Early Esophageal Adenocarcinoma Research Articles

202. MULTI-ARRAY MIRNA APPROACH AND ASSOCIATED PROTEIN EXPRESSION PROFILING FOR THE DEVELOPMENT OF PREDICTIVE AND PROGNOSTIC BIOMARKERS IN ESOPHAGEAL ADENOCARCINOMA

Abstract Background Esophageal adenocarcinoma (EA) may develop metastases even in early stage (pT1) disease, but molecular bi-omarkers are lacking to guide therapeutic decisions regarding the type of treatment. Endoscopic submucosal dis-section (ESD) is an effective treatment of early esophageal adenocarcinomas. However, ESD only an option for patients without lymph node metastases. The aim of this study is to detect possible biomarkers with which one could estimate lymphatic metastasis. Methods A multi-array miRNA study with consecutive in silico analysis of dependent genes and in situ analysis of selected proteins was chosen to detect possible biomarkers. A retrospective analysis including twenty cases of EA of the distal esophagus/esophagogastric junction after ESD without or after esophagectomy with lymph node metastasis (each n=10) was performed. The DNA of the Formalin-Fixed Paraffin-Embedded (FFPE) material of these patients was analysed using an advanced miRNA Human Card (spotted with 754 unique microRNAs) with consecutive in silico gene regulation and immunohistochemical analysis of the associated proteins. Result The multi-array miRNA of the tumour sample with EA showed an upregulation of 25 and a downregulation of 20 microRNAs, with the highest differences for the miRNAs miR-100-5p, miR-501-3p and miR-576-5p (upregulation) and miR-150-3p, miR-190a-5p and miR-545-3p (downregulation). The in silico analysis of these mirRNAs revealed the downstream paired partners RDX-Rock2, DICER1-AGO2, YAF2-EZF6 and TET2-5HMC, which were significantly differentially expressed by in-situ immunohistochemical staining. Biologically relevant downstream gene and pro-tein targets, which were also significantly differentially expressed in-situ in relation to the tumour stage of EA could be found. Conclusion This molecular study provides evidence for a specific miRNA marker profile when comparing cases with localized and advanced EA. These preclinical experimental biomarker analyses may help to guide therapeutic decisions in cases with EA, although validation in a larger cohort of EA is necessary to draw firm conclusions.

Long-term outcomes of endoscopic submucosal dissection for early esophageal adenocarcinoma in the Eastern population: a comprehensive analysis

BackgroundEndoscopic submucosal dissection (ESD) is a preferred method for early esophageal cancer, yet its application to esophageal adenocarcinoma (EAC), especially in the Eastern population with its relative rarity, lacks sufficient literature. This study evaluated ESD’s long-term outcomes for EAC, focusing on noncurative resections and diagnostic accuracy. MethodsBetween 2012 and 2022, a retrospective study included 68 patients undergoing ESD for early EAC at Jiangsu Province Hospital. Primary outcomes encompassed ESD efficacy, en bloc resection, R0 resection, curative resection rates, and follow-up. Secondary outcomes involved noncurative ESD, T1a/T1b stage comparison, and diagnostic consistency. ResultsPostoperative staging revealed T1a (n = 53) and T1b tumors (n = 15). En bloc resection rate was 97.1%, R0 resection rate was 79.4%, and noncurative rate was 30.9%. T1a had significantly higher R0 rate and curative resection rate. Among noncurative ESDs, 33.3% underwent esophagectomy, 42.9% had surveillance endoscopies, 19.1% repeated curative ESD, and 4.7% were lost to follow-up. Average follow-up was 63.76 ± 28.47 months. Furthermore, 6 patients had recurrence, 3 had residual lesions, and 6 deaths occurred, unrelated to ESD. No significant difference in survival or recurrence rates between curative and noncurative ESD groups was observed. ESD led to a histologic diagnosis change in 70.6% of cases, all upstaged. ConclusionESD is effective for EAC, with higher curative rates for T1a than T1b. Noncurative ESD cases may benefit from conservative approaches. Long-term follow-up underscores poor consistency between residual lesions and positive margins. ESD serves as a valuable diagnostic staging tool, particularly for T1b cases, considering the low accuracy of endoscopic ultrasound and preoperative biopsy.

