The histologic diagnosis of Barrett's esophagus requires the presence of goblet cells, but this finding may not be the earliest indicator of intestinal metaplasia. We used immunohistochemistry to detect Cdx2, a transcriptional regulator important in the early differentiation and maintenance of intestinal epithelium, in 134 esophageal biopsy or resection specimens, including 62 with junctional-type epithelium (13 of which had equivocal histologic features of Barrett's epithelium), 34 with Barrett's epithelium without dysplasia, and 38 with Barrett's epithelium and dysplasia or carcinoma (13 low-grade dysplasias, 19 high-grade dysplasias, and 6 adenocarcinomas). We also performed PAS-alcian blue staining (pH 2.5) on adjacent sections. Cdx2 was observed in all cases of Barrett's epithelium. In some dysplasias (chiefly high-grade) and adenocarcinomas, there was diminution or focal loss of detectable protein. Cdx2 was detected in 20 of 62 cases (30%) of junctional-type epithelium, including 10 of 13 (77%) with equivocal histologic features of Barrett's epithelium. Acid mucin was present in goblet cells and non-goblet columnar cells in all cases of Barrett's esophagus and in non-goblet columnar cells in 48 of 62 cases (77%) with junctional-type epithelium only, including 17 of 20 (85%) that were Cdx2 positive and 31 of 42 (74%) that were Cdx2 negative. These results provide evidence that Cdx2 protein is a sensitive marker of intestinal metaplasia in the upper gastrointestinal tract and may be useful in detecting histologically equivocal cases of Barrett's esophagus. Cdx2 is present in dysplasia and adenocarcinoma, with some loss of protein primarily in high-grade dysplasia and adenocarcinoma. Acid mucin in non-goblet columnar cells is a common feature of Barrett's and junctional-type epithelium and may not always be indicative of intestinal metaplasia.

Cdx2 as a Marker of Epithelial Intestinal Differentiation in the Esophagus

Exercise Associated Muscle Cramps (EAMC) is one of the most common conditions that require medical attention during or immediately after sports events. Despite the high prevalence of this condition the aetiology of EAMC in athletes is still not well understood. The purpose of this review is to examine current scientific evidence in support of (1) the “electrolyte depletion” and “dehydration” hypotheses and (2) the “altered neuromuscular control” hypothesis in the aetiology of EAMC. In this review, scientific evidence will, as far as possible, be presented using evidence-based medicine criteria. This is particularly relevant in this field, as the quality of experimental methodology varies considerably among studies that are commonly cited in support of hypotheses to explain the aetiology of EAMC. Scientific evidence in support of the “electrolyte depletion” and “dehydration” hypotheses for the aetiology of EAMC comes mainly from anecdotal clinical observations, case series totalling 18 cases, and one small (n = 10) case–control study. Results from four prospective cohort studies do not support these hypotheses. In addition, the “electrolyte depletion” and “dehydration” hypotheses do not offer plausible pathophysiological mechanisms with supporting scientific evidence that could adequately explain the clinical presentation and management of EAMC. Scientific evidence for the “altered neuromuscular control” hypothesis is based on evidence from research studies in human models of muscle cramping, epidemiological studies in cramping athletes, and animal experimental data. Whilst it is clear that further evidence to support the “altered neuromuscular control” hypothesis is also required, research data are accumulating that support this as the principal pathophysiological mechanism for the aetiology of EAMC.

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Cause of Exercise Associated Muscle Cramps (EAMC) — altered neuromuscular control, dehydration or electrolyte depletion?

BACKGROUND

The rate of incidence of esophageal adenocarcinoma has surpassed that of all other malignancies in the U.S. Esophageal adenocarcinoma arises from Barrett's esophagus through the multistep accumulation of genetic mutations in metaplastic cells, accompanied by histologic changes from metaplasia to low grade and high grade dysplasia and finally to carcinoma. Although telomerase activity has been demonstrated in 85-90% of human cancers, to the authors' knowledge there are no reports regarding esophageal adenocarcinoma. The objective of this study was to determine whether telomerase RNA is increased in esophageal adenocarcinoma and at what point in the histologic progression such an increase occurs.



METHODS

Formalin-fixed, paraffin-embedded esophageal biopsies from patients with Barrett's esophagus and surgical resection specimens of esophageal adenocarcinoma containing varying stages of neoplastic progression were obtained. Adjacent sections from each specimen were evaluated by routine histology and in situ hybridization for the RNA component of human telomerase.



RESULTS

The authors found that 100% of esophageal adenocarcinomas and high grade dysplasias were strongly positive for telomerase RNA. Basal crypt cells of Barrett's metaplasia demonstrated weak to moderate telomerase RNA in 70% of cases, whereas 90% of low grade dysplasias had moderate levels of telomerase RNA.



CONCLUSIONS

The results of this study showed that 1) Barrett's epithelium may contain a population of immortalized cells, 2) a marked increase in the level of telomerase RNA accompanies the transition from low grade to high grade dysplasia, and 3) high levels of telomerase RNA accompany the development of esophageal adenocarcinoma in the vast majority of cases. Cancer 1998;83:652-659. © 1998 American Cancer Society.

