Comparing outcome of radiofrequency ablation in Barrett's with high grade dysplasia and intramucosal carcinoma: a prospective multicenter UK registry.

BACKGROUND AND STUDY AIM: Mucosal neoplasia arising in Barrett's esophagus can be successfully treated with endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA). The aim of the study was to compare clinical outcomes of patients with high grade dysplasia (HGD) or intramucosal cancer (IMC) at baseline from the United Kingdom RFA registry. PATIENTS AND METHODS: Prior to RFA, visible lesions and nodularity were removed entirely by EMR. Thereafter, patients underwent RFA every 3 months until all visible Barrett's mucosa was ablated or cancer developed (end points). Biopsies were taken at 12 months or when end points were reached. RESULTS: A total of 515 patients, 384 with HGD and 131 with IMC, completed treatment. Prior to RFA, EMR was performed for visible lesions more frequently in the IMC cohort than in HGD patients (77 % vs. 47 %; P < 0.0001). The 12-month complete response for dysplasia and intestinal metaplasia were almost identical in the two cohorts (HGD 88 % and 76 %, respectively; IMC 87 % and 75 %, respectively; P = 0.7). Progression to invasive cancer was not significantly different at 12 months (HGD 1.8 %, IMC 3.8 %; P = 0.19). A trend towards slightly worse medium-term durability may be emerging in IMC patients (P = 0.08). In IMC, EMR followed by RFA was definitely associated with superior durability compared with RFA alone (P = 0.01). CONCLUSION: The Registry reports on endoscopic therapy for Barrett's neoplasia, representing real-life outcomes. Patients with IMC were more likely to have visible lesions requiring initial EMR than those with HGD, and may carry a higher risk of cancer progression in the medium term. The data consolidate the approach to ensuring that these patients undergo thorough endoscopic work-up, including EMR prior to RFA when necessary.

Radiofrequency ablation and endoscopic mucosal resection for dysplastic barrett's esophagus and early esophageal adenocarcinoma: outcomes of the UK National Halo RFA Registry.

BACKGROUND & AIMS: Patients with Barrett's esophagus (BE) and high-grade dysplasia (HGD) or early neoplasia increasingly receive endoscopic mucosal resection and radiofrequency ablation (RFA) therapy. We analyzed data from a UK registry that follows the outcomes of patients with BE who have undergone RFA for neoplasia. METHODS: We collected data on 335 patients with BE and neoplasia (72% with HGD, 24% with intramucosal cancer, 4% with low-grade dysplasia [mean age, 69 years; 81% male]), treated at 19 centers in the United Kingdom from July 2008 through August 2012. Mean length of BE segments was 5.8 cm (range, 1-20 cm). Patients' nodules were removed by endoscopic mucosal resection, and the patients then underwent RFA every 3 months until all areas of BE were ablated or cancer developed. Biopsies were collected 12 months after the first RFA; clearance of HGD, dysplasia, and BE were assessed. RESULTS: HGD was cleared from 86% of patients, all dysplasia from 81%, and BE from 62% at the 12-month time point, after a mean of 2.5 (range, 2-6) RFA procedures. Complete reversal dysplasia was 15% less likely for every 1-cm increment in BE length (odds ratio = 1.156; SE = 0.048; 95% confidence interval: 1.07-1.26; P < .001). Endoscopic mucosal resection before RFA did not provide any benefit. Invasive cancer developed in 10 patients (3%) by the 12-month time point and disease had progressed in 17 patients (5.1%) after a median follow-up time of 19 months. Symptomatic strictures developed in 9% of patients and were treated by endoscopic dilatation. Nineteen months after therapy began, 94% of patients remained clear of dysplasia. CONCLUSIONS: We analyzed data from a large series of patients in the United Kingdom who underwent RFA for BE-related neoplasia and found that by 12 months after treatment, dysplasia was cleared from 81%. Shorter segments of BE respond better to RFA; http://www.controlled-trials.com, number ISRCTN93069556.

Bone marrow and tumour stroma: an intimate relationship.

In recent years the bone marrow has become recognized as a potential source of cells for non-haematopoietic wound healing, in some instances demonstrating surprising plasticity in providing new epithelial cells. On the other hand, the contribution of bone marrow derived cells to fibrosis and blood vessel formation is more widely acknowledged. Tumour stroma has a vital role to play in determining cancer growth and spread, and there is a growing realization that the bone marrow has a significant input into this desmoplastic response. This review focuses on the contribution of bone marrow cells to tumour stroma, highlighting the bone marrow as a potential new portal through which to direct anti-tumour therapies.

