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BACKGROUND & AIMS: Transformation of stem/progenitor cells has been associated with tumorigenesis in multiple tissues, but stem cells in the stomach have been hard to localize. We therefore aimed to use a combination of several markers to better target oncogenes to gastric stem cells and understand their behavior in the initial stages of gastric tumorigenesis. METHODS: Mouse models of gastric metaplasia and cancer by targeting stem/progenitor cells were generated and analyzed with techniques including reanalysis of single-cell RNA sequencing and immunostaining. Gastric cancer cell organoids were genetically manipulated with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) for functional studies. Cell division was determined by bromodeoxyuridine-chasing assay and the assessment of the orientation of the mitotic spindles. Gastric tissues from patients were examined by histopathology and immunostaining. RESULTS: Oncogenic insults lead to expansion of SOX9+ progenitor cells in the mouse stomach. Genetic lineage tracing and organoid culture studies show that SOX9+ gastric epithelial cells overlap with SOX2+ progenitors and include stem cells that can self-renew and differentiate to generate all gastric epithelial cells. Moreover, oncogenic targeting of SOX9+SOX2+ cells leads to invasive gastric cancer in our novel mouse model (Sox2-CreERT;Sox9-loxp(66)-rtTA-T2A-Flpo-IRES-loxp(71);Kras(Frt-STOP-Frt-G12D);P53R172H), which combines Cre-loxp and Flippase-Frt genetic recombination systems. Sox9 deletion impedes the expansion of gastric progenitor cells and blocks neoplasia after Kras activation. Although Sox9 is not required for maintaining tissue homeostasis where asymmetric division predominates, loss of Sox9 in the setting of Kras activation leads to reduced symmetric cell division and effectively attenuates the Kras-dependent expansion of stem/progenitor cells. Similarly, Sox9 deletion in gastric cancer organoids reduces symmetric cell division, organoid number, and organoid size. In patients with gastric cancer, high levels of SOX9 are associated with recurrence and poor prognosis. CONCLUSION: SOX9 marks gastric stem cells and modulates biased symmetric cell division, which appears to be required for the malignant transformation of gastric stem cells.
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Proteínas Proto-Oncogénicas p21(ras) , Neoplasias Gástricas , Ratones , Animales , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Neoplasias Gástricas/patología , Proliferación Celular , Transformación Celular Neoplásica/patología , Carcinogénesis/patología , División Celular , Células Madre/metabolismoRESUMEN
BACKGROUND & AIMS: Endoscopic Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) detection is invasive and expensive. Nonendoscopic BE/EAC detection tools are guideline-endorsed alternatives. We previously described a 5-methylated DNA marker (MDM) panel assayed on encapsulated sponge cell collection device (CCD) specimens. We aimed to train a new algorithm using a 3-MDM panel and test its performance in an independent cohort. METHODS: Algorithm training and test samples were from 2 prospective multicenter cohorts. All BE cases had esophageal intestinal metaplasia (with or without dysplasia/EAC); control subjects had no endoscopic evidence of BE. The CCD procedure was followed by endoscopy. From CCD cell lysates, DNA was extracted, bisulfite treated, and MDMs were blindly assayed. The algorithm was set and locked using cross-validated logistic regression (training set) and its performance was assessed in an independent test set. RESULTS: Training (N = 352) and test (N = 125) set clinical characteristics were comparable. The final panel included 3 MDMs (NDRG4, VAV3, ZNF682). Overall sensitivity was 82% (95% CI, 68%-94%) at 90% (79%-98%) specificity and 88% (78%-94%) sensitivity at 84% (70%-93%) specificity in training and test sets, respectively. Sensitivity was 90% and 68% for all long- and short-segment BE, respectively. Sensitivity for BE with high-grade dysplasia and EAC was 100% in training and test sets. Overall sensitivity for nondysplastic BE was 82%. Areas under the receiver operating characteristic curves for BE detection were 0.92 and 0.94 in the training and test sets, respectively. CONCLUSIONS: A locked 3-MDM panel algorithm for BE/EAC detection using a nonendoscopic CCD demonstrated excellent sensitivity for high-risk BE cases in independent validation samples. (Clinical trials.gov: NCT02560623, NCT03060642.).
