CDX2 promotes anchorage-independent growth by transcriptional repression of IGFBP-3.

CDX2 is a Drosophila caudal-related homeobox transcription factor that is important for the establishment and maintenance of intestinal epithelial cells. We have reported that CDX2 promotes tumorigenicity in a subset of human colorectal cancer cell lines. Here, we present evidence that CDX2 negatively regulates the well-documented growth inhibitor insulin-like growth factor binding protein-3 (IGFBP-3). Specifically, CDX2 binds to the IGFBP-3 gene promoter and can repress IGFBP-3 transcription, protein expression and secretion. Furthermore, inhibition of IGFBP-3 partially rescues the decreased anchorage-independent growth phenotype observed in CDX2 knockout cells. These data demonstrate for the first time that (1) CDX2 can function as a transcriptional repressor, and (2) one mechanism by which CDX2 promotes anchorage-independent growth is by transcriptional repression of IGFBP-3.

Endoscopic findings predict the histologic diagnosis in gastrointestinal graft-versus-host disease.

BACKGROUND AND STUDY AIMS: Graft-versus-host disease (GvHD) of the gastrointestinal tract is a major cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT). Whether endoscopic findings predict the histologic diagnosis of GvHD in the gastrointestinal tract remains controversial. We performed a study to determine the diagnostic accuracy of macroscopic endoscopy findings in the diagnosis of acute and chronic histologically proven gastrointestinal GvHD (GI-GvHD). PATIENTS AND METHODS: Endoscopic images from the intestinal mucosa of post-BMT patients were blindly graded as positive or negative for GI-GvHD and compared with corresponding histological findings, which were used as the gold standard. RESULTS: 44 BMT patients were referred for 96 endoscopic evaluations. Using 162 endoscopy-biopsy pairs, a positive association between endoscopic grading and histologic grading of GI-GvHD (odds ratio [OR] = 11.97, 95% CI 3.86, 37.16) was observed. Endoscopic diagnosis correctly predicted histologic diagnosis in both acute and chronic GI-GvHD (OR = 9.3 vs. 23.1, P = 0.31). CONCLUSIONS: The diagnostic accuracy of endoscopy was high in both acute and chronic histologically proven GI-GvHD. Accurate diagnosis of GI-GvHD might be obtained with mucosal biopsies from either the upper or lower gastrointestinal tract. Endoscopy may play a significant role in establishing early diagnosis and treatment for GI-GvHD in patients following BMT, but histologic evaluation of the gastrointestinal mucosa is needed to confirm the final diagnosis.

The impact of practice guidelines in the management of Barrett esophagus: a national prospective cohort study of physicians.

BACKGROUND: Surveillance of patients with Barrett esophagus (BE) is recommended to detect dysplasia and early cancer. In 1998, practice guidelines for the surveillance of patients with BE were developed under the auspices of the American College of Gastroenterology (ACG). Our objective is to assess physicians' awareness of agreement with and adherence to these guidelines. METHODS: A national prospective cohort study of practicing gastroenterologists who completed a self-administered questionnaire containing case studies prior to the release of the guidelines and another survey 18 months later. Analysis of adherence to the guidelines was done using the McNemar chi(2) test. RESULTS: Of the 154 gastroenterologists (66%) who responded to the follow-up survey, more than half (55%) were aware of the guidelines, and members of the ACG were more likely to know of their existence than nonmembers (61% vs 38%; P =.01). Overall, about 27% of physicians reported practicing in accordance with the guidelines at baseline; adherence increased modestly to 38% in the 18-month follow-up (P =.04) and was inversely related to fee-for-service reimbursement. Awareness was not associated with an increased likelihood of adherence, but agreement with the guidelines was strongly correlated with adherence (P<.001). The most frequent reasons for disagreement were concerns about liability, cancer risk, and inadequate evidence. CONCLUSIONS: Awareness of the guidelines published by the ACG was low. Guideline awareness did not predict adherence. Improvement in guideline adherence will require steps beyond mere dissemination and promotion. Addressing disagreements about liability, disease risk, and scientific evidence as well as restructuring payment incentives may help achieve optimal practice.

Very high risk of cancer in familial Peutz-Jeghers syndrome.

BACKGROUND & AIMS: The Peutz-Jeghers syndrome (PJS) is an autosomal dominant polyposis disorder with increased risk of multiple cancers, but literature estimates of risk vary. METHODS: We performed an individual patient meta-analysis to determine the relative risk (RR) of cancer in patients with PJS compared with the general population based on 210 individuals described in 6 publications. RESULTS: For patients with PJS, the RR for all cancers was 15.2 (95% confidence limits [CL], 2, 19). A statistically significant increase of RR was noted for esophagus (57; CL, 2.5, 557), stomach (213; CL, 96, 368), small intestine (520; CL, 220, 1306), colon (84; CL, 47, 137), pancreas (132; CL, 44, 261), lung (17.0; CL, 5.4, 39), breast (15.2; CL, 7.6, 27), uterus (16.0; CL, 1.9, 56), ovary (27; CL, 7.3, 68), but not testicular or cervical malignancies. Cumulative risk for all cancer was 93% from age 15 to 64 years old. CONCLUSIONS: Patients with PJS are at very high relative and absolute risk for gastrointestinal and nongastrointestinal cancers.

