The Power of the Shared Experience: MTN-020/ASPIRE Trial Participants' Descriptions of Peer Influence on Acceptability of and Adherence to the Dapivirine Vaginal Ring for HIV Prevention.

Women are disproportionately at risk of acquiring HIV in East and Southern Africa, despite global declines in incidence. Female-initiated HIV prevention methods, like the dapivirine vaginal ring, are needed to end the HIV epidemic. In-depth interviews and focus groups retrospectively explored peer influence on acceptability of and adherence to the ring during the ASPIRE trial, a phase III placebo-controlled trial. Results were analyzed using an inductive analytic approach. Study participants (peers) of all ages and adherence groups developed important interpersonal connections and reported being more open and honest with each other than with external peers or study staff. Study peers who knew each other prior to joining appeared to have a stronger influence on each other's adherence than peers who met in the study. External peers provided primarily negative input about the ring and study, which sometimes led to ring removals. Peers' influence on each other's behavior in both prosocial and detrimental manners could have repercussions on adherence to a biomedical intervention, and consequently, individual disease risk and clinical trial outcomes. Future ring demonstration and implementation studies could use peer networks to intentionally influence uptake and adherence to the ring.

Relationship Type and Use of the Vaginal Ring for HIV-1 Prevention in the MTN 020/ASPIRE Trial.

Gender roles and imbalances in sexual power contribute to the heightened HIV-1 risk faced by women in Sub-Saharan Africa. This has led prevention research to focus on the development of female controlled methods. Despite the design of products such as vaginal rings to be used autonomously by women, male partners and women's perceptions of relationships influence HIV prevention choices. To understand the influences that male partners and dyadic dynamics had on the use of the Dapivirine Vaginal Ring in the ASPIRE trial, this analysis of qualitative data explored the types of intimate partner relationships that women engaged in. This paper describes how partners facilitated or challenged women's ring use and how women dealt with these challenges within six different types of relationships characterized by power dynamics and commitment levels. We offer insights into how future use of female-initiated HIV prevention products can be promoted through recognition of different relationship types.

Perspectives from Young South African and Zimbabwean Women on Attributes of Four (Placebo) Vaginal Microbicide Delivery Forms.

INTRODUCTION: Incorporating end-user input into the design of new vaginal microbicides for women is key to optimizing their uptake, consistent use, and, ultimately, success in combatting the heterosexual HIV epidemic. METHODS: The Quatro Study assessed four placebo forms of vaginally inserted HIV-microbicides among young microbicide-naïve African women: on-demand film, insert and gel, and monthly ring. Participants randomly used each product for 1 month and provided product satisfaction ratings (1-5 scale), and opinions on product attributes and potential alternative designs. Qualitative data were collected through focus group discussions at study exit. Multivariable associations between attribute opinions and overall product rating were examined using Poisson regression models with robust standard errors to assess the attributes most influential to satisfaction. RESULTS: Overall opinions of products and their individual attributes were generally positive; all products were rated either 4 or a 5 by ≥ 50% of participants. Attributes related to ease of use and interference with normal activities were the most salient predictors of satisfaction. Preferences for duration of use tended toward relatively shorter use periods for the ring (i.e., 1-3 months vs. 12 months) and for coitally independent dosing for the on-demand products. CONCLUSIONS: How well a product fit in with participants' lifestyles was important to their overall satisfaction. For on-demand products, greater flexibility around timing of use was desired, to avoid coital dependency of the dosing.

Histopathological and immunophenotypic features of ipilimumab-associated colitis compared to ulcerative colitis.

