Development Of High-grade Dysplasia Research Articles

Clinical supervision of chronic atrophic gastritis

Patients with chronic gastritis (CG) with the development of atrophy of the gastric mucosa are at an increased risk of developing gastric cancer (GC). In the management of such patients, the development of high-grade dysplasia and invasive gastric cancer should be defined as adverse outcomes that must be prevented. To this end, patients with a diagnosis of «Chronic atrophic fundic/multifocal gastritis» are subject to dynamic dispensary observation to assess the achievement of target indicators, take into account information about changes in the diagnosis and concomitant diseases, emerging complications, as well as to enter data on ongoing therapeutic and preventive measures. This article presents the main aspects of prevention and dispensary monitoring of patients with an increased risk of gastric cancer.

S467 CDX2 Immunohistochemical Positivity Confirms Barrett Esophagus in the Absence of Goblet Cells and Confers Significant Risk for High Grade Dysplasia and Esophageal Adenocarcinoma: A Pilot Study

Introduction: Barrett’s esophagus (BE) is a premalignant condition defined by intestinal metaplasia (IM) and can develop into esophageal adenocarcinoma (EAC). The standard tool for diagnosing BE is esophagogastroduodenoscopy (EGD). Based on American College of Gastroenterology (ACG) guidelines, patients that do not have goblet cells GCs on the initial or subsequent biopsies do not qualify for surveillance EGDs. The absence of GCs on subsequent biopsy could be due to tissue sampling error, medication effects, or true goblet cells loss over time. The caudal-related homeobox transcription factor 2 (CDX2) is a well-established marker for intestinal mucosa and is present in BE mucosa, consistent with IM. In this paper, we examine the role of CDX2 staining as a marker for BE IM when patients do not have GCs on subsequent biopsies and determine the risk for high-grade dysplasia (HGD) or EAC. Methods: Serial biopsies of the esophagus were obtained during surveillance EGDs, with the initial biopsy set confirming BE with GCs and a second set that did not show GC. The CDX2 stains were prepared from paraffin blocks (Figure a,b). Results: 35 patients met all inclusion criteria and had initial biopsies that were positive for CDX2. Of those 35 patients, 34 were positive for CDX2 on subsequent slides. Of these 34 patients, one had HGD, and one had HGD and EAC. One patient was negative for GCs and CDX2 on the subsequent slides; this patient had HGD. In total, 3 of 35 patients (9%) had HGD or EAC on subsequent slides. Conclusion: This study, while small, shows that CDX2 may be an important adjunctive test for the surveillance of BE. Our results demonstrate that BE patients with proven GCs IM on initial biopsy, but not subsequent biopsies, are overwhelmingly positive for CDX2 and still have a significant risk of HGD or EAC. Our study has important limitations, including the small sample size due to strict inclusion criteria required by the IRB. Despite this, our study provides valuable information concerning CDX2 and the development of HGD and EAC in BE patients, especially those without GCs on subsequent biopsies. Our study supports the use of CDX2 as an adjunctive test for the initial diagnosis of BE. More importantly, the patients with previously diagnosed BE who no longer have GCs on subsequent biopsies but are CDX2 positive continue to have a significant risk for HGD or EAC and warrant continued surveillance. We believe that CDX2 can help identify this at-risk group.Figure 1.: a. H&E stain with HGD and adenocarcinoma (102x80mm; 220 x 220 DPI) b. CDX2 Immunohistochemical stain with HGD and adenocarcinoma (101x79mm, 220 x 220 DPI).

Genomic characterization of malignant progression in neoplastic pancreatic cysts

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.

