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S J Spechler

Publications and source records attributed to S J Spechler.

At least 19 recordsLinked to original sources
PubMed2004

Review article: screening and surveillance of Barrett's oesophagus: what is a cost-effective framework?

There is a strong association between symptomatic gastro-oesophageal reflux and oesophageal adenocarcinoma. With this in mind, the American College of Gastroenterology has recently revised its practice guidelines for the screening of patients with chronic gastro-oesophageal reflux disease (GERD) to identify those at risk of oesophageal adenocarcinoma, and recommends surveillance to identify curable oesophageal neoplasms in patients with established Barrett's oesophagus. Patients with chronic GERD symptoms, particularly those aged over 50 years, should undergo upper endoscopy. Patients found to have Barrett's oesophagus should be treated with acid suppression for GERD symptoms and then undergo regular surveillance endoscopy. Surveillance endoscopy every 3 years is recommended for those without dysplasia. For patients with verified low-grade dysplasia, yearly surveillance endoscopy is recommended. For those with focal high-grade dysplasia (defined as high-grade dysplastic changes involving fewer than five crypts), the condition may be followed with endoscopic surveillance performed at 3-month intervals. If there is verified, multifocal high-grade dysplasia, intervention (e.g. oesophagectomy) may be considered. Both observational and computer models suggest a benefit associated with screening and surveillance. Endoscopic screening and surveillance for Barrett's oesophagus compares favourably with mammography for the detection of breast cancer and other accepted medical practices.

Adenocarcinoma↗
PubMed2004

Review article: what I do now to manage adenocarcinoma risk, and what I may be doing in 10 years' time.

This article summarizes the present recommendations for the screening, surveillance and treatment of Barrett's oesophagus, and identifies those areas in which change seems likely within the next decade. As a result of economic constraints and emerging data on ethnic variations in the frequency of Barrett's oesophagus, future screening programmes will probably focus on those individuals most likely to develop Barrett's adenocarcinomas: older white men whose gastro-oesophageal reflux symptoms are of long duration. The present surveillance strategy for patients with Barrett's oesophagus relies heavily on random biopsy sampling of the oesophagus to find dysplasia. In the future, biomarkers other than dysplasia may be used to identify patients at high risk for carcinogenesis, and physicians may use endoscopic techniques, such as fluorescence spectroscopy, to identify areas of dysplasia for biopsy sampling. Indirect evidence suggests that super-aggressive antisecretory therapy and treatment with non-steroidal anti-inflammatory drugs may reduce the risk of cancer in Barrett's oesophagus. Well-designed prospective studies will be needed to determine whether these treatments have sufficient efficacy in cancer prophylaxis to justify the large numbers needed to treat. Finally, recent data are reviewed, which suggest that the gastro-oesophageal junction is exposed repeatedly to concentrated acid and to potentially genotoxic concentrations of nitric oxide generated from dietary nitrate. Future studies on carcinogenesis in Barrett's oesophagus may well focus on the combined roles of nitric oxide and gastric acid.

Adenocarcinoma↗
PubMed2003

Characterisation of telomerase immortalised normal human oesophageal squamous cells.

BACKGROUND AND AIMS: Oesophageal cell lines derived from malignancies have numerous genetic abnormalities and therefore are of limited value for studying the early events in carcinogenesis. Reported attempts to establish normal human oesophageal cell lines either have failed to achieve immortalisation or have achieved it by disrupting important cell functions. We have used telomerase technology to establish normal human oesophageal cell lines. METHODS: Endoscopic biopsy specimens of normal oesophageal squamous epithelium were trypsinised, dispersed into single cell suspensions, and cocultivated with ATCC Swiss 3T3 cells. Oesophageal cells were infected with the catalytic subunit of human telomerase (hTERT) using a defective retroviral vector. The integrity of cell cycle checkpoints was tested by measuring p53 response to UV irradiation, and p16 response to infection with H-RasGV12. Expression of a differentiation marker was tested by measuring involucrin response to calcium exposure. RESULTS: Cultures of uninfected oesophageal cells had weak telomerase activity at baseline but exhibited loss of telomerase activity and progressive telomere shortening before undergoing senescence between population doublings (PD) 40-45. In contrast, hTERT infected cells exhibited sustained telomerase activity and stabilisation of telomere length. These cells have reached PD 100 with no diminution in growth rate, while cell cycle checkpoint integrity and involucrin response to calcium exposure have remained intact. CONCLUSIONS: By introducing telomerase into normal human oesophageal squamous cells cocultivated with feeder layers, we have established a cell line that retains normal cell cycle checkpoints and normal differentiation markers. This cell line may be useful for studying the early events in oesophageal carcinogenesis.

