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Background: Helicobacter pylori is a major risk factor for gastric cancer. Screening and treatment of H. pylori may reduce the risk of gastric cancer and peptic ulcer disease. Polymerase chain reaction (PCR) of gastric biopsies provides superior sensitivity and specificity for the detection of H. pylori. This study explores whether population-based H. pylori screening with PCR is cost-effective in the US.Methods: A Markov cohort state-transition model was developed to compare three strategies: no screening with opportunistic eradication, 13C-UBT population screening and treating of H. pylori, and PCR population screening and treating of H. pylori. Estimates of risks and costs were obtained from published literature. Since the efficacy of H. pylori therapy in gastric cancer prevention is not certain, we broadly varied the benefit 30-100% in sensitivity analysis.Results: PCR screening was cost-effective and had an incremental-cost effectiveness ratio per quality adjusted life-year (QALY) of $38,591.89 when compared to 13C-UBT strategy with an ICER of $2373.43 per QALY. When compared to no screening, PCR population screening reduced cumulative gastric cancer incidence from 0.84% to 0.74% and reduced peptic ulcer disease risk from 14.8% to 6.0%. The cost-effectiveness of PCR screening was robust to most parameters in the model.Conclusion: Our modeling study finds PCR screening and treating of H. pylori to be cost-effective in the prevention of gastric cancer and peptic ulcer disease. However, the potential negative consequences of H. pylori eradication such as antibiotic resistance could change the balance of benefits of population screening.

The increasing incidence of esophageal adenocarcinoma (EAC) is mirrored by the increasing prevalence of Barrett esophagus, a precursor lesion resulting in a large number of individuals “at risk” for this lethal malignancy. Among patients with Barrett esophagus, only about 0.3% annually will develop EAC. Because large numbers of patients are followed in endoscopic surveillance, there is a need for risk prediction among a growing population of patients with Barrett esophagus. We identified four potential biomarkers from an inflammation (IL1β)-dependent mouse model of Barrett esophagus and tested them in 189 patients with Barrett esophagus with and without high-grade dysplasia (HGD)/early cancer (T1). The primary goal was to distinguish patients with Barrett esophagus with no evidence of dysplasia from those with dysplasia. Increasing stem cell marker LGR5 and niche cell marker DCLK1 and decreasing differentiation marker (secretory mucus cells, TFF2+ cells) correlated with elevated tumor score in the mouse. Having outlined the origin of those markers in the Barrett esophagus mouse model, we showed the applicability for human Barrett esophagus. We compared 94 patients with nondysplastic Barrett esophagus tissue with 95 patients with Barrett esophagus and HGD or early cancer. Low levels of TFF2 (AUC 87.2%) provided the best discrimination between nondysplastic Barrett esophagus and Barrett esophagus with cancer, followed by high levels of DCLK1 (AUC 83.4%), low goblet cell ratio (AUC 79.4%), and high LGR5 (AUC 71.4%). The goblet cell ratio, rather than the presence of goblet cells per se, was found to be an important discriminator. These findings may be useful in developing future risk prediction models for patients with Barrett esophagus and ultimately to improve EAC surveillance. Cancer Prev Res; 10(1); 55–66. ©2016 AACR.

The joint linearity of the categorical covariates on the logit scale

Background: Barrett's esophagus is often asymptomatic and only a small portion of Barrett's esophagus patients are currently diagnosed and under surveillance. Therefore, it is important to develop risk prediction models to identify high-risk individuals with Barrett's esophagus. Familial aggregation of Barrett's esophagus and esophageal adenocarcinoma, and the increased risk of esophageal adenocarcinoma for individuals with a family history, raise the necessity of including genetic factors in the prediction model. Methods to determine risk prediction models using both risk covariates and ascertained family data are not well developed.Methods: We developed a Barrett's Esophagus Translational Research Network (BETRNet) risk prediction model from 787 singly ascertained Barrett's esophagus pedigrees and 92 multiplex Barrett's esophagus pedigrees, fitting a multivariate logistic model that incorporates family history and clinical risk factors. The eight risk factors, age, sex, education level, parental status, smoking, heartburn frequency, regurgitation frequency, and use of acid suppressant, were included in the model. The prediction accuracy was evaluated on the training dataset and an independent validation dataset of 643 multiplex Barrett's esophagus pedigrees.Results: Our results indicate family information helps to predict Barrett's esophagus risk, and predicting in families improves both prediction calibration and discrimination accuracy.Conclusions: Our model can predict Barrett's esophagus risk for anyone with family members known to have, or not have, had Barrett's esophagus. It can predict risk for unrelated individuals without knowing any relatives' information.Impact: Our prediction model will shed light on effectively identifying high-risk individuals for Barrett's esophagus screening and surveillance, consequently allowing intervention at an early stage, and reducing mortality from esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 25(5); 727–35. ©2016 AACR.

