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Background: Elevated IgE levels in patients with chronic urticaria have been noted previously, but the significance of these findings has not been appreciated., Objective: To measure the IgE levels in such patients and to examine the relationship between these levels and urticarial severity, autologous serum skin test, anti-thyroid antibodies and duration., Methods: Serum total IgE levels from 203 patients with chronic urticaria were measured and compared with nonatopic individuals. Additionally, patients were assessed for urticarial severity, the presence of autologous serum skin test and anti-thyroid antibodies., Results: Of the chronic urticaria patients, 47 (23.2%) were classified as mild, whereas 67 (33%) were classified as having moderate and 89 (43.8%) as having severe chronic urticaria. Total IgE levels were elevated, above 175 U/ml, in 69/203 (34%) of patients, compared with 7/81 (8.6%) of healthy controls (p < 0.001). A significant association between increased total IgE and chronic urticaria severity was found. Whereas 93% of patients with increased level of total IgE suffered from moderate-to-severe chronic urticaria, this was observed in only 69% of patients with normal IgE (p < 0.0001). Autologous serum skin test and anti-thyroid antibodies were positive in 59/163 (36%) and 28/189 (15%) patients, respectively. A significant association between increased total IgE levels and the presence of autologous serum skin test, anti-thyroid antibodies and urticarial duration lasting more than 25 months (p < 0.0001, p < 0.0001 and p = 0.021, respectively) was also detected., Conclusions: Total serum IgE levels are frequently elevated in patients with chronic urticaria and these are associated with disease severity and duration., (Copyright © 2010 S. Karger AG, Basel.)

Differentiating eosinophilic esophagitis from gastroesophageal reflux disease is important given their pathogenetic differences and responses to therapy. Eotaxins are a family of chemokines important for activation and recruitment of eosinophils mediated by their receptor, chemokine receptor-3 (CCR-3). Interleukin 5 (IL-5) is a key cytokine involved in many steps of eosinophil production and recruitment. The aim of this study was to compare the messenger RNA expression of the eotaxins, CCR-3, and IL-5 between well-characterized groups of patients with eosinophilic esophagitis, patients with gastroesophageal reflux disease, and healthy individuals. This was a retrospective study using esophageal biopsies from 33 patients with eosinophilic esophagitis, 20 patients with gastroesophageal reflux disease, and 17 healthy controls. Parameters studied included demographic features, presenting symptoms, endoscopic findings, histopathologic features, and messenger RNA levels of eotaxins 1, 2, and 3, CCR-3, and IL-5 by quantitative real-time polymerase chain reaction using formalin-fixed, paraffin-embedded tissue. Patients with eosinophilic esophagitis were predominantly males (M/F=3:1), with a mean age of 15.9 years and a mean eosinophil count of 55 per x400 high-power field. Patients with gastroesophageal reflux disease had a mean age of 31.5 years and a mean eosinophil count of 5.8 per high-power field. Total intraepithelial eosinophil and lymphocyte counts, the presence of superficial eosinophil clusters, microabscesses, and basal cell hyperplasia were all significantly associated with eosinophilic esophagitis as opposed to gastroesophageal reflux disease (P<.0001). The mean expression levels of eotaxin-3 were markedly elevated in patients with eosinophilic esophagitis as compared with the gastroesophageal reflux disease and healthy control groups (731+/-276, 31+/-12, and 1.5+/-0.4 pg/ng beta-actin, respectively; P<.001). Mean expression levels of eotaxins 1 and 2, IL-5, and CCR-3 were also significantly increased in the patients with eosinophilic esophagitis, albeit at lower levels than eotaxin-3. In conclusion, our results highlight the important contribution of eotaxin-3 in the pathogenesis of eosinophilic esophagitis. Determination of eotaxin-3 levels by real-time polymerase chain reaction on paraffinized, formalin-fixed tissue may be a useful test in the differentiation of eosinophilic esophagitis from gastroesophageal reflux disease.

We have used monoclonal antibodies against cell-surface developmental epitopes in combination with micromagnetic beads to isolate phenotypically defined subpopulations of cholangiocyte marker-positive fetal liver epithelial cells (CMP-FLEC). Differentiation potential was evaluated by injecting cell isolates from dipeptidyl peptidase IV (DPPIV) positive (DPPIV+) Fischer donor rats into the spleen of partially hepatectomized, DPPIV negative (DPPIV-) Fischer host rats exposed to retrorsine. At various time points, liver tissue was harvested and cells in DPPIV+ colonies were phenotyped by immunofluorescence and histochemical protocols. Functional differentiation and liver replacement were determined by comparing donor and host hepatocyte protein expression patterns and DPPIV enzyme activity in extracts from livers of host rats receiving CMP-FLEC. Our results showed that bipotentiality was retained during differentiation and maturation of CMP-FLEC, indicating that the acquisition of ductal morphology and phenotype were not indicative of lineage commitment. CMP-FLEC transplanted into the adult rat liver lost ductal and gained hepatocyte markers, and acquired protein expression patterns in 2D gels with a close similarity (>75% spot match) to host hepatocytes but differing significantly from the transplanted CMP-FLEC cell isolate (<25% spot match). The average size of donor hepatocyte colonies increased with time so that by 1 year, up to 70% of the host rat liver was replaced by CMP-FLEC derived DPPIV+ hepatocytes. Depletion of CMP-FLEC from fetal liver isolates resulted in a marked decrease in adult liver colonization, suggesting that a high percentage of the hepatocyte colonies in animals receiving total fetal liver isolates are derived from CMP-FLEC.