Stem cell plasticity and tumour formation.

Stem cell plasticity refers to the ability of certain stem cells to switch lineage determination and generate unexpected cell types. This review applies largely to bone marrow cells (BMCs), which appear to contribute positively to the regeneration of several damaged non-haematopoietic tissues. This beneficial effect on regeneration may be a direct result of BMCs giving rise to organ parenchymal cells. Alternatively, it could be due to BMCs fusing with existing parenchymal cells, or providing paracrine growth factor support, or contributing to neovascularisation. In the context of oncology, BMC derivation of the tumour stroma and vasculature has profound biological and therapeutic implications, and there are several examples of carcinomas seemingly being derived from BMCs.

Bone marrow-derived stromal cells express lineage-related messenger RNA species.

Evidence has emerged that bone marrow cells have a greater degree of plasticity than previously thought. However, there has been a call to establish proof that these bone marrow-derived cells function appropriately in their new environment. We have already shown that the bone marrow contributes to myofibroblasts in multiple organs and that this is exacerbated by injury and occurs in a mouse tumor model. Here, we provide evidence that these cells are functioning appropriately by showing that bone marrow-derived myofibroblasts are expressing mRNA for the alpha(1) chain of type I (pro)collagen using a new customized technique. This provides evidence that the bone marrow-tumor stroma axis is functionally relevant and may therefore subsequently be exploited to develop new strategies for anticancer therapy.

Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts.

The role of myofibroblasts in tissue repair and fibrosis is well documented, but the source of these myofibroblasts is unclear. There is evidence of a circulating population of fibrocytes that can home to areas of injury and contribute to myofibroblast populations. Previously, we have shown that the bone marrow is a source of myofibroblasts for many tissues including the gut, lung, and kidney and that this phenomenon is exacerbated by injury. We now show that the bone marrow can contribute to myofibroblast and fibroblast populations in tumor stroma in a mouse model of pancreatic insulinoma. Mice transgenic for the rat insulin promoter II gene linked to the large-T antigen of SV40 (RIPTag) develop solid beta-cell tumors of the pancreas. Approximately 25% of myofibroblasts in these pancreatic tumors were donor-derived, and these were concentrated toward the edge of the tumor. Thus, the development of tumor stroma is at least in part a systemic response that may ultimately yield methods of targeting new therapy.

Multiple organ engraftment by bone-marrow-derived myofibroblasts and fibroblasts in bone-marrow-transplanted mice.

Myofibroblasts are ubiquitous cells with features of both fibroblasts and smooth muscle cells. We suggest that the bone marrow can contribute to myofibroblast populations in a variety of tissues and that this is exacerbated by injury. To assess this, female mice were transplanted with male bone marrow and the male cells were tracked throughout the body and identified as myofibroblasts. Skin wounding and paracetamol administration were used to assess whether myofibroblast engraftment was modulated by damage. Following radiation injury, a proportion of myofibroblasts in the lung, stomach, esophagus, skin, kidney, and adrenal capsule were bone-marrow derived. In the lung, there was significantly greater engraftment following paracetamol administration (17% versus 41% p < 0.005). Bone-marrow-derived fibroblasts were also found. We suggest that bone marrow contributes to a circulating population of cells and, in the context of injury, these cells are recruited and contribute to tissue repair.

Plastic adult stem cells: will they graduate from the school of hard knocks?

Notwithstanding the fact that adult bone marrow cell engraftment to epithelial organs seems a somewhat uncommon event, there is no doubt it does occur, and under appropriate conditions of a strong and positive selection pressure these cells will expand clonally and make a significant contribution to tissue replacement. Likewise, bone-marrow-derived cells can be amplified in vitro and differentiated into a multitude of tissues. These in essence are the goals of regenerative medicine using any source of stem cells, be it embryonic or adult. Despite such irrefutable evidence of what is possible, a veritable chorus of detractors of adult stem cell plasticity has emerged, some doubting its very existence, motivated perhaps by more than a little self-interest. The issues that have led to this state of affairs have included the inability to reproduce certain widely quoted data, one case where the apparent transdifferentiation was due to contamination of the donor tissue with haematopoietic cells and, most notoriously, extrapolating from the behaviour of embryonic stem cells to suggest that adult bone marrow cells simply fuse with other cells and adopt their phenotype. While these issues need resolving, slamming this whole new field because not everything is crystal clear is not good science. The fact that a phenomenon is quite rare in no way mitigates against its very existence: asteroid collisions with the Earth are rare, but try telling the dinosaurs they do not occur! When such events do occur (transdifferentiation or collision), they certainly can make an impact.