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INTRODUCTION: elderly patients appear to have a more aggressive form of gastro-oesophageal reflux disease than younger patients. Reduced pain perception with age is a possible underlying mechanism. AIMS: to compare the extent of oesophageal mucosal injury, acid exposure, symptom severity and perception thresholds for acid infusion in older (aged 60 or older) and younger patients with gastro-oesophageal reflux. METHODS: twenty-five younger and 23 older patients completed the study. We determined acid exposure and oesophageal mucosal injury by ambulatory 24-h oesophageal pH monitoring and upper endoscopy, respectively. We determined chemosensitivity by infusing 0.1 N hydrochloric acid into the mid-oesophagus for 10 min at 10 ml/min after a 2-min infusion of normal saline at a similar rate. We quantified acid perception thresholds by the lag time to initial typical symptom perception, intensity rating at the end of acid infusion and an acid perfusion sensitivity score, calculated from the fractional duration of symptom perception and intensity rating. RESULTS: mean percentage of total time with pH <4 was higher in the older (15.8+/-2.4) than in the younger patients (11.9+/-1.8; P = 0.18). Of the older group, 74% had erosive oesophagitis versus 64% in the younger group. Frequency of symptoms (heartburn, acid regurgitation and dysphagia) was lower in the elderly group. Older patients perceived heartburn and acid regurgitation as much less severe than younger patients (P < 0.05).Younger patients had a significantly shorter lag time to initial symptom perception (P < 0.05) and a higher sensory intensity rating (P < 0.08). The acid perfusion sensitivity score was significantly lower in the older group (P < 0.05). CONCLUSIONS: older patients with gastro-oesophageal reflux disease have reduced symptom severity for heartburn despite a tendency towards increased severity of oesophageal mucosal injury and acid exposure. Age-related reduction in chemosensitivity to acid is a possible underlying mechanism. [ABSTRACT FROM AUTHOR]

Objectives: Barrett's esophagus (BE) is a metaplastic lesion characterized by replacement of the normal squamous epithelium by columnar intestinal epithelium containing goblet cells. It is speculated that this process is an adaptation to protect cells from components of refluxate, such as gastric acid and bile acids. In contrast to the normal squamous epithelium, enterocytes of the distal ileum are adapted to transport bile acids from the intestinal lumen. Several bile acid transporters are utilized for effective removal of bile acids, including the apical sodium-dependent bile acid transporter (ASBT), the ileal bile acid-binding protein (IBABP), and the multidrug-resistant protein 3 (MRP3). We hypothesized that one of the possible functions of newly arising metaplastic epithelium, in the esophagus, is to transport bile acids. Our major goal was to evaluate the expression of bile acid transporters in normal squamous epithelium, BE with different grades of dysplasia, and esophageal adenocarcinoma (EAC)., Methods: A total of 101 patients were included in this study. Immunohistochemistry (IHC) and reverse transcriptase (RT)-PCR were used to detect the expression of these transporters at the mRNA and protein levels., Results: Our immunohistochemical studies showed that all three bile acid transporters are expressed in BE glands, but not in squamous epithelium. ASBT was found in the apical border in BE biopsies. The highest frequency of ASBT expression was in patients with nondysplastic BE (9 of 15, 60%), and a progressive loss of ASBT was observed through the stages of dysplasia. ASBT was not detected in EAC (0 of 15). IBABP staining was observed in the cytoplasm of BE epithelial surface cells. Expression of IBABP was found in 100% of nondysplastic BE (14 of 14), in 93% of low-grade dysplasia (LGD, 15 of 16), in 73% of high-grade dysplasia (HGD, 10 of 14), and in 33% of EAC (5 of 15). MRP3 was expressed in the basolateral membrane in 93% of nondysplastic BE (13 of 14), in 60% of LGD (10 of 16), and in 86% of HGD (11 of 13). Only weak MRP3 staining was detected in EAC biopsies (5 of 15, 33%). In addition, RT-PCR studies showed increased expression of mRNA coding for ASBT (6.1x), IBABP (9.1x), and MRP3 (2.4x) in BE (N=13) compared with normal squamous epithelium (N=15). Significantly increased mRNA levels of IBABP (10.1x) and MRP3 (2.5x) were also detected in EAC (N=21) compared with normal squamous epithelium., Conclusions: We found that bile acid transporters expression is increased in BE tissue at the mRNA and protein levels and that expression of bile acid transporter proteins decreased with progression to cancer.

Purpose: The Response Evaluation Criteria in Solid Tumors (RECIST) have largely replaced the World Health Organization (WHO) criteria as a preferred method for assessing tumor response in clinical trials. We hypothesized that due to frequent asymmetric growth pattern, as well as somewhat diffuse margins of pancreatic cancer, the use of WHO vs. RECIST criteria may result in significantly different tumor response assessments. The purpose of this retrospective study was to compare the WHO (bidimensional) to RECIST (unidimensional) in assessing treatment response in pancreatic cancer patients enrolled in clinical trials., Materials and Methods: We have evaluated the contrast- enhanced computed tomography (CT) images from 12 pancreatic cancer patients with measurable disease enrolled in two phase I/II clinical trials at the Arizona Cancer Center, between July 2000 and July 2003. The tumor measurements were re-calculated by RECIST and WHO criteria and were compared., Results: In 3 out of the 12 patients (25%) there was discordant response categorization when WHO criteria were used instead of RECIST. Clinical presentations in all 3 patients were more consistent with WHO categorization., Conclusion: Our retrospective data analysis suggests that use of different tumor response criteria (RECIST vs. WHO) may result in different assessments of treatment efficacy in patients with pancreatic cancer on clinical trials. This finding warrants further confirmation in a larger prospectively designed trial.

Background: Barrett's oesophagus is a premalignant condition associated with an increased risk for the development of oesophageal adenocarcinoma (ADCA). Previous studies indicated that oxidative damage contributes to the development of ADCA., Objective: To test the hypothesis that bile acids and gastric acid, two components of refluxate, can induce oxidative stress and oxidative DNA damage., Methods: Oxidative stress was evaluated by staining Barrett's oesophagus tissues with different degrees of dysplasia with 8-hydroxy-deoxyguanosine (8-OH-dG) antibody. The levels of 8-OH-dG were also evaluated ex vivo in Barrett's oesophagus tissues incubated for 10 min with control medium and medium acidified to pH 4 and supplemented with 0.5 mM bile acid cocktail. Furthermore, three oesophageal cell lines (Seg-1 cells, Barrett's oesophagus cells and HET-1A cells) were exposed to control media, media containing 0.1 mM bile acid cocktail, media acidified to pH 4, and media at pH 4 supplemented with 0.1 mM bile acid cocktail, and evaluated for induction of reactive oxygen species (ROS)., Results: Immunohistochemical analysis showed that 8-OH-dG is formed mainly in the epithelial cells in dysplastic Barrett's oesophagus. Importantly, incubation of Barrett's oesophagus tissues with the combination of bile acid cocktail and acid leads to increased formation of 8-OH-dG. An increase in ROS in oesophageal cells was detected after exposure to pH 4 and bile acid cocktail., Conclusions: Oxidative stress and oxidative DNA damage can be induced in oesophageal tissues and cells by short exposures to bile acids and low pH. These alterations may underlie the development of Barrett's oesophagus and tumour progression.

