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Contains fulltext : 203159.pdf (Publisher’s version ) (Closed access) BACKGROUND AND AIMS: Barrett's esophagus (BE) screening is currently not considered to be cost effective in the general population but may be effective in high-risk subgroups, such as 50-year-old white men with chronic reflux disease (GERD). A new modality for screening is unsedated transnasal endoscopy using endosheath technology (uTNE), which has been shown to be safe and effective in clinical practice. In this study, we determined the cost-utility of uTNE in a high-risk subgroup compared with no screening or screening with standard endoscopy. METHODS: A Markov model was used to simulate screening of 50-year-old white men with symptoms of GERD with either uTNE or standard endoscopy compared with no screening, over a lifetime horizon. Input variables were based on the literature and recent data on uTNE screening for BE. The study was designed from a healthcare payer perspective by using direct costs. Primary outcome measures were costs, quality-adjusted life years (QALYs), and the incremental cost-utility ratio (ICUR) of uTNE and standard endoscopy compared with no screening. Sensitivity analysis was performed for several factors, such as prevalence of BE. RESULTS: Costs of uTNE, standard endoscopy, and no screening were estimated at, $2495, $2957, and $1436, respectively. Compared with no screening, uTNE screening resulted in an overall QALY increase of 0.039 (95% percentile 0.018; 0.063) and an ICUR of $29,446 per QALY gained (95% confidence interval [CI], 18.516-53.091), whereas standard endoscopy compared with no screening resulted in a QALY increase of 0.034 (95% CI, 0.015-0.056) and an ICUR of $47,563 (95% CI, 31,036-82,970). CONCLUSION: Both uTNE and standard endoscopy seem to be cost-effective screening methods in a screening cohort of 50-year-old white men with GERD at a willingness-to-pay cutoff of $50,000.

Contains fulltext : 203172.pdf (Author’s version postprint ) (Open Access) BACKGROUND & AIMS: The risk of esophageal adenocarcinoma (EAC) in patients with non-dysplastic Barrett's esophagus (NDBE) is low, so there is debate over the role of ongoing surveillance for patients with NDBE. It is important to identify patients at low risk for progression. We assessed cancer risk based on the subsequent number of endoscopies showing persistence of NDBE in a nationwide study in the Netherlands. METHODS: In a population-based study, patients with a first diagnosis of NDBE were selected from the Dutch nationwide registry of histopathology. We calculated incidence rates and incidence rate ratios (IRR) for high-grade dysplasia (HGD) and EAC to determine whether the number of endoscopies negative for dysplasia and the persistence of NDBE over time associate with progression to malignancy. RESULTS: We identified 12,728 patients with NDBE during 2003 and 2013. HGD or EAC developed in 436 patients (3.4%) during 64,537 person-years of follow up (median, 4.9 years). The rate of progression to HGD or EAC was 0.68 (95% CI, 0.61-0.74) per 100 person-years. In patients with 2 consecutive endoscopies showing NDBE, the rate of progression to HGD or EAC decreased to 0.55 (95% CI, 0.46-0.64) per 100 person-years (IRR, 0.72; 95% CI, 0.60-0.87). Overall, the incidence of HGD or EAC decreased by 14% for each year of progression-free follow-up (IRR, 0.86; 95% CI, 0.81-0.92). CONCLUSION: In a population-based study in the Netherlands, we found patients with stable NDBE to have a low risk of progression to HGD or EAC. These findings indicate that surveillance intervals might be lengthened or even discontinued in subgroups patients with persistent NDBE.