BACKGROUND: Use of the immune checkpoint inhibitor ipilimumab is sometimes complicated by ipilimumab-associated colitis (Ipi-AC), an immune-mediated colitis that mimics inflammatory bowel disease. OBJECTIVE: We sought to characterize the histopathologic and immunophenotypic features of Ipi-AC and to directly compare these features to ulcerative colitis (UC). METHODS: This is a retrospective cohort study of 22 patients with Ipi-AC, 12 patients with treatment-naïve UC and five controls with diarrhoea but normal endoscopic findings. Immunohistopathologic features were described, and quantitative immunohistochemistry (IHC) was performed for CD4, CD8, CD20, CD138 and FOXP3. RESULTS: Endoscopic findings in both the Ipi-AC and UC groups included ulcerated, oedematous and erythematous mucosa. Involvement of the GI tract was more diffuse in Ipi-AC. As compared to UC, a smaller proportion of Ipi-AC biopsies had basal plasmacytosis (14% for Ipi-AC vs. 92% for UC, P < 0.0001) and crypt distortion (23% for Ipi-AC vs. 75% for UC, P = 0.003), whereas Ipi-AC biopsies had more apoptotic bodies in the left colon (17.6 ± 15.3 for Ipi-AC vs. 8.2 ± 4.2 for UC, P = 0.011). Cryptitis, ulcerations and crypt abscesses were common in both groups. Biopsy specimens from Ipi-AC had a lower density of CD20-positive lymphocytes than UC (275.8 ± 253.3 cells mm-2 for Ipi-AC vs. 1173.3 ± 1158.2 cells mm-2 for UC, P = 0.022) but had a similar density of CD4, CD8, CD138 and FOXP3-positive cells. CONCLUSIONS: Ipi-AC is a distinct pathologic entity with notable clinical and histopathological differences compared to UC. These findings provide insights into the pathophysiology of immune-related adverse events (iAEs) from ipilimumab therapy.

Patterns and Drivers of Egg Pigment Intensity and Colour Diversity in the Ocean: A Meta-Analysis of Phylum Echinodermata.

Egg pigmentation is proposed to serve numerous ecological, physiological, and adaptive functions in egg-laying animals. Despite the predominance and taxonomic diversity of egg layers, syntheses reviewing the putative functions and drivers of egg pigmentation have been relatively narrow in scope, centring almost exclusively on birds. Nonvertebrate and aquatic species are essentially overlooked, yet many of them produce maternally provisioned eggs in strikingly varied colours, from pale yellow to bright red or green. We explore the ways in which these colour patterns correlate with behavioural, morphological, geographic and phylogenetic variables in extant classes of Echinodermata, a phylum that has close phylogenetic ties with chordates and representatives in nearly all marine environments. Results of multivariate analyses show that intensely pigmented eggs are characteristic of pelagic or external development whereas pale eggs are commonly brooded internally. Of the five egg colours catalogued, orange and yellow are the most common. Yellow eggs are a primitive character, associated with all types of development (predominant in internal brooders), whereas green eggs are always pelagic, occur in the most derived orders of each class and are restricted to the Indo-Pacific Ocean. Orange eggs are geographically ubiquitous and may represent a 'universal' egg pigment that functions well under a diversity of environmental conditions. Finally, green occurs chiefly in the classes Holothuroidea and Ophiuroidea, orange in Asteroidea, yellow in Echinoidea, and brown in Holothuroidea. By examining an unprecedented combination of egg colours/intensities and reproductive strategies, this phylum-wide study sheds new light on the role and drivers of egg pigmentation, drawing parallels with theories developed from the study of more derived vertebrate taxa. The primary use of pigments (of any colour) to protect externally developing eggs from oxidative damage and predation is supported by the comparatively pale colour of equally large, internally brooded eggs. Secondarily, geographic location drives the evolution of egg colour diversity, presumably through the selection of better-adapted, more costly pigments in response to ecological pressure.

MRI characteristics associated with high-grade myxoid liposarcoma.

AIM: To identify magnetic resonance imaging (MRI) features differentiating high-grade (>5% round-cell component) from low-grade myxoid liposarcomas (LPS) (≤5% round-cell component). MATERIALS AND METHODS: Informed consent was waived. Patients with myxoid LPS and MRI before biopsy, neoadjuvant therapy, and surgery were included retrospectively. High-grade components were recorded from histological specimens by a pathologist (24 years of experience). Images were evaluated by a senior radiologist (>12 years of experience) for tumour size, location, tissue layer, and MRI features (signal intensity, heterogeneity, margin, and perilesional characteristics). Descriptive statistics, Fisher's exact test to identify associations with a round-cell component, and multivariate logistic regression to identify independent predictors of high-grade tumours were used. RESULTS: Thirty-one patients (16 women [mean 51.1 years; range 19-79 years] and 15 men [mean 45.5 years; range 18-95 years]) with myxoid LPS (23 low-grade, eight high-grade) were included. All high-grade lesions had lipid signal, a peritumoural capsule and peritumoural contrast enhancement, and more commonly exhibited heterogeneous signal; however, the average size of ≥10 cm was the strongest independent indicator of high-grade status (odds ratio [OR], 14.6; 95% confidence interval [CI]: 1.6, 131). CONCLUSION: Size ≥10 cm is most strongly associated with high-grade myxoid LPS (round-cell component >5%). Other features possibly differentiating high-grade from low-grade status include lesion margin, lipid signal, and perilesional characteristics.

