Multicenter, Prospective Trial of Nonendoscopic Biomarker-Driven Detection of Barrett's Esophagus and Esophageal Adenocarcinoma.

INTRODUCTION: Preliminary data suggest that an encapsulated balloon (EsoCheck), coupled with a 2 methylated DNA biomarker panel (EsoGuard), detects Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) with high accuracy. The initial assay requires sample freezing upon collection. The purpose of this study was to assess a next-generation EsoCheck sampling device and EsoGuard assay in a much-enlarged multicenter study clinically enhanced by using a Clinical Laboratory Improvement Amendments of 1988-compliant assay and samples maintained at room temperature. METHODS: Cases with nondysplastic BE (NDBE), dysplastic BE (indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia), EAC, junctional adenocarcinoma, plus endoscopy controls without esophageal intestinal metaplasia, were prospectively enrolled. Medical assistants at 6 institutions delivered the encapsulated balloon per orally with inflation in the stomach. The inflated balloon sampled the distal 5 cm of the esophagus and then was deflated and retracted into the capsule, preventing sample contamination. EsoGuard bisulfite sequencing assayed levels of methylated vimentin and methylated cyclin A1. RESULTS: A total of 243 evaluable patients-88 cases (median age 68 years, 78% men, 92% White) and 155 controls (median age 57 years, 41% men, 88% White)-underwent adequate EsoCheck sampling. The mean procedural time was approximately 3 minutes. Cases included 31 with NDBE, 16 with indefinite for dysplasia/low-grade dysplasia, 23 with high-grade dysplasia, and 18 with EAC/junctional adenocarcinoma. Thirty-seven NDBE and dysplastic BE cases (53%) were short-segment BE (<3 cm). Overall sensitivity was 85% (95% confidence interval 0.78-0.93) and specificity was 85% (95% confidence interval 0.79-0.90). Sensitivity for NDBE was 84%. EsoCheck/EsoGuard detected 100% of cancers (n = 18). DISCUSSION: EsoCheck/EsoGuard demonstrated high sensitivity and specificity in detecting BE and BE-related neoplasia.

Patients With Esophageal Adenocarcinoma With Prior Gastroesophageal Reflux Disease Symptoms Are Similar to Those Without Gastroesophageal Reflux Disease: A Cross-Sectional Study.

INTRODUCTION: A substantial proportion of patients with esophageal adenocarcinoma (EAC) do not report gastroesophageal reflux disease (GERD) symptoms. This study aimed to compare the risk factor profiles and cancer stage at presentation of patients with EAC with and without prior GERD. METHODS: In this retrospective cross-sectional study, patients with EAC were divided into 2 cohorts: (i) EAC with prior GERD: patients who reported typical GERD symptoms (heartburn or regurgitation) ≥1 year before cancer diagnosis and (ii) EAC without prior GERD: patients who did not report prior GERD symptoms or reported symptoms within 1 year of their cancer diagnosis. Baseline demographics, risk factors, and cancer stage at presentation were compared between the 2 cohorts. In addition, the distribution of patients based on numbers of BE/EAC-associated risk factors (1, 2, 3, 4, and 5 or more) was examined in the symptomatic and asymptomatic cohorts. RESULTS: Over 13 years, 388 patients with EAC with prior GERD and 245 patients with EAC without prior GERD were recruited. Both groups had similar baseline demographics and risk factors, but patients with EAC with prior GERD were more likely to have a history of BE. Asymptomatic patients had more advanced disease. Patients with 3 or more BE/EAC-related risk factors formed the largest proportion of patients in both the symptomatic and asymptomatic cohorts. DISCUSSION: Patients with EAC with and without prior GERD symptoms are phenotypically similar, suggesting that BE screening efforts to prevent or detect early EAC should not be restricted to just those with GERD.

Patient Factors Affect Ergonomic Strain of Endoscopists During Colonoscopy.

