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The relationship between 'bulky' locoregional lymphadenopathy and survival has not been investigated in the setting of esophageal adenocarcinoma (EAC). This study aimed to explore whether bulky regional lymphadenopathy at diagnosis affected survival outcomes in patients with EAC treated with neoadjuvant chemotherapy and en bloc resection. A single-center retrospective review of a prospectively maintained upper GI cancer surgical database was performed between January 2012 and December 2019. Patients with locally advanced EAC (cT2-3, N+, M0) treated with neoadjuvant docetaxel-based chemotherapy and transthoracic en bloc esophagogastrectomy were identified. Computed tomography scans from before the initiation of treatment were reviewed, and patients were stratified according to whether bulky loco-regional lymph nodes were present. This was defined as lymphadenopathy >2 cm in any axis. Overall survival was compared, and a Cox multivariate regression model was calculated. Two hundred twenty-five of the eight hundred seventy patients identified met the inclusion criteria. Forty-eight (21%) had bulky lymphadenopathy, leaving 177 allocated to the control group. More patients with bulky lymphadenopathy had ypN3 disease (18/48, 38% vs. 39/177, 20%, P  = 0.025). Among patients with bulky lymphadenopathy, overall survival was generally worse (32.6 vs. 59.1 months, P  = 0.012). However, among the 9/48 (19%) patients with bulky lymphadenopathy who achieved ypN− status survival outcomes were similar to those with non-bulky lymphadenopathy who also achieved lymph node sterilization. Poor differentiation (HR 1.8, 95% CI 1.0–2.9, P  = 0.034), ypN+ (HR 1.9, 95% CI 1.1–3.6, P  = 0.032), and bulky lymphadenopathy were independently associated with an increased risk of death (HR 1.7, 1.0–2.9, P  = 0.048). Bulky regional lymphadenopathy is associated with a poor prognosis. Efforts to identify the ideal treatment regimen for these patients are urgently required. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

This study was completed to evaluate the relationship between tumor length and the prognosis of patients with pathological stage IA-IC esophageal adenocarcinoma (EAC). Patients were identified from the Surveillance, Epidemiology, and End Results Program database (United States, 2006–2015). X-tile software and ROC analysis were mainly used to explore the best threshold of tumor length for dividing patients into different groups, and then propensity score matching (PSM) was used to balance other variables between groups. The primary outcome assessed was overall survival (OS). A total of 762 patients were identified, and 500 patients were left after PSM. Twenty millimeters were used as the threshold of tumor length. Patients with longer tumor lengths showed worse OS (median: 93 vs. 128 months; P  = 0.006). Multivariable Cox regression analysis showed that longer tumor length was an independent risk factor (hazard ratio 1.512, 95% confidence interval, 1.158–1.974, P  = 0.002). Tumor length has an impact on patients with pathological stage IA-IC EAC who undergo surgery alone. The prognostic value of the pathological stage group may be improved after combining it with tumor length and age. [ABSTRACT FROM AUTHOR]

Locally advanced esophageal adenocarcinomas (EACs) are treated with multimodal therapy, namely surgery, neoadjuvant chemotherapy (NAC) or chemoradiotherapy (CRT) depending on patient and tumor level factors. Yet, there is little consensus on choice of the optimum systemic therapy. To compare the pathological complete response (pCR) after FLOT, non-FLOT-based chemotherapy and chemoradiotherapy regimes in patients with EACs. A systematic review of the literature was performed using MEDLINE, EMBASE, the Cochrane Review and Scopus databases. Studies were included if they had investigated the use of chemo(radio)therapy regimens in the neoadjuvant setting for EAC and reported the pCR rates. A meta-analysis of proportions was performed to compare the pooled pCR rates between FLOT, non-FLOT and CRT cohorts. We included 22 studies that described tumor regression post-NAC. Altogether, 1,056 patients had undergone FLOT or DCF regimes, while 1,610 patients had received ECF or ECX. The pCR rates ranged from 3.3% to 54% for FLOT regimes, while pCR ranged between 0% and 31% for ECF/ECX protocols. Pooled random-effects meta-meta-analysis of proportions showed a statistically significant higher incidence of pCR in FLOT-based chemotherapy at 0.148 (95%CI: 0.080, 0.259) compared with non-FLOT-based chemotherapy at 0.074 (95%CI: 0.042, 0.129). However, pCR rates were significantly highest at 0.250 (95%CI: 0.202, 0.306) for CRT. The use of enhanced FLOT-based regimens have improved the pCR rates for chemotherapeutic regimes but still falls short of pathological outcomes from CRT. Further work can characterize clinical responses to neoadjuvant therapy and determine whether an organ-preservation strategy is feasible. [ABSTRACT FROM AUTHOR]

Pathologic complete response (pCR) to neoadjuvant chemoradiation for locally advanced esophageal adenocarcinoma (EAC) confers significantly improved survival. The ability to infer pCR may spare esophagectomy in some patients. Currently, there are no validated biomarkers of pCR. This study sought to evaluate whether a distinct signature of DNA copy number alterations (CNA) can be predictive of pCR in EAC. Pretreatment biopsies from 38 patients with locally advanced EAC (19 with pCR and 19 with pathologic partial/poor response) were assessed for CNA using OncoScan assay. A novel technique was employed where within every cytogenetic band, the quantity of bases gained by each sample was computed as the sum of gained genomic segment lengths weighted by the surplus copy number of each segment. A threefold cross-validation was used to assess association with pCR or pathologic partial/poor response. Forty patients with locally advanced EAC from The Cancer Genome Atlas (TCGA) constituted an independent validation cohort. Gains in the chromosomal loci 14q11 and 17p11 were preferentially associated with pCR. Average area under the receiver operating characteristic curve (AUC) for predicting pCR was 0.80 among the threefold cross-validation test sets. Using 0.3 megabases as the cutoff that optimizes trade-off between sensitivity (63%) and specificity (89%) in the discovery cohort, similar prediction performance for clinical and radiographic response was demonstrated in the validation cohort from TCGA (sensitivity 61%, specificity 82%). Copy number gains in the 14q11 and 17p11 loci may be useful for prediction of pCR, and, potentially, personalization of esophagectomy in EAC. [ABSTRACT FROM AUTHOR]