3T3 Cells↗
PubMed2002

Racial differences in the frequency of symptoms and complications of gastro-oesophageal reflux disease.

BACKGROUND: A number of reports have suggested that there are substantial racial differences in the frequency of gastro-oesophageal reflux disease and its complications, but few studies have compared directly the frequency of this disorder amongst different racial groups. AIM: To explore the racial differences in the frequency of gastro-oesophageal reflux disease and its complications. METHODS: We reviewed endoscopy reports and medical records for data on race and complications of gastro-oesophageal reflux disease in 2,477 consecutive patients who had endoscopic examinations at the general endoscopy unit of an academic hospital. In addition, we prospectively interviewed 129 out-patients attending general medical clinics in the hospital and in an Asian community health centre in Boston to obtain data on race and gastro-oesophageal reflux disease symptoms. RESULTS: One or more gastro-oesophageal reflux disease complications (peptic oesophageal ulcer, stricture or Barrett's oesophagus) were observed in 267 of 2,174 white patients (12.3%), seven of 249 black patients (2.8%), one of 21 West Asian patients (4.8%) and none of 33 East Asian patients seen at the general endoscopy unit (P < 0.001); 34.6% of whites, 46.1% of blacks and 2.6% of East Asian patients interviewed claimed that they had heartburn (P < 0.01), but the term 'heartburn' was understood by only 34.6%, 53.8% and 13.2% of whites, blacks and East Asians, respectively (P < 0.01). CONCLUSIONS: Asian patients in Boston infrequently complain of heartburn, whereas heartburn is commonly reported by both white and black patients. Many patients do not understand the meaning of the term heartburn, however, and so physicians should be cautious when using the term during patient interviews. Complicated gastro-oesophageal reflux disease appears to be predominantly a disorder of whites.

Adult↗
PubMed2001

Screening and surveillance for complications related to gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) and columnar-lined esophagus with intestinal metaplasia (Barrett's esophagus) are the major recognized risk factors for adenocarcinoma of the esophagus. The American College of Gastroenterology recommends that patients with long-standing GERD symptoms (particularly those 50 years of age or older) undergo endoscopic screening to identify Barrett's esophagus and that those patients who have Barrett's esophagus undergo regular endoscopic surveillance. These recommendations are made with the expectation that screening and surveillance will decrease mortality from esophageal cancer, although this association is unclear. Nonetheless, retrospective studies have shown that endoscopic surveillance can detect some early, curable neoplasms in patients with Barrett's esophagus. Dysplasia in Barrett's esophagus is widely regarded as the precursor of invasive malignancy. Although grading dysplastic changes is largely subjective, dysplasia remains the most appropriate biomarker for clinical evaluation of Barrett's esophagus. Flow-cytometric and p53 abnormalities may be earlier and more specific markers for cancer development, but application of these abnormalities is not yet recommended for clinical practice. Endoscopic surveillance also is adversely affected by biopsy sampling error. Techniques that may minimize biopsy sampling error include chromoendoscopy, endosonography, optical coherence tomography, and fluorescence detection techniques. Further studies are needed to clearly define the role of these techniques in surveillance, and none is practical for routine clinical use at this time. Although not specifically recommended, experimental ablative therapies, such as photodynamic therapy, can be considered by physicians for their patients with high-grade dysplasia in Barrett's esophagus, if they are provided as part of an established, approved research protocol.

Adenocarcinoma↗
PubMed2001

Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial.