In Situ Hybridization for the Detection of Telomerase RNA in the Progression from Barrett's Esophagus to Esophageal Adenocarcinoma

Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE as most people with BE never develop EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histological definitions of BE and early EAC; prevalence, incidence, natural history, and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic, and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability.

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Australian clinical practice guidelines for the diagnosis and management of Barrett's esophagus and early esophageal adenocarcinoma

Lansoprazole is a proton pump inhibitor that reduces gastric acid secretion. It has proved effective in combination regimens for the eradication of Helicobacter pylori and as monotherapy to heal and relieve symptoms of gastric or duodenal ulcers and gastro-oesophageal reflux. After initial healing, it may be used to prevent recurrence of oesophageal erosions or peptic ulcers in patients in whom H. pylori is not the major cause of ulceration and to reduce basal acid output in patients with Zollinger-Ellison syndrome. Usual dosages are 15 to 60 mg/day, although dosages of 90%. Lansoprazole was as effective a component of H. pylori eradication regimens as omeprazole, tripotassium dicitrato bismuthate (colloidal bismuth subcitrate) or ranitidine. Lansoprazole was superior to ranitidine in symptom relief and healing of gastro-oesophageal reflux disease and tended to relieve symptoms more rapidly than omeprazole, although initial healing was similar. As maintenance treatment, lansoprazole was similar to omeprazole and superior to ranitidine in relieving symptoms and preventing relapse. Lansoprazole was also superior to ranitidine in healing and relieving symptoms of oesophageal erosions associated with Barrett's oesophagus; healing was maintained for a mean of 2.9 years in > or = 70% of patients. Lansoprazole was also superior to ranitidine in prophylaxis of redilatation of oesophageal strictures. After > or = 4 years of use in patients with Zollinger-Ellison syndrome, lansoprazole 60 to 180 mg/day effectively controlled basal acid output. Dosages may be reduced in some patients once healing and symptom relief has been achieved. Preliminary studies of lansoprazole in patients at risk of aspiration pneumonia or stress ulcers show promise. Although studies show lansoprazole is potentially effective in treating gastrointestinal bleeding, future studies should assess patients' H. pylori status. Lansoprazole has been well tolerated in clinical trials, with headache, diarrhoea, dizziness and nausea appearing to be the most common adverse effects. Tolerability of lansoprazole does not deteriorate with age and the drug is well tolerated in long term use (< or = 4 years) in patients with Zollinger-Ellison syndrome or reflux disease. Thus, lansoprazole is an important alternative to omeprazole and H2 receptor antagonists in acid-related disorders. In addition to its efficacy in healing or maintenance treatment, it may provide more effective symptom relief than other comparator agents.

Lansoprazole. An update of its pharmacological properties and clinical efficacy in the management of acid-related disorders.

The cause of leg cramps and knee pains: an hypothesis and effective treatment

Background: Barrett's oesophagus is thought to be a complication of severe gastro-oesophageal reflux.



Aim: To determine whether the proton pump inhibitor, lansoprazole, is effective in healing erosive reflux oesophagitis in patients with Barrett's oesophagus.



Methods: An 8-week, randomized, double-blind study was conducted using patients with both erosive reflux oesophagitis and Barrett's oesophagus. Erosive reflux oesophagitis was defined as grades 2–4 oesophagitis; Barrett's oesophagus, as specialized columnar epithelium obtained by biopsy from the tubular oesophagus; and healing, as a return to grade 0 or 1 oesophageal mucosa (complete re-epithelialization). One-hundred and five (105) patients from one centre were randomized to receive either lansoprazole 30 mg daily or ranitidine 150 mg twice daily. Unhealed or symptomatic lansoprazole patients at week 4 were randomized to receive the same 30 mg dose daily or an increased dose of 60 mg daily. Endoscopy was performed at baseline and at weeks 2, 4, 6 and 8.



Results: The treatment groups were similar in regards to baseline characteristics, erosive reflux oesophagitis grades and length of Barrett's oesophagus. At each 2-week interval, lansoprazole patients had significantly greater healing rates and less day and night heartburn and regurgitation than ranitidine patients. There were no significant differences between treatment groups in antacid use, quality of life parameters, or rate of reported adverse events. Median values for fasting serum gastrin levels remained within the normal range for both groups.



Conclusion: In patients with both Barrett's oesophagus and erosive reflux oesophagitis, lansoprazole is significantly more effective than ranitidine in relieving reflux symptoms and healing erosive reflux oesophagitis.

Stephen J. Sontag

Papers

The cause of leg cramps and knee pains: an hypothesis and effective treatment

Lansoprazole heals erosive reflux oesophagitis in patients with Barrett's oesophagus

Barrett's esophagus. A preneoplastic disorder.

CLINICAL-ALIMENTARY TRACT Five-Year Colon Surveillance After Screening Colonoscopy