Furhawn A. Shah

The severity of duodeno-esophageal reflux influences the development of different histological types of esophageal cancer in a rat model†

The mechanism through which each histological type of carcinoma arises from the esophageal mucosa remains unknown. This study was designed to investigate whether there is an association between the severity of duodeno‐esophageal reflux and the histological type of esophageal cancer. A series of 120 male Fischer rats, weighing ∼180 g, were randomized to receive one of the following procedures: duodeno‐forestomach reflux (DFR) with reduced exposure to duodenal contents, duodeno‐esophageal reflux (DER) with increased exposure to duodenal contents and three control operations (DFR, DER control and sham). The reflux of bile was estimated with 99mTc‐PMT scintigraphy. All animals were fed a standard diet without carcinogen. The esophageal mucosa was assessed 50 weeks after surgery for carcinoma. The median scanned fraction rate of duodeno‐esophageal reflux was significantly lower for the rodents in the DFR group than those in the DER group. Five of 28 rodents in the DFR group and 17 of the 22 rodents in the DER group developed esophageal carcinoma. None of the controls developed carcinoma. The five rodents in the DFR group developed SCC. Of 22 esophageal carcinomas for the DER group, nine were SCC, 12 ADC and one was adenosquamous carcinoma. The fraction of esophageal SCC for the DFR group was significantly higher than that for the DER group, while the fraction of esophageal ADC for the DFR group was significantly lower than that for the DER group. These observations suggest that the severity of duodeno‐esophageal reflux in rodents is related to the development of different histological types of esophageal carcinoma.

Impact of Inflammation-Metaplasia- Adenocarcinoma Sequence and Prevention in Surgical Rat Models

The incidence of esophageal cancer continues to rise in the Western world. Prior studies have suggested that gastroduodenal content reflux from gastroesophageal reflux disease induces the inflammation-mediated progression from hyperplasia to metaplasia, and to adenocarcinoma. We further investigated the sequential development of esophageal adenocarcinoma (EADC) with the use of an established surgical rat model. The present paper will describe the impact of the inflammation-metaplasia-adenocarcinoma sequence and chemoprevention in surgical rat models. A clinically relevant rat reflux model was used to investigate the cause of carcinogenesis, the sequential development of adenocarcinoma and chemoprevention with the use of a proton pump inhibitor. We found that duodenal reflux plays an important role in the inflammation-induced transformation of esophageal mucosa to adenocarcinoma. We were able to inhibit this transformation with rabeprazole, a proton pump inhibitor. Duodenal reflux promotes inflammation in the esophagus. The inflammation-metaplasia-adenocarcinoma sequence is important in the progression and development of EADC. Carcinogenesis can be prevented with chemoprevention agents such as rabeprazole. These results will need to be validated in clinical trials.

Do proton pump inhibitors protect against cancer progression in GERD

Gastro-duodenal content reflux from gastro-esophageal reflux disease (GERD) induces the inflammation–metaplasia–dysplasia–adenocarcinoma sequence. Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, which are widely used for treating GERD and peptic ulcer-associated acid-secreting diseases. The effect of PPI therapy on esophageal carcinogenesis remains unclear. While some studies suggest PPIs result in a significant reduction in the risk of developing dysplasia and adenocarcinoma in patients with Barrett’s esophagus, others suggest that PPIs have no effect. Recent studies have revealed that PPIs can exert anti-inflammatory effects such as anti-oxidant properties and immunomodulatory effects through their interactions with neutrophils, monocytes, endothelial and epithelial cells. In addition, PPIs have the ability to prevent adhesion molecule binding in malignant cells and suppress metastasis. This article reviews the role of PPIs in esophageal carcinogenesis and their use as antitumor agents.

