John T. Woosley

Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease.

BACKGROUND & AIMS Features of eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD) overlap; because they cannot be differentiated on the basis of eosinophil counts alone, it can be a challenge to distinguish these disorders. We aimed to characterize the clinical, endoscopic, and histologic features of EoE and GERD and to identify factors that might be used to differentiate them. METHODS We performed a retrospective case-control study on data collected from 2000 to 2007. Cases were patients of any age with EoE, as defined by recent consensus guidelines; controls were patients of any age with GERD. Clinical and endoscopic data were collected, and all esophageal biopsy specimens were reassessed by gastrointestinal pathologists. Cases and controls were compared, unconditional logistic regression was performed to develop a model to predict EoE, and receiver operator characteristic curves were constructed. RESULTS Data from 151 patients with EoE and 226 with GERD were analyzed. Compared with GERD, features that independently predicted EoE included younger age; symptoms of dysphagia; documented food allergies; observations of esophageal rings, linear furrows, white plaques, or exudates by upper endoscopy; an absence of a hiatal hernia, observed by upper endoscopy; a higher maximum eosinophil count; and the presence of eosinophil degranulation observed in biopsy specimens. The area under the curve for this model was 0.934. CONCLUSIONS We identified a set of readily available and routinely measured variables that differentiate EoE from GERD. Use of this type of analysis with patients suspected to have EoE might lead to more accurate diagnoses.

Variability in diagnostic criteria for eosinophilic esophagitis: A systematic review

BACKGROUND:Eosinophilic esophagitis (EoE) is an emerging clinicopathologic entity defined by abnormal esophageal eosinophilic infiltration. Our understanding of this disease is hampered by the lack of a uniform diagnostic standard. The aim of this systematic review was to determine the range of diagnostic strategies and histologic criteria in the EoE literature.METHODS:The MEDLINE-indexed literature from 1950 through December 31, 2006 was independently searched by two investigators. To identify additional relevant studies, bibliographies were hand searched, as were the published proceedings of the 2000–2006 American College of Gastroenterology and American Gastroenterological Association national meetings. Data were extracted from all human EoE case reports, case series, cross-sectional and cohort studies, and clinical trials.RESULTS:Of 318 publications initially identified, 116 original articles, 39 abstracts, and 69 reviews were included. We found 10 different histologic definitions of EoE, ranging from 5 to 30 eosinophils per high-powered field (hpf), though 41 (35%) of the original articles did not state their diagnostic criteria. In the 13 original articles (11%) reporting an hpf area, the eosinophil density per mm2 varied 23-fold. There was also variation in esophageal biopsy protocols, but specific protocols were reported in just 45 (39%) original articles.CONCLUSIONS:Significant variability in diagnostic criteria for eosinophilic esophagitis exists, and in a large proportion of studies, criteria are not reported. Because of this lack of a common disease definition, conclusions drawn from the cumulative EoE literature should be viewed with caution. A consensus research-quality standard for diagnosis of eosinophilic esophagitis is needed.

Circulating levels of inflammatory cytokines and risk of colorectal adenomas

The association between obesity and colorectal neoplasia may be mediated by inflammation. Circulating levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) are elevated in the obese. Adipose tissue can produce and release the inflammatory cytokines that are potentially procarcinogenic. We examined circulating levels of CRP, IL-6, and TNF-alpha in relation to risk factors and the prevalence of colorectal adenomas. Plasma levels of CRP, IL-6, and TNF-alpha were quantified in 873 participants (242 colorectal adenoma cases and 631 controls) in a colonoscopy-based cross-sectional study conducted between 1998 and 2002. Multivariable logistic regression was used to estimate associations between known risk factors for colorectal neoplasia and circulating levels of inflammatory cytokines and associations between inflammatory cytokines and colorectal adenomas. Several known risk factors for colorectal neoplasia were associated with higher levels of inflammatory cytokines, including older age, current smoking, and increasing adiposity. The prevalence of colorectal adenomas was associated with higher concentrations of IL-6 and TNF-alpha and, to a lesser degree, with CRP. For IL-6, adjusted odds ratios (OR) for colorectal adenomas were 1.79 [95% confidence interval (CI), 1.19-2.69] for the second highest plasma level and 1.85 (95% CI, 1.24-2.75) for the highest level compared with the reference level. A similar association was found with TNF-alpha, with adjusted ORs of 1.56 (95% CI, 1.03-2.36) and 1.66 (95% CI, 1.10-2.52), respectively. Our findings indicate that systemic inflammation might be involved in the early development of colorectal neoplasia.

