Julian A. Abrams

Bile Acid and Inflammation Activate Gastric Cardia Stem Cells in a Mouse Model of Barrett-Like Metaplasia

Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5(+) gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1β-IL-6 signaling cascade and Dll1-dependent Notch signaling.

Safety and efficacy of endoscopic spray cryotherapy for Barrett's esophagus with high-grade dysplasia.

BACKGROUND Endoscopic ablation to treat Barretts esophagus (BE) with high-grade dysplasia (HGD) is associated with a decreased incidence of esophageal adenocarcinoma. Endoscopic spray cryotherapy (CRYO) demonstrates promising preliminary data. OBJECTIVE To assess the safety and efficacy of CRYO in BE with HGD. DESIGN Multicenter, retrospective cohort study. SETTING Nine academic and community centers; treatment period, 2007 to 2009. PATIENTS Subjects with HGD confirmed by 2 pathologists. Previous EMR was allowed if residual HGD remained. INTERVENTIONS CRYO with follow-up biopsies. MAIN OUTCOME MEASUREMENTS Complete eradication of HGD with persistent low-grade dysplasia, complete eradication of all dysplasia with persistent nondysplastic intestinal metaplasia, and complete eradication of all intestinal metaplasia. RESULTS Ninety-eight subjects (mean age 65.4 years, 83% male) with BE and HGD (mean length 5.3 cm) underwent 333 treatments (mean 3.4 treatments per subject). There were no esophageal perforations. Strictures developed in 3 subjects. Two subjects reported severe chest pain managed with oral narcotics. One subject was hospitalized for bright red blood per rectum. Sixty subjects had completed all planned CRYO treatments and were included in the efficacy analysis. Fifty-eight subjects (97%) had complete eradication of HGD, 52 (87%) had complete eradication of all dysplasia with persistent nondysplastic intestinal metaplasia, and 34 (57%) had complete eradication of all intestinal metaplasia. Subsquamous BE was found in 2 subjects (3%). LIMITATIONS Nonrandomized, retrospective study with no control group, short follow-up (10.5 months), lack of centralized pathology, and use of surrogate outcome for decreased cancer risk. CONCLUSIONS CRYO is a safe and well-tolerated therapy for BE and HGD. Short-term results suggest that CRYO is highly effective in eradicating HGD.

Adherence to Biopsy Guidelines for Barrett's Esophagus Surveillance in the Community Setting in the United States

BACKGROUND & AIMS Current surveillance guidelines for Barretts esophagus (BE) recommend extensive biopsies to minimize sampling error. Biopsy practice patterns for BE surveillance in the community have not been well-described. We used a national community-based pathology database to analyze adherence to guidelines and to determine whether adherence was associated with dysplasia detection. METHODS We identified 10,958 cases of established BE in the Caris Diagnostics pathology database from January 2002-April 2007. Demographic, pathologic, and endoscopic data were recorded. Dysplasia was categorized as low grade, high grade, or adenocarcinoma. Adherence was defined as > or =4 esophageal biopsies per 2 cm BE or a ratio > or =2.0. Generalized estimating equation multivariable analysis was performed to assess factors associated with adherence, adjusted for clustering by individual gastroenterologist. RESULTS A total of 2245 BE surveillance cases were identified with linked endoscopy reports that recorded BE length and could be assessed for adherence. Adherence to guidelines was seen in 51.2% of cases. In multivariable analysis, longer segment BE was associated with significantly reduced adherence (3-5 cm, odds ratio [OR] 0.14, 95% confidence interval [CI] 0.10-0.19; 6-8 cm, OR 0.06, 95% CI 0.03-0.09; > or =9 cm, OR 0.03, 95% CI 0.01-0.07). Stratified by BE length, nonadherence was associated with significantly decreased dysplasia detection (summary OR 0.53, 95% CI 0.35-0.82). CONCLUSIONS Adherence to BE biopsy guidelines in the community is low, and nonadherence is associated with significantly decreased dysplasia detection. Future studies should identify factors underlying nonadherence as well as mechanisms to increase adherence to guidelines to improve early detection of dysplasia.