Background There is no consensus or guidelines internationally to inform clinicians of how patients should be monitored for recurrence after esophagogastric resections. Aim This systematic review and meta-analysis summarizes the latest evidence investigating the usefulness of surveillance protocols in patients who underwent esophagectomy or gastrectomy. Methods A systematic review of the literature was performed using MEDLINE, EMBASE, the Cochrane Review and Scopus databases. Articles were evaluated for the use of surveillance strategies including history-taking, physical examination, imaging modalities and endoscopy for monitoring patients post-gastrectomy or esophagectomy. Studies that compared surveillance strategies and reported detection of recurrence and post-recurrence survival were also included in the meta-analysis. Results Fifteen studies that described a surveillance protocol for post-operative patients were included in the review. Seven studies were used in the meta-analysis. Random-effects analysis demonstrated a statistically significant higher post-recurrence survival (standardized mean difference [SMD] 14.15, 95% CI 1.40–27.26, p  = 0.03) with imaging-based planned surveillance post-esophagectomy. However, the detection of recurrence (OR 1.76, 95% CI 0.78–3.97, p  = 0.17) for esophageal cancers as well as detection of recurrence (OR 0.73, 95% CI 0.11–5.12, p  = 0.76) and post-recurrence survival (SMD 6.42, 95% CI –2.16–18.42, p  = 0.14) for gastric cancers were not significantly different with planned surveillance. Conclusion There is no consensus on whether surveillance carries prognostic survival benefit or how surveillance should be carried out. Surveillance may carry prognostic benefit for patients who underwent surgery for esophageal cancer. Randomized controlled trials are required to evaluate the survival benefits of intensive surveillance strategies, determine the ideal surveillance protocol and tailor it to the appropriate population. [ABSTRACT FROM AUTHOR]

Endoscopic mucosal resection (EMR) can be an effective therapy for superficial esophageal cancer. Many patients with cT2 invasion by endoscopic ultrasound (EUS) receive surgery but are subsequently found to have superficial disease. The purpose of this study was to investigate the safety profile and the added value of attempting EMR for EUS-staged cT2N0 esophageal cancer. A retrospective review was performed at a single institution from 2008 to 2017. Patients who were staged cT2N0 by EUS were identified from a prospectively maintained surgical database. Among 75 patients identified for analysis, 30 underwent an attempt at EMR. No perforations or other immediate complications occurred. EMR was more likely to be attempted among older patients (P = 0.001) with smaller tumor size (P < 0.001) and diminished SUVmax (P = 0.001). At the time of treatment, EMR was successful in clearing all known disease among 17/30 patients, with 12 representing pT1a or less and 5 representing pT1b with negative margins. Among the 17 patients for whom EMR was able to clear all known disease, there were no recurrences or cancer-related deaths. Although all the patients were staged as cT2N0 by EUS, many patients were identified by EMR to have superficial disease. There were no perforations or other adverse events related to EMR. Furthermore, EMR cleared all known disease among 17 patients with no known recurrences or cancer-related deaths. The results indicate that EMR for cT2N0 esophageal cancer is a safe diagnostic option that is therapeutic for some. [ABSTRACT FROM AUTHOR]

High-risk human papillomavirus (hr-HPV) infection is causal for almost all cervical malignancy (both squamous and adenocarcinoma), 90% of anal neoplasia, 70% of penile tumors, and 25% of head and neck cancers. The shared immunogenetics of cervical and esophageal malignancy suggests that HPV infection could well be a common denominator in the etiology of both cancers. In this regard, we have demonstrated that transcriptionally active hr-HPV (genotypes 16 and 18) is strongly associated with Barrett's dysplasia and esophageal adenocarcinoma. Increasing hr-HPV viral load and integration status has been linked with greater disease severity along the Barrett metaplasia–dysplasia–adenocarcinoma sequence as has been demonstrated in cervical intraepithelial neoplasia and cancer. HPV infections in both the cervix and esophagus are both focal, i.e. present in greater quantities at the squamocolumnar junction (SCJ). HPV affinity is to junctional tissue, as basal cells are particularly accessible at the squamocolumnar transformation zone and especially susceptible to this viral infection. We have postulated that progressive acid damage to the esophagus increases the likelihood of mucosal breaks enabling the virus to enter the basal layer of the transformation zone. The SCJ is the transformation zone of the esophagus and is strikingly similar to the transition zone (ectoendocervical SCJ) of the uterine cervix where almost all high-grade cervical lesions and cancers arise including 80% of adenocarcinomas. These transition zone cells exhibit features of squamous epithelium as well as glandular cells, which have been described in both Barrett's esophagus and cervical mucosa. Barrett's esophagus (BE) is derived from a discrete population of embryonic cells residing at the SCJ. There is loss of SCJ immune-phenotype following excision without regeneration at other junctional sites. Prevention of cervical cancer in up to 80–95% of patients with screen-detected CIN is dependent on the excision/ablation of the entire transformation zone. The persistence of hr-HPV 16/18 following eradication of CIN is a significant risk factor for recurrence. Similarly, we have demonstrated that persistent hr-HPV infection 16/18 and p53 overexpression are associated with treatment failure after endoscopic ablation of BD/EAC. Thus, we believe that excision/ablation of the SCJ in patients with BD/intramucosal EAC should be performed to reduce the potential malignant risk. We propose to test this hypothesis by a multicenter randomized controlled trial whereby patients (both HPV positive and those which are virus negative) will be allocated into two arms: complete excision of the SCJ via endoscopic mucosal resection (EMR) in addition to radiofrequency ablation (RFA) ± EMR of BD/intramucosal EAC (experimental arm) versus current standard of care (RFA ± EMR) of said lesions. Treatment efficacy in both groups will be evaluated by comparing disease elimination, regression/progression, and recurrence (if any). All patients would be entered into an intensive endoscopic surveillance protocol (biannually) for at least 2 years with lesional/neosquamous biopsies to compare the recurrence rate of both dysplasia/neoplasia in both arms. Viral (HPV DNA/p16INK4A/E6/E7 mRNA) and host biomarkers (e.g. p53) will be analyzed both at baseline and posttreatment intervals. A positive study would initiate development of tools best suited for SCJ destruction. [ABSTRACT FROM AUTHOR]