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Algoritmos , Esófago de Barrett , Humanos , Esófago de Barrett/diagnóstico , Esófago de Barrett/patología , Estudios Prospectivos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Sensibilidad y Especificidad , Adulto , Metilación de ADN , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patología , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologíaRESUMEN
INTRODUCTION: The incidence of esophagogastric junction adenocarcinoma (EGJAC) has been rising. Intestinal metaplasia of the esophagogastric junction (EGJIM) is a common finding in gastroesophageal reflux (irregular Z-line) and may represent an early step in the development of EGJAC in the West. Worldwide, EGJIM may represent progression along the Correa cascade triggered by Helicobacter pylori . We sought to evaluate the cost-effectiveness of endoscopic surveillance of EGJIM. METHODS: We developed a decision analytic model to compare endoscopic surveillance strategies for 50-year-old patients after diagnosis of non-dysplastic EGJIM: (i) no surveillance (standard of care), (ii) endoscopy every 3 years, (iii) endoscopy every 5 years, or (iv) 1-time endoscopy at 3 years. We modeled 4 progression scenarios to reflect uncertainty: A (0.01% annual cancer incidence), B (0.05%), C (0.12%), and D (0.22%). RESULTS: Cost-effectiveness of endoscopic surveillance depended on the progression rate of EGJIM to cancer. At the lowest progression rate (scenario A, 0.01%), no surveillance strategies were cost-effective. In moderate progression scenarios, 1-time surveillance at 3 years was cost-effective, at $30,989 and $16,526 per quality-adjusted life year for scenarios B (0.05%) and C (0.12%), respectively. For scenario D (0.22%), surveillance every 5 years was cost-effective at $77,695 per quality-adjusted life year. DISCUSSION: Endoscopic surveillance is costly and can cause harm; however, low-intensity longitudinal surveillance (every 5 years) is cost-effective in populations with higher EGJAC incidence. No surveillance or 1-time endoscopic surveillance of patients with EGJIM was cost-effective in low-incidence populations. Future studies to better understand the natural history of EGJIM, identify risk factors of progression, and inform appropriate surveillance strategies are required.
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Adenocarcinoma , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Progresión de la Enfermedad , Neoplasias Esofágicas , Unión Esofagogástrica , Metaplasia , Humanos , Unión Esofagogástrica/patología , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/epidemiología , Persona de Mediana Edad , Metaplasia/patología , Adenocarcinoma/patología , Adenocarcinoma/epidemiología , Lesiones Precancerosas/patología , Masculino , Femenino , Años de Vida Ajustados por Calidad de Vida , Neoplasias Gástricas/patología , Neoplasias Gástricas/epidemiología , Incidencia , Infecciones por Helicobacter/complicaciones , Esófago de Barrett/patologíaRESUMEN
Prior studies have conflicting findings regarding the association between gastroesophageal reflux disease (GERD) and esophageal squamous cell carcinoma (ESCC). We examined this relationship in a prospective cohort in a region of high ESCC incidence. Baseline exposure data were collected from 50 045 individuals using in-person interviews at the time of cohort entry. Participants were followed until they developed cancer, died, or were lost to follow up. Participants with GERD symptoms were categorized into any GERD (heartburn or regurgitation), mixed symptoms, or heartburn alone. Multivariable Cox regression was used to assess the relationship between GERD symptom group and histologically confirmed ESCC. The model was adjusted for known risk factors for GERD and ESCC. 49 559 individuals were included in this study, of which 9005 had GERD symptoms. Over 13.0 years of median follow up, 290 individuals were diagnosed with ESCC. We found no association between any GERD and risk of ESCC (aHR 0.90, 95% CI: 0.66-1.24, P = .54). Similar findings were observed for the GERD symptom subtypes. Significant interactions between any GERD and sex (P = .013) as well as tobacco smoking (P = .028) were observed. In post-hoc analyses, GERD was associated with a decreased risk of ESCC in men (aHR 0.51, 95% CI: 0.27-0.98 P = .04) and in smokers (aHR 0.26, 95% CI: 0.08-0.83 P = .02). While there was little evidence for an overall association between GERD symptoms and ESCC risk, significant interactions with sex and smoking were observed. Men and smokers with GERD symptoms had a lower risk of ESCC development.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Reflujo Gastroesofágico , Masculino , Humanos , Carcinoma de Células Escamosas de Esófago/epidemiología , Estudios de Cohortes , Neoplasias Esofágicas/etiología , Neoplasias Esofágicas/complicaciones , Pirosis/complicaciones , Estudios Prospectivos , Incidencia , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/epidemiología , Factores de Riesgo , Fumar/efectos adversos , Fumar TabacoRESUMEN
Esophageal atresia (EA) with or without trachea-esophageal fistula is relatively common congenital malformation with most patients living into adulthood. As a result, care of the adult patient with EA is becoming more common. Although surgical repair has changed EA from a fatal to a livable condition, the residual effects of the anomaly may lead to a lifetime of complications. These include effects related to the underlying deformity such as atonicity of the esophageal segment, fistula recurrence, and esophageal cancer to complications of the surgery including anastomotic stricture, gastroesophageal reflux, and coping with an organ transposition. This review discusses the occurrence and management of these conditions in adulthood and the role of an effective transition from pediatric to adult care to optimize adult care treatment.