415 External Validation of the Progression in Barrett’s Score in a Prospective Multicenter BE Cohort

INTRODUCTION: Endoscopic surveillance guidelines in Barrett’s esophagus (BE) to detect progression to high grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) are based solely on dysplasia grade. Given low rates of progression, identification of predictors (and scores) of progression may help to focus surveillance or intervention in those at higher risk. We aimed to assess predictors of progression and externally validate the Progression in Barrett’s (PIB) score in an independent multicenter prospective BE and EAC cohort. METHODS: The EA and Barrett’s esophagus (EABE) registry is a prospective cohort of patients recruited from three medical centers. Progressors were defined as those with the development of HGD or EAC more than 12 months after initial diagnosis. Demographic and clinical variables were abstracted. The annual incidence rate and predictors of progression were assessed using univariate and multivariable Cox proportional hazards analysis. The ability of the PIB score (incorporating weighted scores for male gender, smoking (ever versus never), BE length and confirmed LGD) to risk stratify the cohort into low (0-10 points), intermediate (11-20 points) and high risk (> 20 points) groups was assessed. RESULTS: 429 patients were included. 84% were men, with a mean (SD) age of 61.5 (9.9) years. 65% were ever smokers and most (76.7%), had NDBE at diagnosis. Mean (SD) maximal BE segment length was 5.9 (3.2) cm. Eighty-two patients (19.1%) progressed to HGD (n = 65) or EAC (n = 17) over a median (IQR) follow up of 7.5 (3.7, 12.5) years. Annual incidence rates of progression to EAC and EAC/HGD were 0.5% and 2.0% respectively. Univariate and multivariable predictors of progression are displayed in Table 1. The PIB score divided patients into three groups (Table 2) with progressively increasing rates of progression. The risk in the high risk group was three fold higher than the low risk group (P = 0.024). The risk in the intermediate group was twofold higher but not statistically significantly higher (P = 0.13). The PIB score had a c-statistic score of 0.76 in the original cohort. In this cohort the c-statistic value was lower at 0.64, suggesting moderate performance. CONCLUSION: Male sex and BE length predicted progression in this independent multicenter cohort. The PIB score was also able to risk-stratify patients in this validation cohort with the high risk cohort being 3x more likely to progress compared to the low risk cohort.

DNA flow cytometric and interobserver study of crypt cell atypia in inflammatory bowel disease.

The pathological features and diagnostic reliability of crypt cell atypia (CCA) arising in inflammatory bowel disease (IBD) and its clinical significance are unknown. DNA flow cytometry (FCM) was performed on 14 colon biopsies of CCA from seven IBD patients (male-to-female ratio, 5:2; mean age, 53years; mean IBD duration, 15years) using paraffin-embedded tissue. Seven gastrointestinal pathologists were asked to diagnose each biopsy as negative for dysplasia (NEG), indefinite for dysplasia (IND), low-grade dysplasia (LGD) or high-grade dysplasia (HGD) by morphology alone, then again with knowledge of FCM results. Aneuploidy was detected in all 14 biopsies, and five of eight biopsies (63%) also showed strong and diffuse nuclear staining for p53 in the areas of CCA. Six (86%) patients developed HGD (n=5) or adenocarcinoma (n=1) in the same colonic segment where CCA had been diagnosed within a mean follow-up time of 27months. No follow-up information was available in the remainingone patient. When diagnoses were grouped as NEG or 'atypical' (including IND, LGD or HGD), the overall agreement rate of 76% (kappa=0.51) based on morphology alone improved to 90% (kappa=0.81) with knowledge of FCM results. Even when categorised as NEG or dysplasia (LGD or HGD) with each of the IND diagnoses reclassified into three categories (NEG, LGD or HGD) based on the degree of suspicion for dysplasia, the overall agreement rate of 63% (kappa=0.25) based on morphology alone improved to 73% (kappa=0.46) with knowledge of FCM results. However, when grouped as NEG, LGD or HGD, the overall agreement rate was less than 40% (kappa<0.09) regardless of knowledge of FCM results. The presence of aneuploidy, p53 positivity and development of HGD or adenocarcinoma on follow-up indicate that CCA likelyrepresents a dysplastic lesion (at least LGD) and is a histological marker of neoplastic progression. Although the grading of CCA, largely based on cytological abnormalities, is subject to significant interobserver variability, CCA can be histologically identified and should lead to a recommendation of increased endoscopic surveillance, especially if aneuploidy is detected.

