Kamran Ayub

NSAIDs Modulate CDKN2A, TP53, and DNA Content Risk for Progression to Esophageal Adenocarcinoma

Background Somatic genetic CDKN2A, TP53, and DNA content abnormalities are common in many human cancers and their precursors, including esophageal adenocarcinoma (EA) and Barretts esophagus (BE), conditions for which aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as possible chemopreventive agents; however, little is known about the ability of a biomarker panel to predict progression to cancer nor how NSAID use may modulate progression. We aimed to evaluate somatic genetic abnormalities with NSAIDs as predictors of EA in a prospective cohort study of patients with BE. Methods and Findings Esophageal biopsies from 243 patients with BE were evaluated at baseline for TP53 and CDKN2A (p16) alterations, tetraploidy, and aneuploidy using sequencing; loss of heterozygosity (LOH); methylation-specific PCR; and flow cytometry. At 10 y, all abnormalities, except CDKN2A mutation and methylation, contributed to EA risk significantly by univariate analysis, ranging from 17p LOH (relative risk [RR] = 10.6; 95% confidence interval [CI] 5.2–21.3, p < 0.001) to 9p LOH (RR = 2.6; 95% CI 1.1–6.0, p = 0.03). A panel of abnormalities including 17p LOH, DNA content tetraploidy and aneuploidy, and 9p LOH was the best predictor of EA (RR = 38.7; 95% CI 10.8–138.5, p < 0.001). Patients with no baseline abnormality had a 12% 10-y cumulative EA incidence, whereas patients with 17p LOH, DNA content abnormalities, and 9p LOH had at least a 79.1% 10-y EA incidence. In patients with zero, one, two, or three baseline panel abnormalities, there was a significant trend toward EA risk reduction among NSAID users compared to nonusers (p = 0.01). The strongest protective effect was seen in participants with multiple genetic abnormalities, with NSAID nonusers having an observed 10-y EA risk of 79%, compared to 30% for NSAID users (p < 0.001). Conclusions A combination of 17p LOH, 9p LOH, and DNA content abnormalities provided better EA risk prediction than any single TP53, CDKN2A, or DNA content lesion alone. NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities.

Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett's oesophagus: a prospective study

BACKGROUND Aspirin and other non-steroidal anti-inflammatory drugs (NSAID) probably decrease the risk of colorectal neoplasia; however their effect on development of oesophageal adenocarcinoma is less clear. We aimed to assess the role of NSAID in the development of oesophageal adenocarcinoma and precursor lesions in people with Barretts oesophagus--a metaplastic disorder that confers a high risk of oesophageal adenocarcinoma. METHODS We did a prospective study of the relation between duration, frequency, and recency of NSAID use and the risk of oesophageal adenocarcinoma, aneuploidy, and tetraploidy in a cohort of 350 people with Barretts oesophagus followed for 20,770 person-months. We used proportional-hazards regression to calculate hazard ratios (HR) adjusted for age, sex, cigarette use, and anthropometric measurements. FINDINGS Median follow-up was 65.5 months (range 3.1-106.9). Compared with never users, HR for oesophageal adenocarcinoma (n=37 cases) in current NSAID users was 0.32 (95% CI 0.14-0.76), and in former users was 0.70 (0.31-1.58). 5-year cumulative incidence of oesophageal adenocarcinoma was 14.3% (95% CI 9.3-21.6) for never users, 9.7% (4.5-20.5) for former users, and 6.6% (3.1-13.6) for current NSAID users. When changes in NSAID use during follow up were taken into account, the associations were strengthened: HR for oesophageal adenocarcinoma for current users at baseline or afterwards was 0.20 (95% CI 0.10-0.41) compared with never users. Compared with never users, current NSAID users (at baseline and follow-up) had less aneuploidy (n=35 cases; 0.25 [0.12-0.54]) and tetraploidy (n=45 cases; 0.44 [0.22-0.87]). INTERPRETATION NSAID use might be an effective chemopreventive strategy, reducing the risk of neoplastic progression in Barretts oesophagus.

Exercise Effect on Weight and Body Fat in Men and Women

Objectives: The effect of national exercise recommendations on adiposity is unknown and may differ by sex. We examined long‐term effects of aerobic exercise on adiposity in women and men.

Leukocyte telomere length predicts cancer risk in Barrett's esophagus.

