic testing raises clinical, ethical, legal, and psychosocial questions that must urgently be discussed. This review highlights areas of knowledge and uncertainty about genetic predisposition testing for colorectal cancer and provides clinicians with practical recommendations regarding the proper indications and procedures for this testing.

Update on upper gastrointestinal bleeding. Basing treatment decisions on patients' risk level.

Acute upper gastrointestinal bleeding is a common reason for hospitalization. Mortality rates range from 5% to 15%; patients with severe comorbidities and those with persistent or recurrent bleeding are at highest risk. Accurate preliminary risk assessment and resuscitation can proceed simultaneously at initial presentation. Risk assessment can guide treatment decisions. Early upper gastrointestinal endoscopy, a cornerstone of management, allows for rapid diagnosis, application of endoscopic therapy, and completion of risk assessment. Endoscopic therapy can alter the natural history of upper gastrointestinal bleeding by reducing rates of further bleeding and, consequently, mortality. Complete risk assessment of both clinical and endoscopic factors can likely result in shorter hospital stays and improved outcomes. Early assessment helps identify low-risk patients in whom discharge on the day of presentation is appropriate.

Gastrointestinal bleeding in the hospitalized patient: a case-control study to assess risk factors, causes, and outcome.

PURPOSE: To determine the risk factors, etiology, and outcome of clinically important gastrointestinal bleeding that occurs after hospital admission (nosocomial gastrointestinal bleeding). PATIENTS AND METHODS: Cases consisted of consecutive patients who developed gastrointestinal bleeding more than 24 hours after admission to the hospital. Cases were compared with two control populations: a set of hospitalized patients without gastrointestinal bleeding matched with cases for age, gender, and length of stay; and all patients admitted to the hospital with clinically important gastroduodenal ulcer bleeding during the study period. Case and controls were compared with respect to risk factors for gastrointestinal bleeding and outcomes. Data were obtained through a comprehensive review of medical records. RESULTS: Clinically important nosocomial gastrointestinal bleeding occurred in 67 inpatients after a mean hospital length of stay of 14 +/- 10 days. The majority (64%) of the patients were not hospitalized in the intensive care unit at the onset of the bleeding. Seventy-two percent of the patients who developed bleeding had been receiving some form of bleeding prophylaxis. In a multivariate analysis, a prior intensive care unit stay (odds ratio 2.5; 95% confidence interval 1.0 to 6.1; P <0.05) and mechanical ventilation (OR 3.4; 95% CI 1.1 to 10.7; P = 0.03) were independent risk factors for the onset of bleeding. Nosocomial gastrointestinal bleeding was associated with poor outcome, with an associated mortality of 34%. Duodenal ulcer disease was the most common source of nosocomial gastrointestinal bleeding, accounting for 36% of cases overall. Nosocomial ulcer bleeders were less likely to have a previous history of ulcer disease (13% versus 50%; P <0.05) Helicobacter pylori infection (14% versus 62%; P <0.0001), chronic active gastritis (29% versus 91%; P <0.0001), or to be taking NSAIDs (48% versus 68%; P <0.08) than patients admitted to the hospital with ulcer bleeding. CONCLUSIONS: Gastrointestinal bleeding remains an important complication of hospitalization, with a high associated mortality. Our current approaches to prevention of this complication are imperfect. Bleeding tends to occur after a prolonged hospital stay and is more likely to occur in patients with more severe underlying illnesses. Duodenal ulcer disease is the most common source of this bleeding. Nosocomial gastroduodenal ulcer disease is distinct in etiology from the ulcer disease that occurs in outpatients.

The importance of accurate diagnosis and vigorous care of the patient with liver disease and gastrointestinal hemorrhage.