Background: It is relatively difficult in a community setting to perform salivary gland biopsy or reliable diagnostic tests for salivary gland involvement in a patient suspected to suffer from Sjögren's syndrome (SS)., Objective: To investigate whether anti-Ro/La antibodies are a good substitute for salivary gland biopsy in community patients suspected to suffer from SS., Methods: Forty-one patients suspected as having SS due to dry eyes and mouth, articular complaints, and/or serological findings were examined for the presence of anti-Ro/La, and underwent minor salivary gland biopsy., Results: Sixteen patients (39%) were classified as primary SS by the American-European Consensus Group criteria. Twelve subjects had anti-Ro/La antibodies and 11 subjects in this group had positive biopsy findings. Of 29 patients without anti-Ro/La antibodies, only four manifested positive biopsy findings. A significant association was found between the presence of anti-Ro/La antibodies and positive salivary gland findings characteristic for SS (p<0.0001, Fisher's exact test)., Conclusion: These findings tend to support the suggestion that a patient suspected to suffer from SS in a community setting may be first tested for the presence of anti-Ro/La antibodies to confirm the diagnosis. Only those with a negative result for the presence of anti-Ro/La antibodies need to be referred for salivary gland biopsy.

Purpose: Through the use of molecular markers, it may be possible to identify aggressive tumor phenotypes and tailor therapies to treat them. This approach would be particularly useful for stage II colon cancer. The purpose of this study was to define the prognostic value of epidermal growth factor receptor (EGFR), c-MET, beta-catenin, and p53 protein expression in TNM stage II colon cancer using tissue microarray technology., Experimental Design: In this study, we retrospectively analyzed, resected, and otherwise untreated paraffin-embedded specimens from 134 consecutive patients with Tumor-Node-Metastasis stage II colonic carcinomas for EGFR, c-MET, beta-catenin, and p53 protein expression by immunohistochemistry., Results: Thirty-five percent, 77, and 65% of tumors exhibited strong (+2 and +3 immunopositivity) expression of EGFR, c-MET, and beta-catenin, respectively. Fifty-four percent exhibited nuclear staining for p53 in >10% of the tumor cells. Univariate analysis revealed that increased nuclear p53 expression (P = 0.001), strong membranous EGFR expression (P = 0.04), and lymphovascular invasion (P = 0.01) were significantly related to disease recurrence and that p53 (P = 0.02) and EGFR (P = 0.05) expression were associated with decreased survival. Increased nuclear p53 expression also correlated with the presence of distal metastasis (P = 0.027). No significant association was seen between c-MET expression and prognosis, whereas a strong trend was detected between loss of beta-catenin (P = 0.065) expression and poor outcome. Multivariate analysis indicated that p53 (P = 0.04), EGFR (P = 0.05), and lymphovascular invasion (P = 0.03) were independent predictors of recurrence and that p53 (P = 0.02) and EGFR (P = 0.01) expression were both associated with poor survival., Conclusions: This retrospective tumor microarray study, restricted to Tumor-Node-Metastasis stage II colon cancer patients who did not undergo adjuvant therapy, supports the use of EGFR and p53 as biological markers, which may assist in predicting disease recurrence and survival.

The article presents a study which explores role of p63 immunodetection in the prognosis of adenoid cystic carcinoma (ACC) of salivary gland. It states that an image analyzing algorithm was developed using conditional morphological operations to establish precisely the proportions of negatively and positively stained tumor cells. The results show that a cutoff of 35% of tumor cells with p63 positivity distinguished patients with morbidity and mortality from individuals with long-term survival.