Thus far, there has been a paucity of studies that have assessed the value of the different gastroesophageal reflux disease (GERD) symptom characteristics in identifying patients with long-segment Barrett's esophagus versus those with short-segment Barrett's esophagus. To determine if any of the symptom characteristics of GERD correlates with long-segment Barrett's esophagus versus short-segment Barrett's esophagus. Patients seen in our Barrett's clinic were prospectively approached and recruited into the study. All patients underwent an endoscopy, validated GERD symptoms questionnaire and a personal interview. Of the 88 Barrett's esophagus patients enrolled into the study, 47 had short-segment Barrett's esophagus and 41 long-segment Barrett's esophagus. Patients with short-segment Barrett's esophagus reported significantly more daily heartburn symptoms (84.1%) than patients with long-segment Barrett's esophagus (63.2%, P = 0.02). There was a significant difference in reports of severe to very severe dysphagia in patients with long-segment Barrett's esophagus versus those with short-segment Barrett's esophagus (76.9%vs. 38.1%, P = 0.02). Longer duration in years of chest pain was the only symptom characteristic of gastroesophageal reflux disease associated with longer lengths of Barrett's mucosa. Reports of severe or very severe dysphagia were more common in long-segment Barrett's esophagus patients. Only longer duration of chest pain was correlated with longer lengths of Barrett's esophagus.

Background: Assessment of clinical factors associated with Barrett's esophagus (BE) length remained within the realm of anecdotal reports or one center's experience. The aim of this multicenter study was to determine which clinical factors are highly correlated with the length of BE., Methods: Patients diagnosed with BE were recruited into the study from 5 academic centers in the United States. All patients had an upper endoscopy that documented BE by the presence of intestinal metaplasia in biopsy specimens. All patients were evaluated by a validated demographic questionnaire and the GERD Symptom Checklist., Results: A total of 263 patients with BE were recruited into the study. Mean BE length length for the entire sample was 4 +/- 3.3 cm. A longer hiatal hernia (r = 0.22, p < 0.01), any dysplasia (t = -2.3, p < 0.05), H2 receptor antagonist (H2-RA) consumption (t = 1.98, p < 0.05), and nonsmoking (t = -2.5, p < 0.05) were correlated with a longer segment of BE. Proton pump inhibitors (PPI) (t = 1.96, p < 0.05) were correlated with a shorter segment of BE., Conclusions: PPIs were correlated with shorter lengths of BE. In contrast, a longer hiatal hernia, any dysplasia, nonsmoking, or use of H2-RAs were correlated with a longer BE segment.

Purpose: To develop a technology assessment of chemotherapy sensitivity and resistance assays in order to define the role of these tests in routine oncology practice., Methods: The American Society of Clinical Oncology (ASCO) established a Working Group to develop the technology assessment. The Working Group collaborated with the Blue Cross and Blue Shield Association (BCBSA) Technology Evaluation Center. The Working Group developed independent criteria for selecting articles for inclusion in the ASCO assessment, and developed a structured data abstraction tool to facilitate review of selected manuscripts. One Working Group member and an ASCO staff member independently reviewed the 1,139 abstracts identified by the BCBSA comprehensive literature search, and by an updated literature search performed by ASCO using the BCBSA search strategy (1966 to January 2004). Of the 12 articles included in this technology assessment, eight were identified by the original BCBSA systematic review, one was provided by industry, and three were identified by the ASCO updated literature review., Results: Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice., Recommendations: The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.

Objectives: Accurate measurements of Barrett's esophagus length are important in clinical follow-up as well as in studies of therapeutic intervention in Barrett's esophagus. Our aim was to evaluate both the inter- and intraobserver reliability in measuring Barrett's length during two consecutive endoscopies by either the same or different experienced endoscopists. The relationship between Barrett's mucosa length and the absolute change in Barrett's length measurements on a follow-up endoscopy was also evaluated., Methods: A total of 96 Barrett's patients underwent two consecutive endoscopies. The diagnosis of Barrett's esophagus was confirmed by the presence of intestinal metaplasia on biopsy. The Barrett's esophagus length was carefully measured and recorded during the two endoscopies. Procedures were performed by only two experienced endoscopists, who were not aware of previous endoscopic measurements. Only patients with long-segment (> or =3 cm) Barrett's esophagus were included in this study., Results: The 55 patients who had their consecutive endoscopies performed by the same endoscopist had a mean 1.6-cm difference between the two measurements as compared to 1.4 cm in the 41 patients who had their endoscopies performed by different endoscopists (p = 0.3). The agreement between the two Barrett's length measurements was high in both groups, although it was slightly higher for endoscopies performed by the same endoscopist (r = 0.79 vs r = 0.67). Linear regression analysis of the absolute change in Barrett's length between the two endoscopic measurements and Barrett's mucosa length demonstrated a significant relationship (r = 0.28, p = 0.005). For every 1-cm increase in the mean length of Barrett's mucosa, a 0.15-cm increase in the absolute difference between two consecutive endoscopic measurements of Barrett's length was observed., Conclusions: Consecutive measurements of Barrett's length performed by different experienced endoscopists or by the same experienced endoscopist demonstrated a high degree of agreement. A range of variability in Barrett's length measurement was determined (+/-1.4-1.6 cm). True regression or progression of Barrett's mucosa should be considered only if the change is greater than the range of variability. In addition, endoscopists should be well aware that the longer the Barrett's mucosa the greater the absolute difference in Barrett's length measurement on follow-up endoscopy.

Background: The objective was to evaluate the efficacy and safety of a novel intratumoral cisplatin/epinephrine injectable gel (CDDP/epi gel) for local control and palliation of tumor-related symptoms in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)., Patients and Methods: Eighty-seven patients were randomly assigned to either CDDP/epi or placebo gel in this phase III, double-blind study. Tumors were < or =20 cm(3); most recurrences (88%) were in a previously irradiated field. The most symptomatic or threatening tumor was designated as the target tumor. DOSE: 0.25 mL CDDP/epi gel/cm(3) tumor volume., Treatments: < or =6 weekly intratumoral injections in an 8-week period., Primary Outcomes: target tumor response and symptom relief., Results: During the blinded phase, 34% (21 of 62) of patients achieved an objective response (CR or PR) in the target tumor treated with CDDP/epi gel vs 0% (0 of 24) treated with placebo gel (p <.001). Responses occurred within a median of four treatments (range, 2-6) and were durable (median, 95 days; range, 34-168+ days). More patients treated with CDDP/epi gel achieved palliative benefit than did those treated with placebo gel (37% vs 12%, p =.036). Most frequent side effects were local pain and local cutaneous reactions, which resolved over 3-12 weeks. Renal and hematologic toxicities were rare., Conclusions: This phase III trial showed that CDDP/epi gel significantly reduces tumor burden, palliates tumor-related symptoms, and is an effective local treatment for recurrent tumors., (Copyright 2003 Wiley Periodicals, Inc. Head Neck 25: 717-731, 2003)