INTRODUCTION: Endoscopic procedures place a great deal of muscular strain on providers, especially over the span of their careers. In this study we quantitatively analyzed the effects of patient factors such as age, body mass index, and sex on the ergonomics of endoscopists performing colonoscopies. METHODS: Surface electromyography (sEMG) was used to measure ergonomic strain of physicians while performing colonoscopies in several key muscle groups. The percent of the maximum voluntary contraction (%MVC) was used as a measure of muscular strain. Data was then analyzed based on the patient characteristics above. RESULTS: Endoscopists performing colonoscopies on female patients (n = 47) experienced significantly higher ergonomic strain in their right trapezius and right posterior forearm muscle groups when compared to colonoscopies performed on males (n = 35) (%MVC R-trapezius: Male: 8.2; Female: 8.9; p = 0.048); (%MVC R-posterior forearm: Male: 10.4; Female: 11.6; p = 0.0006). Operators experienced greater strain in the same muscle groups when performing colonoscopies on patients with BMI ≤ 25 (n = 25) when compared to patients with BMI > 25 (n = 57) (%MVC R-trapezius: BMI < 25: 9.7; BMI ≥ 25: 8.2; p = 0.0002); (%MVC R-posterior forearm: BMI < 25: 11.9; BMI ≥ 25: 10.8; p = 0.0001). CONCLUSION: Physicians experienced greater ergonomic strain when performing colonoscopies on female patients and on patients with a BMI < 25. We believe that these factors potentially impact the tortuosity of the colon and therefore influence the difficulty of navigating the endoscope. These results may aid physicians in gauging the anticipated difficulty of colonoscopies based on patient factors. Increased awareness of their posturing and ergonomics during challenging cases will alleviate musculoskeletal injuries in the long run.

Massively Parallel Sequencing of Esophageal Brushings Enables an Aneuploidy-Based Classification of Patients With Barrett's Esophagus.

BACKGROUND & AIMS: Aneuploidy has been proposed as a tool to assess progression in patients with Barrett's esophagus (BE), but has heretofore required multiple biopsies. We assessed whether a single esophageal brushing that widely sampled the esophagus could be combined with massively parallel sequencing to characterize aneuploidy and identify patients with disease progression to dysplasia or cancer. METHODS: Esophageal brushings were obtained from patients without BE, with non-dysplastic BE (NDBE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (EAC). To assess aneuploidy, we used RealSeqS, a technique that uses a single primer pair to interrogate ∼350,000 genome-spanning regions and identify specific chromosome arm alterations. A classifier to distinguish NDBE from EAC was trained on results from 79 patients. An independent validation cohort of 268 subjects was used to test the classifier at distinguishing patients at successive phases of BE progression. RESULTS: Aneuploidy progression was associated with gains of 1q, 12p, and 20q and losses on 9p and 17p. The entire chromosome 8q was often gained in NDBE, whereas focal gain of 8q24 was identified only when there was dysplasia. Among validation subjects, a classifier incorporating these features with a global measure of aneuploidy scored positive in 96% of EAC, 68% of HGD, but only 7% of NDBE. CONCLUSIONS: RealSeqS analysis of esophageal brushings provides a practical and sensitive method to determine aneuploidy in BE patients. It identifies specific chromosome changes that occur early in NDBE and others that occur late and mark progression to dysplasia. The clinical implications of this approach can now be tested in prospective trials.

Smaller hands and less experience are associated with greater ergonomic strain during endoscopic procedures.