365. METHYLATION BIOMARKERS TO STRATIFY BARRETT’S ESOPHAGUS PATIENTS PROGRESSING AND NON-PROGRESSING TO ESOPHAGEAL ADENOCARCINOMA

Abstract Background Over the last forty years, North America and Europe have witnessed a notable surge in cases of esophageal adenocarcinoma (EAC). This malignancy typically arises from Barrett esophagus (BE), a condition characterized by the replacement of normal squamous epithelium with specialized metaplastic cells. Our study aims to identify specific methylation markers capable of distinguishing between BE patients that will and will not progress to EAC. Methods We conducted differential expression analysis on RNASeq public dataset GSE210647 to distinguish BE progressors from non-progressors. Reads were aligned to hg38 genome using STAR aligner, normalized and analyzed with DESeq2. Significant genes were selected by |log2 fold change| ≥ 0.2 and padj < 0.01. GO, pathway enrichment, and transcription factor (TF) network analyses were performed to uncover biological disparities. Integration with previous methylation data (N.R. Dehkordi et al., 292. Specific methylation markers associated with changes in gene expression distinguish EAC and sub-types of BE patients, ISDE 2023) allowed the identification of overlapping biomarkers, aiding in better discrimination between the two groups. Results Differential expression analysis of GSE210647 identified 2261 significative DEGs between BE progressors and non-progressors. Pathway enrichment analysis in BE progressors revealed significant associations with cellular morphogenesis and reprogramming, alongside the induction of the bile acid pathway, known for its implications in invasiveness and cancer stem cell expansion. TF network analysis identified key regulators such as TBX20, FOXS1, and ZNF454, shedding light on their roles in esophageal carcinogenesis. Among the 505 CpG markers acquired in prior analyses, 127 genomic regions were linked with overexpressed genes either in progressors or in non-progressors BE patients. Leveraging this marker panel, BE samples were stratified into discrete subtypes, aligning either with normal esophageal tissue or EAC, and suggesting a potential stratification by disease progression. Conclusions The integration of expression and methylation analyses allows the identification of key genomic and epigenomic loci able to distinguish BE patients progressing or not-progressing towards EAC. The identified biomarkers are pivotal for personalized risk assessment and for the design of targeted interventions, holding promises for enhanced surveillance protocols, refined early EAC detection approaches, and improved therapeutic strategies aimed at mitigating the risk of EAC development in BE population.

Validation of an Epigenetic Prognostic Assay to Accurately Risk-Stratify Patients with Barrett's Esophagus.

INTRODUCTION: Esophageal adenocarcinoma (EAC) is the second-most lethal cancer in the United States, with Barrett esophagus (BE) being the strongest risk factor. Assessing the future risk of neoplastic progression in patients with BE is difficult; however, high-grade dysplasia (HGD) and early EAC are treatable by endoscopic eradication therapy (EET), with survival rates of 90%. Thus, it would be beneficial to develop a molecular assay to identify high-risk patients, who merit more frequent endoscopic surveillance or EET, as well as low-risk patients, who can avoid EET and undergo less frequent surveillance. METHODS: Deidentified endoscopic biopsies were acquired from 240 patients with BE at 6 centers and confirmed as future progressors or nonprogressors. Tissues were analyzed by a set of methylation-specific biomarker assays. Test performance was assessed in an independent validation set using 4 stratification levels: low risks, low-moderate risks, high-moderate risks, and high risks. RESULTS: Relative to patients in the low-risk group, high-risk patients were 15.2 times more likely to progress within 5 years to HGD or EAC. For patients in the high-risk category, the average risk of progressing to HGD or EAC within 5 years was 21.5%, 4-fold the BE population prevalence within 5 years, whereas low-risk patients had a progression risk of only 1.85%. DISCUSSION: This clinical assay, Esopredict, stratifies future neoplastic progression risk to identify higher-risk patients with BE who can benefit from EET or more frequent surveillance and lower-risk patients who can benefit from reduced surveillance.