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Atresia Esofágica , Estenosis Esofágica , Fístula Traqueoesofágica , Transición a la Atención de Adultos , Humanos , Adulto , Niño , Atresia Esofágica/cirugía , Atresia Esofágica/complicaciones , Fístula Traqueoesofágica/cirugía , Fístula Traqueoesofágica/complicaciones , Tráquea/cirugía , Complicaciones Posoperatorias/epidemiología , Estenosis Esofágica/etiología , Estenosis Esofágica/cirugíaRESUMEN
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.
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In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown. In the case of Barrett's oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells. On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett's oesophagus in terms of the presence of intestinal goblet cells. Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63+KRT5+KRT7+) at the squamous-columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous-columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett's metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett's oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63+KRT5+KRT7+ basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett's oesophagus.
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Esófago de Barrett/patología , Linaje de la Célula , Células Epiteliales/patología , Epitelio/patología , Unión Esofagogástrica/patología , Células Madre/patología , Animales , Esófago de Barrett/genética , Esófago de Barrett/metabolismo , Factor de Transcripción CDX2/genética , Factor de Transcripción CDX2/metabolismo , Rastreo Celular , Esofagitis/metabolismo , Esofagitis/patología , Unión Esofagogástrica/metabolismo , Reflujo Gastroesofágico , Células Caliciformes/metabolismo , Células Caliciformes/patología , Humanos , Queratina-5/metabolismo , Queratina-7/metabolismo , Metaplasia/metabolismo , Metaplasia/patología , Ratones , Fosfoproteínas/metabolismo , Células Madre/metabolismo , Transactivadores/metabolismoRESUMEN
Recent guidelines recommend screening for patients with chronic gastroesophageal reflux disease who have three or more additional risk factors for Barrett's esophagus (BE). Failure to screen high-risk individuals represents a missed opportunity in esophageal adenocarcinoma prevention and early detection. We aimed to determine the frequency of upper endoscopy and prevalence of BE and esophageal cancer in a cohort of United States veterans who possessed four or more risk factors for BE. All patients at VA New York Harbor Healthcare System with at least four risk factors for BE between 2012 and 2017 were identified. Procedure records were reviewed for upper endoscopies performed between January 2012 and December 2019. Multivariable logistic regression was used to determine risk factors associated with undergoing endoscopy and factors associated with BE and esophageal cancer. 4505 patients with at least four risk factors for BE were included. 828 patients (18.4%) underwent upper endoscopy, of which 42 (5.1%) were diagnosed with BE and 11 (1.3%) with esophageal cancer (10 adenocarcinoma; 1 squamous cell carcinoma). Among individuals who underwent upper endoscopy, risk factors associated with undergoing endoscopy included obesity (OR, 1.79; 95% CI, 1.41-2.30; P < 0.001) and chronic reflux (OR, 3.86; 95% CI, 3.04-4.90; P < 0.001). There were no individual risk factors associated with BE or BE/esophageal cancer. In this retrospective analysis of patients with 4 or more risk factors for BE, fewer than one-fifth of patients underwent upper endoscopy, supporting the need for efforts aimed at improving BE screening rates.
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Adenocarcinoma , Esófago de Barrett , Neoplasias Esofágicas , Reflujo Gastroesofágico , Veteranos , Humanos , Esófago de Barrett/diagnóstico , Esófago de Barrett/epidemiología , Esófago de Barrett/complicaciones , Estudios Retrospectivos , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/etiología , Factores de Riesgo , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiología , Adenocarcinoma/etiología , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/epidemiología , Esofagoscopía/efectos adversosRESUMEN
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.