INTRODUCTION: Up to 89% of physicians who routinely perform endoscopy experience some type of musculoskeletal pain. In this study, we sought to quantitatively analyze provider factors that influence ergonomic strain during live endoscopic procedures. METHODS: Surface electromyography (sEMG) was used to measure ergonomic strain on physicians while performing upper and lower endoscopies. EMG data were normalized to a maximal voluntary contraction (MVC) recording for each muscle group, yielding a %MVC value. Subgroup analyses were performed based on glove size, physician training level, specialty, and handedness. RESULTS: A total of 165 upper (n = 68) and lower (n = 97) endoscopies were recorded. Endoscopists with small hand sizes had significantly higher ergonomic strain in the left anterior and posterior forearm muscle compartments as compared to endoscopists with medium or large hands (%MVC L-anterior: small: 9.1 ± 1.1; medium: 6.4 ± 1.2; large: 5.9 ± 1.6; p < 0.001); (%MVC L-posterior: small: 12.0 ± 0.8; medium: 9.4 ± 1.3; large: 8.8 ± 1.4; p < 0.001). Additionally, upper body muscle groups had significantly higher ergonomic strain in endoscopists with less lifetime endoscopic experience (%MVC R-trapezius: expert: 8.4 ± 1.2; novice: 9.3 ± 1.2; p < 0.05); (%MVC R-deltoid: expert: 6.1 ± 1.4; novice: 8.5 ± 1.3; p < 0.001). There were no significant ergonomic differences between surgeons or gastroenterologists and no differences between right- and left-handed dominant individuals. CONCLUSIONS: Endoscopists with small hands experienced great ergonomic strain in their left forearm. Our data support the widely held belief that "one size does not fit all" and will hopefully spark change in the design of future endoscopes by device manufacturers. Our data also support that the experience level of the endoscopist contributed significantly to ergonomic performance, likely due to postural differences leading to decreased upper body strain. Therefore, it remains critically important to educate young proceduralists on strategies for ergonomic relief early in his or her endoscopic training program that can ameliorate ergonomic strain that accrues over the lifetime of a physician's career.

Implementing Educational and Systems-Level Changes to Improve Cancer Screening Rates Among State Employees in Missouri.

As of 2022, only 51% of active eligible state employees in Missouri have been screened for colorectal cancer and 67% for breast cancer, despite having state-sponsored health insurance. In fall 2020, the Missouri Department of Health and Senior Services Comprehensive Cancer Program partnered with the Missouri Cancer Consortium to create a strategy to improve cancer screening rates among state employees. The project was designed to include 3 phases: 1) a colorectal cancer education phase, 2) an expanded education phase that included additional cancers, and 3) a proposed intervention phase that will include screening events. In the first phase, in 2020, colorectal cancer educational materials were sent to all state employees. In the second phase, in 2022, educational resources were expanded to include additional cancers and screening tools. In both initiatives, educational materials and information on current screening recommendations were distributed to approximately 40,000 state employees. A database of screening rates was developed to monitor screening rates and challenge state employees to complete screenings. Evidence-informed interventions were implemented with a focus on health equity. We used a regional approach to identify geographic areas with the greatest need. These efforts will support the next phase of the project, which involves planning breast and colorectal cancer screening events. Policy changes will be encouraged to remove systems-level barriers that discourage employees from being screened for cancer. Recommended tools and strategies can be adopted by similar organizations with complex, multitier employee structures.

Systems Biology Analyses Show Hyperactivation of Transforming Growth Factor-ß and JNK Signaling Pathways in Esophageal Cancer.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) is resistant to standard chemoradiation treatments, and few targeted therapies are available. We used large-scale tissue profiling and pharmacogenetic analyses to identify deregulated signaling pathways in EAC tissues that might be targeted to slow tumor growth or progression. METHODS: We collected 397 biopsy specimens from patients with EAC and nonmalignant Barrett's esophagus (BE), with or without dysplasia. We performed RNA-sequencing analyses and used systems biology approaches to identify pathways that are differentially activated in EAC vs nonmalignant dysplastic tissues; pathway activities were confirmed with immunohistochemistry and quantitative real-time polymerase chain reaction analyses of signaling components in patient tissue samples. Human EAC (FLO-1 and EsoAd1), dysplastic BE (CP-B, CP-C, CP-D), and nondysplastic BE (CP-A) cells were incubated with pharmacologic inhibitors or transfected with small interfering RNAs. We measured effects on proliferation, colony formation, migration, and/or growth of xenograft tumors in nude mice. RESULTS: Comparisons of EAC vs nondysplastic BE tissues showed hyperactivation of transforming growth factor-ß (TGFB) and/or Jun N-terminal kinase (JNK) signaling pathways in more than 80% of EAC samples. Immunohistochemical analyses showed increased nuclear localization of phosphorylated JUN and SMAD proteins in EAC tumor tissues compared with nonmalignant tissues. Genes regulated by the TGFB and JNK pathway were overexpressed specifically in EAC and dysplastic BE. Pharmacologic inhibition or knockdown of TGFB or JNK signaling components in EAC cells (FLO-1 or EsoAd1) significantly reduced cell proliferation, colony formation, cell migration, and/or growth of xenograft tumors in mice in a SMAD4-independent manner. Inhibition of the TGFB pathway in BE cell lines reduced the proliferation of dysplastic, but not nondysplastic, cells. CONCLUSIONS: In a transcriptome analysis of EAC and nondysplastic BE tissues, we found the TGFB and JNK signaling pathways to be hyperactivated in EACs and the genes regulated by these pathways to be overexpressed in EAC and dysplastic BE. Inhibiting these pathways in EAC cells reduces their proliferation, migration, and formation of xenograft tumors. Strategies to block the TGFB and JNK signaling pathways might be developed for treatment of EAC.