Barrett's esophagus with high-grade dysplasia (BEHGD) and intramucosal esophageal adenocarcinoma (IMC) can be treated by radiofrequency ablation (RFA) and endoscopic mucosal resection (EMR). Efficacy of RFA and EMR in academic medical centers has been demonstrated in previous studies. However, the clinical effectiveness of this approach in community clinical practice is not fully established. All patients with biopsy-proven BEHGD and IMC (T1a), who were treated endoscopically between 2007 and 2014, were prospectively enrolled. Treatment algorithms were determined by consensus opinion after presentation at gastrointestinal tumor board. Patients underwent EMR and/or RFA until eradication-of-dysplasia and complete remission of intestinal metaplasia (CRIM) was achieved. Patients were then enrolled in an endoscopic surveillance program. A total of 60 patients underwent endoscopic therapy for BEHGD (32) or IMC (28). Median length BE was 4 cm. Forty-six patients had EMR. Median treatment interval was nine months. Median follow-up was 33 months (Interquartile range: 16-50). Fifty-five (92%) patients achieved eradication-of-dysplasia and 52(87%) CRIM. One patient with BEHGD did not achieve any benefit six months into treatment. Nine (15%) patients relapsed after CRIM with nondysplastic-BE (6), BE with low-grade dysplasia (1), and BEHGD (2). After retreatment, eradication-of-intestinal metaplasia was achieved in five patients. BE length was a negative predictor for achieving CRIM (OR 0.81; P = 0.04). There were no procedure-related severe complications. Eleven patients with prior EMR developed symptomatic strictures, which were all successfully dilated. Endoscopic management of BEHGD and IMC can be safely and effectively performed in a community clinical practice similarly to high-volume academic medical centers when performed by advanced endoscopists following multidisciplinary approach. [ABSTRACT FROM AUTHOR]

Dissection of lymph nodes (LN) immediately after esophagectomy is utilized by some surgeons to aid determination of LN stations involved in esophageal cancer. Some suggest that this increases LN yield and gives information regarding the pattern of lymphatic spread, others feel that this may compromise a circumferential resection margin (CRM) assessment. The aim of this study is to evaluate the effect of ex vivo dissection on the assessment of the CRM and the pattern of lymph node dissemination in patients with adenocarcinoma of the esophagus and gastroesophageal junction (GEJ) undergoing radical surgery after neoadjuvant chemotherapy and their prognostic impact. Data from consecutive patients with potentially curable adenocarcinoma of the distal esophagus and GEJ who received neoadjuvant treatment followed by surgery were analyzed. Clinical and pathological findings were reviewed and LN burden and location correlated with clinical outcome. Pathology specimens were dissected into individual LN groups 'ex-vivo' by the surgeon. A total of 301 patients were included: 295 had a radical proximal and distal resection margin however in 62(20.6%) CRM could not be assessed. A median of 33(10-77) nodes were recovered. A 117(38.9%) patients were ypN0 while 184(61.1%) were LN positive (ypN1-N3). LN stations close to the tumor were most frequently involved. Twenty-seven (14.7%) patients had only thoracic stations involved, 48(26.1%) only abdominal stations and 109 (59.2%) had both. Median survival for yN0 patients was 171 months compared to 24 months for those LN positive (P < 0.001). Multivariate analyses identified ypT-category, ypN-category, male gender, and nonradical resection (proximal or distal) margin as significant prognostic factors. Surgical dissection of nodes after esophagectomy enables accurate LN assessment, but may compromise CRM assessment in up to 20% of cases. It also provides valuable information regarding the pattern of nodal spread. [ABSTRACT FROM AUTHOR]

High-risk submucosal esophageal adenocarcinoma's might be treated curatively by means of radical endoscopic resection, followed by thoracolaparoscopic lymphadenectomy without concomitant esophagectomy. A preclinical study has shown the feasibility and safety of this approach; however, no studies are performed in a clinical setting. In addition, sentinel node navigation surgery could be valuable in tailoring the extent of the lymphadenectomy. This study aimed to evaluate the feasibility and safety of thoracolaparoscopic lymphadenectomy without esophagectomy (phase I) and sentinel node navigation surgery (phase II) in patients with early esophageal adenocarcinoma. Patients with T1N0M0 early esophageal adenocarcinoma scheduled for esophagectomy without neoadjuvant therapy were included. Phase I: Two-field, esophagus preserving, thoracolaparoscopic lymphadenectomy was performed, followed by esophagectomy in the same session. Primary outcome parameters were the number of lymph nodes resected, and number of retained lymph nodes in the esophagectomy specimen. Phase II: A radioactive tracer was injected endoscopically the day before surgery. Static imaging was performed 15 and 120 minutes after injection. The day of surgery, sentinel node navigation surgery followed by esophagectomy was performed. Primary outcome parameters were the percentage of patients with a detectable sentinel node, and the concordance between static imaging and probe-based detection of sentinel node. Phase I: Five patients were included, and amedian of 30 (IQR: 25-46) lymph nodes was resected. A median of 6 (IQR: 2-9) retained lymph nodes was found in the esophagectomy specimen. No acute adverse events occurred, but near the end of lymphadenectomy esophageal discoloration was observed, possibly indicating ischemia. Phase II: In all five included patients sentinel nodes could be visualized and resected, at a median of 3 (IQR: 2-5) locations. There was a high concordance between imaging and probe-based detection of sentinel nodes. In conclusion, sentinel node navigation surgery followed by lymphadenectomy without concomitant esophagectomy seems feasible in patients with high-risk submucosal early esophageal adenocarcinoma. More evidence is however needed before applying this technique in clinical practice. [ABSTRACT FROM AUTHOR]