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Esófago de Barrett , Neoplasias Esofágicas , Esófago de Barrett/diagnóstico por imagen , Esófago de Barrett/patología , Biopsia , Neoplasias Esofágicas/patología , Esofagoscopía/métodos , Estudios de Factibilidad , Femenino , Humanos , Masculino , Tomografía de Coherencia Óptica/métodosRESUMEN
BACKGROUND: Adults with cystic fibrosis (CF) have an increased risk of a variety of cancers, notably gastrointestinal cancers. In CF higher body mass index (BMI) is associated with improved long-term outcomes, yet in the general population high BMI is associated with increased cancer risk. We aimed to delineate associations between BMI and other factors with cancer risk in adults with CF. METHODS: This was a retrospective cohort study using CF Foundation Patient Registry data from 1992 to 2015. Data were collected on age, sex, CFTR mutation class, pancreatic insufficiency, and annualized data on BMI and FEV1. The primary analysis was the association between BMI and cancer, with secondary analyses focused on BMI trajectory. Multivariable logistic regression was performed, with analyses stratified by history of transplant. RESULTS: Of 26,199 adults with CF, 446 (1.7%) had cancer diagnosed by histology at a mean age of 40.0 years (SD 12.2), with a higher proportion of transplanted patients developing cancer (137 (3.8%) v 309(1.4%), p < 0.001). Among non-transplanted patients, there was no association between BMI and cancer (p for trend = 0.43). Pancreatic insufficiency (p < 0.01) and higher FEV1 (p < 0.01) were associated with increased cancer risk. In transplanted patients, higher BMI was associated with reduced risk of cancer (p for trend = 0.04). Older age was associated with increased risk in both groups (p < 0.001). BMI trajectories were not associated with cancer risk in either group. CONCLUSION: Higher BMI is associated with a reduced risk of cancer in transplanted adults with CF. Pancreatic insufficiency is a risk factor for cancer in non-transplanted CF patients.
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Fibrosis Quística , Insuficiencia Pancreática Exocrina , Neoplasias , Adulto , Humanos , Fibrosis Quística/complicaciones , Fibrosis Quística/epidemiología , Fibrosis Quística/diagnóstico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Índice de Masa Corporal , Estudios Retrospectivos , Insuficiencia Pancreática Exocrina/epidemiología , Insuficiencia Pancreática Exocrina/complicaciones , Neoplasias/etiología , Neoplasias/complicaciones , Factores de RiesgoRESUMEN
Esophageal squamous cell carcinoma (ESCC) accounts for the large majority of esophageal cancer cases worldwide. In this review, we examine the potential role of non-acidic fluid (NAF) exposure in ESCC carcinogenesis. Esophageal NAF consists of a mixture of salivary, esophageal, gastric, and duodenal fluids, containing inflammatory constituents such as digestive enzymes and bile acids that induce DNA damage, as well as known carcinogens such as acetaldehyde and N-nitrosamines. Exposure to NAF can occur in the setting of increased non-acid reflux, decreased gastric acidity, and decreased esophageal fluid clearance. Non-acid reflux has been associated with ESCC in small observational studies, and in animal models bile reflux can promote the development of ESCC. Associations have been found between increased ESCC risk and atrophic gastritis, a history of partial gastrectomy, and proton pump inhibitor use, all of which raise the pH of refluxate. Additionally, a minimally or non-acidic gastric environment contains an altered microbiome that can increase the production of acetaldehyde and N-nitrosamines. Esophageal motility disorders such as achalasia and opioid-induced esophageal dysfunction result in increased stasis and exposure to these potentially proinflammatory constituents of NAF. NAF may promote the development of ESCC via multiple mechanisms and is an understudied area of research.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Nitrosaminas , Acetaldehído/efectos adversos , Animales , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/inducido químicamente , Neoplasias Esofágicas/genética , Humanos , Nitrosaminas/efectos adversosRESUMEN
BACKGROUND: Chemoprevention for colorectal neoplasia has attracted growing interest, with multiple medications investigated. Metformin may decrease the overall incidence of cancer in patients with diabetes and may decrease the incidence of colorectal cancer. AIMS: We aimed to determine the impact of metformin use on the behavior of colorectal adenomas in a US veteran population. METHODS: All patients with at least two high-quality colonoscopies between January 1997 and December 2013 at Veterans Affairs New York Harbor Healthcare System were identified. Outpatient prescription records were used to determine metformin exposure, and colonoscopy findings were recorded. Multivariable logistic regression was used to determine factors associated with adenoma detection on baseline and interval colonoscopy. RESULTS: In total, 1869 patients with two successive colonoscopies (median 4.5 years) were included. Four hundred and sixty patients had metformin exposure prior to baseline and/or interval colonoscopy. Overall adenoma detection rate was 59.7% at baseline and 45.9% at interval colonoscopy. On multivariable analysis, metformin use was associated with decreased adenoma prevalence at baseline (OR 0.68; 95% CI 0.51-0.92; p = 0.015). Metformin did not impact adenoma incidence at interval colonoscopy whether prescribed before baseline (OR 1.26; 95% CI 0.60-2.67), after baseline (OR 1.25; 95% CI 0.91-1.72), or before and after baseline (OR 1.14; 95% CI 0.82-1.58). CONCLUSIONS: In this retrospective analysis of an average-risk cohort, metformin use was associated with a decreased prevalence of colorectal adenomas at baseline colonoscopy. This inverse association did not persist on interval colonoscopy. Prospective studies are needed to evaluate potential chemoprotective effects of metformin over time.