Columnar islands in Barrett's esophagus: Do they impact Prague C&M criteria and dysplasia grade?

BACKGROUND AND AIM: The standard for classifying Barrett's metaplasia on endoscopy, the Prague C&M criteria, ignores all islands of metaplastic-appearing tissue. The aims of the present study were to measure the prevalence of columnar islands, quantify their impact on metaplasia extent, and determine if they harbor advanced dysplasia. METHODS: Data from two prospective patient cohorts were retrospectively analyzed. They included adults who underwent upper endoscopy to evaluate for gastroesophageal reflux disease, Barrett's esophagus (BE), dysplasia, or adenocarcinoma between 2003 and 2012 at tertiary care centers in the USA and Germany. The BE pattern, location, and pathology were examined. The extent of BE as defined by the Prague criteria (disregarding the location of islands) was compared with the complete maximal extent of BE (incorporating the location of islands). RESULTS: A total of 555 patients underwent endoscopy (mean age 60.1 years, 67.2% male, 91.9% white). Among those patients, 191 (34.4%) showed metaplastic-appearing mucosa in islands. Endoscopically, in 101 (52.9%) cases, islands were proximal to the farthest segment of BE as defined by the Prague M location. Histologically, intestinal metaplasia was confirmed in 60 (58.8%) of the 102 esophagogastroduodenoscopies (EGDs) where islands were biopsied. In 41 (40.2%) cases, the histologically confirmed BE islands extended farther than the maximal segment based on the Prague criteria. Pathology from biopsies of islands either changed the diagnosis or worsened the BE dysplasia grade in 16 (15.7%) of the 102 patients. CONCLUSIONS: Columnar islands are commonly seen on EGD. The Prague C&M criteria may underestimate the maximal extent of BE and overlook the area of highest dysplasia grade.

Predictors of Poor Adherence of US Gastroenterologists with Colonoscopy Screening and Surveillance Guidelines.

BACKGROUND: The US Multi-Society Task Force on Colorectal Cancer published guidelines for colonoscopy screening and surveillance in 2008 and affirmed them in 2012. Characteristics associated with guideline adherence among US gastroenterologists have not been assessed. AIM: Assess awareness and adherence of US gastroenterologists with national guidelines for colonoscopy screening and surveillance and predictors of adherence to guidelines. METHODS: A Web-based survey was administered to gastroenterologists in various practice settings across the USA. RESULTS: A total of 306 gastroenterologists completed the survey; 86 % reported awareness of the guidelines. Low-volume colonoscopists (<20/month) were less likely to be aware of the guidelines (OR 0.26, p = 0.03) compared to high-volume colonoscopists (>100/month). Those completing training before 1990 were less likely to report following guidelines (OR 0.37, p = 0.01). Adherence with guidelines was then assessed via clinical scenarios. Compared to physicians finishing training in 1991-2010, less adherence was seen in those finishing before 1990 (OR 0.75, p < 0.001) or currently in training (OR 0.72, p = 0.004). Compared to the Western USA, less adherence was seen in the Midwest (OR 0.69, p = 0.001), Northeast (OR 0.63, p < 0.001), and South (OR 0.59, p < 0.001). Lower adherence was seen among non-academic physicians (OR 0.72, p = 0.001) and low-volume colonoscopists (OR 0.52, p < 0.001). CONCLUSIONS: There is poor adherence with colonoscopy screening and surveillance guidelines among US gastroenterologists. Poor adherence was associated with being in training or finishing training before 1990, practicing in the South, non-academic settings, and low colonoscopy volume. These findings can target interventions for quality improvement in colorectal cancer screening and surveillance.