Development and Validation of a Model to Determine Risk of Progression of Barrett’s Esophagus to Neoplasia

A system is needed to determine the risk of patients with Barrett's esophagus for progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). We developed and validated a model to determine of progression to HGD or EAC in patients with BE, based on demographic data and endoscopic and histologic findings at the time of index endoscopy. We performed a longitudinal study of patients with BE at 5 centers in United States and 1 center in Netherlands enrolled in the Barrett's Esophagus Study database from 1985 through 2014. Patients were excluded from the analysis if they had less than 1 year of follow-up, were diagnosed with HGD or EAC within the past year, were missing baseline histologic data, or had no intestinal metaplasia. Seventy percent of the patients were used to derive the model and 30% were used for the validation study. The primary outcome was development of HGD or EAC during the follow-up period (median, 5.9 years). Survival analysis was performed using the Kaplan-Meier method. We assigned a specific number of points to each BE risk factor, and point totals (scores) were used to create categories of low, intermediate, and high risk. We used Cox regression to compute hazard ratios and 95% confidence intervals to determine associations between risk of progression and scores. Of 4584 patients in the database, 2697 were included in our analysis (84.1% men; 87.6% Caucasian; mean age, 55.4 ± 20.1 years; mean body mass index, 27.9 ± 5.5 kg/m2; mean length of BE, 3.7 ± 3.2 cm). During the follow-up period, 154 patients (5.7%) developed HGD or EAC, with an annual rate of progression of 0.95%. Male sex, smoking, length of BE, and baseline-confirmed low-grade dysplasia were significantly associated with progression. Scores assigned identified patients with BE that progressed to HGD or EAC with a c-statistic of 0.76 (95% confidence interval, 0.72-0.80; P < .001). The calibration slope was 0.9966 (P= .99), determined from the validation cohort. We developed a scoring system (Progression in Barrett's Esophagus score) based on male sex, smoking, length of BE, and baseline low-grade dysplasia that identified patients with BE at low, intermediate, and high risk for HGD orEAC. This scoring system might be used in management ofpatients.

Association of Aneuploidy and Flat Dysplasia With Development of High-Grade Dysplasia or Colorectal Cancer in Patients With Inflammatory Bowel Disease

There is controversy over how to best manage patients with inflammatory bowel disease and flat low-grade dysplasia (fLGD) in the colon. We performed a retrospective analysis of formalin-fixed paraffin-embedded colon tissues with fLGD from 37 patients undergoing surveillance colonoscopy for inflammatory bowel disease from 1990 to 2015 at the University of California at San Francisco Medical Center, to determine whether detection of aneuploidy is associated with later development of high-grade dysplasia (HGD) or colorectal cancer. Medical data were collected from the patients for a mean follow-up time of 37 months. Using flow cytometry analysis of paraffin-embedded colon tissue, we detected aneuploidy in 15 of 37 samples with fLGD (40.5%). By comparison, aneuploidy was detected in 14 of 15 samples with flat HGD (93.3%) and 2 of 45 samples that were negative for dysplasia (4.4%). The univariate hazard ratio for subsequent detection of HGD or colorectal cancer in patients with fLGD and aneuploidy was 5.3 (95% CI, 1.542-24.121) within a mean follow-up time of 37 months. The presence of aneuploidy therefore identifies patients with fLGD in colon tissue who have an increased risk for HGD or colorectal cancer and may provide supportive evidence to a morphologic impression or suspicion of flat HGD.

Low-grade dysplasia in ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer.

OBJECTIVES:The aim of this study was to identify risk factors associated with development of high-grade dysplasia (HGD) or colorectal cancer (CRC) in ulcerative colitis (UC) patients diagnosed with low-grade dysplasia (LGD).METHODS:Patients with histologically confirmed extensive UC, who were diagnosed with LGD between 1993 and 2012 at St Mark's Hospital, were identified and followed up to 1 July 2013. Demographic, endoscopic, and histological data were collected and correlated with the development of HGD or CRC.RESULTS:A total of 172 patients were followed for a median of 48 months from the date of initial LGD diagnosis (interquartile range (IQR), 15–87 months). Overall, 33 patients developed HGD or CRC (19.1% of study population; 20 CRCs) during study period. Multivariate Cox proportional hazard analysis revealed that macroscopically non-polypoid (hazard ratio (HR), 8.6; 95% confidence interval (CI), 3.0–24.8; P<0.001) or invisible (HR, 4.1; 95% CI, 1.3–13.4; P=0.02) dysplasia, dysplastic lesions ≥1 cm in size (HR, 3.8; 95% CI, 1.5–13.4; P=0.01), and a previous history of “indefinite for dysplasia” (HR, 2.8; 95% CI, 1.2–6.5; P=0.01) were significant contributory factors for HGD or CRC development. Multifocal dysplasia (HR, 3.9; 95% CI, 1.9–7.8; P<0.001), metachronous dysplasia (HR, 3.5; 95% CI, 1.6–7.5; P=0.001), or a colonic stricture (HR, 7.4; 95% CI, 2.5–22.1; P<0.001) showed only univariate correlation to development of HGD or CRC.CONCLUSIONS:Lesions that are non-polypoid or endoscopically invisible, large (≥1 cm), or preceded by indefinite dysplasia are independent risk factors for developing HGD or CRC in UC patients diagnosed with LGD.