CONTEXT: Severe gastroesophageal reflux disease (GERD) is a lifelong problem that can be complicated by peptic esophageal stricture and adenocarcinoma of the esophagus. OBJECTIVE: To determine the long-term outcome of medical and surgical therapies for GERD. DESIGN AND SETTING: Follow-up study conducted from October 1997 through October 1999 of a prospective randomized trial of medical and surgical antireflux treatments in patients with complicated GERD. Mean (median) duration of follow-up was 10.6 years (7.3 years) for medical patients and 9.1 years (6.3 years) for surgical patients. PARTICIPANTS: Two hundred thirty-nine (97%) of the original 247 study patients were found (79 were confirmed dead). Among the 160 survivors (157 men and 3 women; mean [SD] age, 67 [12] years), 129 (91 in the medical treatment group and 38 in the surgical treatment group) participated in the follow-up. MAIN OUTCOME MEASURES: Use of antireflux medication, Gastroesophageal Reflux Disease Activity Index (GRACI) scores, grade of esophagitis, frequency of treatment of esophageal stricture, frequency of subsequent antireflux operations, 36-item Short Form health survey (SF-36) scores, satisfaction with antireflux therapy, survival, and incidence of esophageal adenocarcinoma, compared between the medical antireflux therapy group and the fundoplication surgery group. Information on cause of death was obtained from autopsy results, hospital records, and death certificates. RESULTS: Eighty-three (92%) of 90 medical patients and 23 (62%) of 37 surgical patients reported that they used antireflux medications regularly (P<.001). During a 1-week period after discontinuation of medication, mean (SD) GRACI symptom scores were significantly lower in the surgical treatment group (82.6 [17.5] vs 96.7 [21.4] in the medical treatment group; P =.003). However, no significant differences between the groups were found in grade of esophagitis, frequency of treatment of esophageal stricture and subsequent antireflux operations, SF-36 standardized physical and mental component scale scores, and overall satisfaction with antireflux therapy. Survival during a period of 140 months was decreased significantly in the surgical vs the medical treatment group (relative risk of death in the medical group, 1.57; 95% confidence interval, 1.01-2.46; P =.047), largely because of excess deaths from heart disease. Patients with Barrett esophagus at baseline developed esophageal adenocarcinomas at an annual rate of 0.4%, whereas these cancers developed in patients without Barrett esophagus at an annual rate of only 0.07%. There was no significant difference between groups in incidence of esophageal cancer. CONCLUSION: This study suggests that antireflux surgery should not be advised with the expectation that patients with GERD will no longer need to take antisecretory medications or that the procedure will prevent esophageal cancer among those with GERD and Barrett esophagus.

Adenocarcinoma↗
PubMed2001

Review article: a conceptual approach to understanding the molecular mechanisms of cancer development in Barrett's oesophagus.

Oesophageal adenocarcinoma is one of the most deadly human malignancies. Gastro-oesophageal reflux disease (GERD) has been established as a strong risk factor for oesophageal adenocarcinoma, and more than 40% of adult Americans experience regular GERD symptoms. GERD can be complicated by oesophagitis, and by replacement of oesophageal squamous mucosa with metaplastic, intestinal-type epithelium (Barrett's oesophagus) that is predisposed to malignancy. Cancers in Barrett's oesophagus arise through a sequence of genetic alterations which endow unlimited proliferative capacity upon the cells by affecting components of the cell cycle clock apparatus-the pivotal molecular machinery in the cell nucleus that controls whether a cell will proliferate, differentiate, become quiescent or die. This report describes how the genetic abnormalities that have been recognized in Barrett's oesophagus might promote carcinogenesis through effects on the cell cycle clock machinery. The goal of this review is to provide the clinician with a useful conceptual basis for evaluating studies on the molecular mechanisms underlying the progression from metaplasia to carcinoma in Barrett's oesophagus.

Adenocarcinoma↗
PubMed2001

Phenotype of Barrett's esophagus and intestinal metaplasia of the distal esophagus and gastroesophageal junction: an immunohistochemical study of cytokeratins 7 and 20, Das-1 and 45 MI.