Physical activity affects the functioning of the gastrointestinal system through both local and systemic effects and may play an important role in reducing the risk of esophageal adenocarcinoma. This review assesses the biological mechanisms and epidemiological evidence for the relationship between physical activity and the development of esophageal adenocarcinoma and its precursor diseases: gastroesophageal reflux disease (GORD) and Barrett's esophagus. A search of PubMed, Medline, Embase, and CINAHL was conducted from their inceptions to 25thMarch 2017 for analytical studies that examined associations between recreational and/or occupational levels of physical activity and the risk of GORD, Barrett's esophagus, and esophageal adenocarcinoma. Where appropriate, a meta-analysis of effects was undertaken. Seven studies were included (2 cohort, 5 case control). For GORD, there were three case-control studies with 10 200 cases among 78 034 participants, with a pooled estimated OR of 0.67 (95% CI 0.57-0.78) for high versus low levels of recreational physical activity. In Barrett's esophagus, there was a single case-control study, which reported no association, OR 1.19 (95% CI 0.82-1.73). For esophageal adenocarcinoma, there were three studies (two prospective cohort, one case control) with 666 cases among 910 376 participants. The largest cohort study reported an inverse association for high versus low levels of recreational physical activity, RR 0.68, 95% CI 0.48-0.96. The remaining two studies reported no associations with either occupational or combined recreational and occupational activity. Heterogeneity in the measurement of exposure (recreational, occupational, and both) made a pooled estimate for esophageal adenocarcinoma inappropriate. Although limited, there is some evidence that higher levels of recreational physical activity may reduce the risk of both GORD and esophageal adenocarcinoma, but further large cohort studies examining the type, intensity and duration of activities that may be beneficial are needed. [ABSTRACT FROM AUTHOR]

Esophageal adenocarcinoma has poor 5-year survival rates. Increased survivalmight be achieved with earlier treatment, but requires earlier identification of the precursor, Barrett's esophagus. Population screening is not cost effective, this may be improved by targeted screening directed at individuals more likely to have Barrett's esophagus. To develop a risk prediction tool for Barrett's esophagus, this study compared individuals with Barrett's esophagus against population controls. Participants completed a questionnaire comprising 35 questions addressing medical history, symptom history, lifestyle factors, anthropomorphic measures, and demographic details. Statistical analysis addressed differences between cases and controls, and entailed initial variable selection, checking of model assumptions, and establishing calibration and discrimination. The area under the curve (AUC) was used to assess overall accuracy. One hundred and twenty individuals with Barrett's esophagus and 235 population controls completed the questionnaire. Significant differences were identified for age, gender, reflux history, family reflux history, history of hypertension, alcoholic drinks per week, and body mass index. These were used to develop a risk prediction model. The AUC was 0.82 (95% CI 0.78-0.87). Good calibration between predicted and observed risk was noted (Hosmer-Lemeshow test P=0.67). At the point minimizing false positives and false negatives, the model achieved a sensitivity of 84.96% and a specificity of 66%. A well-calibrated risk prediction model with good discrimination has been developed to identify patients with Barrett's esophagus. The model needs to be externally validated before consideration for clinical practice. [ABSTRACT FROM AUTHOR]

Abdominal obesity is associated with gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE). Increased body mass index (BMI) and waist-to-hip ratio (WHR) have been associated with BE. Abdominal diameter index (ADI, sagittal abdominal diameter divided by thigh circumference) was previously shown to be a more accurate predictor of incident cardiovascular disease compared to other measurements. Our aim is to examine whether abdominal diameter index was a more accurate predictor of prevalent BE compared to other anthropometric measurements. We conducted a case-control study of patients presenting to our institution. Our study population was consecutive Caucasian men with a known history of BE, and we recruited control patients who had GERD without BE. Both groups completed a questionnaire about demographics, smoking, and medications and underwent a series of anthropometric body measurements using standardized measuring tools. BMI, waist-to-hip ratio, and abdominal diameter index were calculated. Thirty-one BE patients and 27 control patients were recruited. The BE cohort were older and had a higher rate of hiatal hernia. The mean abdominal diameter index for patients with BE was 0.65 ± 0.07 and without BE was 0.60 ± 0.07 (p = 0.01). The predictive value of abdominal diameter index was analyzed using a receiver-operator characteristic (ROC) curve and was a more powerful predictor of BE than waist-to-hip ratio or BMI (AUROC = 0.70 vs. 0.60 vs. 0.52, respectively). Using a cut-point abdominal diameter index value of 0.60, abdominal diameter index had a sensitivity of 77.4% and a specificity of 63.0% for the presence of BE. When controlling for age, smoking status, and BMI, an abdominal diameter index =0.60 was a significant independent risk factor for BE (OR = 5.7, 95% CI = 1.29-25.4). In this pilot study, the abdominal diameter index appears to be a more powerful predictor of the presence of BE than BMI and waist-to-hip ratio and remained the only significant predictor of BE in multivariate analysis. We propose further validation of abdominal diameter index before inclusion in future prediction tools for BE. [ABSTRACT FROM AUTHOR]

Barrett's esophagus (BE) is a premalignant condition associated with the development of esophageal adenocarcinoma (EAC). Despite the low risk of progression to EAC, evidence highlights the notably poor survival rates of this malignancy. The mainstay form of diagnosis of BE is endoscopy and biopsy sampling. However, research emphasizes limitations with regards to the histological detection of BE and associated dysplasia. The aim of this study is to evaluate the clinical significance of CEACAM6 as a potential biomarker for the diagnosis of BE and beyond. Retrospective tissue samples were obtained from columnar lined esophagus without goblet cells (n = 27), BE (n = 18), BE associated dysplasia (n = 16), and EAC (n = 24). Standardized immunohistochemistry for CEACAM6 was performed followed by quantitative staining analysis. Statistical analysis across the BE spectrum for CEACAM6 was undertaken and a P value <0.05 was considered significant. CEACAM6 expression increased from columnar lined epithelium (CLE) to BE with a subsequent decrease to dysplasia and adenocarcinoma. The expression of CEACAM6 was significant from CLE to BE at p 0.001, CLE to dysplasia at p 0.001, BE to dysplasia at p 0.006, CLE to adenocarcinoma at p 0.001 and BE to adenocarcinoma at p 0.001. There was no significant difference in expression between dysplasia and adenocarcinoma (P = 0.15). Our findings highlight the increasing expression of CEACAM6 from CLE to BE with a subsequent decrease to dysplasia and adenocarcinoma. In view of this, we advocate the utilization of this marker for the enhanced diagnosis of BE and for the distinction of BE and dysplasia. [ABSTRACT FROM AUTHOR]

