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Biomedical subjects

G W Falk

Publications and source records attributed to G W Falk.

At least 19 recordsLinked to original sources
PubMed2003

Can extent of high grade dysplasia in Barrett's oesophagus predict the presence of adenocarcinoma at oesophagectomy?

BACKGROUND: Optimal management of Barrett's oesophagus complicated by high grade dysplasia is controversial. Recently, the extent of high grade dysplasia was described as a predictor of subsequent development of cancer in patients undergoing continued surveillance. However, there is no universal agreement on the definition of extent of high grade dysplasia. AIM: To determine if extent of high grade dysplasia in Barrett's oesophagus is a predictor of the presence of adenocarcinoma at the time of oesophagectomy. METHODS: Forty two patients with Barrett's oesophagus and high grade dysplasia who underwent oesophagectomy between 1985 and 1999 were identified from a prospective database. All pathological specimens, including preoperative endoscopic biopsies and post-oesophagectomy sections, were reviewed in a blinded fashion by one expert gastrointestinal pathologist to determine the extent of high grade dysplasia. The extent of high grade dysplasia was defined using two different criteria, one from the Cleveland Clinic and one from the Mayo Clinic. RESULTS: Twenty four of 42 patients (57%) had unsuspected cancer at the time of oesophagectomy. Using the Cleveland Clinic definition, 10 of 21 (48%) patients with focal high grade dysplasia had carcinoma compared with 14 of 21 patients (67%) with diffuse high grade dysplasia (p=0.35). Using the Mayo Clinic definition, adenocarcinoma was found in five of seven (72%) patients with focal high grade dysplasia compared with 19 of 35 (54%) with diffuse high grade dysplasia (p=0.68). CONCLUSIONS: The extent of high grade dysplasia, regardless of how it is defined, does not predict the presence of unsuspected adenocarcinoma at oesophagectomy. There is no evidence as yet that the extent of high grade dysplasia can be used as a basis for decision making in these patients.

Adenocarcinoma↗
PubMed2003

Demographic and phenotypic features of 70 families segregating Barrett's oesophagus and oesophageal adenocarcinoma.

BACKGROUND: Based on reported familial patterns, inheritance of a predisposition of developing Barrett's oesesophagus (BO) and oesophageal adenocarcinoma (OAC) likely follows an autosomal dominant model of most inherited cancer syndromes. oesophagus (BO) and oesophageal adenocarcinoma (OAC) likely follows an autosomal dominant model of most inherited cancer syndromes. AIMS: We analysed the phenotypic features of 70 familial BO/OAC families accrued for the purpose of initiating a linkage study to search for genes that contribute to susceptibility for BO/OAC. METHODS: Families with young or familial BO/OAC were recruited from participating institutions and self-referral from advertisement. RESULTS: A total of 70 families (173 affected and 784 unaffected individuals) were recruited into this study. Mean ages of diagnosis of BO and OAC among males were 50.6 and 57.4 years, respectively; among females, 52.1 and 63.5 years, respectively. The standardised incidence ratio (SIR) of cancers other than OAC or oesophagogastric junctional adenocarcinoma (OGJAC), among probands was 0.71. Seventy one percent of the pedigrees have "typical" structures with less than three affected individuals. Power calculations under realistic model assumptions suggest that if genetic heterogeneity is absent or limited, then DNA collection from members of these pedigrees could enable the identification of a novel candidate susceptibility gene for BO/OAC in a genome scan. CONCLUSIONS: This is the largest series of families with BO/OAC yet reported, features of which are consistent with inherited germline predisposition. Further, the SIR of cancers other than OAC/OGJAC was 0.71 among 70 probands, indicating these individuals were not more likely to develop non-OAC cancers.

Adenocarcinoma↗
PubMed2001

Pathogenesis of gastroesophageal reflux and Barrett esophagus.

Barrett esophagus is a metaplastic condition that affects the lower esophagus and is a complication of gastroesophageal reflux disease (GERD). Under normal circumstances, the reflux of gastric contents into the esophagus is prevented by a complex barrier at the esophagogastric junction. Dysfunction of the lower esophageal sphincter and the presence of a hiatal hernia lead to failure of this barrier. Esophageal mucosal damage results from the chronic exposure of the esophageal mucosa to gastroduodenal contents and the lack of an effective mucosal defense. This article is an overview of the dysfunction of the esophagogastric junction that leads to GERD. The role of the contents of the reflux and that of Helicobacter pylori infection in the pathogenesis of Barrett esophagus are also summarized.

