Patients with cirrhosis who have coronary artery disease treated with cardiac stents have high rates of gastrointestinal bleeding, but no increased mortality.

BACKGROUND: Patients with coronary artery disease (CAD) treated with stents require dual antiplatelet therapy (DAPT). For cirrhotics, who often have varices and coagulopathy, it is not clear if the risk of gastrointestinal bleeding (GIB) should preclude use of DAPT. AIM: To compare GIB and mortality rates in cirrhotics with CAD treated medically or with stents. METHODS: Using institutional databases, we identified patients with cirrhosis and CAD treated with stents or medical therapy between January 2000-September 2015. Primary outcomes were GIB and mortality. RESULTS: We identified 148 cirrhotics with CAD; 68 received stents (cases), 80 were treated with medical therapy (controls). Cases and controls had similar demographics, comorbidities, MELD scores and clinical presentation; DAPT was used in 98.5% of cases vs 5% of controls. The incidence of GIB was significantly higher in cases than controls (22.1% vs 5% at 1 year, P=.003; 27.9% vs 5% at 2 years, P=.0002), whereas all-cause mortality was similar (20.6% vs 21.3%). No patient required surgery or angiography for GIB, and no known patients died due to GIB. Multivariate analysis revealed use of a proton pump inhibitor (PPI) was highly protective against GIB (OR=0.26, 95%CI=0.08-0.79). CONCLUSIONS: CAD treatment with stents in our cirrhotics was associated with a significantly increased risk of GIB, but no adverse effects on survival. Although it remains unclear whether the cardiovascular benefits of stents outweigh the GIB risk, our findings suggest that DAPT should not be withheld from stented cirrhotics for fear of GIB. Moreover, the use of a PPI should be strongly considered.

Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett's esophagus.

Barrett's esophagus develops when refluxed gastric juice injures the esophageal squamous lining and the injury heals through a metaplastic process in which intestinal-type columnar cells replace squamous ones. The progenitor cell that gives rise to Barrett's metaplasia is not known, nor is it known why the condition is predisposed to malignancy. We studied the contribution of bone marrow stem cells to the development of Barrett's esophagus in an animal model. Twenty female rats were given a lethal dose of irradiation followed by tail vein injection of bone marrow cells from male rats. Ten days later, the female rats were randomly assigned to undergo either esophagojejunostomy, a procedure that causes reflux esophagitis with intestinal metaplasia, or a sham operation. The rats were killed at 8 weeks and serial sections of the snap-frozen esophagi were cut and mounted on slides. The first and last sections were used for histological evaluation and the intervening sections were immunostained for cytokeratin to identify epithelial cells and analyzed for Y chromosome by fluorescence in situ hybridization (FISH). Histological evaluation of the esophagi from rats that had esophagojejunostomy revealed ulcerative esophagitis and multiple areas of intestinal metaplasia. FISH analyses showed that some of the squamous epithelial cells and some of the columnar epithelial cells lining the glands of the intestinal metaplasia were positive for Y chromosome. These observations suggest that multi-potential progenitor cells of bone marrow origin contribute to esophageal regeneration and metaplasia in this rat model of Barrett's esophagus.

Characterization of telomerase-immortalized, non-neoplastic, human Barrett's cell line (BAR-T).

Barrett's esophagus, a metaplasia predisposed to malignant transformation, has been studied in vitro using esophageal adenocarcinoma cell lines. However, findings in such transformed cells may not be applicable to the non-neoplastic cells of benign Barrett's esophagus. Therefore, we have developed and characterized a Barrett's cell line derived from a patient without malignancy or dysplasia. Human Barrett's epithelial cells were immortalized with the insertion of hTERT (human telomerase reverse transcriptase) using a Cre-lox recombination system. We then examined properties of this continuous cell line, such as in vitro tumorigenicity, growth patterns, histological differentiation characteristics, karyotype, and checkpoint arrest mechanisms (e.g., p16, p21, and p53). Non-neoplastic Barrett's epithelial cells infected with hTERT (BAR-T cells) have been sustained in culture beyond 200 population doublings. BAR-T cells maintain a diploid chromosome number and exhibit non-neoplastic properties, such as contact inhibition and anchorage-dependent growth. BAR-T cells express differentiation Barrett's epithelial markers, such as villin and cytokeratins 4, 8 and 18, and stain positive for Alcian blue, indicating the presence of mucin-producing cells. Expression of checkpoint arrest proteins p21 and p53 are intact, while p16 expression is lost. Thus, we have created a human Barrett's cell line that is not malignantly transformed, and yet can be maintained indefinitely in culture. BAR-T cells are diploid, have histological differentiation markers characteristic of benign Barrett's epithelium, and also maintain appropriate expression of p21 and p53. This cell line should be a useful model for the study of the early events in carcinogenesis in Barrett's esophagus.

Molecular targets for treatment of Barrett's esophagus.

SUMMARY. Esophageal cancer is one of the most deadly forms of gastrointestinal cancer with a mortality rate exceeding 90%. The major risk factors for esophageal adenocarcinoma are gastroesophageal reflux disease (GERD) and its sequela, Barrett's esophagus. GERD commonly leads to esophagitis. In a minority of patients however, ongoing GERD leads to replacement of esophageal squamous mucosa with metaplastic, intestinal-type Barrett's mucosa. In the setting of continued peptic injury, Barrett's mucosa can give rise to esophageal adenocarcinoma. Despite the widespread use of potent acid suppressive therapies for patients with GERD, the incidence of esophageal adenocarcinoma, among white men in the USA, the UK and Europe has continued to rise. Cancers in Barrett's esophagus arise through a sequence of genetic events that endow the cells with six essential physiologic hallmarks of cancer as described by Hanahan and Weinberg in 2000. These cancer hallmarks include the ability to proliferate without exogenous stimulation, to resist growth-inhibitory signals, to avoid triggering the programmed death mechanism (apoptosis), to resist cell senescence, to develop new vascular supplies (angiogenesis), and to invade and metastasize. While the acquisition of these essential attributes is not specific to the neoplastic progression of Barrett's esophagus, this review will focus on the genetic alterations that occur in Barrett's cells that contribute to the acquisition of each of the hallmarks. Moreover, potential diagnostic and therapeutic strategies for Barrett's patients aimed at each of these cancer hallmarks will be reviewed.