Supplementary Methods of imputation of age and estimating the parameters of the prediction model. Supplementary Table S1 Missing rates on the 8 covariates in the training and validation datasets. Supplementary Table S2 Stepwise removal of covariates in the MLM model on the basis of LRT tests and AIC. Supplementary Table S3. Description of the eight predictor covariates. Supplementary Table S4 Number of informative pedigrees without missing covariate data.

PURPOSE: 3-indoxyl sulfate (3-IS) is an indole metabolism byproduct produced by commensal gut bacteria and excreted in the urine; low urinary 3-IS has been associated with increased mortality in bone marrow transplant recipients. This study investigated urinary 3-IS and patient outcomes in the ICU. MATERIALS AND METHODS: Prospective study that collected urine samples, rectal swabs, and clinical data on 78 adult ICU patients at admission and again 72 hours later. Urine was analyzed for 3-IS by mass spectrometry. RESULTS: Median urinary 3-IS levels were 17.1 μmol/mmol creatinine (IQR 9.5 to 26.2) at admission and 15.6 (IQR 4.2 to 30.7) 72 hours later. 22% of patients had low 3-IS (≤6.9 μmol/mmol) on ICU admission and 28% after 72 hours. Low 3-IS at 72 hours was associated with fewer ICU-free days (22.5 low versus 26 high, p=0.03) and with death during one year of follow-up (36% low versus 9% high 3-IS, p

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.

Background and Aims High sodium consumption has been associated with an increased risk of gastric cancer. The mean daily sodium intake in the United States substantially exceeds the national recommended amount. The low sodium‐DASH diet has been shown to decrease the risk of cardiovascular disease in the United States, but its impact on gastric cancer has not been well studied. We therefore aimed to model the impact and cost‐effectiveness of the low sodium‐DASH diet for gastric cancer prevention in the U.S. population. Methods A Markov cohort state‐transition model was developed to simulate the impact of the low sodium‐DASH diet on gastric cancer outcomes for the average 40‐year‐old in the United States compared to no intervention. Primary outcomes of interest were gastric cancer incidence and incremental cost‐effectiveness ratios (ICER). Results Our model found that compared to the no intervention cohort, the risk of gastric cancer decreased by 24.8% for males and 21.2% for females on the low sodium‐DASH diet. 27 cases and 14 cases per 10,000 individuals were prevented for males and females, respectively, in the intervention group. The ICER for the low sodium‐DASH diet strategy was $287,726 for males and $423,878 for females compared to the no intervention strategy. Conclusions Using a Markov model of gastric cancer risk, we found that adherence to a low sodium‐DASH diet could decrease the risk of gastric cancer. This intervention was not cost‐effective due to the high cost of a low sodium‐DASH accordant diet, but significantly improved for high‐risk populations and when the cost of the diet became slightly more affordable., Using a Markov model of gastric cancer risk, we found that adherence to a low sodium‐DASH diet decreases the risk of gastric cancer in the U.S. population. This intervention was not cost‐effective due to the high cost of a low sodium‐DASH accordant diet, but significantly improved for certain high‐risk populations and when the cost of the diet became slightly more affordable.

Introduction Ablation of Barrett's esophagus (BE) is the preferred approach for the treatment of neoplasia without visible lesions. Limited data on cryoballoon ablation (CBA) suggest its potential clinical utility. We evaluated the safety and efficacy of CBA in a multicenter study of patients with neoplastic BE. Methods In a prospective clinical trial, 11 academic and community centers recruited consecutive patients with BE of 1-6 cm length and low-grade dysplasia, high-grade dysplasia (HGD), or intramucosal adenocarcinoma (ImCA) confirmed by central pathology. Patients with symptomatic pre-existing strictures or visible BE lesions had dilation or endoscopic mucosal resection (EMR), respectively, before enrollment. A nitrous oxide cryoballoon focal ablation system was used to treat all visible columnar mucosa in up to 5 sessions. Study end points included complete eradication of all dysplasia (CE-D) and intestinal metaplasia (CE-IM) at 1 year. Results One hundred twenty patients with BE with ImCA (20%), HGD (56%), or low-grade dysplasia (23%) were enrolled. In the intention-to-treat analysis, the CE-D and CE-IM rates were 76% and 72%, respectively. In the per-protocol analysis (94 patients), the CE-D and CE-IM rates were 97% and 91%, respectively. Postablation pain was mild and short lived. Fifteen subjects (12.5%) developed strictures requiring dilation. One patient (0.8%) with HGD progressed to ImCA, which was successfully treated with EMR. Another patient (0.8%) developed gastrointestinal bleeding associated with clopidogrel use. One patient (0.8%) had buried BE with HGD in 1 biopsy, not confirmed by subsequent EMR. Discussion In patients with neoplastic BE, CBA was safe and effective. Head-to-head comparisons between CBA and other ablation modalities are warranted (clinicaltrials.gov registration NCT02514525).