Preinjection With Ligation-Assisted Endoscopic Mucosal Resection for Barrett's Dysplasia and Early Esophageal Adenocarcinoma: Characteristic Histological Features of the Depth of Resection.

Endoscopic mucosal resection (EMR) is an established technique for the diagnosis and treatment of high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EAC) in Barrett's esophagus. Submucosal preinjection is not universally used or generally recommended when performing routine ligation-assisted EMR. Prior studies, however, have demonstrated evidence of at least superficial muscle injury on ligation-assisted EMR without submucosal injection. There are limited published data supporting any potential benefit of submucosal preinjection. Our aim was to review this technique and determine the rate of any degree of muscle injury in patients with Barrett's HGD and EAC treated with submucosal preinjection before ligation-assisted EMR. Patients undergoing submucosal preinjection before ligation-assisted EMR for Barrett's esophagus at a single institution between 2012 and 2016 were identified. Data were collected regarding patient demographics and medical history, endoscopy and histopathology findings, adverse events, and subsequent outcomes. All EMR specimens were reviewed by an expert gastrointestinal pathologist. One hundred fifty consecutive EMR procedures were performed on 70 patients. Of 70 patients, 85.7% of patients were men, with a median age of 68 years. EAC was identified in 75 specimens (50%) and HGD in 44 specimens (29.3%). Deep resection margins were clear of adenocarcinoma in all specimens. Muscularis propria was not identified in any of the 150 specimens. There were no cases of post-EMR perforation. Preinjection before ligation-assisted EMR achieved complete excision with histologically clear margins, without histological evidence of any inadvertent muscularis propria.

Endoscopic Advances in the Diagnosis and Management of Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) is one of the most common diseases that occurs secondary to failure of the antireflux barrier system, resulting in the frequent and abnormal reflux of gastric contents to the esophagus. GERD is diagnosed in routine clinical practice based on the classic symptoms of heartburn and regurgitation. However, a subset of patients with atypical symptoms can pose challenges in diagnosing GERD. An esophagogastroduodenoscopy (EGD) is the most common initial diagnostic test used in the assessment for GERD, although half of these patients will not have any positive endoscopic findings suggestive of GERD. The advanced endoscopic techniques have improved the diagnostic yield of GERD diagnosis and its complications, such as Barrett's esophagus and early esophageal adenocarcinoma. These newer endoscopic tools can better detect subtle irregularities in the mucosa and vascular structures. The management options for GERD include lifestyle modifications, pharmacological therapy, and endoscopic and surgical interventions. The latest addition to the armamentarium is the minimally invasive endoscopic interventions in carefully selected patients, including the electrical stimulation of the LES, Antireflux mucosectomy, Radiofrequency therapy, Transoral Incisionless Fundoplication, Endoscopic Full-Thickness plication (GERDx™), and suturing devices. With the emergence of these advanced endoscopic techniques, it is crucial to understand their selection criteria, advantages, and disadvantages.

Premature mortality for patients after completely resected early adenocarcinoma of the esophagus or stomach.