Background: A significant correlation between the duration and height of esophageal acid exposure and the length of Barrett's mucosa has been demonstrated. The aims of this study were to determine if there is a correlation between hiatal hernia length and Barrett's esophagus length, and to develop a predictive model for Barrett's esophagus length by using hiatal hernia length and duration of esophageal acid exposure., Methods: Consecutive patients with Barrett's esophagus diagnosed endoscopically were enrolled in the study. Barrett's esophagus was defined by the presence of intestinal metaplasia in biopsy specimens obtained from salmon-colored mucosa extending into the esophagus. Barrett's mucosa 3 cm or greater in length was considered long-segment Barrett's esophagus; and less than 3 cm long was considered short-segment Barrett's esophagus. Hiatal hernia was considered present if the esophagogastric junction was displaced 1 cm or more proximal to the diaphragmatic hiatus., Results: Twenty-four men (mean age 66.1 +/-2.4 [SE]) with Barrett's esophagus were included in this study. Mean Barrett's length was 4.1 +/-0.7 cm. The Pearson correlation coefficient between hiatal hernia length and Barrett's esophagus length was 0.62 (p < 0.01). Similarly, there was a significant correlation between esophageal acid exposure and Barrett's length (r = 0.62; p < 0.01). Multiple linear regression analysis revealed that hiatal hernia length and duration of esophageal acid exposure were associated significantly with length of Barrett's mucosa (R(2) = 0.54; p < 0.001). A regression equation was developed expressing mean Barrett's length (cm) = 0.79 + (0.68) hernia length (cm) + (0.075) duration of esophageal acid exposure (% time pH < 4)., Conclusions: The length of Barrett's mucosa correlated with the length of hiatal hernia. A predictive model for Barrett's length by using hiatal hernia length and duration of esophageal acid exposure was developed. This suggested that these two pathophysiologic factors are good predictors of the length of Barrett's mucosa.

Studies show Barrett's esophagus prevalence increases with age, while mean length of Barrett's esophagus is unchanged. Few data are available about the relationship between age and length on the development of dysplasia. Our aim was to assess age and length as risk factors for dysplasia. Consecutive patients with Barrett's esophagus were enrolled in a multicenter study establishing a tissue bank of Barrett's esophagus patients 1994 and 1998. Demographics, length of Barrett's esophagus (centimeters), and histology were recorded. Risk factors for dysplasia were assessed, including patient age, gender, and length of Barrett's esophagus. Statistical analysis was performed comparing prevalence of dysplasia (which included the presence of any carcinoma and high- or low-grade dysplasia) to age and length. In all, 309 patients were studied [278 (90%) male and 31 (10%) female]: 5 had adenocarcinoma of the esophagus, 11 had high-grade dysplasia, and 29 had low-grade dysplasia. Patients with Barrett's esophagus without dysplasia were younger than those with dysplasia [62 +/- 0.8 years vs 67 +/- 1.7 years (mean +/- SEM, P = 0.02)]. The risk of dysplasia increased by 3.3%/yr of age. Mean length of Barrett's esophagus in patients with Barrett's alone vs dysplasia was 4.0 +/- 0.2 cm vs 5.4 +/- 0.4 cm (P = 0.003). Patients with Barrett's esophagus length > or = 3 cm had a significantly greater prevalence of dysplasia compared to length < 3 cm (23% vs 9%, P = 0.0001). The risk of dysplasia increased by 14%/cm of increased length. Multivariate analysis showed age and length to be independent risk factors. In conclusions: prevalence of dysplasia is strongly associated with age and length of Barrett's esophagus. These preliminary results can be used to develop a strategy for screening/surveillance based on age and length of Barrett's epithelium.

Background: Recent reports suggest that patients with non-erosive reflux disease (NERD) treated with anti-reflux medications show lower symptom improvement rates than patients with erosive oesophagitis treated with the same medications., Aim: To determine the acid reflux and symptom patterns of patients with NERD in comparison with those with erosive oesophagitis and Barrett's oesophagus, and to identify different NERD subgroups., Methods: One hundred and forty-nine consecutive patients seen for classic heartburn symptoms were evaluated for the study. Oesophageal mucosal injury was assessed by upper endoscopy and classified by Hetzel-Dent criteria. Patients with Hetzel-Dent grades 0-1 were considered to have NERD. The extent of oesophageal acid exposure was determined by ambulatory 24-h oesophageal pH monitoring., Results: Seventy-one patients were found to have NERD, 36 erosive oesophagitis and 42 Barrett's oesophagus. Compared with patients with erosive oesophagitis (75%) and Barrett's oesophagus (93%), those with NERD (45%) were significantly less likely to have an abnormal pH test (P = 0.0001). Patients with Barrett's oesophagus had the highest mean number of acid reflux events (210 +/- 17.7), compared with those with erosive oesophagitis (139.7 +/- 15.2) and NERD (95.3 +/- 9.4) (P = 0.0001); however, the rate of perceived acid reflux events was similar and very low in all groups (NERD, 3.6%; erosive oesophagitis, 2.9%; Barrett's oesophagus, 2.17%). NERD-positive patients (abnormal pH test) had a similar extent of oesophageal acid exposure to those with erosive oesophagitis. NERD-positive patients were more likely to demonstrate a symptom index greater than 75% than NERD-negative patients (normal pH test) (61.9% vs. 10.5%; P = 0.0001). In the NERD-negative group, those with a negative symptom index reported having heartburn at pH < 4 only 12.7% of the time, compared with 70.7% of the time in those with a positive symptom index, despite a similar mean number of heartburn episodes., Conclusions: Patients with NERD commonly demonstrate a negative pH test. Acid reflux characteristics and symptom patterns suggest a heterogeneous group of patients.

Objective: To determine the safety and efficacy of targeted antitumor therapy with cisplatin/epinephrine injectable gel in patients with advanced squamous cell carcinoma of the head and neck., Design: Two prospective, double-blind, placebo-controlled phase III trials of identical design. Crossover from blinded to open-label phase was permitted for patients with disease progression., Setting: Tertiary referral centers in North America and Europe., Patients: One hundred seventy-nine intensively pretreated patients with recurrent or refractory squamous cell carcinoma of the head and neck., Intervention: Cisplatin/epinephrine injectable or placebo gel was administered by direct intratumoral injection; up to 6 weekly treatments. Dose was 0.25 mL of active or placebo gel per cubic centimeter of tumor up to 10 mL total. Patient benefit after local tumor control of the most symptomatic tumor was assessed by patients and physicians using the Treatment Goals Questionnaire., Main Outcome Measures: Local tumor response and patient benefit attributable to improvements in tumor-related symptoms., Results: Combined results for the 178 patients with evaluable data in the 2 trials confirmed objective tumor responses in 35 (29%) of 119 patients, including 23 (19%) complete responses achieved with cisplatin/epinephrine gel, vs 1 (2%) of 59 for placebo (P<.001). Tumor response and patient benefit were significantly correlated (P=.006): 47% (17/36) of patients with target tumor responses achieved a rigorously defined benefit based on a prospectively selected treatment goal vs 15% (22/142) of nonresponders., Conclusion: Cisplatin/epinephrine injectable gel reduces tumor burden, ameliorates tumor symptoms, and provides a new therapeutic option for treating patients with squamous cell carcinoma of the head and neck.