Purpose: Leukocyte telomere length has gained attention as a marker of oxidative damage and age-related diseases, including cancer. We hypothesize that leukocyte telomere length might be able to predict future risk of cancer and examined this in a cohort of patients with Barretts esophagus, who are at increased risk of esophageal adenocarcinoma and thus were enrolled in a long-term cancer surveillance program. Patients and Methods: In this prospective study, telomere length was measured by quantitative PCR in baseline blood samples in a cohort of 300 patients with Barretts esophagus followed for a mean of 5.8 years. Leukocyte telomere length hazard ratios (HR) for risk of esophageal adenocarcinoma were calculated using multivariate Cox models. Results: Shorter telomeres were associated with increased esophageal adenocarcinoma risk (age-adjusted HR between top and bottom quartiles of telomere length, 3.45; 95% confidence interval, 1.35-8.78; P = 0.009). This association was still significant when individually or simultaneously adjusted for age, gender, nonsteroidal anti-inflammatory drug (NSAID) use, cigarette smoking, and waist-to-hip ratio (HR, 4.18; 95% confidence interval, 1.60-10.94; P = 0.004). The relationship between telomere length and cancer risk was particularly strong among NSAID nonusers, ever smokers, and patients with low waist-to-hip ratio. Conclusion: Leukocyte telomere length predicts risk of esophageal adenocarcinoma in patients with Barretts esophagus independently of smoking, obesity, and NSAID use. These results show the ability of leukocyte telomere length to predict the risk of future cancer and suggest that it might also have predictive value in other cancers arising in a setting of chronic inflammation. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2649–55)

Extent of low-grade dysplasia is a risk factor for the development of esophageal adenocarcinoma in barrett's esophagus

OBJECTIVES:Previous studies that evaluated extent of high-grade dysplasia (HGD) as a risk factor for esophageal adenocarcinoma (EA) in Barretts esophagus (BE) were conflicting, and no prior study has evaluated extent of low-grade dysplasia (LGD) as a risk factor. The aim of this discovery study was to evaluate the hypothesis that extent of LGD and HGD are risk factors for progression to EA.METHODS:We evaluated baseline biopsies from 77 BE patients with dysplasia including 44 who progressed to EA and 33 who did not progress during follow-up. The total numbers of LGD and HGD crypts were determined separately by counting all crypts and the extent of LGD, HGD, and total dysplasia were correlated with EA outcome.RESULTS:Thirty-one and 46 patients had a maximum diagnosis of LGD and HGD, respectively. When the crypts were stratified by dysplasia grade, the mean number of LGD crypts per patient was borderline higher in progressors (93.9) compared with nonprogressors (41.2, P = 0.07), and the mean proportion of LGD crypts per patient was significantly higher in progressors (46.4% vs 26.0%, P = 0.037). Neither the mean number of HGD crypts per patient (P = 0.14) nor the mean proportion of HGD crypts per patient (P = 0.20) was significantly associated with EA outcome.CONCLUSIONS:The extent of LGD is a significant risk factor for the development of EA in BE in this study. Although the presence of HGD is significantly associated with a greater relative risk for development of EA, the extent of HGD was not an independent risk factor for progression.

Crypt dysplasia with surface maturation: a clinical, pathologic, and molecular study of a Barrett's esophagus cohort.

Little is known regarding the significance of esophageal biopsies that show dysplasia-like atypia limited to the bases of the crypts, without involvement of the surface epithelium in Barretts esophagus (BE). The aim of this study was to evaluate the clinical, pathologic, immunohistochemical, and molecular characteristics of basal crypt dysplasia-like atypia (BCDA) with surface maturation in surveillance endoscopic mucosal biopsies to gain insight into its biologic significance. The Seattle Barretts Esophagus Project is a prospective cohort study in which patients and their biopsies have been evaluated prospectively for clinical, pathologic, and molecular markers. As part of continued surveillance of the cohort, 206 consecutive BE patients were evaluated prospectively for BCDA between July 1, 2001 and August 13, 2003; 15 patients had BCDA (prevalence rate=7.3%). These 15 patients were evaluated for clinical, pathologic, and immunohistochemical (p53 and MIB-1) features during the study period (2001–2003) as well as associations with clinical, pathologic, and molecular markers [17p(TP53) loss of heterozygosity (LOH), 9p(p16) LOH, tetraploidy, and aneuploidy] that were detected previously in the same patients in the cohort study (1983–2001). All BE patients with BCDA (male-to female ratio, 12:3; mean age, 72 years; mean length of BE, 7.0 cm; mean duration of BE, 95.1 months), except 2 (87%), had dysplasia or adenocarcinoma detected in biopsies either prior to or concurrent to the one that contained BCDA. In contrast, only 112 of 191 (59%) controls had neoplasia during the same time period (59%, P=0.05). The difference between BCDA and controls was particularly significant with regard to the association with high-grade dysplasia (P=0.004). Compared with adjacent nonatypical and nondysplastic (metaplastic) BE, areas of BCDA showed a significantly elevated prevalence rate of p53 positivity (60% vs. 13%, P<0.02) and a significantly elevated total crypt and basal crypt MIB-1 proliferation rate (P<0.001). Indeed, the MIB-1 proliferation rate in the basal portion of the crypts in BCDA was similar to that detected in conventional low- or high-grade dysplasia. Patients with BCDA showed a significantly increased rate of 17p(TP53) LOH (P=0.016), aneuploidy (P=0.004), and a trend in increased 9p(p16) LOH (P=0.08), compared with control patients without BCDA. The clinical, pathologic, immunohistochemical, and molecular abnormalities were similar in BCDA cases that were considered low-grade versus those considered high-grade by histologic evaluation, except that high-grade cases tended to be older (79 years vs. 68 years, P=0.06). BCDA with surface maturation, in mucosal biopsies from patients with BE, is an uncommon but significant pathologic change that shows a variety of proliferative and molecular abnormalities and has a high association with conventional dysplasia and/or adenocarcinoma. Based on these findings, BCDA warrants further investigation as a possible subtype of true dysplasia despite the morphologic appearance of surface maturation.