Chronic tamoxifen use is associated with a decreased risk of intestinal metaplasia in human gastric epithelium.

BACKGROUND: Intestinal metaplasia (IM), a premalignant lesion, is associated with an increased risk of gastric cancer. Although estrogen exposure, including tamoxifen, has been studied in correlation with gastric cancer, little has been investigated about its effects on IM. AIMS: Therefore, we investigated whether chronic tamoxifen use was associated with the risk of IM in human stomach. METHODS: We evaluated 512 gastric biopsies from 433 female breast cancer patients that underwent endoscopic gastroduodenoscopy (EGD) ≥6 months after breast surgery. Histopathological findings were scored according to the updated Sydney classification. Demographic and clinical characteristics were also included to identify predictive factors for IM. RESULTS: In a multivariate logistic regression analysis, age at EGD (odds ratio [OR], 1.04; P = 0.002), biopsies from antrum (OR 2.08; P < 0.001), and Helicobacter pylori positivity (OR 1.68; P = 0.016) were significantly associated with an increased risk of IM, whereas chronic tamoxifen use (≥3 months) was associated with a decreased risk of IM (OR 0.59; P = 0.025). After stratifying by biopsy site, association between tamoxifen use and IM persisted for corpus (OR 0.42; P = 0.026) but not for antrum (OR 0.74; P = 0.327). In analysis limited to patients with follow-up EGD, chronic tamoxifen use also correlated with improved IM score compared to no tamoxifen use (improved, 77.8 vs. 22.2%; no change, 65.4 vs. 34.6%; worsened, 30.0 vs. 70.0%; P = 0.019). CONCLUSIONS: This study suggests that chronic tamoxifen use can decrease the risk of IM in human stomach. The effect of tamoxifen is predominantly observed in the corpus.

Physician recommendations and patient adherence after inadequate bowel preparation on screening colonoscopy.

BACKGROUND AND AIMS: It has been suggested that bowel preparation quality may influence decision-making about appropriate follow-up interval after screening colonoscopy. We sought: (1) to assess physician recommendations for timing of subsequent colonoscopy in average-risk patients with inadequate bowel preparation on initial screening, and (2) to measure the association between physician recommendations and patient adherence to repeat colonoscopy. METHODS: Patients undergoing average-risk screening colonoscopy from 2004 to 2009 found to have inadequate bowel preparation were identified. Physician recommendations for timing of subsequent colonoscopy and patient adherence to repeat colonoscopy were assessed through examination of endoscopy records. Data from repeat colonoscopies were collected through August 2010. RESULTS: There were 373 patients with inadequate bowel preparation on initial screening colonoscopy. There was a wide range of physician recommendations for timing of repeat colonoscopy: next day (4.6 % of patients), 2 days to 6 months (9.9 %), 7 months to 1 year (34.0 %), 2-5 years (38.3 %), 6-10 years (5.1 %), and timing not specified (8.0 %). Physicians were significantly more likely to recommend repeat colonoscopy within 1 year if any polyps were detected (OR = 2.2, p = 0.001). Patients instructed to have next day follow-up were significantly more likely to adhere to the recommendation compared to patients who were instructed to return after longer intervals (OR 4.4, p = 0.005). CONCLUSIONS: Patients with inadequate bowel preparation on screening colonoscopy were subject to a wide range of physician recommendations for follow-up. Patient adherence to physician recommendations was significantly higher when repeat colonoscopy was recommended the next day.

The microRNAs, MiR-31 and MiR-375, as candidate markers in Barrett's esophageal carcinogenesis.

