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Irving, TX, United States

Schomisch S.J.,University Hospitals Case Medical Center | Yu L.,University Hospitals Case Medical Center | Wu Y.,University Hospitals Case Medical Center | Pauli E.M.,University Hospitals Case Medical Center | And 5 more authors.
Endoscopy | Year: 2014

Background and study aims: Endoscopic mucosal resection (EMR) offers a minimally invasive therapy for advanced esophageal dysplasia and early cancers but stricture formation limits its applicability. We aimed at assessing the efficacy of placement of a commercially available biological mesh for preventing stricture formation following esophageal EMR. Methods: 25 swine were submitted to circumferential esophageal EMR with 10-cm extent and divided in five groups: one group with EMR only (control); one receiving an uncovered stent (stent-only group); and three groups receiving a stent covered with one of three extracellular matrices, namely small intestine submucosa (SIS group), acellular dermal matrix (ADMgroup), or urinary bladder matrix (UBM group). Stricture formation was evaluated with weekly esophagograms. Results: The stent-only group had significantly less stricture formation and survival was extended compared with controls (4.8 vs. 2.4 weeks). Compared with stenting only, the addition of a biological mesh did not reduce stricture formation: percent reductions in esophageal diameter for the groups were SIS 86%, ADM94%, and UBM 94%, compared with 82% in the stent-only group. Conclusions: Placement of commercially available biological meshes did not alter remodeling sufficiently to prevent stricture formation after esophageal EMR. © Georg Thieme Verlag KG Stuttgart · New York.

Wu Y.,University Hospitals Case Medical Center | Schomisch S.J.,University Hospitals Case Medical Center | Cipriano C.,University Hospitals Case Medical Center | Chak A.,University Hospitals Case Medical Center | And 3 more authors.
Surgical Endoscopy and Other Interventional Techniques | Year: 2014

Background: Esophageal endoscopic submucosal dissection (ESD) is an effective minimally invasive therapy for early esophageal cancer and high-grade Barrett dysplasia. However, esophageal stricture formation after circumferential or large ESD has limited its wide adoption. Mitomycin C (MMC), halofuginone (Hal), and transforming growth factor β3 (TGF-β3) exhibits antiscarring effects that may prevent post-ESD stricture formation. Methods: Using endoscopic mucosectomy (EEM) technique, an 8- to 10-cm-long circumferential esophageal mucosal segment was excised in a porcine model. The site was either untreated (control, n = 6) or received 40 evenly distributed injections of antiscarring agent immediately and at weeks 1 and 2. High and low doses were used: MMC 5 mg (n = 2), 0.5 mg (n = 2); Hal 5 mg (n = 2), 1.5 mg (n = 2), 0.5 mg (n = 2); TGF-β3 2 μg (n = 2), 0.5 μg (n = 2). The degree of stricture formation was determined by the percentage reduction of the esophageal lumen on weekly fluoroscopic examination. Animals were euthanized when strictures exceeded 80% or the animals were unable to maintain weight. Results: The control group had a luminal diameter reduction of 78.2 ± 10.9% by 2 weeks and were euthanized by week 3. Compared at 2 weeks, the Hal group showed a decrease in mean stricture formation (68.4% low dose, 57.7% high dose), while both TGF-β3 dosage groups showed no significant change (65.3% low dose, 76.2% high dose). MMC was most effective in stricture prevention (53.6% low dose, 35% high dose). Of concern, the esophageal wall treated with high-dose MMC appeared to be necrotic and eventually led to perforation. In contrast, low dose MMC, TGF-β3 and Hal treated areas appeared re-epithelialized and healthy. Conclusions: Preliminary data on MMC and Hal demonstrated promise in reducing esophageal stricture formation after EEM. More animal data are needed to perform adequate statistical analysis in order to determine overall efficacy of antiscarring therapy. © Springer Science+Business Media 2013.

Kostic A.D.,Harvard University | Kostic A.D.,Dana-Farber Cancer Institute | Kostic A.D.,The Broad Institute of MIT and Harvard | Chun E.,Harvard University | And 22 more authors.
Cell Host and Microbe | Year: 2013

Increasing evidence links the gut microbiota with colorectal cancer. Metagenomic analyses indicate that symbiotic Fusobacterium spp. are associated with human colorectal carcinoma, but whether this is an indirect or causal link remains unclear. We find that Fusobacterium spp. are enriched in human colonic adenomas relative to surrounding tissues and in stool samples from colorectal adenoma and carcinoma patients compared to healthy subjects. Additionally, in the ApcMin/+ mouse model of intestinal tumorigenesis, Fusobacterium nucleatum increases tumor multiplicity and selectively recruits tumor-infiltrating myeloid cells, which can promote tumor progression. Tumors from ApcMin/+ mice exposed to F. nucleatum exhibit a proinflammatory expression signature that is shared with human fusobacteria-positive colorectal carcinomas. However, unlike other bacteria linked to colorectal carcinoma, F. nucleatum does not exacerbate colitis, enteritis, or inflammation-associated intestinal carcinogenesis. Collectively, these data suggest that, through recruitment of tumor-infiltrating immune cells, fusobacteria generate a proinflammatory microenvironment that is conducive for colorectal neoplasia progression. © 2013 Elsevier Inc.

Zhang Q.,University of Texas at Dallas | Yu C.,University of Texas at Dallas | Peng S.,University of Texas at Dallas | Peng S.,Sun Yat Sen University | And 20 more authors.
Gastroenterology | Year: 2014

Background & Aims Tumor cells express vascular endothelial growth factor (VEGF), which induces angiogenesis. VEGF also activates VEGF receptors (VEGFRs) on or within tumor cells to promote their proliferation in an autocrine fashion. We studied the mechanisms of autocrine VEGF signaling in Barrett's esophagus cells. Methods Using Barrett's epithelial cell lines, we measured VEGF and VEGFR messenger RNA and protein, and studied the effects of VEGF signaling on cell proliferation and VEGF secretion. We studied the effects of inhibiting factors in this pathway on levels of phosphorylated phospholipase Cγ1 (PLCG1), protein kinase C, and extracellular signal-regulated kinases (ERK)1/2. We performed immunohistochemical analysis of phosphorylated VEGFR2 on esophageal adenocarcinoma tissues. We studied effects of sunitinib, a VEGFR2 inhibitor, on proliferation of neoplastic cells and growth of xenograft tumors in mice. Results Neoplastic and non-neoplastic Barrett's cells expressed VEGF and VEGFR2 messenger RNA and protein, with higher levels in neoplastic cells. Incubation with recombinant human VEGF significantly increased secretion of VEGF protein and cell number; knockdown of PLCG1 markedly reduced the recombinant human VEGF-stimulated increase in levels of phosphorylated PLCG1 and phosphorylated ERK1/2 in neoplastic cells. Esophageal adenocarcinoma tissues showed immunostaining for phosphorylated VEGFR2. Sunitinib inhibited VEGF signaling in neoplastic cells and reduced weight and volume of xenograft tumors in mice. Conclusions Neoplastic and non-neoplastic Barrett's epithelial cells have autocrine VEGF signaling. In neoplastic Barrett's cells, VEGF activation of VEGFR2 initiates a PLCG1-protein kinase C-ERK pathway that promotes proliferation and is self-sustaining (by causing more VEGF production). Strategies to reduce autocrine VEGF signaling (eg, with sunitinib) might be used to prevent or treat cancer in patients with Barrett's esophagus. © 2014 by the AGA Institute.

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