The pathogenesis of short segment Barrett's esophagus (SSBE) and intestinal metaplasia (IM) of the gastroesophageal junction (IMGEJ) are poorly understood. Also, these conditions are difficult to distinguish from one another based solely on endoscopic and pathologic criteria. Therefore, the aim of this study was to evaluate the immunophenotypic features of SSBE and IMGEJ and to compare the results with lesions of known etiologies: long segment BE (LSBE) caused by reflux disease and Helicobacter pylori-induced IM of the gastric antrum (IMGA). Routinely processed mucosal biopsy specimens from 11 patients with LSBE, 17 with SSBE, 10 with IMGEJ, 16 with IMGA, 17 with a normal nonmetaplastic GEJ, and 7 patients with a normal gastric antrum were immunohistochemically stained with monoclonal antibodies to: Das1, an antibody shown to react specifically with colonic goblet cells; 45M1, an antibody that recognizes the M1 gastric mucin antigen; and cytokeratin (CK) 7 and 20, antibodies that have previously been reported to show specific staining patterns in BE versus IMGA. Also evaluated was nonintestinalized mucinous epithelium from LSBE, SSBE, and also the normal GEJ and gastric antrum. LSBE, SSBE, and IMGEJ showed similar prevalences of Das1 (91% versus 88% versus 100%) and 45M1 reactivity (100% versus 100% versus 100%), and a similar pattern of CK7/20 reactivity (diffuse strong CK7 staining of the surface and crypt epithelium, and strong surface and superficial crypt CK20 staining) (91% versus 94% versus 90%). In contrast, although 45M1 reactivity in IMGA (93%) was similar to that of the other three groups, IMGA showed a significantly lower prevalence of Das positivity (13%, p < 0.001), and only a 14% prevalence of the CK7/20 staining pattern that was predominant in the other three groups (p < 0.001). Das1, 45M1, and CK7/20 staining were similar in nonintestinalized "cardia-type" mucinous epithelium from LSBE, SSBE, and the GEJ, but all were distinct from the normal gastric antrum. In summary, the immunophenotypic features of SSBE and IMGEJ are similar and closely resemble those seen in classic LSBE, but are distinct from IMGA. This may indicate that IM in LSBE, SSBE and at the GEJ have similar biologic properties. Based on our data, SSBE and IMGEJ cannot be distinguished on the basis of their immunophenotype.

Antibodies↗
PubMed2001

Classification of oesophageal motility abnormalities.

Manometric examination of the oesophagus frequently reveals abnormalities whose cause is unknown and whose physiological importance is not clear. A large body of literature dealing with oesophageal motility abnormalities has evolved over the past few decades but comparisons among studies have been compromised by the lack of a widely accepted system for classifying the abnormal motility patterns, and by the lack of uniform diagnostic criteria for the putative disorders. Based on an extensive review and analysis of the literature, this report suggests an operational scheme to be used for the general classification of oesophageal motility abnormalities, and proposes standardised manometric criteria for the putative oesophageal motility disorders. By applying the guidelines proposed in this report, clinicians and researchers can determine if their patients fulfil the manometric criteria for a putative motility disorder. This should facilitate and improve comparisons among patients and studies. However, it is important to emphasise that fulfilment of the proposed criteria does not establish the clinical importance of the motility abnormalities.

Adult↗
PubMed2000

Selective inhibition of cyclooxygenase-2 suppresses growth and induces apoptosis in human esophageal adenocarcinoma cells.

Adenocarcinoma in Barrett's esophagus has been increasing in incidence at a rapid rate for more than two decades. Cyclooxygenase (COX)-2 appears to play an important role in gastrointestinal carcinogenesis, and COX-2 overexpression has been demonstrated both in esophageal adenocarcinomas and in the metaplastic epithelium of Barrett's esophagus. The aim of our study was to determine whether selective inhibition of COX-2 by NS-398 would alter the rates of cell growth and apoptosis in human Barrett's-associated esophageal adenocarcinoma cell lines. COX-1 and COX-2 expression in adenocarcinoma cell lines was determined using reverse transcription-PCR and Western blotting for mRNA and protein, respectively. Esophageal adenocarcinoma cell lines were treated with various concentrations of NS-398 (selective for COX-2 inhibition) and flurbiprofen (selective for COX-1 inhibition). Cell growth was compared in flurbiprofen-treated and untreated tumor cell lines; cell growth and apoptosis were compared in NS-398-treated and untreated tumor cell lines. COX-2 mRNA and protein were detected in two of three cell lines (SEG-1 and FLO); the third cell line, BIC-1, did not express COX-2 mRNA or protein under basal conditions or after stimulation with phorbol 12-myristate 13-acetate. Treatment with COX-1-selective concentrations of flurbiprofen did not affect cell growth in any of the three tumor cell lines. In contrast, treatment with COX-2-selective concentrations of NS-398 significantly suppressed cell growth and increased apoptosis in the cell lines that expressed COX-2 (SEG-1 and FLO), but not in the cell line that did not express COX-2 (BIC-1). We conclude that the administration of a selective inhibitor of COX-2 significantly decreases cell growth and increases apoptosis in Barrett's-associated adenocarcinoma tumor cells that express COX-2. These observations suggest a potential role for selective COX-2 inhibitors in the prevention and treatment of esophageal adenocarcinoma for patients with Barrett's esophagus.