Barrett's esophagus is a well-recognized risk factor for esophageal adenocarcinoma. The natural history of Barrett's esophagus classified as 'indefinite for dysplasia' (IND) is poorly characterized. The aim of this study is to characterize the natural history of IND by determining the rate of neoplastic progression and identifying risk factors for progression. Patients from the University of Pennsylvania Health System pathology database and Barrett's esophagus registry with a diagnosis of IND between 2000 and 2014 were identified. Exclusion criteria included: (1) prior diagnosis of low-grade dysplasia (LGD), high-grade dysplasia (HGD), or esophageal adenocarcinoma (EAC); (2) presence of LGD, HGD, or EAC at the time of diagnosis of IND; and (3) lack of follow-up endoscopy after diagnosis. Patients with neoplastic progression were classified as having either prevalent disease (LGD, HGD, or EAC on surveillance biopsy within 12 months of IND diagnosis) or incident disease (LGD, HGD, or EAC on surveillance biopsy >12 months after IND diagnosis). One hundred six patients were eligible for analysis. Of 87 patients with follow-up endoscopy and biopsies within 1 year of IND diagnosis, 7 (8%) had prevalent disease (2 LGD, 4 HGD, 1 EAC). The prevalence of LGD was 2.3%, HGD was 4.6%, and EAC was 1.1%. Importantly, four of the seven prevalent (2 LGD, 2 HGD) cases were found to have dysplasia within 6 months of IND diagnosis. No demographic or endoscopic characteristics studied were associated with prevalent disease. Of the 106 IND patients, there were 66 patients without prevalent dysplasia with >1-year follow-up. Three (4.5%) progressed (1 to LGD after 12 months, 2 to HGD after 16.5 and 28 months), yielding an incidence rate for any dysplasia of 1.4 cases/100 person-years and HGD/EAC of 0.9/100 person-years. Risk factors for incident disease were smoking (p = 0.02) and Barrett's esophagus segment length (p = 0.03). IND is associated with considerable risk of prevalent dysplasia, especially within the first 6 months after diagnosis. However, the incidence of HGD/EAC is low and similar to previous studies of IND. These data suggest that IND patients should have repeat endoscopy within 6 months with careful surveillance protocols. Longer BE length and smoking history may help predict which patients are more likely to develop dysplasia, and therefore identify patients who may warrant even closer monitoring. [ABSTRACT FROM AUTHOR]

Volumetric laser endomicroscopy ( VLE) is a novel balloon-based optical coherence tomography ( OCT) imaging technique that may improve detection of early neoplasia in Barrett's esophagus ( BE). Most OCT studies lack a direct correlation between histology and OCT images. The aim is to investigate the optimal approach for achieving one-to-one correlation of ex-vivo VLE images of endoscopic resection ( ER) specimens with histology. BE patients with and without early neoplasia underwent ER after delineating areas with electrocoagulation markers ( ECM). After ER, specimens underwent additional ex-vivo marking with several different markers (ink, pin, Gold Probe) followed by ex-vivo VLE scanning. ER specimens were carefully sectioned into tissue blocks guided by the markers. Histology and VLE slides were considered a match if ≥ 2 markers were visible on both modalities and mucosal patterns aside from these markers matched on both histology and VLE. From 16 ER specimens 120 tissue blocks were sectioned of which 23 contained multiple markers. Fourteen histology- VLE matches were identified. ECMs and ink markers proved to be the most effective combination for matching. The last 6/16 ER specimens yielded 9/14 matches, demonstrating a learning curve due to methodological improvements in marker placement and tissue block sectioning. One-to-one correlation of VLE and histology is complex but feasible. The groundwork laid in this study will provide high-quality histology- VLE correlations that will allow further research on VLE features of early neoplasia in BE. [ABSTRACT FROM AUTHOR]

Barrett's esophagus ( BE) with high-grade dysplasia ( HGD) defines a group of individuals at high risk of progression to esophageal adenocarcinoma ( EA). Fluorescence in situ hybridization ( FISH) has been shown to be useful for the detection of dysplasia and EA in endoscopic brushing specimens from BE patients. The aim of this study was to determine whether FISH in combination with histological findings would further identify more rapid progressors to EA. This is a retrospective cohort study of high-risk patients, having a history of biopsy-confirmed HGD without EA, with an endoscopic brushing specimen analyzed by FISH while undergoing endoscopic surveillance and treatment between April 2003 and October 2010. Brushing specimens were assessed by FISH probes targeting 8q24 ( MYC), 9p21 ( CDKN2A), 17q12 ( ERBB2), and 20q13 ( ZNF217) and evaluated for the presence of polysomy, defined as multiple chromosomal gains (displaying ≥ 3 signals for ≥ 2 probes). Specimens containing ≥ 4 cells exhibiting polysomy were considered polysomic. HGD was confirmed by at least two experienced gastrointestinal pathologists. Of 245 patients in this study, 93 (38.0%) had a polysomic FISH result and 152 (62.0%) had a non-polysomic FISH result. Median follow-up was 3.6 years (interquartile range [ IQR] 2-5 years). Patients with a polysomic FISH result had a significantly higher risk of developing EA within 2 years (14.2%) compared with patients with a non-polysomic FISH result (1.4%, P < 0.001). These findings suggest that a polysomic FISH result in BE patients with simultaneous HGD identifies patients at a higher risk for developing EA compared with those with non-polysomy. [ABSTRACT FROM AUTHOR]