Background and purpose: Neoadjuvant chemoradiotherapy (nCRT) improves survival in esophageal cancer (EC) patients, but the response to treatment is heterogeneous and little is known regarding prognostic and predictive markers in these patients. CD44, SOX2 and SHH have been implicated in resistance to CRT, possibly through an association with a cancer stem cell phenotype.Material and methods: 101 EC patients treated with nCRT and surgery were included. Sufficient pretreatment biopsy material was present in 71 patients, of which 53 patients were non-complete responders on nCRT (nCR). Protein expression was examined using immunohistochemistry (IHC). Prognostic factors were determined using Cox regression analysis for disease free survival (DFS) and cause specific survival (CSS) in the complete cohort, the pre-treatment biopsies group and post-treatment nCR group.Results: Low CD44 expression in the nCR group was an independent prognostic factor for both DFS and CSS (DFS HR 2.81, p = 0.002 and CSS HR 3.48, p = 0.002). Absent SOX2 expression in pretreatment biopsies was related to systemic recurrence (p = 0.029) while low,SHH in pretreatment biopsies was an independent prognostic factor for a poor DES (HR 2.27, p = 0.036). No relation between marker expression and response to nCRT was observed.Conclusions: Low expression of CD44 and SHH are associated with a poor survival outcome in EC patients treated with nCRT. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Background: Barrett's oesophagus can progress towards oesophageal adenocarcinoma through a metaplasia-dysplasia-carcinoma sequence, but the underlying mechanisms are poorly understood. The transcription factor GATA6 is known to be involved in columnar differentiation and proliferation, and GATA6 gene amplification was recently linked with poor survival in oesophageal adenocarcinoma.Aim: To study the expression of GATA6 during Barrett's oesophagus development and malignant transformation. To determine the prognostic value of GATA6 in oesophageal adenocarcinoma.Methods: Two retrospective cohorts were derived from the pathological archive of the University Medical Center Groningen. The first cohort contained 130 tissue samples of normal squamous epithelium, metaplasia, dysplasia and oesophageal adenocarcinoma. The second cohort consisted of a tissue microarray containing tissue from 92 oesophageal adenocarcinoma patients. Immunohistochemistry was used to examine GATA6 protein expression and to correlate GATA6 expression in oesophageal adenocarcinoma with overall and disease-free survival.Results: The percentage of GATA6-positive cells was low in squamous epithelium (10%) but increased progressively in Barrett's oesophagus (30%, P Conclusion: GATA6 expression is progressively increased during Barrett's oesophagus development and its malignant transformation. However, no prognostic value of GATA6 expression could be found in oesophageal adenocarcinoma. (C) 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Background. It has been suggested that markers associated with cancer stem cells (CSC) may play a role in esophageal cancer. Our aim was to investigate the expression pattern of proposed CSC markers ALDH1, Axin2, BMI1, CD44, and SOX2 in esophageal adenocarcinoma (EAC) and to relate their expression to survival.Methods. In this study we included 94 EAC patients and examined the expression of the above-mentioned markers by using immunohistochemistry on tissue microarrays. Expression was scored as positive or negative or categorized as low or high in terms of an immunoreactivity score (IRS). Expression rates were related to clinicopathologic characteristics and overall and disease-free survival (DFS).Results. In a multivariate analysis, negative expression of CD44 and of SOX2 were both significant prognostic factors for DFS [hazard ratio (HR), 1.73; 95 % confidence interval (CI), 1.00-2.96; P = 0.046 and HR, 2.06; 95 % CI 1.14-3.70 P = 0.016). When CD44 and SOX2 expression were analyzed together, negative SOX2 expression was an independent prognostic factor for DFS (HR, 1.91; 95 % CI 1.05-3.46; P = 0.034). Low IRS scores for ALDH1 or Axin2 were associated with a reduced median survival (12.8 vs. 28.7 and 12.1 vs. 25.5 months, respectively). However, these markers and BMI1 were not prognostic factors for survival.Conclusions. Loss of CD44 expression and loss of SOX2 expression are prognostic factors of poor survival in EAC patients. This suggests a role of these proteins in EAC that requires further investigation.