A Markov cohort state-transition model was developed to compare three strategies: no screening with opportunistic eradication,PCR screening was cost-effective and had an incremental-cost effectiveness ratio per quality adjusted life-year (QALY) of $38,591.89 when compared toOur modeling study finds PCR screening and treating of

BACKGROUND AND AIMS: Guidelines cite extensive gastric intestinal metaplasia (GIM) as a bigger risk factor for gastric cancer (GC) than limited GIM and an indication for endoscopic surveillance. Data on progression of extensive GIM to GC in the USA are limited. This study aimed to estimate the prevalence and progression rates of extensive GIM in a US cohort. METHODS: This retrospective study assessed the prevalence of extensive GIM between 1/1/1990 and 8/1/2019 at a large academic medical center. Multivariable regression was used to identify predictors of extensive GIM. Incidence of GC on follow-up was calculated as number of new diagnoses divided by person-years of follow-up. Presence of GIM on subsequent follow-up endoscopy was assessed. RESULTS: Of 1256 individuals with GIM, 352 (28%) had extensive GIM and 904 (72%) had limited GIM. On multivariable analysis, older age (OR 1.01, 95% CI 1.00–1.02) and Hispanic ethnicity (OR 1.55, 95% CI 1.11–2.16) were predictive of extensive GIM. The annual incidence of GC for GIM overall was 0.09%. There was no difference in progression to GC between extensive or limited GIM (IRR 0, 95% CI 0–2.6), or to advanced lesions overall (IRR 0.37, 95% CI 0.04–1.62). 70% of individuals had persistent GIM on follow-up biopsy, and 22% with limited GIM had extensive GIM on follow-up biopsy. CONCLUSIONS: 28% of individuals with GIM have the extensive subtype, and are more likely to be older and of Hispanic ethnicity. There was no difference in progression to GC between extensive and limited GIM. Further research is needed to better assess risk of GIM in the US context.

Background: The incidence of esophageal adenocarcinoma has risen dramatically over the past half century, and the underlying reasons are incompletely understood. Broad shifts to the upper gastrointestinal microbiome may be partly responsible. The goal of this study was to describe alterations in the esophageal microbiome that occur with progression from Barrett's esophagus to esophageal adenocarcinoma. Methods: A case–control study was performed of patients with and without Barrett's esophagus who were scheduled to undergo upper endoscopy. Demographic, clinical, and dietary intake data were collected, and esophageal brushings were collected during the endoscopy. 16S rRNA gene sequencing was performed to characterize the microbiome. Results: A total of 45 patients were enrolled and included in the analyses [16 controls; 14 Barrett's esophagus without dysplasia (NDBE); 6 low-grade dysplasia (LGD); 5 high-grade dysplasia (HGD); and 4 esophageal adenocarcinoma]. There was no difference in alpha diversity between non–Barrett's esophagus and Barrett's esophagus, but there was evidence of decreased diversity in patients with esophageal adenocarcinoma as assessed by Simpson index. There was an apparent shift in composition at the transition from LGD to HGD, and patients with HGD and esophageal adenocarcinoma had decreased Firmicutes and increased Proteobacteria. In addition, patients with HGD or esophageal adenocarcinoma had increased Enterobacteriaceae and Akkermansia muciniphila and reduced Veillonella. In the study population, patients taking proton pump inhibitors had increased Streptococcus and decreased Gram-negative bacteria overall. Conclusions: Shifts in the Barrett's esophagus–associated microbiome were observed in patients with HGD and esophageal adenocarcinoma, with increases in certain potentially pathogenic bacteria. Impact: The microbiome may play a role in esophageal carcinogenesis.

Proton pump inhibitors (PPI) are an invaluable therapy option for acid related diseases; however, PPI therapy is also linked to a series of side effects in cirrhosis, such as microbiome alterations, spontaneous bacterial peritonitis and hepatic encephalopathy. Decision tools to balance benefits and risks of PPI therapy are largely missing. In this study, we tested gut-derived biomarkers to identify PPI-associated dysbiosis, its association with gut barrier function and liver-related mortality. In this observational study, faecal microbiome composition data obtained from 16S rDNA sequencing of 90 cirrhotic patients with and without long-term PPI use and additional potential biomarkers identified from the literature were evaluated for their predictive value regarding PPI-associated dysbiosis and liver-related three-year mortality. In addition, faecal calprotectin, faecal zonulin and serum lipopolysaccharides were assessed as markers for intestinal inflammation, gut permeability and bacterial translocation. Streptococcus salivarius, Veillonella parvula and the genus Streptococcus were significantly increased in patients with long-term PPI therapy and performed well as biomarkers for PPI-associated dysbiosis (accuracy: 74%, 72% and 74%, respectively). The abundance of Streptococcus salivarius was linked to intestinal inflammation and gut barrier dysfunction, whereas the abundance of Veillonella parvula showed associations with liver disease severity; both were independent predictors for liver-related three-year mortality. Gut-derived biomarkers of PPI-associated dysbiosis are linked to worse outcome and a potential option to evaluate the risks of adverse events during long-term PPI therapy.