The prognostic significance of epidermal growth factor receptor (EGFR) overexpression in patients with esophageal adenocarcinoma (EAC) remains controversial. Eligible studies that investigated the association between survival in EAC and the expression status of EGFR were identified by an electronic search of PubMed, EMBASE, and ISI Web of Science. A meta-analysis was performed to clarify the impact of EGFR overexpression on clinicopathological parameters or overall survival (OS) in EAC. A total of seven studies including 1028 patients were subjected to the final analysis. The overall results suggested that overexpression of EGFR was significantly correlated with not only the depth of invasion, lymph node status, and tumors stage of EAC, with a pooled odds ratio of 2.99 (95% confidence interval [CI]: 1.07-8.35; Z = 2.09; P = 0.037), 3.05 (95% CI: 1.77-5.27; Z = 4.00; P < 0.001), and 5.37 (95% CI: 2.49-11.57; Z = 4.29; P < 0.001), respectively, but also the poorer OS with a pooled hazard ratio of 2.20 (95% CI: 1.47-3.31; Z = 3.79; P < 0.001). Overexpression of EGFR correlates with not only the clinicopathological features, but also the worse OS, and it might be useful as a predictive biomarker in clinical practice, yet the clinicopathological and prognostic role of EGFR in EAC still needs further confirmation by well-designed prospective studies. [ABSTRACT FROM AUTHOR]

SUMMARY Few studies have examined the temporal trends of length in newly diagnosed Barrett's esophagus ( BE) and arrived at conflicting results. The aim of this study was to identify whether there has been a change over time in the length of BE at the time of diagnosis. This is a retrospective, single-center, observational study from Houston, Texas on newly diagnosed BE between 2008 and 2013. All cases were defined by the presence of endoscopically visible BE and histologic confirmation of intestinalized columnar epithelium with goblet cells. The length of BE was measured using the Prague classification. We examined temporal changes in 1-year intervals in the length of BE at the time of diagnosis. Both the frequency and mean length of BE at diagnosis seemed to decrease over time from February 2008 to July 2013. The proportion of patients diagnosed with BE ≥3 cm per year declined during the study period, while the proportion of patients with BE ≥1 and <3 cm increased, and those with <1 cm remained stable. The mean age and the gender of patients diagnosed with BE ≥3 cm did not differ significantly by BE length or year of diagnosis. The mean length of newly diagnosed BE may be decreasing as a result of a decline in BE ≥3 cm. These observations cannot be explained by changes in age and gender. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 ( HER2) is overexpressed in a subset of esophageal adenocarcinomas. Frequently, biopsy material is used for evaluation of HER2 status. The aim of the study was to determine if HER2 expression in preoperative endoscopic biopsies is representative for the entire tumor. Preoperative endoscopic biopsies and matched resection specimens were collected from 75 patients who underwent esophagectomy for esophageal adenocarcinoma. Immunohistochemical staining ( IHC) on HER2 and dual-color in situ hybridization ( ISH) were performed. HER2 status was determined by following a clinical algorithm, first determining HER2 overexpression on immunohistochemistry and, when equivocal (2+), determining HER2 amplification on ISH. Seventy-one of 75 (95%) biopsies and 69/75 (92%) resection specimens could be analyzed due to technical failure. HER2 positivity was seen in 18/71 (25%) biopsies and in 15/69 (22%) resection specimens. Overall, HER2 status in the biopsy was concordant with HER2 status in the resection specimen in 94% of cases. Interobserver agreement on IHC scoring for all three observers was 83% in biopsies and 85% in resection specimens. HER2 positivity was detected in 22% of esophageal adenocarcinomas. Although interobserver agreement was moderate, HER2 status of a primary tumor can be reliably determined based on the endoscopically obtained pretreatment biopsy. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 ( HER2) is involved in the malignant progression of several human cancers, including esophageal adenocarcinoma ( EAC). The purpose of this study was to evaluate HER2 overexpression and to explore the feasibility of confocal laser endomicroscopy for in vivo molecular imaging of HER2 status in an animal model of Barrett's-related EAC. Rats underwent esophagojejunostomy with gastric preservation. At 30 weeks post-surgery, the esophagus of 46 rats was studied; endoscopic and histological findings were correlated with HER2 immunofluorescence on excised biopsies and gross specimens. At this age, 23/46 rats developed Barrett's esophagus ( BE), and 6/46 had cancer (four EAC and two squamous cell carcinomas). A significant overexpression of HER2 was observed in esophageal adenocarcinoma compared with normal squamous esophagus (9.4-fold) and BE (6.0-fold). AKT and its phosphorylated form were also overexpressed in cancer areas. Molecular imaging was performed at 80 weeks post-surgery in four rats after tail injection of fluorescent-labeled anti- HER2 antibody. At this age, 3/4 rats developed advance adenocarcinoma and showed in vivo overexpression of HER2 by molecular confocal laser endomicroscopy with heterogeneous distribution within cancer; no HER2 signal was observed in normal or Barrett's tissues. Therefore, HER2 overexpression is a typical feature of the surgical induced model of EAC that can be easily quantified in vivo using an innovative mini-invasive approach including confocal endomicroscopy; this approach may avoid limits of histological evaluation of HER2 status on 'blinded' biopsies. [ABSTRACT FROM AUTHOR]