Assessing trauma and mental health in refugee children and youth: a systematic review of validated screening and measurement tools.

Background: : It is estimated that children below 18 years constitute 50% of the refugee population worldwide, which is the highest figure in a decade. Due to conflicts like the Syrian crises, children are continuously exposed to traumatic events. Trauma exposure can cause mental health problems that may in turn increase the risk of morbidity and mortality. Tools such as questionnaires and interview guides are being used extensively, despite the fact that only a few have been tested and their validity confirmed in refugee children and youth. : Our aim was to provide a systematic review of the validated screening and measurement tools available for assessment of trauma and mental health among refugee children and youth. : We systematically searched the databases PubMed, PsycINFO and PILOTS. The search yielded 913 articles and 97 were retained for further investigation. In accordance with the PRISMA guidelines two authors performed the eligibility assessment. The full text of 23 articles was assessed and 9 met the eligibility criteria. Results : Only nine studies had validated trauma and mental health tools in refugee children and youth populations. A serious lack of validated tools for refugee children below the age of 6 was identified. : There is a lack of validated trauma and mental health tools, especially for refugees below the age of 6. Detection and treatment of mental health issues among refugee children and youth should be a priority both within the scientific community and in practice in order to reduce morbidity and mortality.

Validation of a rapid type 1 diabetes autoantibody screening assay for community-based screening of organ donors to identify subjects at increased risk for the disease.

The Network for Pancreatic Organ donors with Diabetes (nPOD) programme was developed in response to an unmet research need for human pancreatic tissue obtained from individuals with type 1 diabetes mellitus and people at increased risk [i.e. autoantibody (AAb)-positive] for the disease. This necessitated the establishment of a type 1 diabetes-specific AAb screening platform for organ procurement organizations (OPOs). Assay protocols for commercially available enzyme-linked immunosorbent assays (elisas) determining AAb against glutamic acid decarboxylase (GADA), insulinoma-associated protein-2 (IA-2A) and zinc transporter-8 (ZnT8A) were modified to identify AAb-positive donors within strict time requirements associated with organ donation programmes. These rapid elisas were evaluated by the international islet AAb standardization programme (IASP) and used by OPO laboratories as an adjunct to routine serological tests evaluating donors for organ transplantation. The rapid elisas performed well in three IASPs (2011, 2013, 2015) with 98-100% specificity for all three assays, including sensitivities of 64-82% (GADA), 60-64% (IA-2A) and 62-68% (ZnT8A). Since 2009, nPOD has screened 4442 organ donors by rapid elisa; 250 (5·6%) were identified as positive for one AAb and 14 (0.3%) for multiple AAb with 20 of these cases received by nPOD for follow-up studies (14 GADA+, two IA-2A(+) , four multiple AAb-positive). Rapid screening for type 1 diabetes-associated AAb in organ donors is feasible, allowing for identification of non-diabetic, high-risk individuals and procurement of valuable tissues for natural history studies of this disease.

Gender is a determinative factor in the initial clinical presentation of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease resulting in symptoms of esophageal dysmotility. Abnormalities include dysphagia, food impaction and reflux. Although men appear to comprise a majority of the EoE population, few studies have directly assessed gender-associated clinical differences. The aim of this study is to identify the effect of gender on the initial clinical presentation of adult-onset EoE patients. We reviewed our electronic medical record database from January 2008 to December 2011 for adults diagnosed with EoE per the 2011 updated consensus guidelines. Patient demographics, presenting symptoms, endoscopy findings and complications were recorded. Proportions were compared using chi-squared analysis, and means were compared using the Student's t-test. A total of 162 patients met the inclusion criteria and 71 (44%) were women. Women were more likely to report chest pain (P = 0.03) and heartburn (P = 0.06), whereas men more commonly reported dysphagia (P = 0.04) and a history of food impaction (P = 0.05). Endoscopic findings were similar between groups. No patients suffered esophageal perforations. These data suggest that men report more fibrostenotic symptoms and women report more inflammatory symptoms at the time of diagnosis. There was no difference in endoscopic findings between genders. This is one of the only reviews comparing differences in clinical presentation, endoscopic findings and complications between gender for EoE. The current recommended guidelines state that any patient with symptoms of esophageal dysfunction should be biopsied for EoE. Our findings support biopsying patients with typical and atypical symptoms of dysmotility including heartburn and chest pain.