The main risk factor for esophageal dysplasia and adenocarcinoma (DAC) is Barrett’s esophagus (BE), characterized by intestinal metaplasia. The critical genomic mechanisms that lead to progression of non-dysplastic BE to DAC remain poorly understood and require analyses of longitudinal patient cohorts and high-resolution assays. We tested BE tissues from 74 patients, including 42 non-progressors from two separate groups of 21 patients each, and 32 progressors (16 in a longitudinal cohort before DAC/pre-progression-BE, and 16 with temporally concurrent but spatially separate DAC/concurrent-BE). We interrogated genome-wide somatic copy number alterations (SCNAs) at the exon level with high-resolution SNP arrays in DNA from formalin-fixed samples histologically confirmed as non-dysplastic BE. The most frequent abnormalities were SCNAs involving FHIT exon 5, CDKN2A/B, or both in 88% longitudinal BE progressors to DAC vs. 24% in both non-progressor groups (P=0.0004). Deletions in other genomic regions were found in 56% of pre-progression-BE but only in 1 non-progressor-BE (P=0.0004). SCNAs involving FHIT exon 5 and CDKN2A/B were also frequently detected in BE temporally concurrent with DAC. TP53 losses were detected in concurrent-BE but not earlier in pre-progression-BE tissues of patients who developed DAC. CDKN2A/p16 immunohistochemistry showed significant loss of expression in BE of progressors vs. non-progressors, supporting the genomic data. Our data suggest a role for CDKN2A/B and FHIT in early progression of BE to dysplasia and adenocarcinoma that warrants future mechanistic research. Alterations in CDKN2A/B and FHIT by high-resolution assays may serve as biomarkers of increased risk of progression to DAC when detected in BE tissues.

Background Cystic fibrosis (CF) patients have increased risks of gastrointestinal cancers, including esophageal adenocarcinoma. Gastroesophageal reflux disease (GERD) is highly prevalent in CF and manifests at early ages. CF patients may be at increased risk for long-term sequelae of chronic GERD, including Barrett's esophagus (BE). We aimed to assess whether patients with CF have an increased risk of BE or related neoplasia. Methods A matched cohort study was performed of adults with and without CF who had undergone upper endoscopy. Non-CF patients were matched in a 4:1 ratio by age, sex, year of exam, and endoscopist. Odds ratios were calculated for the association between CF and BE or related neoplasia, and multivariable logistic regression modeling was performed to adjust for matching variables and additional potential confounders. Results 122 CF patients underwent endoscopy, and 488 matched controls were identified. Seven (5.7%) CF patients had BE or related neoplasia, including one GE junction adenocarcinoma. Mean age of affected CF patients was 36.0, and 85.7% had a prior solid organ transplant. The odds of BE was significantly increased in CF patients (OR 2.91, 95% CI 1.08–7.81). The risk remained significantly increased in a multivariable model including matching variables (OR 3.32, 95% CI 1.19–9.22) and in a parsimonious model (OR 2.99, 95% CI 1.06–8.42). Conclusions Adults with CF have a 3-fold increased risk of BE or related neoplasia and appears to develop at younger ages. Consideration should be given to screening for BE in select CF patients, especially those who have undergone solid organ transplantation.

Hypergastrinemia has been associated with high grade dysplasia and adenocarcinoma in patients with Barrett’s esophagus (BE), and experimental studies suggest pro-inflammatory and pro-neoplastic effects of gastrin on BE. This is of potential concern, as BE patients are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK(2) receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in BE. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with BE without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/ mm(2), SD 620.7; placebo: +307.8 Ki67+ cells/ mm(2), SD 640.3; p=0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype (TFF2, MUC5B) and certain cancer-associated markers (REG3A, PAX9, MUC1), and decreased expression of intestinal markers MUC2, FABP1, FABP2, and CDX1. No serious adverse events related to study drug occurred. The gastrin/CCK(2) receptor antagonist netazepide did not reduce cellular proliferation in patients with non-dysplastic BE. Further research should focus on the biological effects of gastrin in Barrett’s esophagus.