There is a critical need to identify molecular markers that can reliably aid in stratifying esophageal adenocarcinoma (EAC) risk in patients with Barrett's esophagus. MicroRNAs (miRNA/miR) are one such class of biomolecules. In the present cross-sectional study, we characterized miRNA alterations in progressive stages of neoplastic development, i.e., metaplasia-dysplasia-adenocarcinoma, with an aim to identify candidate miRNAs potentially associated with progression. Using next generation sequencing (NGS) as an agnostic discovery platform, followed by quantitative real-time PCR (qPCR) validation in a total of 20 EACs, we identified 26 miRNAs that are highly and frequently deregulated in EACs (≥ 4-fold in >50% of cases) when compared to paired normal esophageal squamous (nSQ) tissue. We then assessed the 26 EAC-derived miRNAs in laser microdissected biopsy pairs of Barrett's metaplasia (BM)/nSQ (n = 15), and high-grade dysplasia (HGD)/nSQ (n = 14) by qPCR, to map the timing of deregulation during progression from BM to HGD and to EAC. We found that 23 of the 26 candidate miRNAs were deregulated at the earliest step, BM, and therefore noninformative as molecular markers of progression. Two miRNAs, miR-31 and -31*, however, showed frequent downregulation only in HGD and EAC cases suggesting association with transition from BM to HGD. A third miRNA, miR-375, showed marked downregulation exclusively in EACs and in none of the BM or HGD lesions, suggesting its association with progression to invasive carcinoma. Taken together, we propose miR-31 and -375 as novel candidate microRNAs specifically associated with early- and late-stage malignant progression, respectively, in Barrett's esophagus.

NON-ENDOSCOPIC ESOPHAGEAL SAMPLING DEVICE AND BIOMARKER PANEL FOR DETECTION OF BARRETT'S ESOPHAGUS (BE) AND ESOPHAGEAL ADENOCARCINOMA (EAC).

BACKGROUND: We previously reported an encapsulated balloon (EsoCheck TM , EC), which selectively samples the distal esophagus, that coupled with a two methylated DNA biomarker panel (EsoGuard TM , EG), detected Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), with a sensitivity and specificity of 90.3% and 91.7%, respectively. This previous study utilized frozen EC samples. AIM: To assess a next generation EC sampling device and EG assay that utilizes a room temperature sample preservative to enable office-based testing. METHODS: Cases with nondysplastic (ND) and dysplastic (indefinite=IND, low grade dysplasia = LGD, high grade dysplasia = HGD) BE, EAC, junctional adenocarcinoma (JAC) and controls with no intestinal metaplasia (IM) were included. Nurses or physician assistants at six institutions, who were trained in EC administration, delivered the encapsulated balloon per orally and inflated it in the stomach. The inflated balloon was pulled back to sample 5 cm of the distal esophagus, then deflated and retracted into the EC capsule to prevent sample contamination from proximal esophagus. Nextgen EG sequencing assays performed on bisulfite-treated DNA extracted from EC samples determined levels of methylated Vimentin (mVIM) and methylated Cyclin A1 (mCCNA1) in a CLIA-certified laboratory, blinded to patients' phenotypes. RESULTS: A total of 243 evaluable patients - 88 cases (median age 68 years, 78% men, 92% white) and 155 controls (median age 57 years, 41% men, 88% white) - underwent adequate EC sampling. Mean time for EC sampling was just over 3 minutes. The cases included 31 NDBE, 16 IND/LGD, 23 HGD, and 18 EAC/JAC. Thirty-seven (53%) of the non-dysplastic and dysplastic BE cases were short-segment BE (SSBE; < 3 cm). Overall sensitivity for detecting all cases was 85% (95% CI= 0.78-0.93) and specificity was 85% (95% CI=0.79-0.90). Sensitivity for NDBE was 84% (n=37). The EC/EG test detected 100% of cancers. CONCLUSION: The next-generation EC/EG technology has been both successfully updated to incorporate a room temperature sample collection preservative and successfully implemented in a CLIA certified laboratory. When performed by trained personnel, EC/EG detects non-dysplastic BE, dysplastic BE, and cancer with high sensitivity and specificity, replicating the operating characteristics of the initial pilot study of this technology. Future applications utilizing EC/EG to screen broader populations at risk for developing cancer are proposed. SIGNIFICANCE: This multi-center study demonstrates the successful performance of a commercially available clinically implementable non-endoscopic screening test for BE in the U.S., as recommended in the most recent ACG Guideline and AGA Clinical Update. It transitions and validates a prior academic laboratory-based study of frozen research samples over to a CLIA laboratory, one that also integrates a clinically practical room temperature method for sample acquisition and storage, enabling office-based screening.