Proton pump inhibitors alter the composition of the gut microbiota

Objective Proton pump inhibitors (PPIs) are drugs used to suppress gastric acid production and treat GI disorders such as peptic ulcers and gastro-oesophageal reflux. They have been considered low risk, have been widely adopted, and are often over-prescribed. Recent studies have identified an increased risk of enteric and other infections with their use. Small studies have identified possible associations between PPI use and GI microbiota, but this has yet to be carried out on a large population-based cohort. Design We investigated the association between PPI usage and the gut microbiome using 16S ribosomal RNA amplification from faecal samples of 1827 healthy twins, replicating results within unpublished data from an interventional study. Results We identified a significantly lower abundance in gut commensals and lower microbial diversity in PPI users, with an associated significant increase in the abundance of oral and upper GI tract commensals. In particular, significant increases were observed in Streptococcaceae. These associations were replicated in an independent interventional study and in a paired analysis between 70 monozygotic twin pairs who were discordant for PPI use. We propose that the observed changes result from the removal of the low pH barrier between upper GI tract bacteria and the lower gut. Conclusions Our findings describe a significant impact of PPIs on the gut microbiome and should caution over-use of PPIs, and warrant further investigation into the mechanisms and their clinical consequences.

Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy.

Our aim was to assess differences in the sensitivities of serologic tests used for the diagnosis of celiac disease among patients with varying degrees of villous atrophy. Among 115 adults with biopsy-proven celiac disease who fulfilled strict criteria, including serologic testing at the time of diagnosis and response to a gluten-free diet, 71% had total villous atrophy and 29% partial villous atrophy. Endomysial antibody was positive in 77% of those with total villous atrophy, compared to 33% with partial villous atrophy (P < 0.001). There was no difference in sensitivity when the type of presentation (classical vs. silent) was compared. Endomysial antibody-positive and negative patients did not differ with respect to age at diagnosis, duration of symptoms, mode of presentation, or family history of celiac disease. All anti-tissue transglutaminase-positive patients had TVA on biopsy. Seronegative celiac disease occurs. Endomysial antibody positivity correlates with more severe villous atrophy and not mode of presentation of celiac disease. Serologic tests, in clinical practice, lack the sensitivity reported in the literature.

Endoscopic spray cryotherapy for esophageal cancer: safety and efficacy

BACKGROUND Few options exist for patients with localized esophageal cancer ineligible for conventional therapies. Endoscopic spray cryotherapy with low-pressure liquid nitrogen has demonstrated efficacy in this setting in early studies. OBJECTIVE To assess the safety and efficacy of cryotherapy in esophageal carcinoma. DESIGN Multicenter, retrospective cohort study. SETTING Ten academic and community medical centers between 2006 and 2009. PATIENTS Subjects with esophageal carcinoma in whom conventional therapy failed and those who refused or were ineligible for conventional therapy. INTERVENTIONS Cryotherapy with follow-up biopsies. Treatment was complete when tumor eradication was confirmed by biopsy or when treatment was halted because of tumor progression, patient preference, or comorbid condition. MAIN OUTCOME MEASUREMENTS Complete eradication of luminal cancer and adverse events. RESULTS Seventy-nine subjects (median age 76 years, 81% male, 94% with adenocarcinoma) were treated. Tumor stage included T1-60, T2-16, and T3/4-3. Mean tumor length was 4.0 cm (range 1-15 cm). Previous treatment including endoscopic resection, photodynamic therapy, esophagectomy, chemotherapy, and radiation therapy failed in 53 subjects (67%). Forty-nine completed treatment. Complete response of intraluminal disease was seen in 31 of 49 subjects (61.2%), including 18 of 24 (75%) with mucosal cancer. Mean (standard deviation) length of follow-up after treatment was 10.6 (8.4) months overall and 11.5 (2.8) months for T1 disease. No serious adverse events were reported. Benign stricture developed in 10 (13%), with esophageal narrowing from previous endoscopic resection, radiotherapy, or photodynamic therapy noted in 9 of 10 subjects. LIMITATIONS Retrospective study design, short follow-up. CONCLUSIONS Spray cryotherapy is safe and well tolerated for esophageal cancer. Short-term results suggest that it is effective in those who could not receive conventional treatment, especially for those with mucosal cancer.