Introduction Although the microbiome is altered in various esophageal diseases, there is no direct evidence for a link between the oral or esophageal microbiome and underlying esophageal tissue. Here, we aimed to address these gaps through use of an antimicrobial mouth rinse to modify the esophageal microbiome and tissue gene expression. Methods In this randomized controlled trial, patients scheduled to undergo endoscopy for clinical indications used chlorhexidine mouth rinse or no treatment for 2 weeks before endoscopy. Oral swabs and saliva were collected at baseline and at follow-up, and the esophagus was sampled on the day of endoscopy. The microbiome was analyzed by 16S rRNA gene sequencing, and esophageal tissue gene expression was ascertained by RNA-Seq. Results Twenty subjects were enrolled and included in the analyses. Within individuals, the oral and esophageal microbiome composition was significantly correlated. Chlorhexidine treatment associated with significant alterations to the relative abundance of several esophageal bacterial taxa, and to expression of genes in the esophagus including reductions in periostin, claudin-18, chemokines CXCL1 and CXCL13, and several members of the tumor necrosis factor receptor superfamily. A taxon in genus Haemophilus in the esophagus also associated with significant changes in tissue gene expression. Discussion The oral and esophageal microbiomes are closely related within individuals, and esophageal microbiome alterations correlate with tissue gene expression changes. The esophageal microbiome may act as an important cofactor that influences pathogenesis and outcomes of diseases such as eosinophilic esophagitis, gastroesophageal reflux, and Barrett's esophagus.

Background and Aims Lifestyle counseling to achieve a healthy weight, quit smoking, and reduce alcohol is a cornerstone in the management of Barrett’s Esophagus (BE). However, little is known about whether patients make these recommended lifestyle changes or the impact of non-adherence on their quality of life (QOL). This study characterized the lifestyle risk factors, QOL, and intervention preferences of BE patients as a first step toward developing lifestyle change interventions for this population. Methods Patients with a confirmed BE diagnosis (N = 106) completed surveys at a surveillance endoscopy visit (baseline) and at 3- and 6-month follow-ups. Patients reported on lifestyle risk factors, adherence determinants (e.g., perceived benefits/barriers, risk, intentions), QOL, and intervention preferences. Results Most patients (56%) had uncontrolled reflux, were overweight/obese (65.1%), and had low dietary fiber intake (91%). Many (45%) reported poor QOL. Patients’ perceived risk of developing esophageal cancer was high, but their behavior change intentions were low. Despite receiving lifestyle counseling from physicians, there were no significant changes in patients’ QOL or lifestyle risk factors over time. Nonetheless, patients indicated strong interest in internet (62.6%) and multimedia programs (57.9%) addressing acid reflux and weight control. Conclusion BE patients reported uncontrolled reflux, poor QOL, and multiple lifestyle risk factors that did not change over time. Despite low levels of intention for making lifestyle changes, patients were interested receiving more information about controlling acid reflux, suggesting a potential teachable moment and opportunity for web-based and multimedia multiple behavior interventions that seek to control acid reflux symptoms through weight loss and a high fiber diet.

Background & Aims Tethered capsule endomicroscopy (TCE) involves swallowing a small tethered pill that implements optical coherence tomography (OCT) imaging, procuring high resolution images of the whole esophagus. Here, we demonstrate and evaluate the feasibility and safety of TCE and a portable OCT imaging system in patients with Barrett’s esophagus (BE) in a multi-center (5-site) clinical study. Methods Untreated patients with BE as per endoscopic biopsy diagnosis were eligible to participate in the study. TCE procedures were performed in unsedated patients by either doctors or nurses. After the capsule was swallowed, the device continuously obtained 10-μm-resolution cross-sectional images as it traversed the esophagus. Following imaging, the device was withdrawn through mouth, and disinfected for subsequent reuse. BE lengths were compared to endoscopy findings when available. OCT-TCE images were compared to volumetric laser endomicroscopy (VLE) images from a patient who had undergone VLE on the same day as TCE. Results 147 patients with BE were enrolled across all sites. 116 swallowed the capsule (79%), 95/114 (83.3%) men and 21/33 (63.6%) women (P = .01). High-quality OCT images were obtained in 104/111 swallowers (93.7%) who completed the procedure. The average imaging duration was 5.55 ± 1.92 minutes. The mean length of esophagus imaged per patient was 21.69 ± 5.90 cm. A blinded comparison of maximum extent of BE measured by OCT-TCE and EGD showed a strong correlation (r = 0.77-0.79). OCT-TCE images were of similar quality to those obtained by OCT-VLE. Conclusions The capabilities of TCE to be used across multiple sites, be administered to unsedated patients by either physicians or nurses who are not expert in OCT-TCE, and to rapidly and safely evaluate the microscopic structure of the esophagus make it an emerging tool for screening and surveillance of BE patients. Clinical trial registry website and trial number: NCT02994693 and NCT03459339.