To establish the life expectancy burden of esophago-gastric cancer by analyzing years of life lost (YLL) for a Western patient population after treatment of early esophageal (EAC) or early gastric (GAC) adenocarcinoma. For patients with early EAC or GAC, the short-term prognosis after surgical resection is very good. Little data is available regarding long-term prognosis when compared to the general population. Two hundred and fourteen patients with pT1 EAC (n = 112) or GAC (n = 102) were included in the study. Patients with EAC underwent transthoracic en-bloc esophagectomy; those with GAC had total or subtotal gastrectomy with D2-lymphadenectomy. Surviving patients had a median follow-up of approximately 14 years. YLL was calculated using average life expectancy data from Germany. Patients with EAC were younger (median age 61 years) than those with GAC (66 years) (p = 0.031). The male:female ratio was 10:1 for EAC and 3:2 for GAC (p < 0.001). Multivariate survival analysis showed the age of the patients ≥60 years and the existence of lymph node metastasis was associated with poor prognosis. The median YLL for all patients who died over follow-up was 8.0 years. For patients under 60 years, it was approximately 20 years, and for older patients, approximately 5 years (p < 0.001) without difference in tumor stage between these age cohorts. YLL did not differ for GAC vs. EAC. After surgical resection, the prognostic burden as measured by YLL is relevant for all patients with early esophageal and gastric adenocarcinomas and especially for younger patients. Reasons for YLL need further studies.

The Public's Intended Uptake of Hypothetical Esophageal Adenocarcinoma Screening Scenarios: A Nationwide Survey.

Screening for early esophageal adenocarcinoma (EAC) may potentially reduce EAC-related mortality and morbidity. This study aimed to examine the Dutch population's intended uptake of 3 hypothetical EAC screening test scenarios and preferences for potential future organization. A total of 8,350 Dutch individuals aged 45-75 years were invited, of whom 2,258 completed a web-based survey. Participants were randomly assigned to 1 of 3 hypothetical screening test scenarios (i.e., transnasal endoscopy, ingestible cell collection device, or breath analysis). The primary outcome was intended uptake. Secondary outcomes included acceptance of screening eligibility criteria and preferences regarding invitation, counseling, and diagnostic follow-up. We performed exploratory univariable and multivariable regression analyses to assess which determinants were associated with EAC screening intent. Intended uptake of screening was highest in the breath analysis scenario (95%), followed by conventional upper endoscopy (78%), an ingestible cell collection device (75%), and transnasal endoscopy (68%) ( P < 0.001). Anticipating discomfort was most strongly associated with decreased intention to undergo transnasal endoscopy (odds ratio 0.18, 95% confidence interval 0.11-0.29) or swallow a cell collection device (odds ratio 0.20, 95% confidence interval 0.13-0.32). Cancer worry and high acceptance of test sensitivity/specificity were consistently associated with a positive intention to participate in screening. Inviting persons for screening based on gastroesophageal reflux disease symptoms, age, or the output of a risk prediction model was acceptable to 74%, 69%, and 66%, respectively. Inviting only men was acceptable for only 41% of women. The majority (58%) preferred to be invited by a public health organization, and 32% of the participants preferred to discuss their decision to participate with a healthcare professional. Participants in this study self-selected through a web-based survey, potentially introducing selection bias. Participants generally intended to participate in EAC screening, although the level of intent depended on the discomfort and performance associated with the offered screening test. Determining eligibility based on gastroesophageal reflux disease symptoms, age, or a risk calculator, but not sex, would be acceptable to most individuals.

Towards personalized management of early esophageal adenocarcinoma.

This review aims to discuss recent advancements in the endoscopic management of early esophageal adenocarcinoma (T1 EAC). Patients with high-risk EAC (defined by the presence of deep submucosal invasion, and/or lymphovascular invasion, and/or poor differentiation) have a higher risk of lymph node metastases than those with low-risk EAC. However, more recent, endoscopically-focused studies report a lower risk of lymph node metastases and distant metastases for high-risk EAC than previously assumed. Instead of referring all high-risk EAC patients for esophagectomy after a radical endoscopic resection, an alternative approach involving regular upper endoscopy with endoscopic ultrasound may allow for detection of intra-luminal recurrence and lymph node metastases at an early and potentially curable stage. Endoscopic resection of mucosal and submucosal EAC might prove to be safe and curative for selected cases in the future, when followed by a strict follow-up protocol. Despite the promising results of preliminary studies, there is an ongoing need for personalized strategies and new risk stratification methods to decide on the best management for individual patients with high-risk T1 EAC.