The association between Barrett's esophagus ( BE) and a personal or family history of cancer other than gastroesophageal remains unknown. To evaluate the effect of personal and family history of certain cancers and cancer treatments on the risk of BE, we analyzed data from a Veterans Affairs case-control study that included 264 men with definitive BE (cases) and 1486 men without BE (controls). Patients with history of esophageal or gastric cancer were excluded. Patients underwent elective esophagogastroduodenoscopy or a study esophagogastroduodenoscopy concurrently with screening colonoscopy to determine BE status. Personal and family history of several types of cancer was obtained from self-reported questionnaires, supplemented and verified by electronic medical-record reviews. We estimated the association between personal and family history of cancer or radiation/chemotherapy, and BE. Personal history of oropharyngeal cancer (1.5% vs. 0.4%) or prostate cancer (7.2% vs. 4.4%) was more frequently present in cases than controls. The association between BE and prostate cancer persisted in multivariable analyses (adjusted odds ratio 1.90; 95% confidence interval 1.07-3.38, P = 0.028) while that with oropharyngeal cancer (adjusted odds ratio 3.63; 95% confidence interval 0.92-14.29, P = 0.066) was attenuated after adjusting for retained covariates of age, race, gastroesophageal reflux disease, hiatal hernia, and proton pump inhibitor use. Within the subset of patients with cancer, prior treatment with radiation or chemotherapy was not associated with BE. There were no significant differences between cases and controls in the proportions of subjects with several specific malignancies in first- or second-degree relatives. In conclusion, the risk of BE in men may be elevated with prior personal history of oropharyngeal or prostate cancer. However, prior cancer treatments and family history of cancer were not associated with increased risk of BE. Further studies are needed to elucidate if there is a causative relationship or shared risk factors between prostate cancer and BE. [ABSTRACT FROM AUTHOR]

The incidence of esophageal adenocarcinoma has increased dramatically over recent years and Barrett's esophagus is considered the most established risk factor for its development. Endoscopic surveillance of Barrett's esophagus is therefore recommended but hinges on histological interpretation of randomly taken biopsies which is poorly reproducible. The use of biomarkers presents an opportunity to improve our ability to risk-stratify these patients.We examined three biomarkers namely p504s, CD133, and Twist in the setting of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma to evaluate differential expression between benign, dysplastic, and malignant Barrett's tissue in an exploratory cross-sectional study. Twenty-five cases each of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma were included along-with 25 cases of esophagectomy resections for Barrett's adenocarcinoma. The biomarkers were immunostained on automated Ventana® immunostainer. The biopsies were assessed for biomarker expression by two independent observers. Granular cytoplasmic staining of p504s was observed in dysplastic Barrett's biopsies and esophageal adenocarcinoma but not in Barrett's esophagus. Apical and membranous CD133 expression was also observed in dysplastic Barrett's and esophageal adenocarcinoma. Nuclear Twist expression was seen predominantly in stromal cells. There was increased p504s expression in dysplastic Barrett's esophagus and esophageal adenocarcinoma compared with controls. CD133 expression was detected for the first time in esophageal adenocarcinoma and dysplastic Barrett's esophagus. Twist expression was not convincing enough to be labeled as Barrett's biomarker. p504s and CD133 have the potential to differentiate benign from malignant Barrett's tissue in this exploratory study. Their validity should be established in prospective longitudinal studies. [ABSTRACT FROM AUTHOR]

Barrett's esophagus ( BE) arising from chronic gastro-oesophageal reflux ( GERD) is the main pathologic precursor of esophageal adenocarcinoma ( EAC). The risk of progression to high-grade dysplasia ( HGD) and EAC is unclear, and recent population studies from Denmark and Northern Ireland suggest that this has been overestimated in the past. No data exist from the Republic of Ireland. A detailed clinical, endoscopic, and pathologic database was established in one center as a proposed pilot for a national registry, and initial and follow-up data were abstracted by a data manager. One thousand ninety-three patients were registered, 60 patients with HGD were excluded, leaving 1033, with a median age of 59 and 2 : 1 male to female ratio, and 3599 person-years of follow-up. The overall incidence of HGD/ EAC was 1.33% per year overall, 0.85% if the first year is excluded. Within the first year after index endoscopy, 18 cases of HGD or EAC were identified, and 30 following the first year. Low-grade dysplasia ( LGD) on index endoscopy was associated with an incidence of progression of 6.5% per year, and 3.1% when tertiary referrals were excluded. These data provide important demographic and clinical information on the population of Irish patients with BE, with incidence rates of progression higher than recently published population-based registry series, perhaps relating to sampling and pathological assessment. Low-grade dysplasia on initial biopsy is a significant proxy marker of risk of progression. [ABSTRACT FROM AUTHOR]

Human esophageal adenocarcinoma ( EAC) cell lines have made a substantial contribution to elucidating mechanisms of carcinogenesis and drug discovery. Model research on EAC relies almost entirely on a relatively small set of established tumor cell lines because appropriate animal models are lacking. Nowadays, more than 20% of all fundamental translational research studies regarding EAC are partially or entirely based on these cell lines. The ready availability of these cell lines to investigators worldwide have resulted in more than 250 publications, including many examples of important biomedical discoveries. The high genomic similarities (but certainly not completely identical) between the EAC cell lines and their original tumors provide rational for their use. Recently, in a collaborative effort all available EAC cell lines have been verified resulting in the establishment of a reliable panel of 10 EAC cell lines. It could be expected that the value of these cell lines increases as unlimited source of tumor material because new biomedical techniques require more tumor cells and the supply of viable tumor cells is diminishing because of neoadjuvant chemo(radio)therapy of patients with EAC. Here, we review the history of the EAC cell lines and their utility in translational research and biomedical discovery. [ABSTRACT FROM AUTHOR]

Risk factors driving sex disparity in esophageal cancer are unclear. Recent molecular evidence suggests hormonal factors. We conducted a national descriptive epidemiological study to assess the hypothesis that estrogen exposure could explain the male predominance in observed esophageal adenocarcinoma incidence. We analyzed the esophageal cancer incidence trends by histology and sex from 1973 to 2008 in nine population-based cancer registries of the Surveillance, Epidemiology, and End Results ( SEER) 9 Registry Database. We used age as a proxy for estrogen exposure in females. The collective age groups annual percentage change in esophageal adenocarcinoma for females is positive (0.03%; 95% confidence interval: 0.02, 0.03%) during the study period. Interestingly, the esophageal adenocarcinoma annual percentage change in incidence rates for females during the same time period is significantly negative from ages 50-54 to ages 60-64. Even though the incidence of esophageal adenocarcinoma rises in both males and females, the male-to-female ratio across age peaks in the 50-54 years then decreases. Furthermore, the esophageal adenocarcinoma age-adjusted incidence rate in postmenopausal females age 80 and above increases with age unlike their male counterparts. Taken together, these data support the hypothesis that the endocrine milieu in pre- and perimenopausal females serves as a protective factor against esophageal adenocarcinoma, and with loss of estrogen or because of the increasing time period away from estrogen exposure, the rate of esophageal adenocarcinoma incidence increases in the older postmenopausal female. Because females comprise the largest portion of the elderly population with esophageal adenocarcinoma, these findings are significant. [ABSTRACT FROM AUTHOR]