Background & Aims Our understanding of outcomes and disease time course of COVID-19 in patients with gastrointestinal (GI) symptoms remains limited. In this study we characterize the disease course and severity of COVID-19 among hospitalized patients with gastrointestinal manifestations in a large, diverse cohort from the Unites States. Methods This retrospective study evaluated hospitalized individuals with COVID-19 between March 11 and April 28, 2020 at two affiliated hospitals in New York City. We evaluated the association between GI symptoms and death, and also explored disease duration, from symptom onset to death or discharge. Results Of 2804 patients hospitalized with COVID-19, the 1,084 (38.7%) patients with GI symptoms were younger (aOR for age ≥75, 0.59; 95% CI, 0.45-0.77) and had more co-morbidities (aOR for modified Charlson comorbidity score ≥2, 1.22; 95% CI, 1.01-1.48) compared to those without GI symptoms. Individuals with GI symptoms had better outcomes, with a lower likelihood of intubation (aHR, 0.66; 95% CI, 0.55-0.79) and death (aHR, 0.71; 95% CI, 0.59-0.87), after adjusting for clinical factors. These patients had a longer median disease course from symptom onset to discharge (13.8 vs 10.8 days, log-rank p = .048; among 769 survivors with available symptom onset time), which was driven by longer time from symptom onset to hospitalization (7.4 vs 5.4 days, log-rank P Conclusion Hospitalized patients with GI manifestations of COVID-19 have a reduced risk of intubation and death, but may have a longer overall disease course driven by duration of symptoms prior to hospitalization.

Supplemental Digital Content is available in the text., Objectives: Dietary fiber increases the abundance of bacteria that metabolize fiber into short-chain fatty acids and confers resistance against gut colonization with multidrug-resistant bacteria. This pilot trial estimated the effect of fiber on gut short-chain fatty acid–producing bacteria in the ICU. Design: Randomized, controlled, open label trial. Setting: Medical ICU. Patients: Twenty ICU adults receiving broad-spectrum IV antibiotics for sepsis. Intervention: 1:1 randomization to enteral nutrition with mixed soy- and oat-derived fiber (14.3 g fiber/L) versus calorie- and micronutrient-identical enteral nutrition with 0 g/L fiber. Measurements: Rectal swabs and whole stools were collected at baseline and on study Days 3, 7, 14, and 30. The primary outcome was within-individual change in the cumulative relative abundance of short-chain fatty acid–producing taxa from baseline to Day 3 based on 16S sequencing of rectal swabs. The secondary outcome was Day 3 cumulative short-chain fatty acid levels based on mass spectrometry of whole stools. Analyses were all intent to treat. Main Results: By Day 3, the fiber group received a median of 32.1 g fiber cumulatively (interquartile range, 17.6–54.6) versus 0 g fiber (interquartile range, 0–4.0) in the no fiber group. The median within-individual change in short-chain fatty acid producer relative abundance from baseline to Day 3 was +61% (interquartile range −51 to +1,688) in the fiber group versus −46% (interquartile range, −78 to +13) in the no fiber group (p = 0.28). Whole stool short-chain fatty acid levels on Day 3 were a median of 707 μg short-chain fatty acids/g stool (interquartile range, 190–7,265) in the fiber group versus 118 μg short-chain fatty acids/g stool (interquartile range, 22–1,195) in the no fiber group (p = 0.16). Conclusions: Enteral fiber was associated with nonsignificant trends toward increased relative abundance of short-chain fatty acid–producing bacteria and increased short-chain fatty acid levels among ICU patients receiving broad-spectrum IV antibiotics. Larger studies should be undertaken and our results can be used for effect size estimates.

Background The need for early antibiotics in the intensive care unit (ICU) is often balanced against the goal of antibiotic stewardship. Long-course antibiotics increase the burden of antimicrobial resistance within colonizing gut bacteria, but the dynamics of this process are not fully understood. We sought to determine how short-course antibiotics affect the antimicrobial resistance phenotype and genotype of colonizing gut bacteria in the ICU by performing a prospective cohort study with assessments of resistance at ICU admission and exactly 72 h later. Methods Deep rectal swabs were performed on 48 adults at the time of ICU admission and exactly 72 h later, including patients who did and did not receive antibiotics. To determine resistance phenotype, rectal swabs were cultured for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). In addition, Gram-negative bacterial isolates were cultured against relevant antibiotics. To determine resistance genotype, quantitative PCR (qPCR) was performed from rectal swabs for 87 established resistance genes. Within-individual changes in antimicrobial resistance were calculated based on culture and qPCR results and correlated with exposure to relevant antibiotics (e.g., did β-lactam antibiotic exposure associate with a detectable change in β-lactam resistance over this 72-h period?). Results Of 48 ICU patients, 41 (85%) received antibiotics. Overall, there was no increase in the antimicrobial resistance profile of colonizing gut bacteria during the 72-h study period. There was also no increase in antimicrobial resistance after stratification by receipt of antibiotics (i.e., no detectable increase in β-lactam, vancomycin, or macrolide resistance regardless of whether patients received those same antibiotics). This was true for both culture and PCR. Antimicrobial resistance pattern at ICU admission strongly predicted resistance pattern after 72 h. Conclusions Short-course ICU antibiotics made little detectable difference in the antimicrobial resistance pattern of colonizing gut bacteria over 72 h in the ICU. This provides an improved understanding of the dynamics of antimicrobial resistance in the ICU and some reassurance that short-course antibiotics may not adversely impact the stewardship goal of reducing antimicrobial resistance.

