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To evaluate the incidence, treatment and postoperative outcomes of an acute hiatal hernia (HH) after totally minimally invasive esophagectomy (tMIE) for oesophageal cancer. The incidence and treatment of acute HH were analysed from our prospective database including all patients that were surgically treated for oesophageal cancer in the period between January 2011 and December 2018. Within the study period, the database contained 307 patients that underwent minimally invasive oesophagectomy. Patients’ characteristics were in line with the literature of Western data. The incidence of acute HH was 2.6% (N = 8). All patients presented with gastro-intestinal obstruction symptoms, that required acute operation, repositioning of the intrathoracic organs in combination with a crural repair. Mesh reinforcement was used in 38% (N = 3). In two patients, the intestines were partially resected due to ischemia. Postoperative complications, as atrial fibrillation, respiratory failure and anastomotic leakage, were seen in 63% (N = 5). Recurrence-rate was 38% (N = 3). This present study demonstrates that an acute HH after tMIE is a serious complication with an incidence of 2.6%. When symptomatic and acute, HH requires surgical intervention and has high postoperative morbidity and recurrence-rate. Therefore, this requires treatment in a centre specialised in oesophageal surgery.

Background: Isolated local recurrent or persistent esophageal cancer (EC) after curative intended definitive (dCRT) or neoadjuvant chemoradiotherapy (nCRT) with initially omitted surgery, is a potential indication for salvage surgery. We aimed to evaluate safety and efficacy of salvage surgery in these patients. Material and methods: A systematic literature search following PRISMA guidelines was performed using databases of PubMed/Medline. All included studies were performed in patients with persistent or recurrent EC after initial treatment with dCRT or nCRT, between 2007 and 2017. Survival analysis was performed with an inverse-variance weighting method. Results: Of the 278 identified studies, 28 were eligible, including a total of 1076 patients. Postoperative complications after salvage esophagectomy were significantly more common among patients with isolated persistent than in those with locoregional recurrent EC, including respiratory (36.6% versus 22.7%; difference in proportion 10.9 with 95% confidence interval (CI) [3.1; 18.7]) and cardiovascular complications (10.4% versus 4.5%; difference in proportion 5.9 with 95% CI [1.5; 10.2]). The pooled estimated 30-and 90-day mortality was 2.6% [1.6; 3.6] and 8.0% [6.3; 9.8], respectively. The pooled estimated 3-year and 5-year overall survival (OS) were 39.0% (95% CI: [35.8; 42.2]) and 19.4% [95% CI:16.5; 22.4], respectively. Patients with isolated persistent or recurrent EC after initial CRT had similar 5-year OS (14.0% versus 19.7%, difference in proportion -5.7, 95% CI [-13.7; 2.3]). Conclusions: Salvage surgery is a potentially curative procedure in patients with locally recurrent or persistent esophageal cancer and can be performed safely after definitive or neoadjuvant chemoradiotherapy when surgery was initially omitted. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

To evaluate the incidence, treatment and postoperative outcomes of an acute hiatal hernia (HH) after totally minimally invasive esophagectomy (tMIE) for oesophageal cancer.The incidence and treatment of acute HH were analysed from our prospective database including all patients that were surgically treated for oesophageal cancer in the period between January 2011 and December 2018.Within the study period, the database contained 307 patients that underwent minimally invasive oesophagectomy. Patients' characteristics were in line with the literature of Western data. The incidence of acute HH was 2.6% (N = 8). All patients presented with gastro-intestinal obstruction symptoms, that required acute operation, repositioning of the intrathoracic organs in combination with a crural repair. Mesh reinforcement was used in 38% (N = 3). In two patients, the intestines were partially resected due to ischemia. Postoperative complications, as atrial fibrillation, respiratory failure and anastomotic leakage, were seen in 63% (N = 5). Recurrence-rate was 38% (N = 3).This present study demonstrates that an acute HH after tMIE is a serious complication with an incidence of 2.6%. When symptomatic and acute, HH requires surgical intervention and has high postoperative morbidity and recurrence-rate. Therefore, this requires treatment in a centre specialised in oesophageal surgery.

