Esophageal adenocarcinoma in Barrett's esophagus after endoscopic ablative therapy: a meta-analysis and systematic review.

OBJECTIVES: The extent of reduction of esophageal adenocarcinoma (EAC) incidence in Barrett's esophagus (BE) patients after endoscopic ablation is not known. The objective of this study was to determine the cancer incidence in BE patients after ablative therapy and compare these rates to cohort studies of BE patients not undergoing ablation. METHODS: A MEDLINE search of the literature on the natural history and ablative modalities in BE patients was performed. Patients with nondysplastic BE (NDBE), low-grade dysplasia (LGD), or high-grade dysplasia (HGD) and follow-up of at least 6 months were included. The rate of cancer in patients undergoing ablation and from the natural history data was calculated using weighted-average incidence rates (WIR). RESULTS: A total of 53 articles met the inclusion criteria for the natural history data. Pooled natural history data showed cancer incidence of 5.98/1,000 patient-years (95% CI 5.05-6.91) in NDBE; 16.98/1,000 patient-years (95% CI 13.1-20.85) in LGD; and 65.8/1,000 patient-years (95% CI 49.7-81.8) in HGD patients. A total of 65 articles met the inclusion criteria for BE patients undergoing ablation (1,457 patients, NDBE; 239 patients, LGD; and 611 patients, HGD). The WIR for cancer was 1.63/1,000 patient-years (95% CI 0.07-3.34) for NDBE; 1.58/1,000 patient-years (95% CI 0.66-3.84) for LGD; and 16.76/1,000 patient-years (95% CI 10.6-22.9) for HGD patients. CONCLUSIONS: Compared to historical reports of the natural history of BE, ablation may be associated with a reduction in cancer incidence, although such a comparison is limited by likely heterogeneity between treatment and natural history studies. The greatest benefit of ablation was observed in BE patients with HGD.

Barrett esophagus.

PURPOSE: The importance of an in-depth understanding about Barrett esophagus is ultimately to decrease the mortality and morbidity from esophageal adenocarcinoma cancer by early detection of metaplasia and dysplasia and appropriate therapy. This review summarizes several publications in the past year related to the epidemiology, pathogenesis, screening and surveillance, new methods for detection of metaplasia/dysplasia, and advances in the treatment of Barrett esophagus. RECENT FINDINGS: Patients with Barrett esophagus are characterized by the presence of risk factors usually indicative of severe types of gastroesophageal reflux disease. Recent insights into epidemiology and pathogenesis have shown that the risk of high-grade dysplasia and adenocarcinoma may be related to the increasing length of Barrett esophagus, size of hiatus hernia, and severity of acid reflux. The role of smoking and alcohol consumption remains controversial. Increasing the number of biopsies by repeat standard endoscopy can enhance the yield of intestinal metaplasia in patients with suspected short-segment Barrett esophagus. Costs of surveillance using standard endoscopy and random biopsies would be very high and using special techniques to target specific areas could ultimately help in cost reduction. Emerging data on new techniques and technology such as vital staining with methylene blue and protoporphyrin fluorescence can increase the yield of metaplasia and dysplasia. Biomarkers studies have revealed that p53 mutation by the loss of heterozygosity can help detect patients with low and high risk for cancer progression. Studies thus far have been unclear whether acid suppression alone can impact the malignant progression in Barrett esophagus patients. Inhibition of cyclooxygenase by aspirin or nonsteroidal anti-inflammatory drugs may be a promising chemoprevention strategy against dysplasia and esophageal adenocarcinoma development as shown in some recent studies. Nonsurgical treatment by photodynamic therapy or mucosal resection may be a less invasive and organ-sparing option for some patients with high-grade dysplasia and early adenocarcinoma. SUMMARY: In the past year we have made major strides in our knowledge of this premalignant lesion. Recent studies have shed light in a better understanding of the epidemiology of Barrett esophagus, including clinical and endoscopic factors associated with high-grade dysplasia or esophageal adenocarcinoma and various biomarkers that would identify patient subsets with low and high risk for cancer progression. This will eventually have significant implications on the screening, surveillance, and treatment of the disease. Advanced endoscopic therapies including mucosectomy or photodynamic therapy may be emerging options in patients with intraepithelial neoplasia.

Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver.

To determine whether disruption of the hepatic sinusoidal endothelium will facilitate engraftment of transplanted cells, we treated Fischer 344 (F344) rats lacking dipeptidyl peptidase IV (DPPIV) activity with cyclophosphamide (CP). Electron microscopy showed endothelial injury within 6 hours following CP, and, after 24 and 48 hours, the endothelium was disrupted in most hepatic sinusoids. CP did not affect Kupffer cell function. Similarly, CP had no obvious effects on hepatocytes. Intrasplenic transplantation of F344 rat hepatocytes followed by their localization with DPPIV histochemistry showed 3- to 5-fold increases in the number of transplanted cells in CP-treated animals. Transplanted cells integrated in the liver parenchyma more rapidly in CP-treated animals, and hybrid bile canaliculi developed even 1 day after cell transplantation, which was not observed in control animals. To demonstrate whether improved cell engraftment translated into superior liver repopulation, recipient animals were conditioned with retrorsine and two-thirds partial hepatectomy (PH), which induces transplanted cell proliferation. CP treatment of these animals before cell transplantation significantly increased the number and size of transplanted cell foci. In conclusion, disruption of the hepatic sinusoidal endothelium was associated with accelerated entry and integration of transplanted cells in the liver parenchyma. These results provide insights into hepatocyte engraftment in the liver and will help in optimizing liver-directed cell therapy.

Hepatic sinusoidal vasodilators improve transplanted cell engraftment and ameliorate microcirculatory perturbations in the liver.

After transplantation, hepatocytes entering liver sinusoids are engrafted, whereas cells entrapped in portal spaces are cleared. We studied whether hepatic sinusoidal dilatation will increase the entry of transplanted cells in the liver lobule, improve cell engraftment, and decrease microcirculatory perturbations. F344 rat hepatocytes were transplanted intrasplenically into syngeneic dipeptidyl peptidase IV (DPPIV)-deficient rats. Animals were treated with adrenergic receptor blockers (phentolamine, labetalol), a calcium channel blocker (nifedipine), and splanchnic vasodilators (nitroglycerine, calcitonin gene-related peptide [CGRP], glucagon). Transplanted cells were localized by histochemistry. The hepatic microcirculation was studied with in vivo videomicroscopy. Changes in cell translocations were analyzed by injection of (99m)Tc-labeled hepatocytes. Pretreatment with phentolamine and nitroglycerine increased transplanted cell entry in liver sinusoids, whereas labetalol, nifedipine, CGRP, and glucagon were ineffective. Increased deposition of transplanted cells in sinusoids resulted in greater cell engraftment. In vivo microscopy showed disruption of sinusoidal blood flow immediately after cell transplantation with circulatory restoration requiring more than 12 to 24 hours after cell transplantation. However, in nitroglycerine-treated animals, sinusoidal blood flow was perturbed less. Nitroglycerine did not meaningfully increase intrapulmonary cell translocations. In conclusion, these findings indicate that hepatic sinusoidal capacitance is regulated by alpha-adrenergic- and nitroglycerine-responsive elements. Sinusoidal vasodilatation benefited intrahepatic distribution of transplanted cells and restored hepatic microcirculation after cell transplantation. This shall facilitate optimization of clinical cell transplantation and offers novel ways to investigate vascular mechanisms regulating hepatic sinusoidal reactivity.