Background: To detect anastomotic leakage after esophagectomy in esophageal carcinoma patients, many surgeons perform a radiological contrast examination routinely. The aim of this retrospective study is to determine the clinical relevance of a routine contrast examination after esophagectomy and to evaluate criteria for contrast examination on demand. Methods: Data were obtained from 211 patients with cancer of the esophagus or gastro-esophageal junction who underwent an esophagectomy during the period 1991–2004. Retrospectively, we analyzed patients regarding anastomosis-related characteristics and clinical signs including sepsis, fever � 39.08C, leukocytosis � 20 � 10 9 /ml and pleural effusion. Results: Anastomotic leakage had appeared in 35 of the 211 patients. The clinical signs sepsis (odds ratio (OR) 6.72: 95% confidence interval (CI) (2.57–17.56); P < 0.0001), leukocytosis (OR 2.62 (1.10–6.22); P < 0.030), and fever (OR 2.34 (1.01–5.42); P < 0.047) were significantly related to anastomotic leakage. Pleural effusion was not significantly related to anastomotic leakage (OR 2.83 (0.98–8.13); P ¼ 0.054). Conclusion: Our study suggests that the clinical value for a routinely performed contrast examination is debatable. We recommend performing a contrast examination based on clinical suspicion and clinical signs of anastomotic leakage including sepsis, fever � 39.08C and leukocytosis � 20 � 10 9 /ml. J. Surg. Oncol. 2009;100:699–702. 2009 Wiley-Liss, Inc.

We compared retrospectively carboplatin/paclitaxel to cisplatinum/5-FU as dCRT treatment in esophageal cancer patients. We found comparable outcome, but lower toxicity rates and higher treatment compliance in the carboplatin/paclitaxel group. Therefore, we suggest carboplatin/paclitaxel as an alternative for cisplatinum/5-FU is a good candidate for further evaluation.In esophageal cancer (EC) patients who are not eligible for surgery, definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5-fluorouracil (5-FU) is the standard chemotherapy regimen. Nowadays carboplatin/paclitaxel is also often used. In this study, we compared survival and toxicity rates between both regimens.This multicenter study included 102 patients treated in five centers in the Northeast Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU (75 mg/m(2) and 1 g/m(2)) and 55 patients carboplatin/paclitaxel (AUC2 and 50 mg/m(2)).Overall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group {[P = 0.879, hazard ratio (HR) 0.97 [confidence interval (CI) 0.62-1.51]}, with a median survival of 16.1 (CI 11.8-20.5) and 13.8 months (CI 10.8-16.9). Median disease-free survival (DFS) was comparable [P = 0.760, HR 0.93 (CI 0.60-1.45)] between the cisplatinum/5-FU group [11.1 months (CI 6.9-15.3)] and the carboplatin/paclitaxel group [9.7 months (CI 5.1-14.4)]. Groups were comparable except clinical T stage was higher in the carboplatin/paclitaxel group (P = 0.008). High clinical T stage (cT4) was not related to OS and DFS in a univariate analysis (P = 0.250 and P = 0.201). A higher percentage of patients completed the carboplatin/paclitaxel regimen (82% versus 57%, P = 0.010). Hematological and nonhematological toxicity (>= grade 3) in the carboplatin/paclitaxel group (4% and 18%) was significantly lower than in the cisplatinum/5-FU (19% and 38%, P = 0.001).In this study, we showed comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared with cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment of cisplatinum/5-FU is a good candidate regimen for further evaluation.