Safety, tolerability, and efficacy of endoscopic low-pressure liquid nitrogen spray cryotherapy in the esophagus

Endoscopic cryotherapy is a new technique for ablation of esophageal dysplasia and neoplasia. Preliminary studies have shown it to be safe and effective for this indication. The objective of this study is to characterize safety, tolerability, and efficacy of low-pressure liquid nitrogen endoscopic spray cryotherapy ablation in a large cohort across multiple study sites. Parallel prospective treatment studies at four tertiary care academic medical centers in the U.S. assessed spray cryotherapy in patients with Barretts esophagus with or without dysplasia, early stage esophageal cancer, and severe squamous dysplasia who underwent cryotherapy ablation of the esophagus. All patients were contacted between 1 and 10 days after treatment to assess for side effects and complications of treatment. The main outcome measurement was the incidence of serious adverse events and side effects from treatment. Complete response for high-grade dysplasia (HGD) (CR-HGD), all dysplasia (CR-D), intestinal metaplasia (CR-IM) and cancer (CR-C) were assessed in patients completing therapy during the study period. A total of 77 patients were treated for Barretts high-grade dysplasia (58.4%), intramucosal carcinoma (16.9%), invasive carcinoma (13%), Barretts esophagus without dysplasia (9.1%), and severe squamous dysplasia (2.6%). Twenty-two patients (28.6%) reported no side effects throughout treatment. In 323 procedures, the most common complaint was chest pain (17.6%) followed by dysphagia (13.3%), odynophagia (12.1%), and sore throat (9.6%). The mean duration of any symptoms was 3.6 days. No side effects were reported in 48% of the procedures (155/323). Symptoms did not correlate with age, gender, diagnosis, or to treatment early versus late in the patients or sites experience. Logit analysis showed that symptoms were greater in those with a Barretts segment of 6 cm or longer. Gastric perforation occurred in one patient with Marfans syndrome. Esophageal stricture developed in three, all successfully treated with dilation. In 17 HGD patients, cryotherapy produced CR-HGD, CR-D, and CR-IM of 94%, 88%, and 53%, respectively. Complete regression of cancer and HGD was seen in all seven patients with intramucosal carcinoma or stage I esophageal cancer. Endoscopic spray cryotherapy ablation using low-pressure liquid nitrogen in the esophagus is safe, well-tolerated, and efficacious.

Proton Pump Inhibitors Alter Specific Taxa in the Human Gastrointestinal Microbiome: A Crossover Trial.

We conducted an open-label crossover trial to test whether proton pump inhibitors (PPIs) affect the gastrointestinal microbiome to facilitate Clostridium difficile infection (CDI). Twelve healthy volunteers each donated 2 baseline fecal samples, 4 weeks apart (at weeks 0 and 4). They then took PPIs for 4 weeks (40 mg omeprazole, twice daily) and fecal samples were collected at week 8. Six individuals took the PPIs for an additional 4 weeks (from week 8 to 12) and fecal samples were collected from all subjects at week 12. Samples were analyzed by 16S ribosomal RNA gene sequencing. We found no significant within-individual difference in microbiome diversity when we compared changes during baseline vs changes on PPIs. There were, however, significant changes during PPI use in taxa associated with CDI (increased Enterococcaceae and Streptococcaceae, decreased Clostridiales) and taxa associated with gastrointestinal bacterial overgrowth (increased Micrococcaceae and Staphylococcaceae). In a functional analysis, there were no changes in bile acids on PPIs, but there was an increase in genes involved in bacterial invasion. These alterations could provide a mechanism by which PPIs predispose to CDI. ClinicalTrials.gov ID NCT01901276.

