Clinical and Molecular Assessment of Men With High Risk for Esophageal Disorders

Patients with elevated central adiposity have an increased risk of esophageal disorders; we
will correlate central adiposity with advanced esophageal pathologies (BE and EAC). This will
be done by comparing body mass and fat distribution to tissue abnormalities found by
pathology review of EGD biopsy. It is anticipated that the group of men in this study will
have an increased likelihood of histopathologic alteration, which we will fit into our scale
(0-no inflammation, 1-inflammation or BE, 2-BE with dysplasia, and 3-carcinoma) according to
the referral pattern at UAB's outpatient gastroenterology clinic.

At the molecular level, there is also a relationship between pro-inflammatory cytokines and
obesity, which may contribute to esophageal disorder [28]. Metabolically active fat cells
secrete cytokines exclusive to adipose tissue (adipokines, leptin/adiponectin) as well as the
more classic signaling molecules, tumor necrosis factor alpha (TNF-α); interleukins (IL)-1,
IL-6, IL-8, and IL-10; monocyte chemoattractant protein 1 (MCP-1); and macrophage
inflammatory protein 1 (MIP 1) [29-33]. Obesity-triggered pro-inflammatory molecules may
promote tissue injury, leading to metaplasia and dysplasia in BE and, subsequently, to
carcinoma.

Thus, by measuring these pro-inflammatory markers in our prospective patient population, it
will be determined if patients with elevated levels exhibit pathologic disorders in the
esophagus and if the differential expression of these molecular markers correlates with
degree of esophageal disorder. We will analyze samples collected from men for adipocytokines
and for inflammatory mediators that are released with tissue injury. Additionally, we will
examine molecular markers that correlate with more advanced esophageal disorders (BE with
high grade dysplasia and EAC).

Persistent stimulation is needed to cause stepwise progression from the early stages of
esophageal injury, to BE, to carcinoma. Since the molecular events that lead to this
transformation are not known, our goal is to profile biopsy tissues collected from the
prospective cohort of 60 men, analyzed by IHC for p53, Ki67, cyclin D1, IL-6, IL-8, Cox-2,
DKK-1, CD44, leptin, and adiponectin. These molecules are known to be involved in
transformation of normal esophageal epithelium to EACs via progression from metaplasia and BE
to low-grade dysplasia and high-grade dysplasia. [34]. The clinical outcome measurements will
be correlated with the levels of these molecules, determined by IHC, with metaplasia, degree
of dysplasia in BE, and stage of EAC. For BE tissues, there is a correlation between the
extent of p53 staining and aggressive clinical features. Our preliminary findings on six BEs,
selected from the patient population at UAB, indicate that a high proportion of p53 staining
directly correlates with high-grade lesions

Inclusion Criteria:

1. Men only who are referred for upper endoscopy for the first time.Or who have had
normal upper endoscopy in the last 10 years

2. Age criteria: 25-75 years in age

3. Patients undergoing EGD and willing to also consent to tissue biopsy, blood work and
CT scan.

4. ECOG PFS 0-1

Exclusion Criteria:

1. Unstable medical condition, such as uncontrolled diabetes mellitus or hypertension or
active infections requiring systemic therapy

2. Clinical evidence of cardiac or pulmonary dysfunction including, but not limited to,
unstable congestive heart failure, uncontrolled arrhythmias, unstable coagulation
disorders, or recent myocardial infarction (within 6 months)

3. Documented history of erosive esophagitis or non-erosive esophageal luminal. No prior
history of Barrett's esophagus.