Summary: Despite improvements in the detection and use of biomarkers, including epidermal growth factor receptor, ERCC1, and p16, the 5-year survival rate with non–small cell lung cancer remains at 15%. This suggests that additional biomarkers are needed to better prognosticate clinical course and guide therapeutic approaches. Previous studies showed that increased levels of aspartyl (asparaginyl)-β-hydroxylase and a highly related molecule, humbug, correlate with clinical course and survival with hepatic, biliary, pancreatic, and colon carcinomas. We now characterize the prognostic use of aspartyl (asparaginyl)-β-hydroxylase/humbug immunoreactivity in different subtypes of non–small cell lung cancer. Tissue microarrays including 375 paraffin-embedded non–small cell lung cancers (195 adenocarcinomas; 18 bronchioloalveolar carcinomas; 113 squamous cell carcinomas; and 49 large cell carcinomas) were immunostained with FB50 monoclonal antibody, which recognizes human aspartyl (asparaginyl)-β-hydroxylase/humbug. Immunoreactivity (intensity and distribution) in neoplastic cells were scored under code, and data were subjected to univariate and Cox multivariate analyses, adjusting for age, stage, and treatment. High levels of FB50 immunoreactivity were more often detected in adenocarcinomas (28% for adenocarcinoma, 17% for bronchioloalveolar carcinoma), compared with squamous cell carcinomas (10%) and large cell carcinomas (10%). Univariate analysis demonstrated inverse relationships between intensity of FB50 immunoreactivity and survival with squamous cell carcinoma (P = .004), and a strong trend with respect to large cell carcinoma (P = .057). Cox multivariate test showed that FB50 immunoreactivity (P = .025), clinical stage (P = .029), and tumor size (P = .0001) were all independent predictors of survival with squamous cell carcinoma. High levels of FB50 immunohistochemical staining correlate with poor prognosis in non–small cell lung cancer, particularly squamous cell carcinoma subtype. Therefore, FB50 immunoreactivity may be useful in defining patient subsets that are likely to benefit from adjuvant therapy. [Copyright &y& Elsevier]

Summary: Undifferentiated or medullary carcinoma is characterized by its distinct histologic appearance and relatively better prognosis compared to poorly differentiated colonic carcinoma. These 2 entities may be difficult to differentiate by light microscopy alone. Only limited immunohistochemical studies investigating medullary carcinoma have been reported. These studies suggest a loss of intestinal differentiation, exemplified by a high percentage of CDX2 negativity. Our aim was to further characterize the immunohistochemical profile of medullary carcinoma, with particular emphasis on intestinal markers. Paraffin blocks from 16 cases of medullary carcinoma and 33 cases of poorly differentiated colonic carcinoma were retrieved, and tissue microarrays were constructed and stained with an immunohistochemical panel including CDX2, CK7, CK20, p53, intestinal trefoil factor 3, chromogranin, synaptophysin, MLH-1, MUC-1, MUC-2, and calretinin. A significantly higher proportion of medullary carcinomas, as opposed to poorly differentiated colonic carcinomas, showed loss of staining for MLH-1 and for the intestinal transcription factor CDX2, in accordance with previous studies. MLH-1 staining was present in only 21% of medullary carcinoma cases compared with 60% of the poorly differentiated colonic carcinoma cases (P = .02), whereas CDX2 was positive in 19% of medullary carcinomas and 55% of poorly differentiated colonic carcinomas (P = .03). Interestingly, calretinin staining was strongly positive in 73% of medullary carcinomas compared to only 12% of poorly differentiated colonic carcinomas (P < .0001). Evidence of intestinal differentiation by MUC-1, MUC-2, and TFF-3 staining was seen in 67%, 60%, and 53% of the medullary carcinomas, respectively. These 3 markers were frequently positive in many of the CDX2-negative medullary carcinoma cases. Medullary carcinoma of the colon retains a significant degree of intestinal differentiation as evidenced by its high percentage of staining for MUC-1, MUC-2, and TFF-3. Calretinin, MLH-1, and CDX2 may help to differentiate medullary carcinoma from poorly differentiated colonic carcinoma of the colon. [Copyright &y& Elsevier]

Summary: The claudins comprise a multigene family of integral membrane proteins, which play a major role in tight junction formation. Aberrations in the expression of certain claudins have been described in a number of malignancies. Our aims were to determine the expression pattern of claudins 1, 3, and 4 as well as ZO-1 in a large series of US patients with gastric cancer and to correlate expression with clinicopathologic and prognostic variables. Tissue microarrays were created from paraffinized samples from 146 patients with distal gastric adenocarcinomas (61 intestinal and 85 diffuse or mixed subtypes). In addition, cores of normal mucosa and intestinal metaplasia were taken from most cases. The microarrays were stained for claudins 1, 3, and 4 and ZO-1, and the intensity of staining was determined using a 3-point scale. Moderate claudin 1 and ZO-1 membranous staining were present, whereas only focal weak claudin 3 and 4 membranous staining was present in normal gastric epithelium. Moderate to strong staining of claudins 1, 3, 4, and ZO-1 was detected in 74%, 48%, 62%, and 74% of the intestinal but in only 46%, 24%, 45%, and 36% of the diffuse subtype of adenocarcinomas (P < .05). Cox multivariate analysis revealed that tumor stage, diffuse subtype, and moderate to strong claudin 4 staining were associated with decreased survival (P < .02). In conclusion, claudins 1, 3, and 4 and ZO-1 are strongly expressed in most gastric intestinal-type adenocarcinomas but less frequently in diffuse gastric cancers. The up-regulation of claudin expression during gastric carcinogenesis suggests their potential utility as diagnostic biomarkers and possible targets for therapeutic intervention. [Copyright &y& Elsevier]