Papillectomy for ampullary neoplasm: results of a single referral center over a 10-year period

BACKGROUND Tumors arising from the duodenal papilla account for approximately 5% of GI neoplasms, but are increasingly identified. OBJECTIVE To describe the clinical characteristics and outcomes in a large single-center experience with patients referred for ampullary lesions. DESIGN A retrospective review of the Virginia Mason Medical Center endoscopy and hospital service database. SETTING Tertiary referral center. PATIENTS One hundred ninety-three patients referred for ampullary lesions from 1997 to 2007. INTERVENTIONS Endoscopic management of ampullary lesions. MAIN OUTCOME MEASUREMENTS The relationship of demographic and clinical data with endoscopic treatment and clinical outcomes in these patients. RESULTS One hundred ninety-three patients underwent endoscopy for ampullary lesions. Fifteen juxta-ampullary lesions and 10 normal variants were excluded. Among 168 patients, there were 112 (67%) adenomas, 38 (23%) adenocarcinomas, and 18 (10%) nonadenomatous lesions. There were 88 men and 80 women, with a mean age of 64 years. Clinical presentation included cholestasis/cholangitis (72 patients), abdominal pain (54 patients), incidental/asymptomatic (51 patients), pancreatitis (9 patients), and bleeding (7 patients). Of the 57 patients referred to surgery, 42 were sent directly without papillectomy, and 16 were sent after papillectomy. Papillectomies were performed in 102 patients with adenomatous lesions. The mean tumor size was 2.4 cm (range 0.5-6 cm). The papillectomy complication rate was 21%: mild pancreatitis in 10 (10%) patients, cholangitis in 1, retroperitoneal perforation in 1 (adenocarcinoma), intraperitoneal perforation in 1 (lateral extension), bleeding in 5 (lateral extension in 2 of these 5), and delayed papillary stenosis in 3. Recurrences were seen in 8%. The endoscopic success rate was 84%. Factors affecting success were a smaller adenoma size and the absence of dilated ducts. CONCLUSIONS Most ampullary adenomas are amenable to endoscopy. Underlying malignancy and lateral extension may be risk factors for bleeding and perforation. Smaller lesion size and the absence of dilated ducts are factors favorably affecting success.

Polyflex self-expanding, removable plastic stents: assessment of treatment efficacy and safety in a variety of benign and malignant conditions of the esophagus.

BackgroundHistorically, esophageal fistulas, perforations, and benign and malignant strictures have been managed surgically or with the placement of permanent endoprostheses or metallic stents. Recently, a removable, self-expanding, plastic stent has become available. The authors investigated the use of this new stent at their institution.MethodsThe study reviewed all the patients who received a Polyflex stent for an esophageal indication at the authors’ institution between January 2004 and October 2006. Duration of placement, complications, and treatment efficacy were recorded.ResultsA total of 37 stents were placed in 30 patients (14 women and 16 men) with a mean age of 68 years (range, 28–92 years). Stent placement included 7 for fistulas, 3 for perforations, 1 for an anastomotic leak, 7 for malignant strictures, and 19 for benign strictures (8 anastomotic, 1 caustic, 5 reflux, 2 radiation, and 2 autoimmune esophagitis strictures, and 1 post-Nissen gas bloat stricture). The mean follow-up period was 6 months. Stent deployment was successful for all the patients, and no complications resulted from stent placement or removal. Nine stents migrated spontaneously. Three of three perforations and three of five fistulas sealed. Only one stent was removed because of patient discomfort. One patient with a radiation stricture experienced tracheoesophageal fistulas secondary to pressure necrosis. Of 20 patients with stricture, 18 experienced improvement in their dysphagia.ConclusionSelf-expanding, removable plastic stents are easily and safely placed and removed from the esophagus. This has facilitated their use in the authors’ institution for an increasing number of esophageal conditions. Further studies to help define their ultimate role in benign and malignant esophageal pathology are warranted.

