Martin Fein

Duodenoesophageal reflux induces esophageal adenocarcinoma without exogenous carcinogen

In the rat model, esophageal adenocarcinoma reproducibly develops following surgically induced duodenal reflux into the esophagus and administration of nitrosamine. In addition, decreasing gastric acid via partial or total gastrectomy increases the prevalence of adenocarcinoma in this model. We questioned whether carcinogen was necessary for cancer development in the gastrectomized model and whether esophageal acidification could reverse the effect of gastrectomy. Three groups of 26 rats each were randomized to a surgical procedure to produce one of the following reflux models: gastroduodenal reflux by esophagojejunostomy, duodenal reflux by total gastrectomy and esophagojejunostomy, or no reflux by Roux-en-Y reconstruction. In a second experiment, 42 rats were operated on to induce duodenal reflux. One week following surgery, they were randomized to receive acidified water (pH 1.8) or tap water. The animals were killed at 24 weeks of age, and the esophagus was evaluated histologically. All animals with reflux had severe esophagitis and 87% developed columnar lining of the distal esophagus. Nearly half (48%) developed adenocarcinoma at the anastomotic site 16 weeks postoperatively and without carcinogen administration. Cancer prevalence did not differ between animals with gastroduodenal or duodenal reflux but tended to be lower in animals receiving acidified water. Duodenoesophageal reflux is carcinogenic in the rat model. Exogenous carcinogen is not necessary for cancer development in gastrectomized rats.

Long-term benefits of Roux-en-Y pouch reconstruction after total gastrectomy: a randomized trial.

Objective:Roux-en-Y reconstruction with and without jejunal pouch was compared in a randomized controlled trial to identify the optimal reconstruction procedure in terms of quality of life. Background Data:Randomized trials comparing techniques of reconstruction after total gastrectomy have shown controversial results. Methods:One hundred and thirty-eight patients with gastric cancer were intraoperatively randomized for Roux-en-Y reconstruction with pouch (n = 71) or without pouch (n = 67) after gastrectomy and stratified into curative or palliative resection. Intra- and postoperative complications were recorded. Body weight and quality of life were determined every 6 months with a follow-up of up to 12 years. Results:Both groups were comparable for age, sex, incidence of concomitant disease, and staging. There were no differences in operative time, postoperative complications, and mortality. Short- and long-term weight loss was similar in both groups. In the first postoperative year, there were no benefits of pouch reconstruction in terms of quality of life, independent of the resection status. In the third, fourth, and fifth year after surgery quality of life was significantly improved for patients with a pouch. Conclusions:Roux-en-Y pouch reconstruction after gastrectomy is simple to perform and safe. Long-term survivors benefit from pouch reconstruction. Therefore, a pouch is recommended for patients with a good prognosis.

Role of the lower esophageal sphincter and hiatal hernia in the pathogenesis of gastroesophageal reflux disease

The relative importance of the lower esophageal sphincter (LES) and hiatal hernia in the pathogenesis of gastroesophageal reflux disease is controversial. To identify the role of hiatal hernia and LES in reflux disease, 375 consecutive patients with foregut symptoms and no previous foregut surgery were evaluated. All patients underwent upper endoscopy, stationary manometry, and 24-hour esophageal pH monitoring. Hiatal hernia was diagnosed endoscopically, when the distance between the crural impression and the gastroesophageal junction was ≥2 cm. The LES was considered structurally defective when the resting pressure was ≤6 mm Hg, the overall length was less than 2 cm, and/or the abdominal length was less than 1 cm. Factors predicting abnormal esophageal acid exposure (composite score >14.7) were analyzed using multivariate analysis. The presence of a hiatal hernia and a defective LES were identified as independent predictors of abnormal esophageal acid exposure. LES pressure and abdominal length were reduced in patients with hiatal hernia by 4 mm Hg and 0.4 cm, irrespective of the presence of gastroesophageal reflux disease. It is concluded that both a structurally defective LES and hiatal hernia are important factors in the pathogenesis of reflux disease. It is hypothesized that in the presence of a structurally normal LES, the altered geometry of the cardia imposed by a hiatal hernia facilitates the ability of gastric wall tension to pull open the sphincter.

The mutagenic potential of duodenoesophageal reflux.