Sleep Behaviors, Genetic Predispositions, and Risk of Esophageal Cancer.

BACKGROUND: Risk factors contributing to more than 10-fold increase in esophageal cancer in the last 50 years remain underexplored. We aim to examine the associations of sleep behaviors with esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). METHODS: We prospectively assessed the associations between sleep behaviors (chronotype, duration, daytime napping, daytime sleepiness, snoring, and insomnia) and EAC and ESCC risk in 393,114 participants in the UK Biobank (2006-2016). Participants with 0, 1, and ≥2 unhealthy behaviors, including sleep <6 or >9 h/d, daytime napping, and usual daytime sleepiness were classified as having a good, intermediate, and poor sleep. For EAC, we also examined interactions with polygenic risk score (PRS). Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: We documented 294 incident EAC and 95 ESCC. Sleep >9 h/d (HR, 2.05; 95% CI, 1.18-3.57) and sometimes daytime napping (HR, 1.36; 95% CI, 1.06-1.75) were individually associated with increased EAC risk. Compared with individuals with good sleep, those with intermediate sleep had a 47% (HR, 1.47; 95% CI, 1.13-1.91) increased EAC risk, and those with poor sleep showed an 87% (HR, 1.87; 95% CI, 1.24-2.82) higher risk (Ptrend < 0.001). The elevated risks for EAC were similar within strata of PRS (Pinteraction = 0.884). Evening chronotype was associated with elevated risk of ESCC diagnosed after 2 years of enrollment (HR, 2.79; 95% CI, 1.32-5.88). CONCLUSIONS: Unhealthy sleep behaviors were associated with an increased risk of EAC, independent of genetic risk. IMPACT: Sleep behaviors may serve as modifiable factors for the prevention of EAC.

Prevalence of missed adenomas in patients with inadequate bowel preparation on screening colonoscopy.

BACKGROUND: The prevalence of missed polyps in patients with inadequate bowel preparation on screening colonoscopy is unknown. OBJECTIVE: To determine the prevalence of missed adenomas in average-risk patients presenting for screening colonoscopy who are found to have inadequate bowel preparation. DESIGN: Retrospective chart review. Endoscopy and pathology reports were examined to determine the characteristics of polyps. Data from repeat colonoscopies were collected through 2010. SETTING: Outpatient endoscopy center at an academic medical center. PATIENTS: This study involved patients who underwent outpatient average-risk screening colonoscopy between 2004 and 2009 documented to have inadequate bowel preparation and who had colonoscopy to the cecum. MAIN OUTCOME MEASUREMENTS: Initial adenoma detection rate and adenoma detection rate on follow-up examination. RESULTS: Inadequate bowel preparation was reported on 373 patients, with an initial adenoma detection rate of 25.7%. Of 133 patients who underwent repeat colonoscopy, 33.8% had at least 1 adenoma detected, and 18.0% had high-risk states detected (≥ 3 adenomas, 1 adenoma ≥ 1 cm, or any adenoma with villous features or high-grade dysplasia). Per-adenoma miss rate was 47.9%. Among patients with at least 1 adenoma on repeat colonoscopy, 31.1% had no polyps on initial colonoscopy; mean time between colonoscopies was 340 days. Among patients with high-risk states, 25.0% had no polyps seen on initial colonoscopy; mean time between colonoscopies was 271 days. LIMITATIONS: Retrospective design. CONCLUSION: Adenomas and high-risk lesions were frequently detected on repeat colonoscopy in patients with inadequate bowel preparation on initial screening colonoscopy, suggesting that these lesions were likely missed on initial colonoscopy.

Age of diagnosis in familial Barrett's associated neoplasia.