Proton Pump Inhibitors and Risk for Recurrent Clostridium difficile Infection Among Inpatients

OBJECTIVES:Observational studies suggest that proton pump inhibitors (PPIs) are a risk factor for incident Clostridium difficile infection (CDI). Data also suggest an association between PPIs and recurrent CDI, although large-scale studies focusing solely on hospitalized patients are lacking. We therefore performed a retrospective cohort analysis of inpatients with incident CDI to assess receipt of PPIs as a risk factor for CDI recurrence in this population.METHODS:Using electronic medical records, we identified hospitalized adult patients between 1 December 2009 and 30 June 2012 with incident CDI, defined as a first positive stool test for C. difficile toxin B and who received appropriate treatment. Electronic records were parsed for clinical factors including receipt of PPIs, other acid suppression, non-CDI antibiotics, and comorbidities. The primary exposure was in-hospital PPIs given concurrently with C. difficile treatment. Recurrence was defined as a second positive stool test 15–90 days after the initial positive test. C. difficile recurrence rates in the PPI exposed and unexposed groups were compared with the log-rank test. Multivariable Cox proportional hazards modeling was performed to control for demographics, comorbidities, and other clinical factors.RESULTS:We identified 894 inpatients with incident CDI. The cumulative incidence of CDI recurrence in the cohort was 23%. Receipt of PPIs concurrent with CDI treatment was not associated with C. difficile recurrence (hazard ratio (HR)=0.82; 95% confidence interval (CI)=0.58–1.16). Black race (HR=1.66, 95% CI=1.05–2.63), increased age (HR=1.02, 95% CI=1.01–1.03), and increased comorbidities (HR=1.09, 95% CI=1.04–1.14) were associated with CDI recurrence. In light of a higher 90-day mortality seen among those who received PPIs (log-rank P=0.02), we also analyzed the subset of patients who survived to 90 days of follow-up. Again, there was no association between PPIs and CDI recurrence (HR=0.87; 95% CI=0.60–1.28). Finally, there was no association between recurrent CDI and increased duration or dose of PPIs.CONCLUSIONS:Among hospitalized adults with C. difficile, receipt of PPIs concurrent with C. difficile treatment was not associated with CDI recurrence. Black race, increased age, and increased comorbidities significantly predicted recurrence. Future studies should test interventions to prevent CDI recurrence among high-risk inpatients.

Dating the Rise of Esophageal Adenocarcinoma: Analysis of Connecticut Tumor Registry Data, 1940–2007

Background: The timing of onset of the rise in incidence of esophageal adenocarcinoma (EAC) has not been clearly defined, and doing so may provide clues with regard to exposures associated with the changed epidemiology of this malignancy. We therefore aimed to investigate historical trends in the incidence of EAC and other upper gastrointestinal malignancies. Methods: We did a population-based study using Connecticut Tumor Registry (1940–2007) and Surveillance, Epidemiology, and End Results (SEER; 1973–2007) data. Age-adjusted incidence rates (per 100,000 person-years) were calculated for EAC and other upper gastrointestinal malignancies. Results: The incidence of EAC remained relatively constant until 1965–69, and then rose from 0.41 (95%CI, 0.26–0.56) to 1.31 (95%CI 1.07–1.54) in 1978–82 and 5.31 (95%CI 4.89–5.73) in 2003–07. The incidence of gastric cardia cancer began to rise in the 1950s and plateaued in the 1990s. The incidence of esophageal squamous cell carcinoma began to decrease around 1980. The trends from Connecticut Tumor Registry data closely mirrored those from SEER data. Conclusions: The incidence of EAC began to rise in the late 1960s, predating the rise in obesity by a decade. Reduced infection rates of Helicobacter pylori, changes in microbiome, or other exposures may have contributed to the changed epidemiology of this malignancy. Impact: Analysis of historical data of trends in EAC incidence implicate a change in environmental factors from the mid-20th century as primarily responsible for the initial rise in EAC incidence, predating the rise in obesity prevalence in the United States by over a decade. Cancer Epidemiol Biomarkers Prev; 20(1); 183–6. ©2011 AACR.