Background: Recent data suggest that subcutaneous adiposity represents an independent prognostic marker in cancer. We aimed to determine whether subcutaneous adiposity estimated by the subcutaneous adiposity tissue index (SATI) was associated with mortality in esophageal cancer. Methods: We conducted a retrospective analysis of a prospectively enrolled cohort from 2009 to 2015 with esophageal cancer at two major cancer centers. CT scans for initial staging were used to quantify adiposity and skeletal muscle areas. Subjects were categorized as above or below median SATI using sex-specific values. Sarcopenia was defined using previously established skeletal muscle area cutoffs. Cox proportional hazards modeling was performed to determine associations between SATI and all-cause mortality. Results: Of the original 167 patients, 78 met inclusion criteria and had CT images available. Mean age was 67 years, 81.8% had adenocarcinoma, and 58.9% had stage 3 or 4 disease. Median follow-up time was 29.5 months. Overall 5-year survival was 38.9% [95% confidence interval (CI), 26.8–50.7]. Lower body mass index, higher Charlson comorbidity score, and more advanced stage were independently associated with low SATI. Patients with low SATI had increased mortality (unadjusted HR 2.23; 95% CI, 1.20–4.12), even when adjusted for sarcopenia or for percent weight loss. In a multivariable model including age, histology, stage, and receipt of curative surgery, the association between low SATI and mortality was attenuated (adjusted HR 1.64; 95% CI, 0.81–3.34). Conclusions: Low subcutaneous adiposity as estimated by SATI may be associated with increased mortality in esophageal cancer. Impact: Interventions to reduce loss of subcutaneous fat may improve survival in esophageal cancer.

Background and AimsThe COVID-19 pandemic has caused widespread mortality and mortality. Famotidine is commonly used for gastric acid suppression but has recently gained attention as an antiviral that may inhibit SARS-CoV-2 replication. This study tested whether famotidine use is associated with improved clinical outcomes in patients with COVID-19 initially hospitalized to a non-intensive care setting.MethodsThis was a retrospective cohort study conducted among consecutive hospitalized patients with COVID-19 infection from February 25 to April 13, 2020 at a single medical center. The primary exposure was famotidine, received within 24 hours of hospital admission. The primary outcome was intubation or death. Propensity score matching was used to balance the baseline characteristics of patients who did and did not use famotidine.Results1,620 hospitalized patients with COVID-19 were identified including 84 (5.1%) who received famotidine within 24 hours of hospital admission. 340 (21%) patients met the study composite outcome of death or intubation. Use of famotidine was associated with reduced risk for death or intubation (adjusted hazard ratio (aHR) 0.42, 95% CI 0.21-0.85) and also with reduced risk for death alone (aHR 0.30, 95% CI 0.11-0.80). After balancing baseline patient characteristics using propensity score matching, these relationships were unchanged (HR for famotidine and death or intubation: 0.43, 95% CI 0.21-0.88). Proton pump inhibitors, which also suppress gastric acid, were not associated with reduced risk for death or intubation.ConclusionFamotidine use is associated with reduced risk of intubation or death in hospitalized COVID-19 patients. Randomized controlled trials are warranted to determine whether famotidine therapy improves outcomes in hospitalized COVID-19 patients.

Esophageal cancers comprise adenocarcinoma and squamous cell carcinoma, two distinct histologic subtypes. Both are difficult to treat and among the deadliest human malignancies. We describe protocols to initiate, grow, passage, and characterize patient-derived organoids (PDO) of esophageal cancers, as well as squamous cell carcinomas of oral/head-and-neck and anal origin. Formed rapidly (

PURPOSE: Loss of colonization resistance within the gastrointestinal microbiome facilitates the expansion of pathogens and has been associated with death and infection in select populations. We tested whether gut microbiome features at the time of intensive care unit (ICU) admission predict death or infection. METHODS: This was a prospective cohort study of medical ICU adults. Rectal surveillance swabs were performed at admission, selectively cultured for vancomycin-resistant Enterococcus (VRE), and assessed using 16S rRNA gene sequencing. Patients were followed up for 30 days for death or culture-proven bacterial infection. RESULTS: Of 301 patients, 123 (41%) developed culture-proven infections and 76 (25%) died. Fecal biodiversity (Shannon index) did not differ based on death or infection (p=0.49). The presence of specific pathogens at ICU admission was associated with subsequent infection with the same organism for Escherichia coli, Pseudomonas spp., Klebsiella spp., and Clostridium difficile, and VRE at admission was associated with subsequent Enterococcus infection. In a multivariable model adjusting for severity of illness, VRE colonization and Enterococcus domination (≥30% 16S reads) were both associated with death or all-cause infection (aHR 1.46, 95% CI 1.06–2.00 and aHR 1.47, 95% CI 1.00–2.19 respectively); among patients without VRE colonization, Enterococcus domination was associated with excess risk of death or infection (aHR 2.13, 95% CI 1.06–4.29). CONCLUSIONS: Enterococcus status at ICU admission was associated with risk for death or all–cause infection, and rectal carriage of common ICU pathogens predicted specific infections. The gastrointestinal microbiome may have a role in risk stratification and early diagnosis of ICU infections.

