Christine Kestens

Adalimumab and Infliximab Are Equally Effective for Crohn's Disease in Patients Not Previously Treated With Anti–Tumor Necrosis Factor-α Agents

BACKGROUND & AIMS Infliximab (IFX) and adalimumab (ADA) are thought to have equal efficacy for the treatment of Crohns disease (CD), although no direct comparison has been performed. We compared the effectiveness and safety of IFX and ADA in carefully matched cohorts. METHODS We performed a retrospective cohort study of 200 patients with CD (100 treated with IFX and 100 treated with ADA, starting in 2006 or later) who had not received anti-tumor necrosis factor α agents previously; the patients were identified from databases of 6 hospitals in The Netherlands. The groups were matched carefully for indication, duration of disease, age, and Montreal classification. The primary end point was the steroid-free clinical response, defined by a combination of multiple clinical parameters, after 1 year. RESULTS Of the total patient population, 63.5% and 45% had a clinical response after 1 and 2 years, respectively. There were no significant differences between treatment groups: at 1 and 2 years, 62% and 41% of those receiving ADA vs 65% and 49% of those receiving IFX had responses, respectively. Kaplan-Meier curves showed identical decreases in response rates over time. Combining IFX or ADA with immunomodulator therapy was associated with a higher clinical response than monotherapy, although this was only significant among patients who received IFX (P = .03). There were no differences in numbers of side effects or opportunistic infections. CONCLUSIONS The effectiveness of ADA or IFX treatment in anti-tumor necrosis factor α-naive patients with CD is comparable after 1 and 2 years of follow-up evaluation. The efficacies of IFX and ADA each seem to increase when given with immunomodulator therapy, although only significantly for IFX.

Treatment of Barrett's esophagus with a novel focal cryoablation device : a safety and feasibility study

BACKGROUND AND AIMS Currently, eradication of Barretts epithelium is preferably achieved using radiofrequency ablation (RFA) or spray cryoablation (SCA). However, both modalities suffer from drawbacks such as the need for sizing, multiple deployment steps, large controller units (RFA), imprecise dosing and need for gas-venting (SCA). The new Cryoballoon Focal Ablation System (CbFAS) may address these limitations. This study assessed the safety, feasibility, and dose response of the CbFAS in patients with flat Barretts epithelium with or without dysplasia. PATIENTS AND METHODS In this multicenter, prospective non-randomized trial, 39 patients were each treated with one or two ablations of 6, 8, or 10 seconds. Symptoms were assessed immediately and 2 days post-cryoablation. Follow-up endoscopy was performed 6-8 weeks post-procedure to assess response. Outcome parameters were incidence of adverse events, pain, esophageal stricture formation, and ablation response by cryogen dose. RESULTS Of 62 ablations, 56 (10 with 6 seconds, 28 with 8 seconds, 18 with 10 seconds) were successfully performed. Six ablations failed because of device malfunction (n=3) and procedural or anatomic issues (n=3). Median procedure time was 7 minutes (interquartile range [IQR] 4-10). No major adverse events occurred; six patients experienced a minor mucosal laceration requiring no intervention. Mild pain was reported by 27% of patients immediately after cryoablation and by 14% after 2 days. No strictures were evident at follow-up.  Full squamous regeneration was seen in 47 treated areas (6 [60%] of the 6-second areas; 23 [82%] of the 8-second areas; 18 [100%] of 10-second areas). CONCLUSIONS Focal cryoablation of Barretts epithelium with the CbFAS is feasible and safe, resulting in squamous regeneration in the majority of patients.

Profiling of circulating microRNAs in patients with Barrett’s esophagus and esophageal adenocarcinoma

BackgroundCirculating microRNAs (miRNAs) have been suggested as novel markers for various diseases. The goal of this pilot study was to identify circulating miRNAs differentially expressed comparing Barrett’s esophagus (BE), esophageal adenocarcinoma (EAC), and controls.MethodsMicroRNA expression profiling was performed by qPCR array using plasma from six controls and eight BE and eight EAC patients. Validation was performed by analyzing the expression of six selected miRNAs, by qRT-PCR in 115 plasma samples of controls, BE, and EAC patients. Diagnostic accuracy was evaluated by area under the curve (AUC) analysis.ResultsWe identified three miRNAs that were elevated in EAC and four miRNAs that were elevated in BE. Further validation showed that miRNA-382-5p was significantly increased and miRNA-133a-3p significantly decreased in EAC. miRNA-194-5p and miRNA-451a were significantly increased and miRNA-136-5p significantly decreased in BE versus controls. A combination of three or more miRNAs was found to have a good diagnostic performance in discriminating BE from controls (AUC: 0.832), EAC from controls (AUC: 0.846), and BE from EAC (AUC: 0.797).ConclusionOur data suggest that circulating miRNAs are differentially expressed in BE and EAC. The miRNAs identified may be used for future non-invasive screening of BE and EAC.