Endoscopic submucosal dissection for early esophageal adenocarcinoma: low rates of metastases in mucosal cancers with poor differentiation

Background and aimsEndoscopic resection (ER) is accepted as standard treatment for intramucosal esophageal adenocarcinoma (EAC) with well or moderate differentiation. Poor differentiation (PD) is judged as a risk factor for lymph node metastasis (LNM) and surgery is recommended. However, the evidence for this recommendation is weak. Study aim was to analyze the clinical course of patients after ER of EAC with PD. Patients and methodsPatients undergoing endoscopic submucosal dissection for EAC were included from 16 German centers. Inclusion criteria were PD in the resection specimen, R0 resection and endoscopic follow-up. Primary outcome was the metastasis rate during follow-up. Analysis was performed retrospectively in a prospectively collected database. Results25 patients with PD as single risk factor (group A) and 15 patients with PD and additional risk factors (submucosal invasion and/or lymphovascular invasion) were included. The metastasis rate was was 1/25 (4.0%; 95%CI 0.4-17.2) in group A and 3/15 (20.0%; 95%CI 6.0-44.4%) in group B, respectively (p=0.293). The rate of EAC-associated deaths was 1/25 (4%; 95%CI 0.4-17.2%) versus 3/15 (20%; 95%CI 6.0-44.4%) in group B (p=0.293) while the overall death rate was 7/25 (28.0%; 95%CI 13.5-47.3%) versus 3/15 (20%; 95%CI 6.0-44.4%) (p=0.715). Median follow-up was 30 months (IQR 15-53). ConclusionsDuring long-term follow-up the risk of metastasis is low after ER of mucosal EAC with PD as single risk factor. A conservative approach seems justified in this small patient group. However, the treatment strategy has to be determined on an individualized basis until further prospective data are available.

Risk of lymph node metastasis in T1 esophageal adenocarcinoma: a meta-analysis.

Patients with early (T1) esophageal adenocarcinoma (EAC) are increasingly having definitive local therapy endoscopically. Endoscopic resection is not able to pathologically stage or treat lymph node metastasis (LNM). Accurate identification of patients having nodal metastasis is critical to select endoscopic therapy over surgery. This study aimed to define the risk of LNM in T1 EAC. A meta-analysis of studies of patients who underwent surgery and lymphadenectomy with assessment of LNM was performed according to PRISMA. Main outcome was probability of LNM in T1a and T1b disease. Secondary outcomes were risk factors for LNM and rate of LNM in submucosal T1b (SM1, SM2, and SM3) disease. Registered with PROSPERO (CRD42022341794). Twenty cohort studies involving 2264 patients with T1 EAC met inclusion criteria: T1a (857 patients) with 36 (4.2%) node positive and T1b (1407 patients) with 327 (23.2%) node positive. Subgroup analysis of T1b lesions was available in 10 studies (405 patients). Node positivity for SM1, SM2, and SM3 was 16.3%, 16.2%, and 29.4%, respectively. T1 substage (odds ratio [OR] 7.72, 95% confidence interval [CI] 4.45-13.38, P < 0.01), tumor differentiation (OR 2.82, 95% CI 2.06-3.87, P < 0.01), and lymphovascular invasion (OR 13.65, 95% CI 6.06-30.73, P < 0.01) were associated with LNM. T1a disease demonstrated a 4.2% nodal metastasis rate and T1b disease a rate of 23.2%. Endoscopic therapy should be reserved for T1a disease and perhaps select T1b disease, which has a moderately high rate of nodal metastasis. There were inadequate data to stratify T1b SM disease into 'low-risk' and 'high-risk' based on tumor differentiation and lymphovascular invasion.

Abstract A001: Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma

Abstract Abstract: The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data. Citation Format: Chunyang Bao. Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A001.