Objective: Gastroesophageal reflux disease (GERD) plays a major role in the development of Barrett's esophagus. Recently, we demonstrated that duration of esophageal acid exposure in the distal esophagus correlates with the length of Barrett's mucosa. The aim of this study was to determine whether there is a relationship between the rate of the change in acid exposure along the esophagus and the length of Barrett's esophagus., Methods: A total of 17 patients (16 men and one woman; mean age 66 +/- 15 yr, range 41-83 yr) with varying lengths of biopsy-proven Barrett's esophagus were recruited prospectively into the study. Ambulatory 24-h esophageal pH monitoring was performed using a commercially available pH probe with four sensors located 5 cm apart. For each patient, a least squares regression line of the fraction of the study that the pH was <4 against the height of the sensor above the lower esophageal sphincter was fit. The slope of the regression line was used to represent the rate of change in acid exposure. Linear regression analysis was conducted to analyze the relationship between the rate of change in acid exposure and the length of Barrett's mucosa., Results: The mean Barrett's length was 5 +/- 3 cm (range 1-11 cm). Linear regression demonstrated a statistically significant relationship between the rate of change in acid exposure and the length of Barrett's esophagus for the 24-h duration of the study, as well as for the fraction of the study that patients were in the upright position (p = 0.0096 and 0.0076, respectively). For the supine position, the relationship did not reach statistical significance (p = 0.095)., Conclusions: We demonstrated a significant relationship between the rate of change in acid exposure and the length of Barrett's mucosa. Thus, as the rate at which recorded acid exposure values increases from the proximal to distal esophagus, the length of Barrett's esophagus significantly increases (for percent total time and upright position).

There is an increasing trend towards alternative medicine usage by the general US population. However, the extent and type of supplemental alternative medicine used specifically by community-based patients with GERD is unknown. A previously validated questionnaire that included questions about patient demographics, 18 types of alternative medicine, and attitudes towards alternative and conventional medicine was utilized. Consecutive patients seen by community-based physicians in Arizona (Tucson, Phoenix, and Flagstaff) and Wisconsin (Milwaukee) for GERD received the questionnaire during the years 1999 and 2000. Patients completed the questionnaire and returned it to the Tucson VA Medical Center by mail. A total of 185 patients were surveyed (82 men, mean age 55.8 years). Of those, 61.6% used alternative medicine for any reason. However, only 3.8% of patients used supplemental alternative medicine for GERD. Females were twice as likely (95% CI, 1.10-3.67) to use alternative medicines for any reason (including GERD). Patients with daily acid regurgitation were 5.75 times (95% CI, 1.03-32.17) more likely than patients with less frequent acid regurgitation to use alternative medicines specifically for GERD. None of the other demographics, health characteristics, or attitudes were predictive of supplemental alternative medicine use for any reason (or specifically for GERD). In conclusion, only a small percentage of GERD patients seen by community-based practitioners use supplemental alternative medicine specifically for GERD symptoms, despite a higher usage of supplemental alternative medicine for non-GERD-related illness. Being female and having acid regurgitation daily were positively associated with alternative medicine usage for GERD.

Objective: Short segment Barrett's esophagus (SSBE) is defined by the presence of intestinal metaplasia in biopsies obtained from mucosa with an appearance suggestive of Barrett's that extends <3 cm into the esophagus. It has been suggested that this lesion may represent a stage in an ongoing process of Barrett's esophagus progression. If so, then the prevalence of SSBE would be expected to decrease with advancing age, and patients followed over time should exhibit an increase in the extent of columnar-lined esophagus. The aim of this study was to determine whether SSBE length progresses or regresses over time by following a prospective cohort and by assessing the relationship between age and the length, as well as prevalence of SSBE., Methods: The study included consecutive patients who were evaluated prospectively by an upper endoscopy and were found to have SSBE between October, 1983, and December, 1999, at the Southern Arizona VA Health Care System. All patients underwent a systematic biopsy protocol, and a designated pathologist who reviewed all specimens confirmed the diagnosis of Barrett's esophagus. Patients were subsequently interviewed for demographic information. In those patients who were enrolled into our surveillance program, SSBE length was remeasured and intestinal metaplasia reconfirmed on follow-up endoscopies., Results: Of 343 patients with endoscopically proven Barrett's esophagus, 116 (33.8%) were found to have SSBE. Almost all were male (97.4%) and white (85.3%), with a mean age of 60.1+/-1.0 yr. The prevalence of SSBE increased with age and reached a plateau during the seventh decade of life. One-way analysis of variance showed that there was no significant difference in the mean length of SSBE among the various age groups (p = 0.84). This trend was maintained when only the white group was assessed. Follow-up endoscopies were performed in 57 patients, revealing a mean interval of 64 months to the latest endoscopy, with no significant difference in SSBE length between the first and last endoscopy (p = 0.16)., Conclusions: The prevalence of SSBE increases with age until the seventh decade of life. Finding that SSBE length does not change across the various age groups and during a 64-month mean follow-up, suggests that SSBE does not progress over time.

Background: The presence of extensions of squamous epithelium into the proximal stomach in patients undergoing routine upper endoscopy has recently been described. The factors that may favor development of squamous epithelium within the proximal stomach remain unknown., Methods: Patients with Barrett's esophagus who agreed to undergo ablation of Barrett's epithelium by using multipolar electrocoagulation were included. Patients were treated with a high dose of a proton pump inhibitor. The columnar-appearing mucosa was systematically treated. Occasionally, thermal injury was inadvertently induced in the proximal stomach. On endoscopy performed 4 to 6 weeks after treatment, the presence of squamous epithelium extending into the proximal stomach was documented. The use of Lugol's stain assisted in confirming the squamous nature of the abnormal tissue, which was confirmed histologically by cytokeratin immunohistochemistry., Results: The 12 patients included in the study had a mean length of Barrett's epithelium of 3.8 +/- 0.7 cm. Patients were treated with omeprazole, mean dose 66 +/- 6.0 mg, and had a mean percent total time that the pH was less than 4 of 1.9 +/- 0.8. The mean length and width of gastric squamous extensions were 1.7 +/- 0.2 cm and 0.8 +/- 0.1 cm, respectively. None of the squamous extensions into the stomach were documented before mucosal ablation. The extensions stained positively for cytokeratin 13 and negatively for cytokeratin 8, thereby confirming their squamous nature., Conclusions: Thermal injury to the proximal stomach in patients undergoing ablation of Barrett's epithelium and profound acid suppression results in repair by squamous epithelium. Recognition of this lesion is essential because it may lead to confusion as to the location of the esophagogastric junction in subsequent endoscopic evaluations.