To detect anastomotic leakage after esophagectomy in esophageal carcinoma patients, many surgeons perform a radiological contrast examination routinely. The aim of this retrospective study is to determine the clinical relevance of a routine contrast examination after esophagectomy and to evaluate criteria for contrast examination on demand.Data were obtained from 211 patients with cancer of the esophagus or gastro-esophageal junction who underwent an esophagectomy during the period 1991-2004. Retrospectively, we analyzed patients regarding anastomosis-related characteristics and clinical signs including sepsis, feveror = 39.0 degrees C, leukocytosisor = 20 x 10(9)/ml and pleural effusion.Anastomotic leakage had appeared in 35 of the 211 patients. The clinical signs sepsis (odds ratio (OR) 6.72: 95% confidence interval (CI) (2.57-17.56); P0.0001), leukocytosis (OR 2.62 (1.10-6.22); P0.030), and fever (OR 2.34 (1.01-5.42); P0.047) were significantly related to anastomotic leakage. Pleural effusion was not significantly related to anastomotic leakage (OR 2.83 (0.98-8.13); P = 0.054).Our study suggests that the clinical value for a routinely performed contrast examination is debatable. We recommend performing a contrast examination based on clinical suspicion and clinical signs of anastomotic leakage including sepsis, feveror = 39.0 degrees C and leukocytosisor = 20 x 10(9)/ml.

26 Background: Barrett’s metaplasia is characterized by the presence of a columnar metaplastic epithelium in the esophagus. Barrett’s metaplasia can show malignant progression towards esophageal adenocarcinoma by a metaplasia-dysplasia-carcinoma sequence. The underlying mechanisms of Barrett’s metaplasia development and malignant progression are poorly understood. The transcription factor GATA-6 is known to be involved in columnar differentiation and carcinogenesis. GATA6 gene amplification was recently linked with aggressiveness in esophageal adenocarcinoma. Here, we studied GATA6 protein expression in normal squamous, metaplastic, dysplastic and esophageal adenocarcinoma tissues in order to identify a possible role of GATA-6 in the development and malignant progression of Barrett’s metaplasia. Methods: Samples of squamous epithelium (N=37), Barrett’s non-intestinal metaplasia (N=16), Barrett’s intestinal metaplasia (N=29), high-grade dysplasia (N= 39), in situ esophageal adenocarcinoma (N=29) and an esophageal adenocarcinoma tissue microarray (N=95) were stained with a polyclonal antibody against GATA6. Staining intensity was categorized as absent, weak, normal or strong. Scoring was performed by two independent observers and validated by a pathologist. Results: GATA6 expression was absent in squamous epithelium but expressed in all samples of Barrett’s metaplasia, preferentially in the lower half of the crypt. Expansion of GATA6-positive cells throughout the crypt was observed in high-grade dysplasia. While all cases of in situ esophageal adenocarcinoma showed GATA6 expression we observed complete loss of GATA6 expression in 17% of esophageal adenocarcinoma samples. Conclusions: GATA6 is absent in squamous epithelium but its expression increases along the metaplasia-dysplasia carcinoma sequence. GATA6 expression remains predominantly present in esophageal adenocarcinoma, however, its expression is lost in a subset of samples. Analysis of the relation between GATA6 expression and clinicopathological characteristics in esophageal adenocarcinoma is pending.

104 Background: In esophageal cancer (EC) patients not eligible for surgery definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5-fluorouracil (5-FU) is the standard regime. Nowadays carboplatin and paclitaxel are also often used. In this study we compared survival and toxicity rates between both regimens. Methods: This multicentre study included 102 patients treated in five centres in the North Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU and 55 patients carboplatin/paclitaxel. Results: Overall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group (P=0.879, Hazard Ratio [HR] 0.97 confidence interval [CI] 0.62-1.51), with a median survival of respectively 16.1 (CI 11.8-20.5) and 13.8 (CI 10.8-16.9) months. Median disease free survival (DFS) was comparable (P=0.760, HR 0.93 CI 0.60-1.45) between the cisplatinum / 5-FU group (11.1 months, CI 6.9-15.3) and the carboplatin/paclitaxel group (9.7 months, CI 5.1-14.4). Groups were comparable except clinical T-stage was higher in the carboplatin/paclitaxel group (P=0.008), but a high clinical T-stage (cT4) was not related to OS and DFS in a univariate analysis (P=0.250 and P=0.201). A higher percentage of patients completed the carboplatin / paclitaxel regimen (82% compared to 57%, P=0.01). Hematological and non-hematological toxicity (≥ grade 3) was significantly lower in the carboplatin / paclitaxel group (4% and 18%) than in the cisplatinum/5-FU (19% and 38%, P=0.001). Conclusions: In this study we show comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared to cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with a higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment for cisplatinum/5-FU is a good candidate regimen for further evaluation.