Biologic properties of columnar epithelium underneath reepithelialized squamous mucosa in Barrett's esophagus.

Chronic proton pump inhibitor (PPI) therapy may lead to partial regression of Barretts esophagus (BE), resulting in the development of reepithelialized islands of squamous mucosa that may cover the underlying BE. The purpose of this study was to evaluate the clinical, histologic, and biologic characteristics of BE that is situated underneath squamous islands (BUSI). A total of 97 mucosal biopsies from 44 BE patients with BUSI were evaluated for a variety of histologic features (eg, type of epithelium, anatomic relationship of the underlying glands to the luminal surface, presence of adjacent mucosal glands or ducts, and the presence and degree of dysplasia), and immunostained for Ki-67, cyclin D1, and p53. BUSI was compared with adjacent areas of BE for all parameters. A clinical control group consisting of 50 BE patients without microscopic evidence of BUSI was selected for comparison of clinical and endoscopic features. The study group (34 males, 10 females; mean age, 67 years; mean length of BE, 5.5 cm) consisted of 27 (61%) and 12 (27%) patients on low- and high-dose PPI, respectively. On endoscopy, visible islands of squamous mucosa were noted in only 43% of study group patients (despite the presence of BUSI microscopically in all cases); one island was noted in 2%, multiple islands in 27%, and extensive islands in 14% of patients. The extent of squamous islands was unrelated to PPI dose. The study group was significantly more likely to have endoscopic evidence of extensive squamous islands compared with the control group (P = 0.009). Histologically, 89% of biopsies with BUSI showed intestinal-type, and 11% showed cardia-type, epithelium. Low- and high-grade dysplasia was noted in 4 (4%) and 5 (5%) biopsies, respectively. All patients with dysplasia in BUSI also showed dysplasia in other areas of the esophagus as well. Interestingly, BUSI reached the mucosal surface either by penetrating directly through, or by wrapping around, islands of squamous epithelium, in 68% of biopsies. Twenty-one percent of biopsies showed BUSI adjacent to submucosal glands or ducts. BUSI showed a significantly lower Ki-67 proliferation rate (29% vs. 49%, P < 0.001), and a lower, albeit nonsignificant, degree of cyclin D1 (16% vs. 29%) and p53 (4% vs. 17%) positivity in comparison to adjacent areas of BE. Furthermore, significantly lower proliferation rates were observed in BUSI that did not reveal an opening to the mucosal surface in comparison to foci that did. BUSI is phenotypically similar to typical surface BE but shows less severe proliferative abnormalities, particularly in buried glands that have no detectable connection to the esophageal lumen. Reduced proliferation may be due either to decreased exposure to luminal contents or to disruption of sloughing of surface epithelial cells into the crypt lumen. Prospective studies of large numbers of patients with BUSI will be required to determine the magnitude of its risk of progression to cancer.

Screening colonoscopy in chinese and western patients : A comparative study

OBJECTIVES:The aim of this study was to compare findings on screening colonoscopy in a Chinese cohort versus a concurrent Western cohort.METHODS:Asymptomatic adults aged 40 years or older concurrently underwent screening colonoscopy in two hospitals, one in Taiwan and the other in Seattle. The prevalence and distribution of colonic neoplasia and advanced neoplasia (defined as an adenoma ≥10 mm or with villous, high-grade dysplastic, or malignant features) were compared between the two groups.RESULTS:The Taiwan cohort was composed of 1,456 subjects. Colonic neoplasms were found in 214 (14.7%), advanced neoplasms in 58 (4%), and colon cancers in 4 subjects (0.3%). The Seattle cohort was composed of 3,403 subjects. Neoplasms were found in 705 (20.7%), advanced neoplasms in 166 (4.9%), and cancers in 11 subjects (0.3%). Age and male sex were risk factors for neoplasia in both groups. The adjusted risk ratio was 1.30 (95% confidence interval: 1.08–1.57) in Western versus Chinese patients. However, the prevalence of advanced neoplasms was not statistically different between the two cohorts. The Chinese cohort had a higher proportion of distal neoplasia (66.4% vs 52.6%; p = 0.0004). The sensitivity of a sigmoidoscopic screening strategy for detecting advanced neoplasia was higher in Chinese (79.3%) than in Western patients (67.5%).CONCLUSIONS:Compared to Westerners, Chinese patients have a slightly lower prevalence of colon neoplasia (but not advanced neoplasia), more distal distribution of neoplasia, and higher likelihood of concomitant proximal advanced neoplasia and distal neoplasia. Colonoscopy is safe, well-tolerated, and a viable screening option in Chinese patients, but its advantage over sigmoidoscopy as a screening tool may be smaller.