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Adenoma , Pólipos del Colon , Neoplasias Colorrectales , Metformina , Adenoma/diagnóstico , Adenoma/epidemiología , Adenoma/prevención & control , Pólipos del Colon/tratamiento farmacológico , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/prevención & control , Detección Precoz del Cáncer , Humanos , Metformina/uso terapéutico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
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.
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Lesiones Precancerosas , Neoplasias Gástricas , Endoscopía Gastrointestinal , Humanos , Hiperplasia , Metaplasia/epidemiología , Lesiones Precancerosas/patología , Prevalencia , Estudios Retrospectivos , Neoplasias Gástricas/patologíaRESUMEN
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 < .01). 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.
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COVID-19 , Enfermedades Gastrointestinales/virología , COVID-19/complicaciones , COVID-19/diagnóstico , COVID-19/mortalidad , Comorbilidad , Femenino , Hospitalización , Humanos , Masculino , Ciudad de Nueva York , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis. METHODS: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5+ (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB. RESULTS: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5+ cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5+ cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5+ cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation. CONCLUSIONS: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.
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Adenocarcinoma/patología , Esófago de Barrett/patología , Carcinogénesis/patología , Neoplasias Esofágicas/patología , Células Caliciformes/patología , Receptores Notch/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Anciano , Animales , Esófago de Barrett/diagnóstico , Esófago de Barrett/genética , Biopsia , Carcinogénesis/genética , Diferenciación Celular/genética , Estudios Transversales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Mucosa Esofágica/citología , Mucosa Esofágica/diagnóstico por imagen , Mucosa Esofágica/patología , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Esofagoscopía , Femenino , Mucosa Gástrica/citología , Mucosa Gástrica/patología , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , FN-kappa B/metabolismo , Estudios Prospectivos , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Receptores Notch/genética , Transducción de SeñalRESUMEN
BACKGROUND AND AIMS: After endoscopic eradication of Barrett's esophagus (BE), recurrence of intestinal metaplasia at the gastroesophageal junction (GEJIM) is common. The clinical significance of this finding is unclear. We assessed whether recurrent GEJIM is associated with increased risk of subsequent dysplasia and whether endoscopic treatment lowers this risk. METHODS: A retrospective, multicenter, cohort study was performed of treated BE patients who achieved complete eradication of intestinal metaplasia (IM). Postablation follow-up was performed at standard intervals. Recurrent GEJIM was defined as nondysplastic IM on gastroesophageal junction biopsy specimens without endoscopic evidence of BE. Patients were categorized as "never-GEJIM," "GEJIM-observed," or "GEJIM-treated." Endoscopic treatment for recurrent GEJIM was at the endoscopists' discretion. The primary outcome was dysplasia recurrence. Analyses were performed using log-rank tests and Cox proportional hazards modeling. RESULTS: Six hundred thirty-three patients were analyzed; median follow-up was 47 months (interquartile range, 24-69). Most patients (81%) had high-grade dysplasia or intramucosal adenocarcinoma before treatment. Dysplasia recurrence was 2.2% per year. GEJIM-observed patients had the lowest rate of recurrence (.6%/y) followed by GEJIM-treated (2.2%/y) and never-GEJIM (2.6%/y) (log-rank P = .07). In multivariate analyses, compared with never-GEJIM, the risk of dysplasia recurrence was significantly lower in GEJIM-observed patients (adjusted hazard ratio, .19; 95% confidence interval, .05-.81) and not different in GEJIM-treated patients (adjusted hazard ratio, .81; 95% confidence interval, .39-1.67). Older age and longer initial BE length were independently associated with recurrence. CONCLUSIONS: Recurrent GEJIM after endoscopic eradication of BE was not associated with an increased risk of subsequent dysplasia. Future studies are warranted to determine if observation is appropriate for this finding.