Summary Background Data:Duodenogastric–esophageal reflux disease is directly linked to Barretts esophagus and to the development of esophageal adenocarcinoma. Despite this link, little is known about the mutagenic potential of refluxed material on the esophageal mucosa. We hypothesize that the reflux of gastric and duodenal content causes mutations in esophageal mucosa in vivo. Methods:Seven Sprague Dawley/Big Blue F1 lacI transgenic rats underwent esophagoduodenostomy (ED) to surgically create duodeno–gastric–esophageal reflux. Fourteen nonoperated rats served as negative (n = 7) and as positive (n = 7/methyl-N-amyl-nitrosamine [MNAN] intraperitoneally) controls. The animals were killed 16 weeks after operation or injection, the entire esophageal mucosa was harvested, and mutation frequency was determined through standard Big Blue Mutagenesis Assay. Results:Gross esophagitis was evident in all operated animals. The frequency of lacI mutations in esophageal mucosal cells of animals with ED was significantly higher, nearly 1.5-fold, than that of nonoperated animals. Nitrosamine administration resulted in a nearly 20-fold increase of lacI mutation frequency. Thirteen mutations were successfully sequenced, 46% occurred at CpG dinucleotide sites and 61% were either C to T or G to A transitions. Conclusions:The data provide preliminary evidence of the mutagenic potential of bile reflux on esophageal epithelium. The specific mutations are markedly higher than would be expected by chance and are similar to that found in p53 mutations of human esophageal adenocarcinoma, providing a link to human esophageal cancer.

Gastroesophageal reflux disease and mucosal injury with emphasis on short-segment Barrett's esophagus and duodenogastroesophageal reflux.

Gastroeosphageal reflux disease has been associated with long segments of Barrett’s esophagus (≥3 cm), but little is known about its association with shorter segments. The aim of this study was to evaluate anatomic and physiologic alterations of the cardia and esophageal exposure to gastric and duodenal juice in patients with short and long segments of Barrett’s esophagus. Furthermore, these patients were compared to each other and to patients with erosive esophagitis and those with no mucosal injury. Two hundred sixty-two consecutive patients with foregut symptoms were divided into the following four groups based on endoscopic and histologic findings: group 1, no mucosal injury; group 2, erosive esophagitis; group 3, short-segment Barrett’s esophagus; and group 4, long-segment Barrett’s esophagus. Esophageal exposure time to acid and bilirubin, lower esophageal sphincter characteristics, and endoscopie anatomy of the cardia were compared between the groups. Patients with short-segment Barrett’s esophagus had elevated esophageal acid and bilirubin exposure, decreased lower esophageal sphincter pressure and length, and a high incidence of hiatal hernia. These abnormalities were similar to those in patients with esophagitis and in general less profound than those found in patients with long-segment Barrett’s esophagus. The length of intestinal metaplasia was higher in patients with a defective lower esophageal sphincter. Short-segment Barrett’s esophagus is a complication of severe gastroesophageal reflux disease and is associated with the reflux of both gastric and duodenal juice similar to that seen in patients with long-segment Barrett’s esophagus.

The Impact of Reflux Composition on Mucosal Injury and Esophageal Function

The components of refluxed gastric juice are known to cause mucosal injury, but their effect on esophageal function is less appreciated. Our aim was to determine the effect of acid and/or bile on mucosal injury and esophageal function. From 1993–2004, 402 patients with reflux symptoms had 24-hour pH and Bilitec monitoring, manometry, and endoscopy with biopsies. Mucosal injury (esophagitis or Barrett’s esophagus) and esophageal function (lower esophageal sphincter [LES] characteristics and body contractility) in patients with acid reflux, bile reflux, or both were compared with patients without reflux. Reflux was present in 273/402 patients; of these, 37 (13.5%) had increased exposure to bile, 82 (30.0%) had increased exposure to acid, and 154 (56.4%) had increased exposure to both. Mucosal injury was most common with increased mixed acid and bile exposure, followed by acid alone, and was uncommon with bile alone (P<0.0001). Functional deterioration paralleled mucosal injury (P<0.0001). Mixed acid and bile exposure was present in more than half of patients with reflux and was associated with the most severe mucosal injury and the greatest deterioration of esophageal function. This suggests that composition of gastric juice is the primary determinant of inflammatory mucosal injury and subsequent loss of esophageal function.

Disseminated tumor cells in the blood of patients with gastric cancer are an independent predictive marker of poor prognosis.

Objective Gastric cancer carries a poor prognosis even after curative resection (R0). Tumor progression in gastric cancer patients has been attributed to the persistence of disseminated tumor cells (DTC) in various body compartments as a sign of minimal residual disease, although the prognostic relevance of DTC is still unclear. In this study the prognostic relevance of DTC in the blood of gastric cancer patients was investigated. Material and methods Venous blood samples of 70 cancer patients were taken intraoperatively before surgical manipulation and examined by reverse transcription-polymerase chain reaction (RT-PCR) for expression of cytokeratin 20 (CK20) as a marker for DTC. Tumor-related survival was analyzed using univariate and multivariate models assessing occurrence of DTC, residual tumor classification, and tumor stage. Median follow-up was 20 months (range 1–57 months). Results Twenty-eight of the 70 patients (40%) were CK20 positive. The prevalence of DTC in patients following R0 resection (15/41, 37%) was similar to that in patients with residual tumor (13/29, 45%, NS). Furthermore, expression of CK20 was independent of TNM stage. Univariate analysis of R0-resected patients revealed CK20 to be a marker for significantly shorter tumor-related survival (p=0.0363). In a multivariate analysis, CK20 was an independent prognostic marker. Detection of CK20 had greatest impact for early tumor stages (T1 and T2, N0; p<0.0032). Conclusions Detection of DTC in venous blood of gastric cancer patients is an independent predictive marker of poor prognosis and thus could help to define patients for adjuvant therapy with this tumor entity.