SOX2 as a novel marker to predict neoplastic progression in Barrett's esophagus.

The value of Barrett's esophagus (BE) surveillance based on the histological diagnosis of low-grade dysplasia (LGD) remains debated given the lack of adequate risk stratification. The aim of this study was to evaluate the predictive value (PV) of SOX2 expression for neoplastic progression in BE patients. We conducted a case-control study within a prospective cohort of 720 BE patients. Patients with neoplastic progression, defined as the development of high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), were classified as cases and patients without neoplastic progression were classified as controls. SOX2 expression was determined by immunohistochemistry in more than 12,000 biopsies from 635 patients; these results were combined with our previous p53 immunohistochemical data. Nondysplastic BE showed homogeneous nuclear staining for SOX2, whereas SOX2 was progressively lost in dysplastic BE. Loss of SOX2 was seen in only 2% of biopsy series without dysplasia, in contrast to 28% in LGD and 67% in HGD/EAC. Loss of SOX2 expression was associated with an increased risk of neoplastic progression in BE patients after adjusting for gender, age, BE length, and esophagitis (adjusted relative risk 4.8; 95% CI 3.2-7.0). The positive PV for neoplastic progression increased from 16% with LGD alone to 56% with concurrent loss of SOX2 and aberrant p53 expression. SOX2 expression is lost during transition from nondysplastic BE to HGD/EAC, and it is associated with an increased risk of neoplastic progression. The highest PV is achieved by concurrent loss of SOX2 and aberrant p53 expression in BE patients with LGD. The use of these markers has the potential to significantly improve risk stratification of Barrett surveillance.

Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: a prospective cohort study.

The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.

OC-080 Low-grade dysplasia in ulcerative colitis: risk factors associated with progression to high-grade dysplasia or colorectal cancer: Abstract OC-080 Table 1

Introduction The aim of this study was to identify risk factors associated with development of high-grade dysplasia (HGD) or colorectal cancer (CRC) in ulcerative colitis (UC) patients diagnosed with low-grade dysplasia (LGD). Method Patients with histologically confirmed extensive UC who were diagnosed with LGD between 1993 and 2012 were identified and followed up to 1 st January 2013. Data on patient demographics, endoscopic and histological variables at the time of the first LGD episode were collected and correlated with progression to HGD or CRC, our primary outcome measure. Time to event analysis was performed using Cox-proportional hazards methods. Results A total of 172 patients were followed for median of 48 months (interquartile range (IQR), 15–87) who underwent 707 follow-up colonoscopies (median, 4; IQR, 2–6) after the initial LGD episode. Overall, 33 patients developed HGD or CRC (19.1%) during study period. Table 1shows variables significantly associated with progression to HGD/CRC on univariate analysis. At multivariate level, only macroscopically non-polypoid (HR, 8.6; 95% CI, 3.0–24.8; p p = 0 .02) lesions, lesions ≥1 cm in size (HR, 3.8; 95% CI, 1.5–13.4; p = 0 .01), and a previous history of indefinite for dysplasia diagnosis (HR, 2.8; 95% CI, 1.2–6.5; P = 0 .01) remained significant contributory factors for developing HGD/CRC. The detection rate for non-polypoid lesions was significantly higher with chromoendoscopy (15.8%) compared with white-light endoscopy (7.8%; p Conclusion The chromoendoscopy was superior at detecting non-polypoid lesions compared with the white-light endoscopy. Lesions that are large (≥1 cm), non-polypoid, and endoscopically invisible or preceded by “indefinite for dysplasia” diagnosis are independent risk factors for the development of HGD/CRC. Disclosure of interest None Declared.