Introduction: Cancer stem cells (CSC) are characterized by stem cell properties such as self-renewal potential and multilineage differentiation capacity. CSC's are thought to be the main drivers of tumor formation and progression and the main cause of therapy resistance and metastatic spread. In contrast to other cancer types such as glioblastoma and colon cancer, attempts thus far have not resulted in the identification of a proven CSC population in esophageal cancer. Therefore in this study we aim to identify and characterize CSC's in esophageal adenocarcinoma (EAC). Methods and Results: To address this goal, we attempted to culture CSC's from primary untreated EAC biopsy material using serum-free medium formulations that, however, have not been successful thus far. As an alternative model we employed two EAC cell lines, OE19 and OE33, which we were able to maintain as spheroids in serum-free Neural Basal Medium thought to enrich for stem cell growth. Dissociation of spheres and limiting dilution assays showed enhanced spheroid forming potential in OE19 but not in OE33 when compared to cells obtained from normal 10% FCS monolayer cultured counterparts. Next, the expression of several known CSC markers was determined by FACS analysis to determine self-renewal potential of sorted fractions in subsequent limited dilution assays. Side population, ALDH1, CD44/CD24 fractions were tested of which only CD44+ /CD24+ cells showed enhanced capacity to form spheroids. Tumor growths of these populations are currently being evaluated on immune-compromised mice. Other stem cell markers such as OCT4 and SOX2 were enhanced in OE19 spheroids compared to 10% FCS cultured cells. However, in OE33 spheroids expression of these markers were unchanged or downregulated. Since EAC derives from dysplastic epithelia with intestinal characteristics in Barrett's esophagus, we examined the status of the Wnt pathway known to be involved in maintenance of intestinal/ colon (cancer) stem cells. In the EAC cells β-catenin expression was present that could be enhanced by LiCl. Reporter assays to determine Wnt- activity are in progress. Finally, the sensitivity of spheroid versus monolayer cultured OE33 cells to 5-FU, cisplatin and paclitaxel was evaluated. Sensitivity did not differ much, although monolayer cultured OE33 cells were more resistant for 5-FU. Conclusion: Given the differences in the two spheroid models regarding spheroid forming potential, CSC-marker expression and chemosensitivity, caution is warranted when using esophageal adenocarcinoma cell line derived spheroids as model for CSC's. However, CD44 and CD24 might have a potential as CSC-markers in EAC, which is currently further corroborated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5360. doi:1538-7445.AM2012-5360

In esophageal cancer, circumferential resection margins (CRMs) are considered to be of relevant prognostic value, but a reliable definition of tumor-free CRM is still unclear. The aim of this study was to appraise the clinical prognostic value of microscopic CRM involvement and to determine the optimal limit of CRM.To define the optimal tumor-free CRM we included 98 consecutive patients who underwent extended esophagectomy with microscopic tumor-free resection margins (R0) between 1997 and 2006. CRMs were measured in tenths of millimeters with inked lateral margins. Outcome of patients with CRM involvement was compared with a statistically comparable control group of 21 patients with microscopic positive resection margins (R1).A cutoff point of CRM at a parts per thousand currency sign1.0 mm and > 1.0 mm appeared to be an adequate marker for survival and prognosis (both P 0 mm was equal to that in patients with CRM of 0 mm (P = 0.43). CRM involvement was an independent prognostic factor for both recurrent disease (P = 0.001) and survival (P Involvement of the circumferential resection margins is an independent prognostic factor for recurrent disease and survival in esophageal cancer. The optimal limit for a positive CRM is a parts per thousand currency sign1 mm and for a free CRM is > 1.0 mm. Patients with unfavorable CRM should be approached as patients with R1 resection with corresponding outcome.