The concurrence of histologically positive resection margins and sessile morphology is an important risk factor for lymph node metastasis after complete endoscopic removal of malignant colorectal polyps

IntroductionThe optimal procedure to be followed after colonoscopic polypectomy of malignant colorectal polyps with nontumour-free resection margins at histology is a matter of controversy. While some authors recommend merely local or segmental follow-up resection, others favour an oncological resection.Patients and methodsOne hundred five patients, each with a single malignant polyp, were investigated. Patients with a macroscopically evident malignant polyp and those in whom the endoscopist reported incomplete polypectomy were excluded from the study.ResultsPostpolypectomy morbidity was 4%, and postoperative was 14%. In only 39 cases were the resection margins adjudged to be tumour-free. Histology following subsequent surgery or the follow-up examinations revealed a local recurrence or residual carcinoma at the polypectomy site in only three (2.8%) cases and lymph node metastasis in eight (7.6%) cases. Five patients had remnant adenoma at the polypectomy site. Of the high-risk factors, histological incomplete removal (n = 66, p = 0.04, odds ratio (OR) 10.2) and lymph vessel infiltration (n = 7, p = 0.02, OR 9.2) revealed a significant correlation with lymph node metastasis, but not with remnant tumour. In the case of sessile polyp, the assessment of histological incomplete removal was highly significantly correlated with lymph node metastasis (n = 55, p = 0.007, OR 18.1).ConclusionsPolypectomy artefacts appear to be responsible for the discrepancy between histology and the tumour remnants actually present. On the other hand, histologically incompletely removed sessile malignant polyps represent an appreciably higher risk for lymph node metastasis. Such cases should, therefore, be submitted to further oncological resection.

Is There a Role for Anything Other Than a Nissen’s Operation?

BackgroundThe Nissen fundoplication is the most frequently applied antireflux operation worldwide. The aim of this review was to compare laparoscopic Nissen with partial fundoplication.MethodsNine randomized trials comparing several types of wraps were analyzed, four for the comparison Nissen vs. Toupet and five for the comparison Toupet or Nissen vs. anterior fundoplication. Similar comparisons in nonrandomized studies were also included.ResultsDysphagia rates and reflux recurrence were not related to preoperative esophageal persistalsis independent of the selected procedure. Overall, Nissen fundoplication revealed slightly better reflux control, but was associated with more side effects, such as early dysphagia and gas bloat. Advantages of an anterior approach were only reported by one group. A significantly higher reflux recurrence rate for anterior fundoplication was observed in all other comparisons.ConclusionTailoring antireflux surgery according to esophageal motility is not indicated. At present, the relevant factor for selection of a Nissen or Toupet fundoplication is personal experience. Anterior fundoplication offers less effective long-term reflux control.

Familial gastrointestinal stromal tumors caused by the novel KIT exon 17 germline mutation N822Y.

Gastrointestinal stromal tumors (GISTs) are most often associated with oncogenic mutations of the KIT gene resulting in activation of the tyrosine kinase receptor KIT. Familial GIST syndrome based on a hereditary predisposition to develop GIST owing to a germline mutation is exceedingly rare. We describe a kindred with familial GIST displaying a novel germline mutation in exon 17. Three siblings (2 females, 1 male; 42 to 49 y) underwent surgery for multiple intra-abdominal tumors within a 3-year period. Their father had been operated on for gastric and jejunal tumors 20 years previously. The GIST was confirmed by immunohistochemistry in each sibling. Tumor and blood samples of the family members were analyzed for mutations in KIT and platelet-derived growth factor receptor (PDGFRα) genes. All examined lesions were of spindle cell type with expression of CD117. The tumor material exhibited a novel point mutation in codon 822 in exon 17 resulting in the replacement of asparagine by tyrosine (N822Y). The same mutation was detected in the fathers blood sample. One healthy brother of the 3 siblings showed a wild-type sequence of the KIT gene. The germline mutation in exon 17 of the KIT gene identified in this kindred is very different from previously reported mutations of the KIT gene in familial GIST. Although the penetrance of KIT mutations is as yet unknown, assessment of the unaffected kindred of GIST patients for the presence of this mutation could help to distinguish individuals at high risk from those at virtually no risk.