Background: Helicobacter pylori infection has been linked with the development of gastric adenocarcinoma and its precursor lesion, intestinal metaplasia (IM). The presence of gastric IM is not associated with symptoms, which makes identification of individuals with this lesion difficult. It is not clear whether eradication of H. pylori infection leads to reversal of gastric IM or the potential decrease in the risk of cancer in these patients., Goals: The purpose of this pilot study was to define the prevalence of gastric IM in a population at high risk for gastric cancer (Southwestern Hispanics), examine the ability of noninvasive testing to identify individuals with the lesion, and determine whether eradication of H. pylori infection reverses gastric IM in this population., Study: Subjects from the Tucson metropolitan area were recruited, and baseline data, including the presence of upper gastrointestinal (UGI) symptoms, urinary sodium, and serum pepsinogen levels, were obtained. Upper endoscopy was performed and six gastric biopsies from specific anatomic sites were obtained, followed by methylene blue staining with targeted biopsies from blue-stained mucosa. Biopsies were evaluated for the presence of H. pylori infection and gastric IM. A subset of patients with gastric IM were treated to eradicate H. pylori infection. Follow-up exams with methylene blue staining, including biopsies for histology and rapid urease testing, were performed for up to 48 months., Results: There were 84 subjects with a mean age of 53.0 years; 24 (29%) had gastric IM and 65 (77%) had H. pylori. There was no significant association between gastric IM and age, gender, UGI symptoms, H. pylori, or urine sodium. There was an association identified between gastric IM and a decreased pepsinogen I:II ratio (p = 0.03). Of the 11 individuals with gastric IM treated for H. pylori infection, 9 had successful therapy and underwent at least 2 follow-up examinations. The mean length of follow-up was 3.3 years. Eight of the nine (89%) had gastric IM identified histologically at the final endoscopic exam., Conclusions: H. pylori infection and gastric IM are frequent findings in Southwestern Hispanics, a high-risk population for gastric cancer. Noninvasive testing is not clinically useful in distinguishing individuals within this group who harbor gastric IM. Although eradication of H. pylori infection may lead to a decrease in the amount of gastric IM in some individuals, the lesion may be detected in the majority of individuals after more than 3 years of follow-up. These data suggest that therapy for H. pylori may not eliminate the risk of gastric cancer once IM has developed.

Background: Gastro-oesophageal reflux disease (GORD) plays a major role in the development of Barrett's oesophagus. However, it has yet to be elucidated what factors determine the length of Barrett's mucosa in each individual patient., Aims: To determine if there is a correlation between oesophageal acid exposure and the length of Barrett's mucosa. We also compared the extent of oesophageal acid exposure between patients with short segment (SSBE) and long segment (LSBE) Barrett's oesophagus., Methods: Twenty seven patients with Barrett's oesophagus were recruited prospectively into the study from the outpatient gastroenterology clinic at the Southern Arizona VA Health Care System. Diagnosis of Barrett's oesophagus and its anatomical characteristics were determined during upper endoscopy. Ambulatory 24 hour oesophageal pH monitoring assessed the extent of oesophageal acid exposure., Results: There was a significant correlation between per cent total time pH less than 4 and length of Barrett's mucosa (r=0.6234, p=0.0005). In addition, there was a significant correlation between per cent upright and supine time pH less than 4 and length of Barrett's mucosa (r=0.5847, p=0.0014 and r=0.6265 p=0.0006, respectively). Patients with SSBE had significantly less oesophageal acid exposure than patients with LSBE, in terms of both per cent total time and per cent supine time pH less than 4 (p<0.05)., Conclusions: The length of Barrett's mucosa correlated with the duration of oesophageal acid exposure. Patients with LSBE experienced significantly more oesophageal acid exposure than patients with SSBE. Duration of oesophageal acid exposure appears to be an important contributing factor in determining the length of Barrett's mucosa.

Background: Normalization of oesophageal acid exposure using high dose proton pump inhibitors in patients who are candidates for ablation therapy has been suggested to be essential for successful Barrett's reversal. However, the success rate for achieving pH normalization has not been determined., Methods: Patients with Barrett's oesophagus (2-6 cm in length) who were found to be eligible for ablation therapy using multipolar electrocoagulation were included in this prospective study. Patients underwent an upper endoscopy to determine Barrett's length and other anatomic characteristics. Biopsies were obtained to rule out dysplasia. Subsequently, patients were treated with omeprazole 40 mg b.d. Twenty-four hour oesophageal pH monitoring was performed after a mean period of 8.4 +/- 0.6 days of therapy., Results: Twenty-five patients were enrolled into the study. The pH test was abnormal in four (16%) of the study subjects. An additional two (8%) patients had abnormal supine percentage time with pH less than 4. There was no significant difference in oesophageal acid control between patients with long vs. short segment Barrett's oesophagus. Elderly (> 60 years) patients tended to have less acid control than younger (

Barrett's esophagus is a precancerous condition in which the squamous esophageal epithelium is replaced by a columnar epithelium. Although different types of columnar epithelium have been described, the most frequently encountered is specialized columnar epithelium or intestinal metaplasia. Most investigators believe that increased cancer risk is only associated with this type. Esophageal adenocarcinoma is increasing in frequency in the United States and in Western Europe. Recent studies highlight the importance of gastroesophageal reflux disease in esophageal adenocarcinoma. Bile-acid reflux may also play a role. Increasing interest has been expressed in short-segment (2-3 cm) Barrett's esophagus. The contribution of short-segment Barrett's esophagus to cancer at the gastroesophageal junction is currently being studied. Although regular surveillance is often recommended, the commonness of Barrett's esophagus makes such a practice impractical for every patient. Biomarker development is needed to identify patients at greatest risk, with p53 a promising candidate based on recent studies. Initial data suggest that redox mechanisms may be involved in Barrett's esophagus. Several methods have recently been described for reversing Barrett's esophagus to squamous epithelium, but the significance of this practice in terms of reducing cancer risk remains to be demonstrated.

Death and dying in America has received limited attention in medical education. The Southern Arizona VA Health Care System and the University of Arizona have collaborated with three nonprofit community hospice programs to develop an end-of-life care curriculum. This formal and comprehensive program is offered as a one-month elective to senior medical students, residents and fellows. The goal of the program is to improve clinical skills in caring for the dying patient and foster research in palliative and supportive care.