Adenocarcinoma↗
PubMed2000

The effects of tegaserod (HTF 919) on oesophageal acid exposure in gastro-oesophageal reflux disease.

BACKGROUND: Tegaserod (HTF 919), a 5-HT4 receptor partial agonist, has prokinetic effects that might be useful in decreasing acid reflux in gastro-oesophageal reflux disease (GERD). METHODS: To investigate the potential clinical utility of tegaserod in GERD, a five-period crossover study (balanced Latin square) was designed to evaluate the efficacy of 4 b.d. doses of tegaserod vs. placebo. Four-hour manometry (1 h fasting and 3 h postprandial) with continuous recording of lower oesophageal sphincter pressure and distal oesophageal pH, was performed at the end of each 2-week treatment period in 19 patients with mild-to-moderate GERD. Recordings were scored for mean lower oesophageal sphincter pressure, number of transient lower oesophageal sphincter relaxations, and distal oesophageal acid exposure. RESULTS: Tegaserod (1 mg/day and 4 mg/day) caused a more than 50% decrease in acid exposure in the postprandial period in patients with abnormal acid exposure, although only the 1 mg/day tegaserod treatment elicited statistically significant decreasing (P < 0.05) for the entire treatment group (percentage time for which pH < 4: placebo=13%; 1 mg/day dose=5%; 4 mg/day dose=8%). A decreased number of reflux episodes was demonstrated with both the 1 mg/day and 4 mg/day tegaserod doses. There was no apparent effect on mean lower oesophageal sphincter pressure, whilst transient lower oesophageal sphincter relaxations frequency decreased in the 1-2.5 h post-dose. CONCLUSIONS: Tegaserod in a dose of 1 mg/day causes a significant decrease in postprandial oesophageal acid exposure. The reduction in oesophageal acid exposure with tegaserod treatment may result from enhanced oesophageal acid clearance, improved gastric emptying, and/or reduced transient lower oesophageal sphincter relaxations.

Adult↗
PubMed2000

Barrett's oesophagus: diagnosis and management.

Gastro-oesophageal reflux disease and its sequela, Barrett's oesophagus, are the major recognized risk factors for oesophageal adenocarcinoma, a tumour whose frequency has increased dramatically in Western countries over the past few decades. Barrett's oesophagus develops through the process of metaplasia in which one adult cell type replaces another. The metaplastic, intestinal-type cells of Barrett's oesophagus are predisposed to develop genetic changes that eventuate in cancer. This report reviews the recent controversy regarding diagnostic criteria for Barrett's oesophagus, and provides practical guidelines for identifying the condition. The risks and benefits of the proposed medical, surgical and endoscopic therapies for Barrett's oesophagus are discussed in detail, and the approach to management recently endorsed by the American College of Gastroenterology is summarized.

Adult↗
PubMed2000

GERD and its complications.

Gastroesophageal reflux disease (GERD) is the condition that results when gastric material that refluxes into the esophagus or oropharynx causes symptoms, tissue injury, or both. Endoscopic examination usually is not required merely to establish a diagnosis of GERD, but endoscopy is the best diagnostic test for Barrett's esophagus, a sequela of GERD that predisposes to esophageal adenocarcinoma. Patients found to have Barrett's esophagus will require regular endoscopic surveillance for early, curable neoplasia. Esophageal pH monitoring is useful for patients who have symptoms or signs suggestive of GERD, but who have little or no response to antisecretory therapy. For patients who have severe, ulcerative reflux esophagitis, the clinician has only two reasonable therapeutic options: (1) lifelong antisecretory therapy with proton pump inhibitors or (2) antireflux surgery. There are no absolute indications for antireflux surgery, but the operation can be considered for patients with severe GERD who are unwilling to accept lifelong medical therapy or for young patients whose GERD symptoms respond only to proton pump inhibitors administered in high dosages.

Esophagoscopy↗