PURPOSE OF REVIEW: Analysis of the esophageal microbiome remains a relatively new field of research, and most studies to date have focused on characterizing the esophageal microbiome in states of health and disease. Microbiome alterations have been implicated in the pathogenesis of inflammatory and neoplastic conditions in the colon and elsewhere in the gastrointestinal tract. The epidemiology of various esophageal conditions including Barrett’s esophagus (BE), esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC) and eosinophilic esophagitis (EoE) point to the microbiome as a potential co-factor in disease pathogenesis, and the possibility exists that these microbiome alterations could contribute directly to the inflammatory environments necessary for the carcinogenesis or atopy involved in these conditions. RECENT FINDINGS: The native esophageal microbiome is similar in composition to the oral microbiome, with a high relative abundance of the phylum Firmicutes and the genus Streptococcus. Limited studies to date suggest that there are certain microbiome alterations associated with esophageal diseases. Additionally, it may be possible to indirectly assess the esophageal microbiome via non-endoscopic means. This raises the possibility that non-invasive microbiome analysis could be used for disease screening and monitoring. SUMMARY: Further understanding of the role of the esophageal microbiome in disease pathogenesis, as well as methods for microbiome alteration may help elucidate future targets for disease modifying therapies, or minimally invasive screening tools in patients at high risk for development of various esophageal conditions.

Endoscopic surveillance of patients with Barrett's Esophagus (BE) is recommended to detect esophageal adenocarcinoma (EAC) and its dysplasia precursors, but survival benefits are unclear. Using Surveillance, Epidemiology, and End Results (SEER) and linked Medicare data, we sought to determine the impact of a prior BE diagnosis on survival in patients with EAC.Our analysis focused on patients over age 65 with primary EAC diagnosed in a SEER region from 2000-2011 and enrolled in Medicare. We identified patients with preexisting BE prior to EAC diagnosis and compared this group to EAC patients without a prior BE diagnosis. A Cox Proportional Hazards model compared survival and included variables such as age, sex, cancer stage, treatment, and medical comorbidities.Among 4,978 SEER-Medicare patients identified with EAC, 577 (12%) had preexisting BE; 4,401 (88%) did not. BE patients had overall lower stage (28.5% stage I vs. 12.8% stage IV) than those without preexisting BE (16.4% stage I vs. 30.6% stage IV). Overall survival was better among patients in the BE group (hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.50-0.61); this benefit persisted in the adjusted model (HR, 0.72; 95%, 0.65-0.80). After adjusting for lead-time bias, the HRs attenuated to the null, with an unadjusted HR of 0.96 (95% CI: 0.86-1.05, P=0.39) and adjusted HR of 0.99 (CI: 0.89-1.10, P=0.92).Survival outcomes in patients with a BE diagnosis prior to EAC were statistically better in both the unadjusted and adjusted Cox proportional hazards model. However, this benefit appears to be predominantly lead-time and length-time bias.

Cancer cachexia is increasingly recognized as a poor prognostic marker for various tumor types. Weight loss in esophageal cancer is multifactorial, as patients with bulky tumors also have reduced ability to eat. We aimed to investigate the relationship between prediagnosis weight loss and mortality in esophageal cancer and to determine whether these associations vary with tumor stage. We conducted a prospective cohort study of esophageal cancer patients at two tertiary centers. We recorded baseline patient characteristics including medications, smoking, body mass index, and weight loss in the year prior to diagnosis, and collected data on treatment and outcomes. We used Cox regression modeling to determine the associations between percent weight loss and outcomes. The main outcome of interest was all-cause mortality; secondary endpoints were esophageal cancer-specific mortality and development of metastases. We enrolled 134 subjects, the majority of whom had adenocarcinoma (82.1%); median percent weight loss was 4.7% (IQR: 0%–10.9%). Increasing percent weight loss was not associated with all-cause mortality (ptrend = 0.36). However, there was evidence of significant interaction by tumor stage (p = 0.02). There was a strong and significant association between prediagnosis weight loss and mortality in patients with T stages 1 or 2 (adjusted HR 8.26 for highest versus lowest tertile, 95%CI 1.11–61.5, ptrend = 0.03) but not for T stages 3 or 4 (ptrend = 0.32). Body mass index one year prior to diagnosis was not associated with mortality. Prediagnosis weight loss was associated with increased all-cause mortality only in patients with early stage esophageal cancer. This suggests that tumor-related cachexia can occur early in esophageal cancer and represents a poor prognostic marker.