Animals↗
PubMed2001

Gastroesophageal reflux disease and Barrett's esophagus.

Gastroesophageal reflux disease (GERD) is a common clinical problem. Circumstantial evidence continues to suggest that infection with Helicobacter pylori may protect some patients from developing GERD and its complications. An empirical trial of a proton-pump inhibitor may now be a reasonable alternative to endoscopy or 24-hour pH testing for the diagnosis of GERD. Long-term follow-up data covering more than over a decade indicate that proton-pump inhibitors are effective and safe agents for the treatment of GERD. Furthermore, a strategy of proton-pump inhibitors first may be the most cost-effective approach to GERD. It remains unclear why some patients with GERD develop Barrett's esophagus, whereas others do not. Recent studies demonstrate the importance of pulses of acid or bile in increasing cell proliferation and cyclooxygenase-2 expression in Barrett's epithelium cell cultures. Short-segment Barrett's esophagus is now clearly associated with an increased risk of dysplasia or cancer compared to intestinal metaplasia of the cardia, and the cancer risk in this condition is similar to that with long-segment Barrett's esophagus. However, the overall cancer risk in patients with Barrett's esophagus is lower than previously estimated, at approximately 0.5% annually. Ablation techniques continue to show promise, but are not yet ready for routine clinical use. Endoscopic mucosal resection is a new treatment option for selected patients with high-grade dysplasia or superficial esophageal adenocarcinoma.

Adenocarcinoma↗
PubMed2001

Superficial adenocarcinoma of the esophagus.

OBJECTIVE: Experience with treatment and outcome of superficial adenocarcinoma of the esophagus is limited. The purpose of this study was to evaluate the results of surgical management and identify predictors of survival. METHODS: Between September 1985 and December 1999, 122 patients underwent resection. Eighty-nine percent were men (mean age 63 +/- 10 years; range 35-83 years). Sixty (49%) patients were in endoscopic surveillance programs and 48 (39%) had the preoperative diagnosis of high-grade dysplasia. Forced expiratory volume in 1 second was less than 2 L in 12 (12%). Seventy-five (61%) patients underwent transhiatal esophagectomy. Pathologic stage was N1 in 8 (7%). Pulmonary complications necessitating reintubation (respiratory failure) occurred in 10 (8%) patients. Time-related survival models were developed for decision-making (preoperative), prognosis (operative), and hospital care (postoperative). RESULTS: Operative mortality was 2.5%. Survival at 1, 5, and 10 years was 89%, 77%, and 68%. Preoperative decision-making factors associated with ideal outcome were 1-second forced expiratory volume of more than 2 L, surveillance, preoperative diagnosis of high-grade dysplasia, and planned transhiatal esophagectomy. Prognosis was decreased in younger patients and in those with N1 disease. Postoperative respiratory failure increased mortality. CONCLUSIONS: Surgery is the treatment of choice for superficial adenocarcinoma of the esophagus. The ideal patient has a preoperative diagnosis of high-grade dysplasia found at surveillance, good pulmonary function, and undergoes a transhiatal esophagectomy. Discovery of N1 disease or development of postoperative respiratory failure reduces the benefits of surgery.

Adenocarcinoma↗
PubMed2001

GERD and H. pylori: is there a link?

The incidence of gastroesophageal reflux disease (GERD) and esophageal adenocarcinoma have increased in recent years as the incidence of peptic ulcer disease and distal gastric cancer have declined. Given the simultaneous decline in Helicobacter pylori infection, it is tempting to propose a relationship between H. pylori infection and these opposing time trends. Although H. pylori infection clearly does not cause GERD, it may protect certain susceptible individuals from developing GERD and its complications. The most likely mechanism in which H. pylori infection protects against GERD is by decreasing the potency of the gastric refluxate in patients with corpus predominant gastritis. A variety of implications of H. pylori infection on GERD treatment have also arisen in recent years. These focus on the risk of gastric atrophy while on proton pump inhibitor therapy and the efficacy of proton pump inhibitors before and after eradication of H. pylori. This article puts into perspective our current understanding of the complex, incompletely understood relationship between H. pylori infection and GERD.