Organ preservation with durvalumab-based immunotherapy in combination with chemoradiation as definitive therapy for early stage, cT1, and cT2N0 esophageal adenocarcinoma with indication for radical surgery: A prospective, multicenter study of the FLOT-AIO Gastric Cancer Group (IKF-t057/PRESTO trial).

TPS431 Background: The outcome of patients (pts) with adenocarcinomas of stomach and esophagogastric junction (GEJ) remains unsatisfactory (5-year survival rates of 24-84%), whereby surgical resection is considered as cornerstone of the curative treatment for pts with early stage esophageal adenocarcinoma (EGA), however, it is associated with mortality, morbidity and an impact on the patient’s quality of life. Recent investigations showed that in locally advanced stage EGA surgery with neoadjuvant chemoradiotherapy (CROSS trial) is beneficial over surgery alone. Further benefit was achieved for locally advanced EGA by perioperative treatment with FLOT acc. to FLOT4- trial data. Immuno-oncology (IO) therapy by using checkpoint inhibitors is approved in the palliative and adjuvant EGA situation. In this trial we aim for the organ preservation treatment of EGA pts with a combination of the anti PD-L1 antibody durvalumab- FLOT - and chemoradio-therapy. Methods: This is a multicenter, single arm, open-label, phase II trial including a total of 32 pts with T1-T2N0 EGA (including GEJ) with indication for radical surgery. Enrolled pts will receive immunotherapy with durvalumab (1500 mg Q4W) in parallel to 2 cycles FLOT (50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 calcium folinate and 2600 mg/m2 5FU, Q2W) induction followed by 3 cycles of mFOLFOX (85 mg/m2 oxaliplatin, 200 mg/m2 calcium folinate, 400 mg/m2 5FU bolus and 1600 mg/m2 5FU over 48h, Q2W) plus concomitant radiation (25 daily fractions with 2.0 Gy = Σ50Gy). 8 weeks after last treatment, pts will undergo tumor assessment by esophagogastroduodenoscopy with biopsies, endoscopic ultrasonography, and CT- or MRI-scans. Surgical resection would be offered only to pts in whom a locoregional persistence is confirmed. Pts with complete remission will enter the maintenance phase and will receive durvalumab monotherapy (1500 mg, Q4W) for a maximum of 12 cycles accompanied by regular tumor re-evaluation. Primary endpoint is the rate of cCR/pCR at time of re-evaluation. Secondary endpoints include rate of cCR/pCR at 1, 2 and 3 years, rate of salvage surgery, 90 day and 1 year mortality after start of treatment, safety and quality of life. In this exploratory trial a cCR/pCR rate of ≥75% would indicate that the study treatment should be further investigated, whereas a rate &lt; 55% indicates no further investigation. First patient was enrolled on 2023-08-28. Currently one patient is recruited. Clinical trial information: NCT05713838 .

Incidence rates of Barrett’s esophagus and esophageal adenocarcinoma: a systematic review and meta-analysis

Background and AimsBarrett’s esophagus (BE) surveillance is commonly performed to detect early dysplasia and esophageal adenocarcinoma (EAC). However, high-quality incidence rates for the development of dysplasia and EAC in patients with BE are limited. This study aims to perform a systematic review and meta-analysis to provide an updated incidence rates for the development of low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC in a population of patients with BE undergoing endoscopic surveillance. MethodsWe performed a systematic search of EMBASE and Medline from inception to September 2022 to identify studies reporting the incidence rates of LGD, EAC, or HGD/EAC as an outcome in patients with non-dysplastic BE (NDBE), LGD, or HGD. Respective pooled incidence rates were estimated using a meta-analysis. ResultsTwenty-five studies were included in this meta-analysis comprising 2,587 patients with a combined follow-up of 218,351 person-years. For patients with NDBE, pooled incidence rates for progression to LGD, HGD, EAC, and HGD/EAC were 4.29, 0.52, 0.21, and 0.57 per 100 person-years, respectively. For patients with LGD, pooled incidence rates were 3.18 (HGD), 1.16 (EAC), and 5.05 (HGD/EAC) per 100 person-years. For those with HGD, the pooled incidence rate for EAC was 14.16 per 100 person-years. ConclusionsProgression to EAC and HGD/EAC remained low for patients with NDBE. Patients with confirmed LGD (≥2 pathologists) may be more likely to develop EAC, prompting a need to assess current BE surveillance strategies in this group.