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Esófago de Barrett , Neoplasias Esofágicas , Anciano , Esófago de Barrett/cirugía , Estudios de Cohortes , Unión Esofagogástrica/cirugía , Esofagoscopía , Humanos , Metaplasia , Recurrencia Local de Neoplasia/epidemiología , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: Guidelines recommend testing patients with peptic ulcer disease for Helicobacter pylori infection. We sought to identify factors associated with adherence to testing for H pylori in patients hospitalized for bleeding ulcers and to evaluate whether performing these tests affect risk for rebleeding. METHODS: We performed a retrospective study of 830 inpatients who underwent endoscopy from 2011 through 2016 for gastrointestinal bleeding from gastric or duodenal ulcers. We searched electronic medical records for evidence of tests to detect H pylori by biopsy, serologic, or stool antigen analyses. We used multivariable models to identify clinical, demographic, and endoscopic factors associated with testing for H pylori. Kaplan-Meier analysis was performed to determine whether H pylori testing altered risk for the composite outcome of rebleeding or death within 1 year of admission. RESULTS: Among the patients hospitalized for bleeding peptic ulcer disease during the 6-year period, 19% were not tested for H pylori within 60 days of index endoscopy. Hospitalization in the intensive care unit (ICU) was the factor most frequently associated with nonadherence to H pylori testing guidelines (only 66% of patients in the ICU were tested vs 90% of patients not in the ICU; P < .01), even after we adjusted for ulcer severity, coagulation status, extent of blood loss, and additional factors (adjusted odds ratio, 0.42; 95% CI, 0.27-0.66). Testing for H pylori was associated with a 51% decreased risk of rebleeding or death during the year after admission (adjusted hazard ratio 0.49; 95% CI, 0.36-0.67). CONCLUSIONS: In an analysis of hospitalized patients who underwent endoscopy for gastrointestinal bleeding from gastric or duodenal ulcers, we found admission to the ICU to be associated with failure to test for H pylori infection. Failure to test for H pylori was independently associated with increased risk of rebleeding or death within 1 year of hospital admission. We need strategies to increase testing for H pylori among inpatients with bleeding ulcers.
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Infecciones por Helicobacter , Helicobacter pylori , Úlcera Péptica , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/diagnóstico , Hospitalización , Humanos , Úlcera Péptica/complicaciones , Estudios RetrospectivosRESUMEN
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).
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Adenocarcinoma/cirugía , Esófago de Barrett/cirugía , Criocirugía/métodos , Mucosa Esofágica/cirugía , Neoplasias Esofágicas/cirugía , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/patología , Biopsia , Criocirugía/instrumentación , Resección Endoscópica de la Mucosa , Mucosa Esofágica/patología , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: The treatment of submucosal (T1b) esophageal adenocarcinoma (EAC) remains in evolution, with some evidence supporting endoscopic management of low-risk lesions. Using a multicenter cohort, we evaluated outcomes of patients with T1b EAC and predictors of survival. METHODS: Patients diagnosed between 2001 and 2016 with T1b EAC were identified from 3 academic medical centers in the United States. Demographic, clinical, and outcome data were collected. Outcomes studied were overall and cancer-free survival. Cox proportional hazards models were constructed to assess independent predictors of survival. RESULTS: One hundred forty-one patients were included, of whom 68 (48%) underwent esophagectomy and 73 (52%) were treated endoscopically. Most patients (85.8%) had high-risk histologic features. Thirty-day operative mortality was 2.9%. Median follow-up in the esophagectomy and endoscopic cohorts was 49.4 and 43.4 months, respectively. Patients treated endoscopically were older with higher comorbidity scores, with 46 (63%) achieving histologic remission. Nineteen patients (26.0%) also received chemoradiation. Five-year overall survival rates in the surgical and endoscopic cohorts were 89% and 59%, respectively, whereas 5-year cancer-free survival rates were 92% and 69%. Presence of high-risk histologic features was associated with reduced overall survival. CONCLUSIONS: In this large multicenter study of patients with T1b EAC, esophagectomy was associated with improved overall but not cancer-free survival. High-risk histologic features were associated with poorer survival.
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Adenocarcinoma , Neoplasias Esofágicas , Adenocarcinoma/patología , Anciano , Estudios de Cohortes , Neoplasias Esofágicas/patología , Esofagectomía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Estados UnidosRESUMEN
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 ß-lactam antibiotic exposure associate with a detectable change in ß-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 ß-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.