Background: Beta-Carotene has been reported to produce regressions in patients with oral leukoplakia, a premalignant lesion. However, previous studies have all been of short duration, with clinical response as the end point., Objective: To evaluate the duration of response and the need for maintenance therapy in subjects who respond to beta-carotene., Methods: In this multicenter, double-blind, placebo-controlled trial, subjects were given beta-carotene, 60 mg/d, for 6 months. At 6 months, responders were randomized to continue beta-carotene or placebo therapy for 12 additional months., Results: Fifty-four subjects were enrolled in the trial, with 50 being evaluable. At 6 months, 26 subjects (52%) had a clinical response. Twenty-three of the 26 responders completed the second, randomized phase. Only 2 (18%) of 11 in the beta-carotene arm and 2 (17%) of 12 in the placebo arm relapsed. Baseline biopsies were performed in all patients, with dysplasia being present in 19 (38%) of the 50 evaluable patients. A second biopsy was obtained at 6 months in 23 subjects who consented to this procedure. There was improvement of at least 1 grade of dysplasia in 9 (39%), with no change in 14 (61%). Nutritional intake was assessed using food frequency questionnaires. There was no change in carotenoid intake during the trial. Responders had a lower intake of dietary fiber, fruits, folate, and vitamin E supplements than did nonresponders. Beta-carotene levels were measured in plasma and oral cavity cells. Marked increases occurred during the 6-month induction. However, baseline levels were not restored in subjects taking placebo for 6 to 9 months after discontinuation of beta-carotene therapy., Conclusions: The activity of beta-carotene in patients with oral leukoplakia was confirmed. The responses produced were durable for 1 year.

Background: Recent studies have suggested that alpha-tocopherol supplementation can help reduce the incidence of coronary disease. Our objectives were to determine the feasibility of providing alpha-tocopherol supplements to male veterans with existing coronary artery disease and determine its effects on alpha-tocopherol levels and the susceptibility of low-density lipoprotein (LDL) to oxidation., Methods: Fifty-seven percent of 138 coronary disease patients were willing to participate in a placebo-controlled trial -25% were already taking antioxidants. Thirty-nine men were randomly assigned to either 400 mg/day of alpha-tocopherol (n = 27) or placebo (n = 12). alpha-Tocopherol levels and LDL oxidation (measured by formation of thiobarbituric acid-reactive substance) were measured at baseline and at 6 months., Results: Thirty-three subjects (22 alpha-tocopherol, 11 placebo) completed the study; 3 subjects withdrew after suffering coronary disease events. Supplement compliance exceeded 90% and alpha-tocopherol was well tolerated. The alpha-tocopherol group had a significantly greater mean increase in lipid-adjusted alpha-tocopherol levels (73% vs. -4.6%, P < 0.0001), but oxidized LDL did not change significantly., Conclusions: A secondary prevention trial among veterans would be feasible because the rates of enrollment, completion, compliance, and clinical events were high. alpha-Tocopherol supplements did not decrease the susceptibility of LDL to oxidation, suggesting that higher dosages or longer duration of supplementation may be required for secondary prevention., (Copyright 1999 American Health Foundation and Academic Press.)

Background: Endoscopic reversal of Barrett's esophagus with multipolar electrocoagulation and high-dose omeprazole has been previously described but long-term results are not available. The aim of this study was to follow patients after endoscopic reversal and to perform a detailed analysis of the "new" squamous mucosa., Methods: After reversal, patients with Barrett's esophagus were maintained on high-dose omeprazole and underwent interval endoscopy, and large biopsies were obtained of the former Barrett's epithelium., Results: Nine of 11 patients were men; the mean age was 62 years. The mean length of Barrett's mucosa was 4.4 cm; the mean dose of omeprazole used was 49 mg/day. All patients had an initial complete response to treatment-no evidence of Barrett's endoscopically and histologically. Three patients had intestinal metaplasia underlying the new squamous mucosa in the latest follow-up biopsies. In these 3 patients, only 0.4%, 2%, and 8% of the total biopsy area had intestinal metaplasia. All but 4 patients had underlying intestinal metaplasia at variable times during the study period. Patients have been followed for a mean of 36 months (range 19 to 53 months)., Conclusions: New squamous mucosa is durable and resembles normal squamous tissue. Underlying glands of intestinal metaplasia are intermittently found. Because the significance of this residual intestinal metaplasia is unclear, surveillance endoscopy with biopsies of the treated segment is recommended even after reversal therapy.

Study Objectives: We hypothesized that micronutrient antioxidant intake may be one factor determining the development of significant COPD. Vitamin E was administered to smokers to determine if exhaled ethane was reduced and if ethane correlated with measures of lung function., Study Design: Longitudinal placebo lead-in trial with posttreatment observation period., Setting: Tucson Veterans Affairs Medical Center., Participants: Twenty-nine current stable smokers having no interest in smoking cessation., Interventions: Spirometry, exhaled breath ethane measurements, and vitamin E and [-carotene plasma levels followed by 3 weeks of placebo with repeat plasma vitamin levels and ethane measurements; next, 3 weeks of vitamin E (dl-a-tocopherol), 400 IU po bid followed by plasma vitamin levels and breath ethane measurements; finally, 3 weeks without vitamins followed by breath ethane and plasma vitamin levels., Results: Vitamin E treatment did not reduce ethane significantly. Exhaled ethane levels (mean + SD: pm/min/kg) were as follows: baseline, 7.39 + 5.39; after run-in period, 6.86 + 4.09; after vitamin E, 6.36+/-3.02; and final, 7.23+/-4.63. After vitamin E therapy, a significant negative correlation existed between exhaled ethane and FEV1/FVC. Pack-years of smoking at baseline and after vitamin E were significantly associated with ethane exhaled. Initial lung function was not significantly negatively associated with vitamin E-induced changes in exhaled ethane but a negative trend was found., Conclusions: Vitamin E alone, unlike the combination of vitamins C, E, and beta-carotene, failed to reduced exhaled ethane in cigarette smokers. Exhaled ethane was correlated with pack-years of smoking. Smokers whose ethane values were found to fall the most tended to have better preserved lung function.

Objective: Squamous islands are frequently visualized at the time of upper endoscopy in patients with Barrett's esophagus, especially those on proton pump inhibitor therapy (PPI). The significance of these islands is not clearly understood. The aim of this study was to systematically biopsy macroscopic squamous islands and to examine their histologic characteristics., Methods: Patients with Barrett's esophagus undergoing surveillance had squamous islands documented and biopsied at the time of endoscopy. Barrett's esophagus was defined as the presence of a columnar lined esophagus on endoscopy with intestinal metaplasia on biopsy. All biopsies were obtained by a single senior endoscopist and were stained with alcian blue at pH 2.5. Biopsy samples with inadequate tissue quantity were not included in the study., Results: A total of 39 biopsies were obtained from 22 patients. Twenty of the 22 patients were male, with a mean age of 65.4 yr (range 47-80 yr). The mean length of Barrett's mucosa was 5.6 cm (range 1-11 cm). Eleven of 22 patients were on omeprazole (mean dose 29.1 mg/day), whereas seven patients were on lansoprazole (60 mg/day). The mean duration of PPI therapy was 2.3 yr (range 9-71 months) at the time of biopsy of the squamous islands. Three patients were on H2-blocker therapy whereas the remaining patient had not been started on acid suppression therapy. On histology, 24 biopsy specimens (61.5%) revealed only squamous epithelium, whereas 15 (38.5%) showed the presence of intestinal metaplasia underlying the squamous epithelium. There was no significant difference between the patients with and without underlying intestinal metaplasia in regard to age, Barrett's length, dose, and duration of PPI therapy., Conclusion: In more than one-third of biopsies of macroscopic squamous islands within Barrett's esophagus, microscopic intestinal metaplasia is detected. The presence of squamous islands should not be equated with regression of Barrett's esophagus or with decreased cancer risk.