Universal agreement on the inclusion of intestinal metaplasia to diagnose Barrett's esophagus ( BE) is lacking. Our aim was to determine the association of intestinal metaplasia and its density with the prevalence of dysplasia/cancer in columnar lined esophagus ( CLE). Patients with CLE but no intestinal metaplasia ( CLE-no IM) were identified by querying the clinical pathology database using SNOMED codes for distal esophageal biopsies. CLE-IM patients were identified from a prospectively maintained database of BE patients. Subsequently, relative risks for prevalent dysplasia and cancer were calculated. Since patients with CLE-no IM are not usually enrolled in surveillance, only prevalent dysplasia/cancer on index endoscopy was analyzed. Goblet cell density and percent intestinal metaplasia were estimated. All biopsy slides were reviewed for dysplasia by two experienced gastrointestinal pathologists. Two hundred sixty-two CLE-IM and 260 CLE-no IM patients were included (age 64 ± 12 vs. 60 ± 11 years, P = 0.001; whites 92% vs. 82%, P = 0.001; males 99.7% vs. 99.3%, P = NS; CLE length 3.4 ± 3.2 vears 1.4 ± 0.4 cm, P = 0.001 and hiatus hernia 64% vs. 56%, P = 0.013). The odds of finding low-grade dysplasia and of high-grade dysplasia ( HGD)/cancer were 12.5-fold (2.9-53.8, P = 0.007) and 4.2-fold (95% CI 1.4-13, P = 0.01) higher, respectively, in the CLE-IM group. Reanalysis after controlling for important variables of age, race, and length did not significantly alter the overall results. In CLE-IM group, when patients with high (>50/ LPF) versus low goblet cell density (<50/ LPF) and <10% versus >10% intestinal metaplasia were compared, the odds of HGD/cancer, OR 1.5 (0.5-4.9, P = 0.5) and 1.97 (0.54-7.22), respectively, were not significantly higher. Demonstration of intestinal metaplasia continues to be an essential element in the definition of BE, but its quantification may not be useful for risk stratification of HGD/cancer in BE. [ABSTRACT FROM AUTHOR]

To evaluate the relationship of H elicobacter pylori and cytotoxin-associated gene A ( CagA) positive strains with esophageal neoplasm, including esophageal adenocarcinoma ( EAC) and esophageal squamous cell carcinoma ( ESCC), the authors conducted a meta-analysis using a predefined protocol. Pub Med, Web of Science, China biology medical literature database, Wanfang, and China National Knowledge Infrastructure were searched for relevant articles from the first available year to April 8, 2013. The fixed or random effect pooled measure was selected based on heterogeneity among studies, which was evaluated using Q test and the I2 of Higgins and Thompson. Metaregression was used to explore the sources of between-study heterogeneity. Publication bias was analyzed by Begg's funnel plot and Egger's regression test. The association was assessed by odds ratio ( OR) with 95% confidence interval ( CI). A total of 28 eligible studies were included in the meta-analysis. There was a significant inverse association between H . pylori infection (pooled OR, 0.57; 95% CI, 0.44-0.73) and EAC; CagA-positive H . pylori strains were less likely to be associated with EAC compared with CagA-negative strains (pooled OR, 0.64; 95% CI, 0.52-0.79). However, there was no statistically significant association between H . pylori/ CagA-positive H . pylori strains infection and ESCC, and the pooled ORs were 1.16 (95% CI, 0.83-1.60) and 0.97 (95% CI, 0.79-1.19). But significant associations between CagA-positive H . pylori strains infection and ESCC risk were found in the stratified analysis of the study location ( Asian and non- Asian), and the summary ORs were 0.74 (95% CI, 0.57-0.97) and 1.41 (95% CI, 1.02-1.94). H . pylori infection and CagA-positive strains are associated with decreased risk of EAC in the overall population. No significant association was found between H . pylori infection/ CagA-positive strains and ESCC. But CagA-positive strains might have a positive association with ESCC in non- Asian population and an inverse association in Asian population. [ABSTRACT FROM AUTHOR]

This study looks at toxicity and survival data when chemoradiation ( CRT) is delivered using intensity-modulated radiation therapy ( IMRT) after induction chemotherapy. Forty-one patients with esophageal adenocarcinoma treated with IMRT from March 2007 to May 2009 at Memorial Sloan- Kettering Cancer Center were analyzed. All patients received induction chemotherapy prior to CRT. Thirty-nine percent ( n = 16) of patients underwent surgical resection less than 4 months after completing CRT. Patients were predominantly male (78%), with a median age of 68 years (range 32-85 years). The majority of acute treatment-related toxicity was hematologic or gastrointestinal, with 17% of patients having grade 3+ hematologic toxicity and 12% of patients having grade 3+ gastrointestinal toxicity. Only two patients developed grade 2-3 pneumonitis (5%) and 5 patients experienced post-operative pulmonary complications (29%). Eight patients (20%) required a treatment break. With a median follow up of 41 months for surviving patients, 2-year overall survival was 61%, and the cumulative incidences of local failure ( LF) and distant metastases were 40% and 51%, respectively. This rate of LF was reduced to 13% in patients who underwent surgical resection. Surgery and younger age were significant predictors of decreased time to LF on univariate analysis. Induction chemotherapy followed by CRT using IMRT in the treatment of esophageal cancer is well tolerated and is not associated with an elevated risk of postoperative pulmonary complications. The use of IMRT may allow for integration of more intensified systemic therapy or radiation dose escalation for esophageal adenocarcinoma, ultimately improving outcomes for patients with this aggressive disease. [ABSTRACT FROM AUTHOR]