Esophageal Metaplasia Using a Novel Antibody: Reversibility by Proton Pump Inhibitor
Esophageal Metaplasia Using a Novel Antibody: Reversibility by Proton Pump Inhibitor
In this project, we are trying to identify patients with the earliest signs of abnormality in
 the lining of the lower part of the food pipe (or esophagus) known as intestinal metaplasia
 (IM); also commonly called Barrett's esophagus or Barrett's Epithelium (BE). IM is sometimes
 difficult to diagnose by routine microscopic examination (called histology). We have
 developed a specific antibody, a protein called immunoglobulin that specifically reacts with
 another partner protein, if it exists. Using this marker antibody (called mAb Das-1) that has
 been patented (US patent #5,888,743), we have shown that this marker can detect the abnormal
 changes in the distal esophagus before it is evident by histology. IM usually develops in the
 face of long-term acid reflux from the stomach to the esophagus and causes the lining to
 change from the normal squamous type (like that of skin) to a type of lining normally seen in
 the small intestine and colon. A subgroup of patients with IM may, subsequently, develop
 histologically evident Barrett's Epithelium and a small percent of these patients may develop
 cancer of the esophagus. Thus, BE is considered as a pre-cancerous condition. We already have
 an ongoing IRB for the portion of the project involving taking biopsies and performing the
 antibody staining to identify patients that react with the antibody but histologically
 negative for BE.
We propose to study prospectively 68 patients who have been identified as positive with mAb
 DAS-1 immunostaining without histological evidence of specialized columnar epithelium ("True
 Barrett's" epithelium) during routine endoscopy for dyspepsia or GERD symptoms. These
 patients have been studied for initial screening for antibody staining under IRB protocol
 #1698. This number is based on the statistical analysis by Fisher's exact test and has 90%
 power to detect a 30% negativity (mAb Das-1 positive to negative) at a p<0.05 level. During
 participation in IRB Protocol #1698, initial biopsy specimens were taken at:

 -  the squamo-columnar junction (at least 2 sites - 12 o'clock and 6 o'clock positions and
 any other area with mucosal "tongues" of columnar epithelium),

 -  one from squamous epithelium at the distal esophagus to seek for the presence of
 esophagitis,

 -  one from antrum for the presence or absence of intestinal metaplasia of the stomach,

 -  and one from the gastric cardia.

 Following endoscopy and participation in IRB Protocol #1698, for the symptomatic patients who
 are not taking any proton pump inhibitor, an H2 blocker, Ranitidine (ZantacÒ) 150 mg twice
 daily, will be started while the biopsy is being analyzed for histology and
 immunocytochemical stainings. This is usually completed within 2 weeks. Patients who showed
 positive reactivity in at least one biopsy sample taken during participation in Protocol
 #1698 with mAb Das-1 will be included in this study. Patients who have been taking a proton
 pump inhibitor (PPI) for longer than 3 months preceeding study entry are not eligible to
 participate in this study. Patients who have been taking proton pump inhibitors for 3 months
 or less at the time of the endoscopy and biopsy screening for mAb Das-1, may participate in
 this study 4 weeks after discontinuing the PPI (i.e., a 4 week washout period).

 Patients will be randomized in a double-blinded fashion to receive either Pantoprazole, 40 mg
 twice daily (34 patients), or continued on Ranitidine, 150 mg twice daily (34 patients) for a
 total period of 6 months. Pantoprazole and Ranitidine will be provided by Wyeth and the code
 will be kept by the pharmacy department at The Cancer Institute of New Jersey. The drugs will
 be provided free of cost to the patients for the entire period. Patients will be followed as
 out-patients at three-month intervals up to 6 months. Patients will be advised to return any
 unused capsules during the follow-up visits. The number of unused capsules as well as review
 of the patient's medication diary will allow assessment of non-compliance. Patients must be
 at least 75% compliant to remain on the study. If any patient complains of persistent
 symptoms, an effort will be made to provide relief with antacids, as much as needed. However,
 if the patient is still symptomatic, they will be taken off the study and unblinded. If the
 patient is on Ranitidine they will be switched to open label Pantoprazole and will be
 followed and further treated in a routine manner. If the patient is taking Pantoprazole, pH
 monitoring to document acid reflux and planning of further management will be determined.

 All patients will have a follow-up endoscopy at 6 months, with no cost to the patient. This
 cost will be born by the grant received by Dr. Das. Additional endoscopy will be performed at
 12 months and 24 months, which is the current "standard care" procedure for surveillance in
 such patients. Follow-up biopsy specimens will be taken the same way as the initial specimens
 and processed to see any changes in histology and mAb Das-1 reactivity.
Inclusion Criteria:

 -  Dyspeptic symptoms, upper abdominal pain, heartburn, regurgitation;

 -  Endoscopically - normal appearing GE junction, irregular z-line, or erosive
 esophagitis up to Grade 2.

 Exclusion Criteria:

 -  Barrett's esophagus (Endoscopically greater than 2 cm of columnar epithelium on
 endoscopy and the presence of specialized columnar epithelium on histology);

 -  Patients who have been taking a PPI longer than the 3 months proceeding study entry.
 Patients currently taking a PPI but for less than 3 months who are not willing to
 discontinue PPI treatment for 4 weeks prior to enrollment into this study.

 -  Severe esophagitis Grade 3 or 4

 -  Documented active duodenal or gastric ulcer (at least 0.5cm diameter). Patients with
 erosions can be included.

 -  Presence of esophageal varices

 -  History of gastric surgery altering normal anatomy (eg, Billroth procedure, gastric
 bypass)

 -  Pregnant or nursing patients