Cryospray Ablation for Barrett’s High-Grade Dysplasia in a Community-Based Barrett’s Registry of 965 Patients: 7 Year Follow-up

Introduction: To report the 7 year experience of a community-based gastroenterology practice using primarily nitrogen based cryospray ablation (CSA) in the treatment of Barrett’s esophagus with highgrade dysplasia (HGD) in a registry of 965 patients. Methods: Over 14 years, a community-based 9 physician gastroenterology practice prospectively enrolled 965 patients with confirmed intestinal metaplasia (IM), with or without dysplasia on initial biopsy of BE, in a Barrett’s registry. Intervention for the ablation of HGD was primarily CSA with follow-up esophageal biopsies per Seattle protocol. Nodular lesions in BE were first treated with endoscopic mucosal resection (EMR). Endpoints were histology based; complete response was defined as all biopsies at most recent endoscopy (EGD) negative for intestinal metaplasia (CR-IM) or dysplasia (CR-D). Results: From within a BE registry of 965 patients begun in 1999, a total of 28 patients had HGD. The mean age of patients with HGD was 69 years (range 47-89), 82% men. Mean BE length was 5cm (range 1-13cm). Eleven patients had HGD on initial EGD, 16 developed HGD during surveillance. The mean time to develop HGD during surveillance was 56 months (range 2-139 mo). We used CSA for ablation in 27 of the 28 patients. Mean CSA to completion: 4. Twenty-one received CSA exclusively, while 7 had EMR as their initial treatment for some element of nodularity. One was cured by a single EMR; the remaining 6 had subsequent CSA. Two patients had EMR followed by radiofrequency ablation (RFA) at an outside tertiary institution and were then referred to our registry/center for CSA after being considered treatment failures. Mean EGD follow-up after HGD was confirmed eradicated was 25 months (range 4-51 months). Mean CSA to achieve eradication: 4 treatments. Conclusion: The development of HGD in a Barrett’s surveillance registry is a relatively uncommon event. Durable, long-term elimination of HGD can be reliably achieved with cryospray ablation with minimal adverse events. Cryospray ablation offers a promising alternative to other ablative modalities such as EMR and RFA.Table 1: Ablation Stats From Registry

Barrett's oesophagus patients with low-grade dysplasia can be accurately risk-stratified after histological review by an expert pathology panel

ObjectiveReported malignant progression rates for low-grade dysplasia (LGD) in Barrett's oesophagus (BO) vary widely. Expert histological review of LGD is advised, but limited data are available on its clinical value....

Genetic Predictors of Cervical Dysplasia in African American HIV-Infected Women: ACTG DACS 268

Objective: To examine genome-wide associations in HIV-infected women with a history of cervical dysplasia compared with HIV-infected women with no history of abnormal Papanicolaou (Pap) tests. Design: Case-control study using data from women analyzed for the HIV Controllers Study and enrolled in HIV treatment-naïve studies in the AIDS Clinical Trials Group (ACTG). Methods: Genotyping utilized Illumina HumanHap 650 Y or 1MDuo platforms. After quality control and principal component analysis, ~610,000 significant single nucleotide polymorphisms (SNPs) were tested for association. Threshold for significance was P < 5 × 10–8 for genome-wide associations. Results: No significant genomic association was observed between women with low-grade dysplasia and controls. The genome-wide association study (GWAS) analysis between women with high-grade dysplasia or invasive cervical cancer and normal controls identified significant SNPs. In the analyses limited to African American women, 11 SNPs were significantly associated with the development of high-grade dysplasia or cancer after correcting for multiple comparisons. The model using significant SNPs alone had improved accuracy in predicting high-grade dysplasia in African American women compared to the use of clinical data (area under the receiver operating characteristic curve for genetic and clinical model = 0.9 and 0.747, respectively). Conclusions: These preliminary data serve as proof of concept that there may be a genetic predisposition to developing high-grade cervical dysplasia in African American HIV-infected women. Given the small sample size, the results need to be validated in a separate cohort.