Interest in multipurpose prevention of HIV and pregnancy: perspectives of women, men, health professionals and community stakeholders in two vaginal gel studies in southern Africa.

OBJECTIVE: The pipeline of vaginal microbicides for HIV prevention has expanded to include products for multipurpose prevention, but the interests of potential users and those advising on use have not been sufficiently investigated. Rather, assumptions about interest in multipurpose prevention technologies (MPTs) are inferred from what is known about acceptability and use of microbicides or contraceptives. DESIGN AND SETTING: This paper presents data on concerns and preferences for multipurpose prevention of HIV and pregnancy. Data were collected in two microbicide gel studies in Malawi and Zimbabwe. Participants were women using candidate vaginal products, their male partners, health professionals and community stakeholders. METHODS: An individual interview was conducted with participants. Interviews were audio-recorded, transcribed, coded for content and analysed for key themes. RESULTS: Participants indicated strong interest in a vaginal HIV prevention product that could also prevent pregnancy. Reasons for this interest were convenience, problems with adverse effects with current contraceptive methods, concerns about long-term effects of contraceptives, and concerns about the health burdens of HIV infection during pregnancy. The main disadvantage of an MPT was recognition that while interest in preventing HIV is constant, contraceptive needs change over time. CONCLUSION: The study population indicated support for an MPT to prevent HIV and pregnancy. This support may be further strengthened if the product is also available for prevention of only HIV. Women and men will be more willing to use an MPT if they can be reassured that its use will have no long-term effect on fertility.

[Inflammation, malignancy and immunology in gastrointestinal spindle cell tumors: what is beyond GIST?]. / Entzündung, Malignität und Immunologie gastrointestinaler Spindelzelltumoren : Was gibt es abgesehen von GIST noch?

Many mesenchymal tumors and tumefactions associated with the gastrointestinal tract feature prominent inflammatory cells but the mechanisms for the inflammation and the processes themselves remain poorly understood. Such classic lesions include Kaposi sarcoma, inflammatory fibroid polyp, sclerosing mesenteritis and inflammatory myofibroblastic tumor but, more recently, the recognition of IgG4-related fibrosclerosing disease has resulted in modification of the views on pathogenesis and treatment of such inflammatory lesions in many anatomical sites. In some lesions the inflammation may reflect viral influences (Kaposi sarcoma) or a bacterial infectious trigger (IgG4-related fibrosclerosing disease) whereas in others such an interaction is unclear and alterations in various genes have been detected, such as anaplastic lymphoma receptor tyrosine kinase gene rearrangements in inflammatory myofibroblastic tumor and platelet-derived growth factor receptor alpha (PDGFRA) gene mutations in inflammatory fibroid polyp and some gastrointestinal stromal tumors (GIST). Even the inflammatory milieu of GISTs may have an impact on the outcome. This article discusses the practical diagnostic considerations as well as the theoretical background.

Massive splenomegaly correlates with malignancy: 180 cases of splenic littoral cell tumors in the world literature.

Littoral cell tumors (LCT) are rare primary splenic neoplasms, unique for their morphologic and immunolabeling features resembling the endothelial littoral cells lining the sinusoids of the red pulp. They include the more common and typically benign littoral cell angioma, as well as the less common, potentially malignant, littoral cell hemangioendothelioma (LCHE) and the aggressive littoral cell angiosarcoma (LCAS). The most common presentation of these neoplasms is splenomegaly, and diagnosis is made histologically following biopsy or resection. To better understand these tumors, a comprehensive, international literature search was performed. Patient and tumor data, including presenting symptoms, comorbid cancers, immunosuppressive states, splenic mass and tumor size were analyzed. Massive splenomegaly (≥ 1500 g) following splenic resection, which correlates with a splenic length of 20 cm preoperatively, was found to be significantly associated with the presence of malignancy in the LCT (P<0.05).