Advanced endoscopic imaging for detection of Barrett's esophagus.

Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma (EAC), and is caused by chronic gastroesophageal reflux. BE can progress over time from metaplasia to dysplasia, and eventually to EAC. EAC is associated with a poor prognosis, often due to advanced disease at the time of diagnosis. However, if BE is diagnosed early, pharmacologic and endoscopic treatments can prevent progression to EAC. The current standard of care for BE surveillance utilizes the Seattle protocol. Unfortunately, a sizable proportion of early EAC and BE-related high-grade dysplasia (HGD) are missed due to poor adherence to the Seattle protocol and sampling errors. New modalities using artificial intelligence (AI) have been proposed to improve the detection of early EAC and BE-related HGD. This review will focus on AI technology and its application to various endoscopic modalities such as high-definition white light endoscopy, narrow-band imaging, and volumetric laser endomicroscopy.

Patients With Esophageal Adenocarcinoma With Prior Gastroesophageal Reflux Disease Symptoms Are Similar to Those Without Gastroesophageal Reflux Disease: A Cross-Sectional Study.

A substantial proportion of patients with esophageal adenocarcinoma (EAC) do not report gastroesophageal reflux disease (GERD) symptoms. This study aimed to compare the risk factor profiles and cancer stage at presentation of patients with EAC with and without prior GERD. In this retrospective cross-sectional study, patients with EAC were divided into 2 cohorts: (i) EAC with prior GERD: patients who reported typical GERD symptoms (heartburn or regurgitation) ≥1 year before cancer diagnosis and (ii) EAC without prior GERD: patients who did not report prior GERD symptoms or reported symptoms within 1 year of their cancer diagnosis. Baseline demographics, risk factors, and cancer stage at presentation were compared between the 2 cohorts. In addition, the distribution of patients based on numbers of BE/EAC-associated risk factors (1, 2, 3, 4, and 5 or more) was examined in the symptomatic and asymptomatic cohorts. Over 13 years, 388 patients with EAC with prior GERD and 245 patients with EAC without prior GERD were recruited. Both groups had similar baseline demographics and risk factors, but patients with EAC with prior GERD were more likely to have a history of BE. Asymptomatic patients had more advanced disease. Patients with 3 or more BE/EAC-related risk factors formed the largest proportion of patients in both the symptomatic and asymptomatic cohorts. Patients with EAC with and without prior GERD symptoms are phenotypically similar, suggesting that BE screening efforts to prevent or detect early EAC should not be restricted to just those with GERD.

Molecular Biology and Clinical Management of Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a highly lethal malignancy. Due to its rising incidence, EAC has become a severe health challenge in Western countries. Current treatment strategies are mainly chosen based on disease stage and clinical features, whereas the biological background is hardly considered. In this study, we performed a comprehensive review of existing studies and discussed how etiology, genetics and epigenetic characteristics, together with the tumor microenvironment, contribute to the malignant behavior and dismal prognosis of EAC. During the development of EAC, several intestinal-type proteins and signaling cascades are induced. The anti-inflammatory and immunosuppressive microenvironment is associated with poor survival. The accumulation of somatic mutations at the early phase and chromosomal structural rearrangements at relatively later time points contribute to the dynamic and heterogeneous genetic landscape of EAC. EAC is also characterized by frequent DNA methylation and dysregulation of microRNAs. We summarize the findings of dysregulations of specific cytokines, chemokines and immune cells in the tumor microenvironment and conclude that DNA methylation and microRNAs vary with each different phase of BE, LGD, HGD, early EAC and invasive EAC. Furthermore, we discuss the suitability of the currently employed therapies in the clinic and possible new therapies in the future. The development of targeted and immune therapies has been hampered by the heterogeneous genetic characteristics of EAC. In view of this, the up-to-date knowledge revealed by this work is absolutely important for future EAC studies and the discovery of new therapeutics.