Objective: Short segments of intestinal metaplasia in the distal esophagus are being recognized with increasing frequency. Both long and short segments of Barrett's esophagus can progress to dysplasia and cancer. However, the risk of short-segment Barrett's esophagus (SSBE) for the development of dysplasia and adenocarcinoma of the esophagus is not yet known. Our purpose, therefore, was to determine the frequency with which dysplasia occurs in patients with SSBE., Methods: Patients with SSBE were followed prospectively for the development of dysplasia. SSBE was defined as <3 cm of Barrett's-appearing epithelium above the gastroesophageal junction at endoscopy, with intestinal metaplasia on biopsy as documented by alcian blue stain at pH 2.5 on at least two endoscopic biopsies 6 months apart. Patients had interval upper endoscopy with systematic biopsy of the Barrett's segment., Results: Fifty-nine SSBE patients were identified. The mean length of Barrett's mucosa was 1.5 +/- 0.1 cm; the mean age of the patients was 63.1 +/- 1.3 yr. Five patients had low-grade dysplasia (LGD) at initial endoscopy, for a prevalence of 8.5%; none had high grade dysplasia (HGD). Thirty-two patients had follow-up endoscopy over a mean period of 36.9 +/- 5.4 months. Five of these patients developed dysplasia on follow-up, three with LGD and two with HGD, the incidence of any dysplasia being 5.7% per year. One patient with HGD that developed during surveillance progressed to adenocarcinoma of the esophagus over a 2-yr period. The other patient with HGD had LGD on follow-up endoscopy. Six patients with initial LGD had no evidence of dysplasia on follow-up., Conclusions: The prevalence of dysplasia was 8.5% with an incidence of 5.7% per year in this group of SSBE patients, followed prospectively. Although dysplastic changes may not be identified on follow-up examination, some patients progress to adenocarcinoma. Therefore, we recommend surveillance endoscopy and biopsy in patients with SSBE just as in those with long-segment Barrett's esophagus.

When compared to patients with erosive esophagitis, patients with Barrett's esophagus have demonstrated reduced chemo- and mechanoreceptor sensitivity to acid infusion and balloon distension, respectively. However, anecdotal clinical experience suggested an increase in symptom perception in patients after successful elimination of Barrett's epithelium, using multipolar electrocoagulation (MPEC) and high-dose proton pump inhibitor (PPI). To determine perception thresholds to acid infusion, we evaluated eight consecutive patients after a series of MPEC treatments resulted in complete elimination of Barrett's mucosa and compared them to 10 age-matched patients with nonreversed Barrett's esophagus and 10 patients with symptomatic, endoscopy-documented erosive esophagitis (Hetzel-Dent grade 2 or greater). Chemosensitivity was determined by a modified acid perfusion test, where acid perception thresholds were quantified by the lag time to initial typical symptom perception, sensory intensity rating, and an acid perfusion sensory score (APSS). While patients after successful elimination of Barrett's esophagus had similar sensory intensity ratings and APSS as patients with erosive esophagitis, the lag times differed significantly between the groups, and both groups had significantly higher sensory intensity ratings and APSS than patients with nonreversed Barrett's esophagus. In conclusion, patients after complete reversal of Barrett's mucosa are unexpectedly as sensitive to acid as symptomatic patients with erosive esophagitis.

Objective: Change in colon polyp size over time has not been well characterized. It has been inferred that some polyps will increase in size, leading to an increased risk of progressing to cancer, whereas other polyps may spontaneously regress. To develop a better understanding of the natural history of colon polyps, we prospectively investigated change in polyp size over a 2-yr period., Methods: Patients were enrolled if they had an endoscopically detected proximal rectal or sigmoid polyp measuring 3-9 mm. The index polyp site was then permanently marked with an adjacent India ink tattoo to allow definitive future localization of the polyp. Patients underwent flexible sigmoidoscopy at 6-month intervals, and at each examination, the polyp size was carefully measured with open biopsy forceps. After a maximum of 2 yr, each polyp was removed and the histology determined., Results: Thirty polyps were followed in 26 patients who completed the study. Twelve polyps were tubular adenomas (TA), one was tubulovillous, 14 were hyperplastic polyps (HP), two had no pathological diagnosis, and one was a leiomyoma. HP were more likely to decrease in size than were TA. Three polyps demonstrated fast growth rates (2-4 mm/yr), and all were TA. Two polyps were removed early because their size had reached 1 cm or more. Both of those polyps were TA. No polyps regressed completely during the 2 yr of the study; neither did we find consistent linear growth rates., Conclusions: In contrast to prior reports, in this study, after polyps had been definitively localized with India ink, we observed no complete polyp regressions.

Objectives: Barrett's esophagus is a premalignant condition defined by the presence of intestinal metaplasia in the esophagus. Estimates of the incidence of adenocarcinoma developing in patients with Barrett's esophagus vary widely. We prospectively followed a cohort of patients to define the incidence., Methods: Between January 1982 and April 1995, all patients undergoing upper endoscopy at the VA Medical Center in Tucson, AZ, were surveyed for Barrett's esophagus. One hundred seventy-seven patients (174 males, three females) were found to have Barrett's esophagus. Seven of 177 were found to have adenocarcinoma either at initial endoscopy or within 6 months, resulting in a prevalence of 4%. One hundred seventy of 177 patients initially lacking cancer were available for systematic survey., Results: The mean age at the time of Barrett's diagnosis was 62 yr (range 30-85 yr). The mean follow-up period was 57 months or 4.8 yr (range 6-156 months), for a total of 834 patient-years. Adenocarcinoma developed in four patients, an incidence of 1/208 patient-years of follow-up., Conclusions: The current series is larger and has a longer follow-up period than previous prospective trials and demonstrates a lower incidence of adenocarcinoma. Surveillance of patients with Barrett's esophagus for dysplasia remains an appropriate clinical practice.

Background: Barrett's esophagus is a premalignant lesion for esophageal adenocarcinoma. This study tests the hypothesis that re-injury of the metaplastic the epithelium in an acid-controlled environment will result in reversal of Barrett's to squamous epithelium., Methods: Patients with at least 2 cm of Barrett's esophagus were treated with omeprazole, and half the circumference of the Barrett's was treated with multipolar electrocoagulation (MPEC); the other half served as an internal control. After 6 months, the remaining Barrett's esophagus was treated with MPEC., Results: Twenty-four hour esophageal pH of less than 4 averaged 1.8% on a mean dose of 56 mg/day of omeprazole. Ten patients had visual and biopsy elimination of the targeted section of Barrett's esophagus after an average of 2.5 MPEC sessions. The remainder of the Barrett's esophagus is being treated in 9 patients; currently 5 have no evidence of Barrett's., Conclusions: The combination of control of esophageal acid exposure and reinjury of the metaplastic epithelium reverses Barrett's esophagus to squamous epithelium as determined by endoscopy and biopsy.