Genetic Predictors of Cervical Dysplasia in African American HIV-Infected Women: ACTG DACS 268

Objective: To examine genome-wide associations in HIV-infected women with a history of cervical dysplasia compared with HIV-infected women with no history of abnormal Papanicolaou (Pap) tests. Design: Case-control study using data from women analyzed for the HIV Controllers Study and enrolled in HIV treatment-naïve studies in the AIDS Clinical Trials Group (ACTG). Methods: Genotyping utilized Illumina HumanHap 650 Y or 1MDuo platforms. After quality control and principal component analysis, ~610,000 significant single nucleotide polymorphisms (SNPs) were tested for association. Threshold for significance was P < 5 × 10–8 for genome-wide associations. Results: No significant genomic association was observed between women with low-grade dysplasia and controls. The genome-wide association study (GWAS) analysis between women with high-grade dysplasia or invasive cervical cancer and normal controls identified significant SNPs. In the analyses limited to African American women, 11 SNPs were significantly associated with the development of high-grade dysplasia or cancer after correcting for multiple comparisons. The model using significant SNPs alone had improved accuracy in predicting high-grade dysplasia in African American women compared to the use of clinical data (area under the receiver operating characteristic curve for genetic and clinical model = 0.9 and 0.747, respectively). Conclusions: These preliminary data serve as proof of concept that there may be a genetic predisposition to developing high-grade cervical dysplasia in African American HIV-infected women. Given the small sample size, the results need to be validated in a separate cohort.

The relationship between smoking and severe dysplastic disease in patients with Barrett’s columnar-lined oesophagus

The aim of this study was to examine the relationship between smoking and oesophageal high-grade dysplasia (HGD) or adenocarcinoma (AC) in a large cohort of patients with Barrett's columnar-lined oesophagus (CLO). A total of 1280 patients diagnosed with CLO and registered with the UK National Barrett's Oesophagus Registry were included. Data, including smoking habits, were collected from the patient's notes and development of HGD or AC noted. Analysis was performed with SPSS using logistic regression for calculation of odds ratios (ORs) for development of HGD/AC. Data on smoking habits were available in 956 (74.6%) patients. There was no significant difference between smokers and nonsmokers in mean age (P=0.877) or length of follow-up (P=0.359). There was a significant risk of HGD/AC in patients with any history of smoking compared with those who had never smoked (P<0.001, OR 2.81). Ex-smokers of 10 years or more remained at a significantly higher risk of HGD/AC compared with those who had never smoked (P=0.001, OR 3.37). Current smokers were not at a significantly higher risk of HGD/AC compared with ex-smokers (P=0.857) nor were those who smoked at least 20 a day compared with those who smoked fewer than 20 a day (P=0.632). In patients with CLO, smoking appears to be a significant risk factor for the development of severe dysplastic disease; however, we did not observe a dose-dependent effect of smoking on progression of disease.