The association between histological subtypes and lymph node metastasis and prognosis in early esophageal cancer: a population-based study.

There is still a lack of high-level clinical evidence and uniform conclusions on whether there are differences in lymph node metastasis (LNM) and prognosis between early esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). Patients with surgically resected, histologically diagnosed, pT1 EAC or ESCC in the Surveillance, Epidemiology and End Results registries database from 2004 to 2015 were included. Multivariable logistic regression, Cox regression, multivariate competing risk model, and propensity score matching were used to analyze association the histology and LNM or prognosis. A total of 570 early esophageal cancer patients were included. The LNM rates were 13.8% and 15.1% for EAC and ESCC ( P = 0.757), respectively. Multivariate logistic regression analysis showed no significant association between histological type and LNM (odds ratio [OR], 1.209; 95% CI, 0.538-2.715; P = 0.646). Moreover, the prognosis of early EAC and ESCC was shown to be comparable in both multivariate Cox regression (hazard ratio [HR], 1.483; 95% CI, 0.699-3.150; P = 0.305) and the multivariate competing risk model (subdistribution HR, 1.451; 95% CI, 0.628-3.354; P = 0.383). After propensity score matching, there were no significant differences between early EAC and ESCC in terms of LNM (10.6% vs.18.2%, P = 0.215), 5-year CSS (89.8% [95% CI, 81.0%-98.6%] vs. 79.1% [95% CI, 67.9%-90.3%], P = 0.102) and 5-year cumulative incidence of CSS (10.2% [95% CI, 1.4%-19.0%] vs. 79.1% [95% CI, 9.7%-32.1%], P = 0.124). The risk of LNM and prognosis of early ESCC and EAC are comparable, so the treatment choice for early esophageal cancer does not depend on the histologic type.

Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma

The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.

ANPEP/CD13 Expression as a Marker of Lymphovascular Invasion and Survival in Esophageal Adenocarcinoma

BackgroundThe presence of lymphovascular invasion (LVI) in early esophageal adenocarcinoma (EAC) is associated with more aggressive disease. Molecular markers associated with LVI are still largely unknown. Using a combination of transcriptomic analysis and validation experiments, we sought to describe markers for LVI and survival. MethodsWe performed NanoString expression profiling using RNA from 60 EAC specimens collected from surgery-only cases between 2000 and 2012. Differentially expressed genes (DEGs) were correlated with pathologic characteristics (T and N status and presence of LVI). Kaplan-Meier and Cox regression analyses were used to correlate gene expression with overall survival. Expression of alanyl aminopeptidase, membrane (ANPEP)/CD13 was validated by immunohistochemistry (IHC) in EAC tissue microarray and in EAC cell lines. ResultsWe identified >20 up-regulated DEGs in tumor samples containing LVI. Multivariable analysis showed depth of invasion and ANPEP/CD13 expression were independently associated with overall survival, whereas nodal status was not. IHC analysis demonstrated overexpression of the ANPEP/CD13 protein in dysplastic Barrett esophagus and EAC tumors. Kaplan-Meier analysis showed that patients with higher RNA expression and strongly positive ANPEP/CD13 membrane IHC-Histoscore staining have shorter survival (P = .002). Down-regulation of ANPEP/CD13 expression by short hairpin RNA vector reduces colony formation, migration, and invasion of FLO-1 EAC cells. Overexpression of CD13 in SKGT4 EAC cells increases colony formation, motility, and invasion in vitro. ConclusionsElevated expression of ANPEP/CD13 indicates shorter survival of EAC patients and a more invasive phenotype of cancer cells in vitro. Validation in a larger sample group is required to better understand the clinical significance of ANPEP/CD13 and other candidate genes.