Anti-Ulcer Agents↗
PubMed2001

The possible role of Helicobacter pylori in GERD.

A variety of abnormalities contribute to the development of gastroesophageal reflux disease (GERD) including transient lower esophageal sphincter relaxation, low esophageal sphincter pressure, presence of a hiatal hernia, diminished esophageal clearance of refluxed gastric contents, and alterations in esophageal mucosal resistance. Helicobacter pylori infection clearly plays a role in the pathogenesis of peptic ulcer disease and mucosa associated lymphoma of the stomach and is a definite risk factor for distal gastric cancer. The role of H. pylori infection in GERD remains controversial and incompletely understood. Although H. pylori infection does not cause reflux disease, circumstantial evidence suggests that it may protect against the development of GERD and its complications in some patients. The most likely mechanism whereby H. pylori infection protects against GERD is by decreasing the potency of the gastric refluxate in patients with corpus predominant gastritis. A variety of implications of H. pylori infection on GERD treatment have also arisen in recent years. These focus on the risk of gastric atrophy while on proton pump inhibitor therapy and the efficacy of proton pump inhibitors before and after eradication of H. pylori. This article puts into perspective our current understanding of the complex, incompletely understood relationship between H. pylori infection and GERD.

Aged↗
PubMed2000

Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. The Esomeprazole Study Investigators.

BACKGROUND: The pharmacologic profile of the new proton pump inhibitor esomeprazole has demonstrated advantages over omeprazole that suggest clinical benefits for patients with acid-related disease. METHODS: 1960 patients with endoscopy-confirmed reflux oesophagitis (RO) were randomized to once daily esomeprazole 40 mg (n=654) or 20 mg (n=656), or omeprazole 20 mg (n=650), the standard recommended dose for RO, for up to 8 weeks in a US, multicentre, double-blind trial. The primary efficacy variable was the proportion of patients healed at week 8. Secondary variables included healing and heartburn resolution at week 4, time to first resolution and sustained resolution of heartburn, and per cent of heartburn-free days and nights. Safety and tolerability were also evaluated. RESULTS: Significantly more patients were healed at week 8 with esomeprazole 40 mg (94.1%) and 20 mg (89.9%) vs. omeprazole 20 mg (86.9%), using cumulative life table estimates, ITT analysis (each P < 0.05). Esomeprazole 40 mg was also significantly more effective than omeprazole for healing at week 4 and for all secondary variables evaluating heartburn resolution. The most common adverse events in all treatment groups were headache, abdominal pain and diarrhoea. CONCLUSION: Esomeprazole was more effective than omeprazole in healing and symptom resolution in GERD patients with reflux oesophagitis, and had a tolerability profile comparable to that of omeprazole.

Adult↗
PubMed2000

Cytokeratin immunoreactivity patterns in the diagnosis of short-segment Barrett's esophagus.

BACKGROUND & AIMS: The origin of intestinal metaplasia in short segments of columnar mucosa at the esophagogastric junction has clinical importance but can be difficult to determine at endoscopy. Cytokeratin (CK) 7 and 20 patterns are specific for long-segment Barrett's esophagus; however, their utility in short-segment Barrett's esophagus has not been assessed. METHODS: Endoscopic biopsy specimens from patients with long-segment Barrett's esophagus (n = 49), suspected short-segment Barrett's esophagus (n = 43), and gastric intestinal metaplasia (n = 26) were immunostained for CK7 and CK20. Comprehensive clinical data were obtained, including age, gender, and hiatal hernia and Helicobacter pylori status. RESULTS: A Barrett's CK7/20 pattern was present in 48 (98%) of 49 patients with long-segment Barrett's esophagus, 35 (82%) of 43 with suspected short-segment Barrett's esophagus, and 0 (0%) of 26 patients with gastric intestinal metaplasia. Patients with suspected short-segment Barrett's esophagus with a Barrett's CK7/20 pattern were clinically similar to those with long-segment Barrett's esophagus. In contrast, patients with suspected short-segment Barrett's esophagus with no Barrett's CK7/20 pattern were clinically similar to those with gastric intestinal metaplasia. CONCLUSIONS: A Barrett's CK7/20 pattern identifies a subset of patients with suspected short-segment Barrett's esophagus who have a patient profile similar to that seen in long-segment Barrett's esophagus. A Barrett's CK7/20 pattern is an objective marker of Barrett's mucosa that in conjunction with appropriate clinical and endoscopic data can be used by clinicians to better define patients with short-segment Barrett's esophagus.