[Subjective grading of Barrett's neoplasia by pathologists: correlation with objective histomorphometric variables]. / Subjektive Graduierung von Barrett-Neoplasien durch den Pathologen: Korrelation mit objektiven histomorphometrischen Variablen.

Even though pathologists are trained to recognize the same histological features for the diagnosis and grading of different histological images, not all pathologists are influenced to a similar level of intensity by the same morphological characteristics of the tissue when scoring Barrett's dysplasia/neoplasia. The variables which most pathologists have intuitively chosen to use for scoring of the severity of Barrett's changes are mainly those related to the general tissue architecture, such as nuclear crowding, orientation and stratification. Interestingly, nuclear size is not used by most pathologists but nuclear pleomorphism and symmetry does influence a significant number of pathologists. Maybe the most difficult variables for the human eye to recognize are variables of chromatin texture (such as margination or heterogeneity), the predictive importance of which has been demonstrated in a previously published work. Textural variables may therefore remain the subject of a computerized analysis. Nevertheless, the fact that a few pathologists do actually correlate with nuclear texture in scoring, argues in favor of making further attempts to train pathologists to also rely on texture, similar to cytologists, when scoring Barrett's dysplasia.

High acceptability of a vaginal ring intended as a microbicide delivery method for HIV prevention in African women.

Vaginal rings (VRs) are new methods for continuous delivery of microbicides. This is the first study to quantitatively and qualitatively explore the acceptability of rings in Africa: 157 HIV-negative, sexually active women aged 18-35 used a placebo silicone elastomer ring for 12 weeks. They completed product acceptability questionnaires every 4 weeks. We conducted 6 exit focus group discussions with a subset of 48 women and 19 in-depth interviews with male partners. Retention in the study was high (97 %). Initial insertion at the clinic was successful on first attempt for 81 % of participants. Most women were comfortable using the ring, and very few (≤2 %) could feel it during daily activities or had ring-related physical or emotional problems. In the qualitative interviews many participants reported that they initially had concerns about using the ring. However, only a minority of women actually reported concerns with the ring during the study. The most frequent concern was that the ring would get lost inside the body (20 %), and this was significantly correlated with study site, frequently thinking about the ring and reporting that the ring was not very easy to remove. Qualitative data suggest that informants grew to like the ring because it felt securely placed, was unnoticeable during daily activities, and felt "normal" during sex. The ring appeared to be highly acceptable for women and men. Initial concerns with this novel method suggest a need for enhanced product counseling when VRs are introduced.

Squamous cell carcinoma in Barrett's esophagus: field effect versus metastasis.

Barrett's esophagus (BE) is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). Risk factors for EAC overlap with those for esophageal squamous cell carcinoma (ESCC), but ESCC is surprisingly rare in BE. We report two cases of ESCC directly surrounded by BE. Both patients had a previous medical history of cancers, i.e., head and neck squamous cell carcinomas, and were using alcohol and smoking tobacco. Using immunohistochemistry for p63, CK5, CK7, and CDX2, it was confirmed that these carcinomas were pure squamous cell carcinomas, and not EACs or esophageal adenosquamous carcinomas arising from BE. Using TP53 mutation and loss of heterozygosity analysis, we established that the ESCCs in BE were not metastases of the previously diagnosed head and neck squamous cell carcinomas but de novo primary ESCCs. This study shows the strength of molecular analysis as an adjunct to the histopathologic diagnosis for distinguishing between metastases of prior cancers and primary cancers. Furthermore, these cases imply that presence of BE is not protective with regards to developing ESCC in the lower one third of the esophagus. We suggest that their ESCCs arose from islets of squamous epithelium in BE.

Trauma, exile and mental health in young refugees.

OBJECTIVE: To review evidence of trauma and exile-related mental health in young refugees from the Middle East. METHOD: A review of four empirical studies: i) a qualitative study of 11 children from torture surviving families, ii) a cohort study of 311 3-15-year-old asylum-seeking children, iii) a qualitative study of 14 members of torture surviving families and iv) a follow-up study of 131 11-23-year-old refugees. RESULTS: The reactions of the children were not necessarily post-traumatic stress disorder specific. Seventy-seven per cent suffered from anxiety, sleep disturbance and/or depressed mood at arrival. Sleep disturbance (prevalence 34%) was primarily predicted by a family history of violence. At follow-up, 25.9% suffered from clinically relevant psychological symptoms. Traumatic experiences before arrival and stressful events in exile predicted internalizing behaviour, witnessing violence and frequent school changes in exile predicted externalizing behaviour. School participation, Danish friends, language proficiency and mother's education predicted less long-term psychological problems. CONCLUSION: Psychological problems are frequent in refugee children, but the extents are reduced over time in exile. Traumatic experience before arrival is most important for the short-term reaction of the children while aspects of life in exile are important for the children's ability to recover from early traumatization.