Clinical and endoscopic characteristics do not reliably differentiate PPI-responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: A Prospective Cohort Study

OBJECTIVES:Proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is a newly recognized entity that must be differentiated from eosinophilic esophagitis (EoE). Little is known about this condition. We aimed to determine the prevalence of PPI-REE and EoE in patients undergoing upper endoscopy and determine features that distinguish the two groups.METHODS:This prospective study conducted at the University of North Carolina from 2009 to 2011 enrolled consecutive adult patients undergoing outpatient upper endoscopy. Subjects had esophageal biopsies to quantify the maximum eosinophil count per high-power field (eos/hpf; hpf=0.24 mm2). If biopsies revealed ≥15 eos/hpf, subjects were treated with twice daily PPI for 8 weeks and endoscopy was repeated. If ≥15 eos/hpf persisted despite PPI therapy, EoE was diagnosed. If there were <15 eos/hpf, PPI-REE was diagnosed. The proportion of patients in each group was calculated, and patients with EoE and PPI-REE were compared.RESULTS:Of the 223 subjects enrolled, 173 had dysphagia and 50 did not. Of those with dysphagia, 66 (38%) had ≥15 eos/hpf. After the PPI trial, 40 (23%) were confirmed to have EoE, and 24 (14%) had PPI-REE. Of those without dysphagia, 2 (4%) had ≥15 eos/hpf, and after the PPI trial, 1 (2%) had EoE. Compared with EoE, PPI-REE patients were more likely to be older and male and less likely to have typical endoscopic findings of EoE. However, none of the individual factors was independently predictive of PPI-REE status on multivariable analysis. Similarly, although some endoscopic findings were differentially distributed between PPI-REE and EoE, none were significantly associated with disease status on multivariable analysis.CONCLUSIONS:Esophageal eosinophilia is common among patients undergoing esophagogastroduodenoscopy for dysphagia. Although EoE was seen in nearly a quarter of patients with dysphagia, PPI-REE was almost as common, and accounted for over one-third of those with ≥15 eos/hpf. No clinical or endoscopic features independently distinguished PPI-REE from EoE before the PPI trial.

A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease

BACKGROUND Phenotypes of eosinophilic esophagitis (EoE) are not well-characterized. OBJECTIVE To describe clinical features of patients with EoE with predefined phenotypes, determine predictors of these phenotypes, and make inferences about the natural history of EoE. DESIGN Retrospective study. SETTING Tertiary-care center. PATIENTS Incident EoE cases from 2001 to 2011 that met consensus diagnostic guidelines. INTERVENTION Review of records. MAIN OUTCOME MEASUREMENTS Endoscopic phenotypes, including fibrostenotic, inflammatory, or mixed. Other groups of clinical characteristics examined included atopy, level of esophageal eosinophilia, and age of symptom onset. Multinomial logistic regression assessed predictors of phenotype status. RESULTS Of 379 cases of EoE identified, there were no significant phenotypic differences by atopic status or level of eosinophilia. Those with the inflammatory phenotype were more likely to be younger than those with mixed or fibrostenotic (13 vs 29 vs 39 years, respectively; P < .001) and less likely to have dysphagia, food impaction, and esophageal dilation (P < .001 for all). The mean symptom length before diagnosis was shorter for inflammatory (5 vs 8 vs 8 years; P = .02). After multivariate analysis, age and dysphagia independently predicted phenotype. The odds ratio (OR) for fibrostenosis for each 10-year increase in age was 2.1 (95% CI, 1.7-2.7). The OR for dysphagia was 7.0 (95% CI, 2.6-18.6). LIMITATIONS Retrospective, single-center study. CONCLUSION In this large EoE cohort, the likelihood of fibrostenotic disease increased markedly with age. For every 10-year increase in age, the odds of having a fibrostenotic EoE phenotype more than doubled. This association suggests that the natural history of EoE is a progression from an inflammatory to a fibrostenotic disease.

Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis

We performed a randomized trial to compare nebulized and viscous topical corticosteroid treatments for eosinophilic esophagitis (EoE). Subjects with incident EoE (n = 25) received budesonide 1 mg twice daily, either nebulized and then swallowed (NEB) or as an oral viscous slurry (OVB), for 8 weeks. Baseline eosinophil counts for the NEB and OVB groups were 101 and 83 (P = .62). Posttreatment counts were 89 and 11 (P = .02). The mucosal medication contact time, measured by scintigraphy, was higher for the OVB group than the NEB group (P < .005) and was inversely correlated with eosinophil count (R = -0.67; P = .001). OVB was more effective than NEB in reducing numbers of esophageal eosinophils in patients with EoE. OVB provided a significantly higher level of esophageal exposure to the therapeutic agent, which correlated with lower eosinophil counts.

A method for normalizing histology slides for quantitative analysis

Inconsistencies in the preparation of histology slides make it difficult to perform quantitative analysis on their results. In this paper we provide two mechanisms for overcoming many of the known inconsistencies in the staining process, thereby bringing slides that were processed or stored under very different conditions into a common, normalized space to enable improved quantitative analysis.

Neuroendocrine tumors of the pancreas: spectrum of appearances on MRI.

We reviewed our 8.5 year experience with magnetic resonance imaging (MRI) in the demonstration of neuroendocrine tumors of the pancreas using precontrast fat‐suppressed T1‐weighted, fat‐suppressed T2‐weighted, and serial post‐gadolinium T1‐weighted images, to describe the spectrum of appearances of these tumors. All MR examinations of patients with histogically proven neuroendocrine tumors were retrospectively reviewed. Histological type, tumor location, tumor diameter, signal intensity on precontrast images, enhancement patterns, and presence and appearance of metastases were determined. Twenty‐two patients had histologically proved neuroendocrine tumors detected by MRI over the 8.5 year period. Histological types were gastrinoma (n = 8), insulinoma (n = 3), glucagonoma (n = 2), somatostatinoma (n = 1), VIPoma (n = 1), ACTHoma (n = 1), carcinoid (n = 1), and five untyped tumors. Primary tumors ranged in diameter from 1 to 6.2 cm. There was one histopathology‐proven false‐positive neuroendocrine tumor. The positive predictive value for MRI in the detection of these tumors was 96%. The most common appearance on precontrast images was low signal intensity on T1‐weighted images and high signal intensity on T2‐weighted images, which was observed in tumors in 18 of 22 patients. Moderate or intense early enhancement of all or portions of the primary tumors was observed in tumors in 19 of 22 patients either as uniform homogeneous, ring, or diffuse heterogeneous enhancement. Enhancement was minimal on these images in the other three patients. Gastrinomas enhanced in a ring pattern in 7 of 8 patients whereas the majority (9 of 11 patients) of noninsulinoma‐nongastrinoma and untyped tumors enhanced in a diffuse heterogeneous fashion. Liver metastases were present in 13/22 patients including 3/8 with gastrinoma and 9/11 with noninsulinoma‐nongastrinoma tumors. Most neuroendocrine tumors of the pancreas are low signal intensity on fat‐suppressed T1‐weighted images and moderately high in signal intensity on fat‐suppressed T2‐weighted images, although variations do exist. Tumors most often enhance in an early moderately intense fashion. Gastrinomas are often different in appearance than other neuroendocrine tumors in that they usually enhance in a ring fashion whereas nongastrinoma‐noninsulinoma tumors usually enhance in a heterogeneous fashion. J. Magn. Reson. Imaging 2000;11:141–148.