Current understanding of the functional roles of aberrantly expressed microRNAs in esophageal cancer

The incidence of esophageal cancer is rising, mostly because the increasing incidence of esophageal adenocarcinoma in Western countries. Despite improvements in diagnosis and treatment, the overall 5-year survival rates remain low. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of target genes. Recently, disease specific miRNAs have been identified, which act as tumor suppressors or oncogenes. In this review, we will summarize the current knowledge about the function of aberrantly expressed miRNAs in esophageal cancer. We selected 5 miRNAs (miRNA-21, -143, -145, -196a and let-7) based on the available literature, and described their potential role in regulating pathways that are deregulated in esophageal cancer. Finally we will highlight the current achievements of using and targeting miRNAs. Because these miRNAs likely have important regulatory roles in cancer development, they open a therapeutic window for new treatment modalities.

BMP4 Signaling Is Able to Induce an Epithelial-Mesenchymal Transition-Like Phenotype in Barrett’s Esophagus and Esophageal Adenocarcinoma through Induction of SNAIL2

[This corrects the article DOI: 10.1371/journal.pone.0155754.].

544 Comprehensive Profiling of Plasma MicroRNAs Reveals Potential Biomarkers for Barrett's Esophagus and Esophageal Adenocarcinoma

Aim: To quantitatively assess complex cancer cell phenotypes after gene inhibition by RNAi interference (RNAi), and assess the effect of these distinct morphologies on cell viability and cell motility using semi-automated image-based high-throughput screening. Method: GOhTRT cells were seeded and treated with the siRNA Human Druggable Genome Library (Dharmacon) by reverse transfection. Cells immunostained for DNA, tubulin and actin were imaged with the InCell Analyzer 1000 and processed using the InCell Analyzer software, CellHTS2 and RNAither. Statistical z-score analysis was performed on the combined A-T metric (F-actin area-α-tubulin area). The effect of RNAi knockdown on cell viability and cell motility were assessed using MTT cell proliferation assay and scratch wound assay. Results:127 high confidence hits (Z-factor>2) was refined to six genes (RRM2, ITGB8, GPS1, SPRY1, NOL1, MYO9B) on the basis of distinct morphologies, reproducible metrics, and functional pathway analysis. In siRRM2 cells nuclear displacement (ND) and A-T area was 1.598±0.076; p <0.0001 and 285.70±35.48; p<0.05, respectively. siGPS1 cells had an ND and A-T area of 0.845±0.036; p =0.0369 and 266.201±25.629; p =0.0326, respectively. Silencing of GPS1, MYO9B and SPRY1 increased the rate of migration in a scratch wound assay, with 86.98%±3.097%, 75.78%±5.454% and 72.97%±5.463% (p =0.0022) respectively. No significant difference in cell viability existed for siGPS1 (0.9037 ± 0.06575; p = 0.1905) and siSPRY1 (0.9088 ± 0.09849; p =0.2985), suggesting that wound closure is by virtue of migratory signalling and not proliferation. Cell viability was decreased considerably in siRRM2 cells (0.2492±0.02798; p <0.0001) and siMYO9B (0.4048±0.04663; p <0.0001) in comparison to siNT cells (1.046±0.07712). Discussion:In summary, this approach successfully identified genes regulating oesophageal cancer cell cytoskeletal remodelling and metastasis using in-vitro assays, some of which are already associated with metastasis in literature and database searches. Further mechanistic studies and gene pathway analysis of candidate genes will provide novel therapeutic targets which can be utilised to block the spread of cancer in oesophageal adenocarcinoma patients.