Combinatorial chemoprevention of intestinal neoplasia.

A combination of two drugs afforded remarkable protection from intestinal neoplasia in APC(Min/+) mice, a murine model of human familial adenomatous polyposis (FAP). One of the drugs was sulindac, a prototypical non-steroidal anti-inflammatory drug with established chemopreventative activity. The second drug was EKI-569, a newly developed, irreversible inhibitor of the epidermal growth factor receptor kinase. Although 100% of the untreated APC(Min/+) mice developed approximately 20 polyps, nearly half the mice treated with these two agents developed no polyps at all. These results suggest a powerful strategy for the chemoprevention of human colonic neoplasia.

An action potential-induced and ryanodine sensitive calcium transient dynamically regulates transmitter release at synapses between Lymnaea neurons.

The notion that calcium released through ryanodine receptors effects presynaptic neurotransmitter release is gaining acceptance with the observation that this calcium does indeed contribute to both action potential-evoked and spontaneous transmitter release in a variety of preparations. However, the dynamics of this calcium release and its impact on transmitter release has not yet been fully elucidated. Moreover, in contrast to vertebrate synapses, much less is known about the involvement of ryanodine receptors in the regulation of transmitter release at invertebrate synapses. In this study, we reconstructed specific synapses between individually identifiable preand postsynaptic neurons from Lymnaea to demonstrate that although ryanodine reduces the amplitude of the action potential-induced calcium transient, it does not however, alter the resting calcium level. These data suggest that action potential-induced calcium release through ryanodine receptors is fast and highly dynamic and in turn regulates transmitter release at reconstructed synapses between Lymnaea neurons. This study thus provides direct evidence that a dynamic ryanodine receptor-mediated calcium transient occurs with the presynaptic action potential.

Genes expressed in human tumor endothelium.

To gain a molecular understanding of tumor angiogenesis, we compared gene expression patterns of endothelial cells derived from blood vessels of normal and malignant colorectal tissues. Of over 170 transcripts predominantly expressed in the endothelium, 79 were differentially expressed, including 46 that were specifically elevated in tumor-associated endothelium. Several of these genes encode extracellular matrix proteins, but most are of unknown function. Most of these tumor endothelial markers were expressed in a wide range of tumor types, as well as in normal vessels associated with wound healing and corpus luteum formation. These studies demonstrate that tumor and normal endothelium are distinct at the molecular level, a finding that may have significant implications for the development of anti-angiogenic therapies.

Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma.

The nel-like1 (NELL1) gene maps to chromosome 11p15, which frequently undergoes loss of heterozygosity in esophageal adenocarcinoma (EAC). NELL1 promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction in 259 human esophageal tissues. Hypermethylation of this promoter showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and EAC from normal esophagus (NE) (P<0.001). NELL1 normalized methylation values were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's (D) and EAC than in NE (P<0.0000001). NELL1 hypermethylation frequency was zero in NE but increased early during neoplastic progression, to 41.7% in BE from patients with Barrett's alone, 52.5% in D and 47.8% in EAC. There was a significant correlation between NELL1 hypermethylation and BE segment length. Three (11.5%) of 26 ESCCs exhibited NELL1 hypermethylation. Survival correlated inversely with NELL1 hypermethylation in patients with stages I-II (P=0.0264) but not in stages III-IV (P=0.68) EAC. Treatment of KYSE220 ESCC and BIC EAC cells with 5-aza-2'-deoxycytidine reduced NELL1 methylation and increased NELL1 mRNA expression. NELL1 mRNA levels in EACs with an unmethylated NELL1 promoter were significantly higher than those in EACs with a methylated promoter (P=0.02). Promoter hypermethylation of NELL1 is a common, tissue-specific event in human EAC, occurs early during Barrett's-associated esophageal neoplastic progression, and is a potential biomarker of poor prognosis in early-stage EAC.