Aged↗
PubMed2000

Practice patterns for surveillance of Barrett's esophagus in the united states.

BACKGROUND: Endoscopic surveillance of Barrett's esophagus is recommended to detect dysplasia or cancer at an early and potentially treatable stage. However, little is known about the clinical practice patterns for endoscopic surveillance in the United States. METHODS: A questionnaire regarding surveillance intervals, techniques and management approaches for patients with Barrett's esophagus was mailed to 1000 randomly selected members of the Clinical Practice Section of the American Gastroenterological Association. RESULTS: The response rate was 455 of 1000 (45%). Not all respondents answered all questions. Seventy-nine percent of respondents were in community practices, and 21% were in academic practices. Nearly all (96%) performed endoscopic surveillance, but it was practiced more commonly in the community (334 of 341 [98%]) than in the academic setting (83 of 93 [89%], p < 0.001). For patients without dysplasia, endoscopic surveillance was most commonly performed every 2 years (264 of 415 [64%]). Patients with low-grade dysplasia usually had surveillance endoscopy at 6-month intervals (215 of 413 [52%]), whereas those with high-grade dysplasia most commonly had endoscopy every 3 months (201 of 404 [50%]). These surveillance patterns did not differ between the academic and community groups. Random biopsies were performed by 93 of 403 (23%), 4-quadrant biopsies by 310 (77%). Most physicians (83%) used standard capacity forceps. Brush cytology was done uncommonly (69 of 414 [17%]). The most common indications for esophagectomy were high-grade dysplasia by 82% and cancer by 83%. Ablation therapy was performed for Barrett's esophagus without dysplasia by 3.5%, Barrett's with dysplasia by 20%, and cancer by 8%. CONCLUSIONS: Surveillance for Barrett's esophagus is widely practiced in the United States but there is considerable variation in interval and technique. A clearer consensus on endoscopic surveillance is warranted to optimize care of patients with Barrett's esophagus.

Adult↗
PubMed2000

The gastric cardia: fact or fiction?

OBJECTIVE: It is unclear whether the gastric cardia is present from birth or is metaplastic and develops as a result of gastroesophageal reflux disease. To this end, we evaluated the histology of the entire esophagogastric junction in consecutive pediatric autopsies to determine the presence and extent of cardiac mucosa. METHODS: The entire esophagogastric junction of 33 consecutive pediatric (< or =18 yr) autopsies was examined. The precise location of the squamocolumnar junction and its relationship to the esophagogastric junction was noted in all cases. Slides were evaluated by two pathologists in a blinded fashion to look for cardiac mucosa, characterized by unequivocal periodic acid-Schiff (PAS)-positive mucous glands in a lobular configuration. Sections from the antrum and esophagogastric junction were examined for the presence of Helicobacter pylori. RESULTS: Three cases were excluded due to autolysis. The mean age of the 30 remaining patients was 6.3 yr (range: 16 days-18 yr). A regular-appearing squamocolumnar junction was identified at the esophagogastric junction in all 30 cases. Cardiac mucosa was present in all specimens (mean length: 1.8 mm; range: 1.0-4.0 mm), always on the gastric side of the esophagogastric junction. There was no significant association between patient age or gender and length of cardiac mucosa. None of the patients had a known history of gastroesophageal reflux disease or Barrett's esophagus, and none were taking acid-suppressing medications before death. All were negative for Helicobacter pylori by Giemsa stain. CONCLUSIONS: In an unselected pediatric patient population with little or no propensity for gastroesophageal reflux disease, a short segment of cardiac mucosa was consistently present on the gastric side of the esophagogastric junction, independent of gender or age. These results support the concept that the gastric cardia is present from birth as a normal structure.