Impact of histone deacetylase 1 and metastasis‑associated gene 1 expression in esophageal carcinogenesis

Animal models are important for the development of novel therapies for esophageal cancer. Histone deacetylase 1 (HDAC1)/metastasis-associated gene (MTA1) complexes inhibit p53 acetylation and thus, inhibit p53-induced apoptosis. The aim of the present study was to evaluate HDAC1 and MTA1 expression in esophageal carcinogenesis in rats. The rats underwent a total gastrectomy followed by esophagojejunostomy to induce chronic duodenal content reflux esophagitis. The rats were sacrificed sequentially at 20, 30, 40 and 50 weeks post-surgery and the esophagi were examined. Immunohistochemical analysis was conducted to assess the expression and localization of HDAC1 and MTA1. At 20 weeks post-surgery, squamous proliferative hyperplasia and Barrett’s metaplasia (BM) were observed. While, adenocarcinoma-associated BM and squamous cell carcinoma were observed at 30–50 weeks post-surgery. The nuclear expression of HDAC1 and MTA1 was observed in all of the stages of squamous carcinogenesis and adenocarcinogenesis, although not in the normal esophageal epithelium. The expression of HDAC1 and MTA1 may be involved in duodenoesophageal reflux-induced neoplastic transformation of the esophageal mucosa into cancer cells with squamous and adeno differentiation.

Tu1756 The Inflammatory Microenvironment in Duodeno-Esophageal Reflux Induced Esophageal Carcinogenesis in a Sequential Rat Model

Introduction: Previous studies have established that surgical trauma is associated with significant transient alterations in cell-mediated immune function. Surgery-related immunosuppression may impact the patients ability to deal with infection. Also, tumor growth has been shown in murine studies to be increased after surgical trauma. Cell-mediated immunosuppression after resection of a primary tumor may impair the hosts ability to eradicate or contain residual tumors cells. This microarray study of perioperative T-lymphocyte (TLC) gene expression was undertaken in an effort to better understand the impact of colorectal resection (CR) on cell-mediated immune function. Method: Patients who underwent elective laparoscopic right hemicolectomy (RHC) for benign colonic disease (BCD) who had enrolled in an IRB approved blood/data bank for whom frozen preand postoperative TLCs were available were eligible for this study. Benign pathology patients were chosen in order to determine the impact of surgical trauma alone, independent of the potential effects of a cancer on immune function. Preoperative (PreOp) and postoperative day1 (POD1) blood samples were utilized. TLCs were isolated from the blood using a combination of gradient centrifugation and magnetic micro-bead separation. TLCs were subsequently lysed and total RNA extracted. cRNA was made from RNA hybridized to HG-U133APLUS oligonucleotide array. PreOp vs POD1 expression data was analyzed via Limma paired analysis to find differently expressed genes. (p.0.05 significant) and consistency of significance was analyzed via Empirical Bayes statistics (B>0 Sig.). Clinical data is presented as mean ± SD. Results: Nineteen patients (12 males/7 female, mean age 65.8± 12.8 years) met the entry criteria. The mean incision length was 7.8± 3.5cm and mean length of stay was 6.3±2.6 days. All TLC expression data met the affymetrix data QC standards. A total of 39 genes showed significant changes on POD1; 21were up-regulated and 18 were down regulated (B=0.055.3). The expression changes of 7 genes in this group were strongly significant (ABCG-1, TMEM49, FAM100B and PIM1 were upregulated and IFI44L, STAT1 and UCP2 were down regulated; P =0.02 and B =4.1-5.3). Enrichment analysis confirmed that these gene changes were likely to have significant effects on 7 signaling pathways and 3 functional categories i.e.; cell proliferation, hematological function and immune response. Conclusion: Surgical trauma affected gene expression of circulating TLCs in the immediate postoperative period. Altered gene expression may impact TLC growth and proliferation as well as immune function. These changes must be validated at the protein level and additional patients studied. Also, the duration of these changes, after surgery, must be determined. Finally, a similar study in cancer patients is also needed.

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M1590 Rabeprazole Impedes the Development of Reflux Induced Esophageal Cancer in a Surgical Rat Model

Background The role of proton pump inhibitors in Barrett’s metaplasia and esophageal adenocarcinoma has been an area of controversy.