Patient case: 72-year-old male with melanoma; genetic feature: TP53 loss of function

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

Summary: In this study,the investigators will evaluate participants that have clinical features associated with an increased risk of esophageal disorders.The investigators will also see if there is a positive association of esophageal disorders in men,40-60 with or without abdominal obesity in the diagnosis of the following diseases; Gastroesophageal reflux disease, Barrett Esophagus and Esophageal Adenocarcinoma. The investigators hypothesize that most obese patients referred for Esophagogastroduodenoscopy will exhibit esophageal disorders. Since currently the rates of obesity and adenocarcinoma of the esophagus have increased significantly over the past 15 years, the investigators hope to find biochemical markers (i.e. pro-inflammatory mediators) in the esophagus. The investigators hope these samples will lead us to a differential expression of molecular markers and inflammatory mediators in the varying degrees of esophageal disorder

Detailed description: 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

Eligibility: 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.

Relevance to patient case: not relevant