Prognostic value of cell cycle and apoptosis regulatory proteins in mismatch repair-proficient colorectal cancer: a tissue microarray-based approach.

Cell cycle and apoptosis regulatory proteins are markers of tumor progression in colorectal cancer. In a series of 1,274 mismatch repair-proficient colorectal cancers, immunohistochemical analysis of p21, p27, p53, and bcl-2 expression was performed using the tissue microarray technique. In univariate analysis, p21 expression was associated with tumor location and pN0; p27 expression with tumor location, lower tumor grade, early pT, and pN; p53 expression with tumor location; and bcl-2 with early pT and pN. Expression of p27 identified subgroups with worse prognosis in pT3 N0 and pT3 N+ patients. None of the 4 tumor markers were independent prognostic indicators of survival. The multimarker phenotypes p21/p27/p53 and p21/p27/bcl-2 were associated with survival. In mismatch repair-proficient colorectal cancer, p27 expression is associated with a better prognosis, and pT, pN, and vascular invasion are independent prognostic factors. In addition, multimarker phenotypes are useful to identify colorectal cancer subgroups with different prognoses.

Cytokine expression in healthy and inflamed mucosa: probing the role of eosinophils in the digestive tract.

BACKGROUND: In eosinophilic esophagitis (EE), the esophagus is infiltrated with activated eosinophils that often evoke tissue damage, but the intestines of these patients remain unaffected. We thus hypothesized that different tissue-dwelling eosinophil populations may coexist: activated eosinophils that infiltrate the esophagus and resting eosinophils that reside in unaffected intestines. We sought to characterize different eosinophil subpopulations by comparing the expression of certain proinflammatory proteins in tissue-dwelling eosinophils at different parts of the gastrointestinal tract. METHODS: The 8 patients participating included 6 men and 2 women with a previously confirmed diagnosis of EE, whose average age was 39.4 years (range, 20-55 yr) and average disease duration was 13.6 years (range, 2-26 yr). Controls were 3 men and 1 woman, with a mean age of 43.3 years (range, 29-56 yr) with untreated functional dyspepsia who underwent diagnostic esophagogastroduodenoscopy. Six additional individuals having normal blood eosinophils were recruited for cytokine measurements in blood eosinophils. Immunofluorescence and immunoassays charted expression of CD25 and the TH2 cytokines, interleukin (IL)-4, IL-5, IL-10, and IL-13, in esophageal, intestinal, and blood eosinophils from controls and patients. RESULTS: Controls showed a small but significant proportion of intestinal, but no blood, eosinophils expressing CD25 and IL-13, suggesting physiologic activation occurring in the digestive tract. On the other hand, eosinophils infiltrating the inflamed esophageal mucosa of patients with EE showed strong evidence of activation, with most expressing CD25, IL-4, and IL-13. Moreover, IL-13-positive intestinal eosinophils were increased in patients compared with controls. CONCLUSIONS: We thus conclude that tissue-dwelling eosinophils show different and distinct cytokine expression patterns under noninflammatory and inflammatory conditions.

Eosinophilic esophagitis: red on microscopy, white on endoscopy.

BACKGROUND/AIMS: The presenting symptom of eosinophilic esophagitis, a chronic T(H)2-type inflammatory disease, is uniform dysphagia attacks. Histology reveals a dense mucosal infiltration with eosinophils. Unfortunately, endoscopic findings are often unremarkable or misleading. This study characterizes the endoscopic manifestations of eosinophilic esophagitis and analyzes the nature and clinical features of the frequently observed white alterations. METHODS: Thirty adult patients (22 males, 8 females; mean age 40.6 years) with previously confirmed EE prospectively underwent a structured interview, physical examination, laboratory tests and upper endoscopy with histomorphometric examination of the esophageal mucosa. RESULTS: On endoscopy, all patients showed mucosal abnormalities in the esophagus. Findings included an unspectacular loss of vascular pattern (93.3%) and white exudates (53.3%). Biopsies demonstrated significantly increased eosinophilia in the white exudates (108.4 vs. 14.0 cells/hpf). A significant correlation was found between white exudates and dysphagia frequency (<1 attack/week = 20%; >1 attack/week = 70%). CONCLUSION: Eosinophilic esophagitis evokes at least 12 different signs resulting in an individually unique endoscopic pattern, but no disease-specific picture. White exudates correspond to foci of dense eosinophilic infiltration reflecting inflammatory activity and are associated with significantly more frequent dysphagia attacks. Both the lack of a typical endoscopic picture as well as the heterogeneity of the eosinophilic infiltration impede diagnosis.

Fragility of the esophageal mucosa: a pathognomonic endoscopic sign of primary eosinophilic esophagitis?

BACKGROUND: Primary eosinophilic esophagitis, a chronic inflammatory disorder of the esophagus, evokes recurrent dysphagia. Endoscopy is often unremarkable, and no consensus exists regarding management of resultant dysphagia. The response of a series of patients with primary eosinophilic esophagitis to dilation is reported together with a description of a possibly pathognomonic sign: fragile esophageal mucosa, for which the term "crêpe-paper" mucosa is introduced. METHODS: Five men underwent endoscopy because of dysphagia confirmed (clinically, endoscopically, and histologically) to be caused by primary eosinophilic esophagitis and were treated by bouginage. OBSERVATIONS: All patients had extremely fragile, inelastic, and delicate mucosa, which tore easily even with minor trauma. After the procedure, patients remained asymptomatic for 3 to 24 months. CONCLUSIONS: Primary eosinophilic esophagitis is characterized by fragile esophageal mucosa that readily tears in response to minor trauma during otherwise uneventful diagnostic endoscopy. This "crêpe-paper" sign may alert endoscopists to the presence of the disease when other mucosal alterations are lacking. Dilation is effective for patients with symptoms with minimal morbidity, despite development of disquieting lesions in response to the procedure.

Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years.

BACKGROUND & AIMS: Primary eosinophilic esophagitis is a chronic, increasingly recognized, interleukin 5-driven inflammatory disorder of the esophagus. The leading symptom in adults is uniform attacks of dysphagia, and the established histologic sign is a dense eosinophilic infiltration of the esophageal epithelium. Before this study, the natural course of eosinophilic esophagitis had not been defined and information regarding potential long-term risks was lacking. METHODS: This prospective case series included 30 adult patients with eosinophilic esophagitis (22 men and 8 women; mean age, 40.6 years) whose diagnosis had been made >1 year before study debut based on typical history, consistent endoscopic abnormalities, and infiltration of the esophageal epithelium with >24 eosinophils/high-power field. After a mean of 7.2 years, patients underwent a comprehensive follow-up examination. RESULTS: All patients survived the study period in good health and stable nutritional state. Dysphagia persisted in 29 patients, exerting a major negative effect on socioprofessional activities on 1 patient and a minor impact on 15. Attacks of dysphagia were more frequent in patients with blood eosinophilia or pronounced endoscopic alterations. The esophageal eosinophilic infiltration persisted in all symptomatic patients, but cell numbers spontaneously decreased significantly (78.7 vs. 40.3 cells/high-power field). The inflammatory process evoked fibrosis of the esophageal lamina propria but did not spread to the stomach or duodenum. No case evolved to a hypereosinophilic syndrome. CONCLUSIONS: Eosinophilic esophagitis, a primary and chronic disease restricted to the esophagus, leads to persistent dysphagia and structural esophageal alterations but does not impact the nutritional state. To date, no malignant potential has been associated with this disease.