Gastrointestinal hemorrhage in the patient with liver disease is often massive and life threatening. Although varices are the most likely cause of hemorrhage, other sources, such as peptic ulcer disease, Mallory-Weiss tears, and portal hypertensive gastropathy, are common. As liver disease is an important risk factor for intractable bleeding and death in patients with gastrointestinal hemorrhage, outcome in these patients is often poor regardless of the cause of the bleeding. Essential elements of initial therapy include prompt and adequate intravascular volume replacement, correction of severe anemia and coagulopathies, and adequate airway management. After initial resuscitation, urgent endoscopy is required to secure the diagnosis and to deliver endoscopic therapy if possible. The specific form of therapy will differ depending on the lesion encountered. Adjunctive measures, such as the administration of antibiotics and drugs that reduce portal pressure, including octreotide, may also improve outcome. Clinical and endoscopic information can be used to predict first bleeding in patients with liver disease. A large body of data supports the use of beta-blockers in the prevention of first bleeding in patients with known varices.

Risk of persistent or recurrent and intractable upper gastrointestinal bleeding in the era of therapeutic endoscopy.

OBJECTIVES: Patients who present to the emergency department with upper gastrointestinal bleeding can have persistent or recurrent (further) bleeding or self-limited bleeding. We performed a study to determine the frequency, risks factors, and impact on outcome of further bleeding. METHODS: Clinical predictors of further bleeding were retrospectively identified in 137 consecutive patients presenting to our institution with upper gastrointestinal bleeding in 1994-1995. RESULTS: Persistent or recurrent bleeding occurred in 30.7% of the cases, bleeding intractable to endoscopic therapy occurred in 15.3%. Hematemesis (odds ratio [OR] 5.7; 95% confidence interval [CI], 2.4-13.1, p = 0.0001) and a initial hemoglobin (OR, 0.8; 95% CI, 0.7-0.96; p = 0.01) were independent risk factors for persistent or recurrent bleeding, whereas liver disease (OR, 6.0; 95% CI, 2.0-18.4; p = 0.002) and hematemesis were independent risk factors for intractable bleeding. The mortality rate was 14.3 and 1%, respectively, in patients with and without further bleeding. In patients who did not present with hematemesis, liver disease, coagulopathy, hypotension, and initial hemoglobin < 11 g/dl, the frequency of further bleeding and mortality was 0%. CONCLUSIONS: Persistent, recurrent, and intractable bleeding occurs in a substantial proportion of patients admitted with upper gastrointestinal bleeding. The risk of further bleeding can be estimated on the basis of clinical presentation. Further bleeding is associated with a worse outcome.

The role of endoscopic evaluation in patients with suspected intestinal graft-versus-host disease after allogeneic bone-marrow transplantation.

BACKGROUND AND STUDY AIMS: Previous reports have suggested that endoscopic evaluation, with histological and microbiological examination of biopsied tissue, is required to diagnose gastrointestinal disease accurately in patients after allogeneic bone-marrow transplantation. We sought to further define the usefulness, yield, and sensitivity of endoscopic tissue biopsy in this patient population. PATIENTS AND METHODS: A retrospective review of the clinical, endoscopic, histological, and microbiological data was obtained during the evaluation and treatment of 61 distinct episodes of unexplained gastrointestinal complaints in 37 adult allogeneic bone-marrow transplant recipients over six years at our institution. RESULTS: Acute gastrointestinal graft-versus-host disease was found in 12 of the 61 episodes (20%). Gastrointestinal infections were found in 14 of the 61 episodes (23%); there were Herpesvirus infections (n = 8) and fungal infections (n = 9). Patients with and without graft-versus-host disease were similar in terms of their age, sex, underlying illness, clinical symptoms and signs, physical examination, laboratory values, and endoscopic findings. Small-bowel biopsy had a sensitivity of 90% for detecting the pathological changes of acute intestinal graft-versus-host disease in this series. CONCLUSION: A high percentage of patients with gastrointestinal complaints after allogeneic bone-marrow transplantation have acute gastrointestinal graft-versus-host disease, or an opportunistic infection. Gastrointestinal graft-versus-host disease cannot be accurately diagnosed from its clinical presentation. Endoscopic small-bowel biopsy is an essential tool in evaluating this patient population.