RNA expression analysis of formalin-fixed paraffin-embedded tumors

RNA expression analysis is an important tool in cancer research, but a limitation has been the requirement for high-quality RNA, generally derived from frozen samples. Such tumor sets are often small and lack clinical annotation, whereas formalin-fixed paraffin-embedded (FFPE) materials are abundant. Although RT-PCR-based methods from FFPE samples are finding clinical application, genome-wide microarray analysis has proven difficult. Here, we report expression profiling on RNA from 157 FFPE tumors. RNA was extracted from 2- to 8-year-old FFPE or frozen tumors of known and unknown histologies. Total RNA was analyzed, reverse-transcribed and used for the synthesis of labeled aRNA after two rounds of amplification. Labeled aRNA was hybridized to a 3′-based 22K spot oligonucleotide arrays, and compared to a labeled reference by two-color microarray analysis. After normalization, gene expression profiles were compared by unsupervised hierarchical clustering. Using this approach, at least 24% of unselected FFPE samples produced RNA of sufficient quality for microarray analysis. From our initial studies, we determined criteria based on spectrophotometric analyses and a novel TaqMan-based assay to predict which samples were of sufficient quality for microarray analysis before hybridization. These criteria were validated on an independent set of tumors with a 100% success rate (20 of 20). Unsupervised analysis of informative gene expression profiles distinguished tumor type and subtype, and identified tumor tissue of origin in three unclassified carcinomas. Although only a minority of FFPE blocks could be analyzed, we show that informative RNA expression analysis can be derived from selected FFPE samples.

MRI of carcinoid tumors: Spectrum of appearances in the gastrointestinal tract and liver

The purpose of this study was to evaluate the spectrum of appearances of gastrointestinal carcinoid tumors at magnetic resonance imaging (MRI) and to elucidate patterns of appearances of carcinoid liver metastases on precontrast and postgadolinium images. The MR examinations of 29 patients (11 men, 18 women; age range, 33–87 years) with histologically confirmed gastrointestinal carcinoid tumors, representing our complete 9.5 years of experience with this entity, were retrospectively reviewed. Twelve patients had MR examinations prior to resection or biopsy of the primary tumor (preoperative group); 17 patients were imaged postsurgically (postoperative group). All MR studies were performed at 1.5 T and comprised T1‐weighted spoiled gradient echo (SGE), T2‐weighted fat‐suppressed turbo spin echo, HASTE, and serial postgadolinium T1‐weighted SGE sequences without and with fat suppression. Morphology, signal intensity, and contrast enhancement of primary tumors and of metastases to the mesentery, peritoneum, and liver were evaluated. Primary tumors were visualized in 8 of 12 patients and best demonstrated on postgadolinium T1‐weighted fat‐suppressed images. The appearance of primary tumors was a nodular mass originating from the bowel wall (4 of 12 patients) or regional uniform bowel wall thickening (4 of 12 patients) with moderate intense enhancement on postgadolinium images. In 4 of 12 patients the primary tumor was prospectively not seen. Mesenteric metastases, seen in eight patients, presented as nodular masses and were associated with mesenteric stranding in seven patients. A total of 156 liver metastases were evaluated in 16 patients. On precontrast T1‐ and T2‐weighted images, 117 metastases (75%) were hypointense and hyperintense, respectively. A total of 146 metastases (94%) were hypervascular, showing moderate intense enhancement during the hepatic arterial phase, and 9 metastases (6%) were hypovascular. Twenty‐three metastases (15%) were visible only on immediate postgadolinium images. MRI is able to demonstrate findings in carcinoid tumors, including the primary tumor, mesenteric metastases, and liver metastases. Liver metastases are commonly hypervascular and may be demonstrable only on immediate postgadolinium images. J. Magn. Reson. Imaging 2001;14:261–269.