Adolescent↗
PubMed2000

CagA-positive strains of Helicobacter pylori may protect against Barrett's esophagus.

OBJECTIVE: Helicobacter pylori (H. pylori) colonization is associated with chronic gastritis, peptic ulcer disease, and adenocarcinoma of the distal stomach. However, the role of H. pylori strain variation in complicated gastroesophageal reflux disease, especially Barrett's esophagus, is unknown. Therefore, the aim of this study was to evaluate the prevalence of colonization by cagA+ and cagA- H. pylori strains in the spectrum of gastroesophageal reflux disease, including Barrett's esophagus. METHODS: A total of 251 patients undergoing endoscopy were categorized into four groups: controls, patients with gastroesophageal reflux disease alone, and patients with short- and long-segment Barrett's esophagus. All patients underwent upper endoscopies with biopsies and serum collections. H. pylori and degree of mucosal inflammation in gastric biopsies were assessed and serological assessment made for H. pylori and cagA status. RESULTS: The overall prevalence of H. pylori colonization in the study population was 35% (95% confidence interval = 29.5-41.4%) which did not differ significantly among the groups. However, colonization by cagA+ H. pylori strains was significantly more prevalent among controls (11/25; 44%) and patients with gastroesophageal reflux disease (13/36; 36%) than in patients with short-segment (2/10; 20%) or long-segment Barrett's esophagus (0/18; 0%). Patients with Barrett's esophagus were less likely to be colonized by cagA+ H. pylori strains than reflux patients without Barrett's esophagus (odds ratio = 0.27, 95% confidence interval = 0.11-0.67, p = 0.004). CONCLUSIONS: Colonization by cagA+ H. pylori strains may be protective against the formation of short- and long-segment Barrett's esophagus and its malignant complications.

Antibodies, Bacterial↗
PubMed1999

Role of Helicobacter pylori cagA(+) strains and specific host immune responses on the development of premalignant and malignant lesions in the gastric cardia.

The incidence rates of gastric cardia and esophageal adenocarcinomas are increasing, but data suggest that carriage of cagA(+) Helicobacter pylori strains may protect against development of Barrett's esophagus and esophageal adenocarcinoma. Our aims were to examine the relationship between pre-malignant and malignant lesions in the gastric cardia and serum antibodies to H. pylori antigens in patients with and without complications of Barrett's esophagus. The prevalence of carditis was 40% in controls compared with 13% in patients with complicated or uncomplicated Barrett's esophagus and cardia adenocarcinoma (p < 0.001). Cardia intestinal metaplasia (IM) and atrophy were present and concordant in 28% of controls but less frequent in patients with Barrett's alone or with dysplasia/adenocarcinoma (0% for each, p < 0.001). Carriage of cagA(+) strains was present in 34% of patients with carditis and significantly associated with increased frequency and severity of cardia inflammation, IM, and atrophy but not with adenocarcinoma. IgA and HspA seropositivity were significantly increased in H. pylori-colonized patients with carditis compared to persons with normal cardia histology (p </= 0.005) but not in persons with esophageal disease or cardia adenocarcinoma. We conclude that carriage of cagA(+) H. pylori strains and induction of particular serological responses are significantly associated with marked histological findings in the gastric cardia but not with adenocarcinoma of either the gastric cardia or esophagus.

Adenocarcinoma↗
PubMed1999

Jumbo biopsy forceps protocol still misses unsuspected cancer in Barrett's esophagus with high-grade dysplasia.