Incidence of Progression of Persistent Non-Dysplastic Barrett’s Esophagus to Malignancy

BACKGROUND & AIMS: The risk of esophageal adenocarcinoma (EAC) in patients with non‐dysplastic Barretts esophagus (NDBE) is low, so there is debate over the role of ongoing surveillance for patients with NDBE. It is important to identify patients at low risk for progression. We assessed cancer risk based on the subsequent number of endoscopies showing persistence of NDBE in a nationwide study in the Netherlands. METHODS: In a population‐based study, patients with a first diagnosis of NDBE were selected from the Dutch nationwide registry of histopathology. We calculated incidence rates and incidence rate ratios (IRR) for high‐grade dysplasia (HGD) and EAC to determine whether the number of endoscopies negative for dysplasia and the persistence of NDBE over time associate with progression to malignancy. RESULTS: We identified 12,728 patients with NDBE during 2003 and 2013. HGD or EAC developed in 436 patients (3.4%) during 64,537 person‐years of follow up (median, 4.9 years). The rate of progression to HGD or EAC was 0.68 (95% CI, 0.61–0.74) per 100 person‐years. In patients with 2 consecutive endoscopies showing NDBE, the rate of progression to HGD or EAC decreased to 0.55 (95% CI, 0.46–0.64) per 100 person‐years (IRR, 0.72; 95% CI, 0.60–0.87). Overall, the incidence of HGD or EAC decreased by 14% for each year of progression‐free follow‐up (IRR, 0.86; 95% CI, 0.81–0.92). CONCLUSION: In a population‐based study in the Netherlands, we found patients with stable NDBE to have a low risk of progression to HGD or EAC. These findings indicate that surveillance intervals might be lengthened or even discontinued in subgroups patients with persistent NDBE.

Endoscopic treatment for dysplastic Barrett's esophagus.

We read the article by Subramanian et al. [1] with great interest. The authors provided a concise but complete overview of the current state of endoscopic treatment modalities for nondysplastic and dysplastic Barrett’s esophagus (BE). They concluded that visible lesions in BE should be treated with endoscopic resection, either endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD), and with radiofrequency ablation (RFA) of residual intestinal metaplasia. We would like to make some additional comments in regard to the treatment of patients with dysplastic BE. As mentioned in the article, current guidelines recommend endoscopic treatment, i.e., ablation, as an option for patients with low-grade dysplasia (LGD) in BE. However, before considering endoscopic treatment for a patient with LGD, it is important that the diagnosis of LGD is confirmed by an expert pathologist. It is known that histological evaluation of BE is associated with a high interobserver variability, especially in cases of LGD. Various studies have shown that a relatively high number of LGD cases are downstaged to nondysplastic BE after revision [2]. Furthermore, even after revision by an expert pathologist, the SURF trial reported that more than 27 % of BE patients with LGD were found to have no dysplasia during follow-up [3]. This high number of patients with no dysplasia during follow-up likely can be explained by an incorrect initial diagnosis and consequently these patients probably had a much lower risk of neoplastic progression. It is also important to emphasize that ablative treatments are not without complications, e.g., stricture formation after RFA has been reported in 7–12 % of cases [3, 4]. For this reason, it is essential that further risk stratification strategies will be developed to identify the subgroup of LGD patients who will benefit from ablative treatment in order to reduce unnecessary adverse events and costs in patients without a risk of neoplastic progression. It can be expected that the inclusion of additional risk factors for developing highgrade dysplasia and adenocarcinoma in BE, e.g., a known duration of BE of C10 years, longer length of BE, and presence of esophagitis [5], may help in risk stratification. Furthermore, it is recommended to ablate LGD only after revision by an expert pathologist and with two consecutive endoscopies confirming a diagnosis of LGD. When it is decided that a segment of Barrett’s esophagus should be ablated, it is advisable that patients are referred to a center with ample experience in ablative techniques in order to improve treatment outcomes. A recent study showed that the rate of complete eradication of intestinal metaplasia after RFA increases when performed by an experienced endoscopist [6]. EMR, ESD, and RFA are all newly developed techniques and therefore long-term follow-up data are limited. Conclusions regarding the (cost-)effectiveness and recommendations on the optimal treatment strategy of different types of patients are preliminary. Furthermore, complete eradication of (dysplastic) BE does not preclude recurrence of BE, and even after complete eradication of BE, endoscopic surveillance is still indicated. A recent retrospective cohort study with a follow-up of up to 5 years reported a recurrence risk of 6.2 and 39.5 % for dysplasia and BE, respectively. Recurrent dysplasia was detected after a median follow-up of 44 months [7]. A small cohort study (n = 54) from The Netherlands reported a recurrence risk C. Kestens (&) P. D. Siersema Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands e-mail: c.kestens@umcutrecht.nl