To determine the effect of nutritional agents on lipid peroxidation, 10 smokers were given 6 mg beta carotene, 200 IU vitamin E, and 250 mg vitamin C 4 times daily for 3 weeks. Lipid peroxidation was assessed by measuring baseline and postsupplementation levels of exhaled ethane. There was a 29% decrease in mean (+/-SD) exhaled ethane (4.06 +/- 1.49 vs 2.90 +/- 1.29 pmol.kg-1.min-1), with individual levels decreasing in 8 of the 10 smokers (p < 0.05, Wilcoxon sign rank test). Three nonsmokers had very low baseline levels of ethane that did not change with supplementation. Ethane production correlated with active (packs per day) and lifelong (pack-years) tobacco consumption. Also, a strong correlation was found between the decline in ethane output after micronutrient supplementation and the presupplement FEV1. Therefore, antioxidant vitamin supplementation resulted in attenuation of smoking-related lipid peroxidation, and the decreases in ethane production appears to be associated with preserved lung function.

Although measures of colonic cell proliferation are being used as potential intermediate markers in chemoprevention studies, measurement standardization is still ongoing. This study was designed to assess the reproducibility of the labeling index quantification, as measured by bromodeoxyuridine, across four laboratories experienced in its use. Each institution submitted 10 slides, with one circled area of each slide to be scored. Each site followed its standard procedures for scoring colonic crypts; no attempts to standardize these procedures were made. There was high concordance among the laboratories on whether scorable crypts were present on a particular slide, but only two pairs of laboratories demonstrated agreement statistically greater than that predicted by chance. The overall difference among the sites on the number of scorable crypts was marginally significant (P = 0.083), and there was a highly significant overall difference in the magnitude of the labeling index (P < 0.0001). Sites 1 and 2 tended to have similar results, as did sites 3 and 4, most likely due to common training. Even with these discrepancies, high correlation (r > 0.75) was observed among the reported labeling index values for each pair of laboratories. Without standardized training, these laboratories may differ in the crypts considered appropriate for counting and in whether cells are counted as labeled or unlabeled. These results suggest that standardized training in scoring across all sites performing labeling index determinations is required to assure reproducibility across sites or studies. These results may also help explain discrepancies in the average values of the labeling index reported in the literature.

We had previously identified p53 mutations in Barrett's esophagus and therefore began a multiinstitutional study to determine their significance as a marker for malignancy. Ninety-eight patients from four institutions were studied. Forty-eight patients (37 men and 11 women, mean age 56.2 years) had Barrett's esophagus with metaplasia or dysplasia but no evidence of malignancy at a mean follow-up of 2.2 years. Barrett's esophagus was classified as metaplasia with no evidence of dysplasia in 32 patients, as low-grade dysplasia in 13, and as high-grade dysplasia in three. The other 50 patients (46 men and four women, mean age 60.2 years) had adenocarcinoma arising in Barrett's esophagus. Tissues from normal stomach or esophagus, tumor, and Barrett's esophagus were obtained for deoxyribonucleic acid analysis by endoscopic biopsy from patients with Barrett's esophagus or cancer or during operations on some patients with Barrett's cancer. Exons 5 through 9 of the p53 gene were studied for mutations by single-strand conformational polymorphism analysis after polymerase chain reaction amplification. Mutations detected by single-strand conformational polymorphism analysis were confirmed by deoxyribonucleic acid sequencing. None of the tissue samples from patients with Barrett's esophagus alone and no dysplasia or low-grade dysplasia had any p53 mutations, but one of the three patients with high-grade dysplasia and no evidence of invasive malignancy did have a p53 mutation. Of the 50 patients with Barrett's cancer, however, 23 (46%) had p53 mutations in Barrett's epithelium, tumors, or both. Twenty of these patients had p53 mutations in the tumor only (n = 16) or in both tumor and Barrett's epithelium (n = 4), suggesting that the mutation plays a direct role in carcinogenesis. Mutations in Barrett's epithelium were found in one patient in the group without malignancy and in seven patients with cancer (one with no dysplasia, two with low-grade dysplasia, and five with high-grade dysplasia). In three patients with cancer, mutations occurred only in Barrett's epithelium, suggesting that such mutations may also be a marker for genomic instability. Mutations were predominantly found in exons 5, 7, and 8, and transitions from guanine to adenine were the most frequent changes. Mutations of p53 are clearly involved in the pathogenesis of Barrett's cancer for a subset of patients (46%), and the fact that we could detect mutations in premalignant Barrett's epithelium supports the hypothesis that p53 mutations may be a useful marker for patients at increased risk for development of invasive cancer.

Background: Accurate knowledge of polyp size is important in assessing cancer risk in both clinical studies and individual patients. We sought to determine if a difference exists between the endoscopic estimation of colon polyp size and the actual measurement after removal., Methods: We measured polyps in a systematic fashion. Using open biopsy forceps as a guide, the largest diameter of 31 pedunculated polyps was estimated endoscopically. The polyp was then removed by snare polypectomy and directly measured by a technician who was blinded to the endoscopic estimate. Each polyp was also measured after formalin fixation by a pathologist who was blinded to previous measurements., Results: There was a significant difference between the endoscopic estimates and the postpolypectomy measurements. Endoscopic estimates on average were 1.6 mm greater than the postpolypectomy measurements (p< 0.05), representing an 18% difference. Twenty-three of the 31 (74%) endoscopic estimates were larger than the postpolypectomy measurements. There was not a significant difference between the postpolypectomy and postfixation measurements., Conclusions: The size of polyps measured endoscopically is significantly larger on average than postpolypectomy measurements. This is most likely due to factors involved in the removal of the in vivo polyp.

Oral mucositis is a frequent side effect of cancer therapy. No effective method of prophylaxis is currently available. We conducted a randomized, double-blind, placebo-controlled, crossover trial of pentoxifylline to evaluate its potential in preventing mucositis in cancer patients receiving chemotherapy. Ten cancer patients were randomized for treatment with a 15-day course of 400 mg of pentoxifylline given orally four times daily. Concurrent chemotherapy consisted of bolus cisplatin and infusional 5-fluorouracil. Mucositis was evaluated with the use of the Oral Assessment Guide developed at the University of Nebraska. Patients completing two cycles of chemotherapy--one with pentoxifylline and one with placebo--were evaluated for prophylaxis efficacy. Comparison of the oral assessment scores of the two cycles with a two-sided Student's t test failed to demonstrate a cytoprotective effect for pentoxifylline over placebo. We conclude that pentoxifylline as given in this study is ineffective for preventing mucositis in patients receiving cisplatin and 5-FU.