Reply

We thank Drs Azoulay and Suissa for their interest in our article and we would like to respond to their comment regarding immortal time bias.1Azoulay L. Suissa S. Gastroenterology. 2012; 142: e20Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 2Kastelein F. et al.Gastroenterology. 2011; 141: 2000-2008Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar In our study, patients were classified as user of nonsteroidal anti-inflammatory drugs (NSAIDs) or statins irrespective of the time patients started with the use of these drugs, since most patients were either in the exposed or nonexposed group for their entire follow-up period. For patients who used NSAIDs and statins only after inclusion in the study, the follow-up time between inclusion in the study and the first drug prescription can be considered as “immortal,” because patients had to survive this period without experiencing an event to be classified as a user of these drugs. Because misclassification of the exposure time is avoided in a time-dependent Cox regression model, we performed such analysis with updated follow-up data. Neoplastic progression was defined as the development of high-grade dysplasia or esophageal adenocarcinoma ≥9 months after inclusion in the study and follow-up time was defined as the time from 9 months after inclusion in the study to the most recent surveillance endoscopy or the endoscopy that resulted in a diagnosis of high-grade dysplasia or esophageal adenocarcinoma. Medication use was defined as a time-dependent variable, with patients classified as nonuser of NSAIDs and statins before the first drug prescription and as user afterward. Five hundred seventy patients were followed in the study for a median duration of 5.4 years (interquartile range, 4.4–6.2) and a total follow-up period of 2912 patient-years. During follow-up, 40 patients developed high-grade dysplasia or esophageal adenocarcinoma. NSAIDs were used by 318 (56%) patients with an exposure time of 1538 (53%) patient-years, statins were used by 209 (37%) patients with an exposure time of 864 (30%) patient-years, and 107 (19%) patients used both NSAIDs and statins with an exposure time of 404 (14%) patient-years. In a time-dependent Cox regression model, NSAID use was associated with a significantly lower risk of neoplastic progression (hazard ratio, 0.49; 95% confidence interval 0.25–0.97) and statin use was associated with a trend toward a lower risk of neoplastic progression (hazard ratio, 0.55; 95% confidence interval 0.23–1.29), after adjusting for age, gender, Barrett length, baseline histology, and use of other medications. Use of both NSAIDs and statins was associated with an additional protective effect (hazard ratio, 0.26; 95% confidence interval, 0.07–0.98). Although time-dependent models do not take into account that patients have no risk of experiencing the event during the immortal time period and therefore may bias against therapy, the results of the time-dependent analyses are not very different from our initial risk estimates.3Levesque L.E. et al.BMJ (Clin Res Ed). 2010; 340: b5087Crossref PubMed Scopus (715) Google Scholar, 4Yang X.L. et al.Diabetes Obes Metab. 2011 Dec 15; ([Epub ahead of print])Google Scholar Thus, our initial conclusion that NSAID and statin use are each associated with approximately 50% reduction in the risk of neoplastic progression, also holds in time-dependent analyses. Immortal Person-Time Bias in Relation to the Use of Nonsteroidal Anti-inflammatory Drugs and Statins in the Prevention of Esophageal Cancer in Patients With Barrett's EsophagusGastroenterologyVol. 142Issue 5PreviewWe read with interest the study published by Kastelein et al1 in a recent issue of Gastroenterology. The authors investigated the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and statins on the risk of neoplastic progression from Barrett's esophagus (BE). The use of NSAIDs and statins was associated with a 53% and 54% risk reduction, respectively (hazard ratio [HR], 0.47 [95% confidence interval (CI), 0.24–0.93] and HR, 0.46 [95% CI, 0.21–0.99]). Furthermore, the use of a combination of NSAIDs and statins was associated with an even stronger risk reduction (HR, 0.22; 95% CI, 0.06–0.85). Full-Text PDF

Prospective study of the progression of low-grade dysplasia in ulcerative colitis using current cancer surveillance guidelines

The goal of this study was to assess the natural history of low-grade dysplasia (LGD) and its risk of progression in ulcerative colitis (UC) patients by prospective endoscopic surveillance. Forty-two UC patients with LGD were followed prospectively using a uniform approach to surveillance colonoscopy with an average of 43 biopsies per exam. The interval between colonoscopies ranged from 3-12 months. Progression was defined as development of high-grade dysplasia (HGD) or cancer at subsequent colonoscopy or at colectomy. Univariate and multivariate analysis were performed to identify risk factors associated with progression. Patients were followed for an average of 3.9 years (range 1-13). Over that period 19% (8/42) of patients progressed to advanced neoplasia (two cancer, six HGD) while 17% (7/42) had persistent LGD and 64% (27/42) had indefinite dysplasia or no dysplasia at the end of follow-up. Multivariate analysis demonstrated that the number of biopsies with LGD at baseline was associated with an increased risk of progression to advanced neoplasia (relative risk [RR] 5.8, 95% confidence interval [CI]: (1.29-26.04). Among the 15 patients who underwent colectomy, four were found to have higher-grade neoplasia on their colectomy specimen than their preoperative colonoscopy, and these patients were more likely to be nonadherent with recommendations for colectomy. The majority (81%) of UC patients with LGD did not progress to higher grades of dysplasia during a 4-year follow-up. Patients with three or more biopsies demonstrating LGD at a single colonoscopy were at increased risk for progression to advanced neoplasia.

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