BACKGROUND: The optimal management of high-grade dysplasia in patients with Barrett's esophagus is controversial. The aim of this study was to assess the prevalence of unsuspected carcinoma at esophagectomy in patients with Barrett's esophagus with high-grade dysplasia after endoscopic surveillance with jumbo biopsy forceps compared with standard biopsy forceps. METHODS: Twelve patients with high-grade dysplasia in Barrett's esophagus without gross or microscopic evidence of carcinoma underwent esophagectomy after preoperative endoscopy with 4-quadrant jumbo biopsies at 2-cm intervals. The findings in this group were compared with those in a group of patients with Barrett's esophagus who underwent esophagectomy for high-grade dysplasia after biopsies obtained at 2-cm intervals with standard biopsy forceps. RESULTS: Unsuspected cancer was found in 4 of 12 (33%) patients in the jumbo biopsy group compared with 6 of 16 (38%) in the standard biopsy group (p = NS). All 6 cancers in the standard biopsy group were intramucosal, whereas 2 were intramucosal and 2 were submucosal in the jumbo biopsy group. No patients in either group had lymph node metastases. CONCLUSIONS: Unsuspected cancer is found frequently in patients with Barrett's esophagus who are undergoing esophagectomy for high-grade dysplasia despite the use of a rigorous jumbo biopsy protocol. Esophageal resection is still indicated in appropriately selected patients with high-grade dysplasia until better markers of cancer risk are available.

Adenocarcinoma↗
PubMed1999

Cytokeratin subsets can reliably distinguish Barrett's esophagus from intestinal metaplasia of the stomach.

The histological distinction between intestinal metaplasia involving the distal esophagus (Barrett's esophagus [BE]) and intestinal metaplasia of the stomach has important clinical implications and can be difficult even with the use of histochemical mucin stains. Cytokeratin (CK) 7 and 20 are cytoplasmic structural proteins that show restricted expression in normal and malignant epithelia of the gastrointestinal tract. The aim of this study was to determine the use of CK7 and 20 expression in the histological distinction of BE from gastric intestinal metaplasia. CK7 and 20 immunostaining was performed on randomly selected surgical resection (n = 31) and biopsy specimens (n = 34) from patients with long-segment BE and gastric resection specimens (n = 11) and gastric cardia biopsy specimens (n = 13) in patients with histological evidence of intestinal metaplasia. A unique pattern of immunoreactivity designated the Barrett's CK7/20 pattern showed superficial CK20 staining and strong CK7 staining of both superficial and deep glands in 29 of 31 (94%) esophageal resection specimens and 34 of 34 (100%) esophageal biopsy specimens form patients with long-segment BE. A Barrett's CK7/20 pattern was not observed in gastric cardia biopsy specimens (n = 13) or gastric resection specimens (n = 11) in patients with histological evidence of intestinal metaplasia. The sensitivity, specificity, and positive predictive value of a Barrett's CK7/20 pattern for a diagnosis of long-segment BE was 97%, 100%, and 100%, respectively. CK7 and 20 reactivity patterns can reliably identify the location of intestinal metaplasia in the esophagus and stomach using histological material from both routine endoscopic biopsy and surgical resection specimens.

Barrett Esophagus↗
PubMed1999

Reflux disease and Barrett's esophagus.

Gastroesophageal reflux disease (GERD) is a common clinical problem. New information suggests that infection with Helicobacter pylori may protect patients from developing GERD and its complications. Endoscopy may be used by clinicians to tailor GERD therapy, but an empirical trial of a proton-pump inhibitor may be an alternative diagnostic approach. Studies continue to show that laparoscopic antireflux surgery is a cost-effective treatment option for patients requiring maintenance therapy with proton-pump inhibitors. However, the minimally invasive nature of the operation should not alter the indications for antireflux surgery, especially for patients with atypical symptoms. It remains unclear why some patients with GERD develop Barrett's esophagus, whereas others do not. Recent guidelines suggest that patients with long-standing GERD symptoms, especially white men over 50 years of age, should undergo endoscopy at least once to screen for Barrett's esophagus. Debate concerning short-segment Barrett's esophagus continues. Intestinal metaplasia at a normal-appearing gastroesophageal junction may be associated with intestinal metaplasia of the stomach and infection with H. pylori, whereas short tongues of intestinal metaplasia in the esophagus are associated with GERD. Cancer surveillance is indicated in short-segment Barrett's esophagus, as dysplasia may develop in these patients. Barrett's esophagus is the only known risk factor for the development of esophageal adenocarcinoma, but the incidence of adenocarcinoma may be lower than previously reported. New clinical guidelines for endoscopic surveillance suggest that the surveillance interval should be lengthened to every two years in patients without dysplasia. Newer treatment options, such as thermal ablation and photodynamic therapy, continue to show promise, but are not yet ready for routine clinical use.

Barrett Esophagus↗