The identification of hereditary cancer genes for esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), may prove critical for the development of novel prevention and treatment strategies. Specifically, efforts for detecting BE and EAC susceptibility genes have focused on families with three or more affected members, since these individuals have an earlier age onset compared to non-familial individuals. Given that the use of BE may overestimate the likelihood of disease heritability, we evaluated the age of diagnosis in kindreds with a restricted definition including only confirmed high-grade dysplasia (HGD) or EAC. The Familial Barrett's Esophagus Consortium database was used to identify individuals with HGD and EAC. These individuals were subsequently split into three kindred groups: non-familial-a single affected family member, duplex-two affected family members, and multiplex-three or more affected family members. Age of cancer diagnosis and other risk factors were compared between individuals in these groups. The study included 441 non-familial, 46 duplex, and 13 multiplex individuals. There was a statistically significant difference for age of diagnosis for individuals in the multiplex families compared to the non-familial and duplex families (56.0 versus 64.3, 63.5; p = 0.049). There was no significant difference between demographic factors and other cancer risk factors between family types. The results of this study support a genetic basis for familial Barrett's associated neoplasia and evaluation of the genetic susceptibility to this disease should continue to focus on families with multiple (three or more) affected members.

Novel DNA Methylation Biomarker Panel for Detection of Esophageal Adenocarcinoma and High-Grade Dysplasia.

PURPOSE: Current endoscopy-based screening and surveillance programs have not been proven effective at decreasing esophageal adenocarcinoma (EAC) mortality, creating an unmet need for effective molecular tests for early detection of this highly lethal cancer. We conducted a genome-wide methylation screen to identify novel methylation markers that distinguish EAC and high-grade dysplasia (HGD) from normal squamous epithelium (SQ) or nondysplastic Barrett's esophagus (NDBE). EXPERIMENTAL DESIGN: DNA methylation profiling of samples from SQ, NDBE, HGD, and EAC was performed using HM450 methylation arrays (Illumina) and reduced-representation bisulfate sequencing. Ultrasensitive methylation-specific droplet digital PCR and next-generation sequencing (NGS)-based bisulfite-sequencing assays were developed to detect the methylation level of candidate CpGs in independent esophageal biopsy and endoscopic brushing samples. RESULTS: Five candidate methylation markers were significantly hypermethylated in HGD/EAC samples compared with SQ or NDBE (P < 0.01) in both esophageal biopsy and endoscopic brushing samples. In an independent set of brushing samples used to construct biomarker panels, a four-marker panel (model 1) demonstrated sensitivity of 85.0% and 90.8% for HGD and EACs respectively, with 84.2% and 97.9% specificity for NDBE and SQ respectively. In a validation set of brushing samples, the panel achieved sensitivity of 80% and 82.5% for HGD and EAC respectively, at specificity of 67.6% and 96.3% for NDBE and SQ samples. CONCLUSIONS: A novel DNA methylation marker panel differentiates HGD/EAC from SQ/NDBE. DNA-methylation-based molecular assays hold promise for the detection of HGD/EAC using esophageal brushing samples.

Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett's metaplasia.

BACKGROUND & AIMS: The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium. METHODS: Immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice. RESULTS: Marked up-regulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barrett's epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barrett's epithelium. We further show that expression of Deleted in Malignant Brain Tumors 1, the human homologue of the columnar cell factor Hensin, occurs in Barrett's epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9, and columnar cytokeratins. CONCLUSIONS: Epithelial Hedgehog ligand expression may contribute to the initiation of Barrett's esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype.

Colonoscopy polyp detection and classification: Dataset creation and comparative evaluations.

Colorectal cancer (CRC) is one of the most common types of cancer with a high mortality rate. Colonoscopy is the preferred procedure for CRC screening and has proven to be effective in reducing CRC mortality. Thus, a reliable computer-aided polyp detection and classification system can significantly increase the effectiveness of colonoscopy. In this paper, we create an endoscopic dataset collected from various sources and annotate the ground truth of polyp location and classification results with the help of experienced gastroenterologists. The dataset can serve as a benchmark platform to train and evaluate the machine learning models for polyp classification. We have also compared the performance of eight state-of-the-art deep learning-based object detection models. The results demonstrate that deep CNN models are promising in CRC screening. This work can serve as a baseline for future research in polyp detection and classification.