Lymphocytic and Collagenous Colitis.

Patients with symptomatic collagenous-lymphocytic colitis should eliminate dietary secretagogues such as caffeine- or lactose-containing food from their diet. When possible, use of nonsteroidal anti-inflammatory drugs should be discontinued. If steatorrhea is documented, a low-fat diet may be helpful. In the presence of bile salt malabsorption, binding resins such as cholestyramine might be useful. Nonspecific diarrheal agents such as loperamide hydrochloride, diphenoxylate hydrochloride and atropine, deodorized tincture of opium, or codeine might prove effective in some patients. Antibacterial agents such as bismuth subsalicylate (8 chewable 262-mg tablets daily) have been effective in symptom control. Metronidazole and erythromycin achieve response rates of 60%. Sulfasalazine, at the usual dose of 2 to 4 g daily, used in collagenous-lymphocytic colitis, demonstrated cessation of diarrhea in 1 to 2 weeks for 50% of patients. Other 5-aminosalicylic (5-ASA) compounds are preferred for patients with a history of sulfa allergy, and those who experience adverse reactions to sulfasalazine. Adrenocorticoid medication is reserved for patients whose conventional treatment with sulfasalazine or 5-ASA has failed. Resolution of diarrhea has been documented in 80% to 90% of patients within 1 week of treatment, however, in most patients, long-term therapy is required. Surgical management is reserved for those patients with disease refractory to medical therapy. Colectomy with ileostomy resulted in clinical and histologic resolution in small case series. If there is no abatement of symptoms, rule out other etiologies of diarrhea such as thyroid dysfunction, celiac disease, or bacterial overgrowth.

Atypical forms of inflammatory bowel disease: microscopic colitis and pouchitis.

Three atypical colitides (and enterides) are collagenous colitis, lymphocytic colitis, and ileal pouchitis. Collagenous and lymphocytic colitis are similar inflammatory bowel disorders of unknown cause with symptoms including chronic watery diarrhea, occurring in middle age. Pouchitis is the most significant long-term complication in patients with ileoanal pouch anastomosis. The clinical and histologic features and management of these entities are discussed.

Alendronate-associated esophageal injury: pathologic and endoscopic features.

Ingestion of alendronate sodium (Fosamax) by osteoporotic patients can be associated with esophagitis and esophageal ulcer. Alendronate can damage the esophagus both by toxicity from the medication itself and by nonspecific irritation secondary to contact between the pill and the esophageal mucosa, similar to other cases of "pill esophagitis." Despite its wide use, the histologic appearances of alendronate-associated esophageal ulceration have not been previously described in detail, nor is this type of medication-induced injury commonly appreciated by pathologists when evaluating biopsies from ulcer sites. We report a series of 10 patients who experienced erosive/ulcerative esophagitis while ingesting alendronate, and describe the associated endoscopic and pathologic features. Biopsies from all patients showed inflammatory exudate and inflamed granulation tissue as characteristic of any ulcer site. Polarizable crystalline foreign material was present in six of 10 biopsies (60%). Multinucleated giant cells within the inflammatory exudate were present near this crystalline foreign material in three of 10 biopsies (30%). Adjacent squamous epithelium typically showed active inflammation and a reactive appearance with enlarged, hyperchromatic nuclei. Multinucleated squamous epithelial giant cells were present in two of 10 cases (20%). Microorganisms were unusual; scattered fungi and/or viral inclusions were present in only two of 10 biopsies (20%). Recognition of alendronate-associated erosive or ulcerative esophagitis, particularly in postmenopausal women, and communication of this possibility to the clinician can improve patient care.

Cerebral thrombosis associated with active Crohn's disease.

An increased incidence of cerebral thromboembolic events has been reported in young patients with inflammatory bowel disease (IBD). It has been suggested that a hypercoagulable state is associated with clinical activity of the disease, with elevation of factors V, VIII, fibrinogen and platelets and a lowering of anti-thrombin III. We present the case of a 35 y/o male with refractory Crohn's disease who complained of headaches, blurred vision and tonic-clonic seizures. The studies demonstrated an ischemic stroke of the left cerebral hemisphere, without vascular abnormalities. Elevation of factor VIII, platelets, and antithrombin III were found. The symptoms were relieved with medical treatment and the patient has continued in good health after resection of the diseased terminal ileum.