Background: Patients with pathologic limited or no response (pNR) to neoadjuvant chemoradiation (nCRT) are subjected to curative intended esophagectomy with subsequent perioperative morbidity and mortality, but potentially only harm from nCRT. The primary aim of this study was to compare the overall survival (OS) of patients with pNR and patients who underwent primary esophagectomy to evaluate potentially benefits of nCRT in these patients. The secondary aim was to identify predictive clinicopathologic factors for pNR and pathologic complete response (pCR) to nCRT with the goal to preselect these patients before the start of treatment.Methods: From the period 2005 to 2016, 206 esophageal cancer (EC) patients treated with Carboplatin/Paclitaxel and radiotherapy with complementary esophagectomy were included in this cohort. OS of patients with pNR was compared with a historical cohort of primary surgically treated patients (n=218) after a propensity score matching resulting in a group of 68 patients with pNR after nCRT versus a group of 68 primary esophagectomy patients.Results: The OS in the pNR group and the primary esophagectomy group was comparable (P=0.986). No predictive factors were found in this cohort for pNR. Female gender (OR 2.5, 95% CI 1.2-5.3) and squamous cell carcinoma (SCC) (OR 2.6, 95% CI 1.3-5.3) were identified as independent predictive factors for pCR.Conclusions: Patients with a pNR do not benefit from nCRT followed by resection. These patients had a similar OS as those who had a primary esophagectomy alone. Although this indicates that nCRT does not negatively impact the OS of patients with pNR, patients still have an increased morbidity because of nCRT. Hence, it is important to identify factors that predict pNR. The ability to predict pNR (and pCR) will enable tailored and personalized care preventing unnecessary nCRT with increased morbidity.

Esophageal cancer (EC) is an aggressive disease with a poor prognosis. Treatment resistance is a major challenge in successful anti-cancer therapy. Pathological complete response after neoadjuvant chemoradiation (nCRT) is low, thus requiring therapy optimization. The Hedgehog (HH) pathway has been implicated in therapy resistance, as well as in cancer stemness. This article focusses on the HH pathway as a putative target in the treatment of EC. Immunohistochemistry on HH members was applied to EC patient material followed by modulation of 3D-EC cell cultures, fluorescence-activated cell sorting (FACS), and gene expression analysis after HH pathway modulation. Sonic Hedgehog (SHH) and its receptor Patched1 (PTCH1) were significantly enriched in EC resection material of patients with microresidual disease (mRD) after receiving nCRT, compared to the control group. Stimulation with SHH resulted in an up-regulation of cancer stemness in EC sphere cultures, as indicated by increased sphere formation after sorting for CD44+/CD24− EC cancer stem-like cell (CSC) population. On the contrary, inhibiting this pathway with vismodegib led to a decrease in cancer stemness and both radiation and carboplatin resistance. Our results strengthen the role of the HH pathway in chemoradiotherapy resistance. These findings suggest that targeting the HH pathway could be an attractive approach to control CSCs.

Background. Circumferential resection margins (CRM) for esophageal cancer (EC), defined by the College of American Pathologists (CAP; >0 mm) or the Royal College of Pathologists (RCP; >1 mm) as tumor-free (R0), are based on a surgery-alone approach. We evaluated the usefulness of both definitions in current practice with neoadjuvant chemoradiotherapy (nCRT).Methods. CRMs were measured in 209 patients (104 with nCRT) with locally advanced EC after transthoracic esophagectomy. Local recurrence and cancer related death were scored as events. Patients were followed for at least 2 years or until death. Prognostic factors (P Results. Independent prognostic factors (P Conclusions. nCRT affected the CRM cutoff values. After nCRT, the CRM R0 according to the CAP was only prognostic for 2-year LRFS. However, in the surgery-alone group, it was prognostic for both the 2-year DFS and LRFS.

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. 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.

To analyze the association between pretreatment 18-F-fluoro-deoxyglucose (FDG) uptake and characteristics of aggressive tumor biology in predicting outcome in esophageal cancer (EC).Tumor FDG-uptake was measured by maximum standardized uptake values (SUVmax) in 47 patients undergoing esophagectomy with curative intent. ROC analyses were used to predict an optimal SUVmax cutoff for survival. Expression of hexokinase-II (HK-II), glucose transporter I (GLUT-I), hypoxia inducible factor-1 alpha (HIF-I alpha), vascular endothelial growth factor-C (VEGF-C), p53, and proliferative activity (Ki-67) were correlated with SUVmax values and clinicopathological characteristics.A SUVmax > 3.67 predicted a significantly lower disease-free survival (DFS) and distant recurrence-free survival (p = 0.022 and p = 0.005). High HK-II expression was correlated with reduced SUVmax values (p = 0.002) and was significantly higher in esophageal adenocarcinoma compared with squamous cell carcinoma (p = 0.005). Preoperative high FDG uptake in primary tumors was associated with nodal metastases (pN1; Spearman correlation 0.39, p = 0.01). We found no positive correlation between SUVmax and GLUT-1, HK-1, HIF-I alpha 1, VEGF-C, p53, and Ki-67 expression.High preoperative FDG-uptake strongly predicts poor survival outcome and is associated with lymph node metastases in EC patients. HK-II expression was related to SUVmax and DFS.

BACKGROUND: The risk of tumor progression during neoadjuvant chemoradiotherapy (CRT) in esophageal cancer (EC) is around 8% to 17%. We assessed the efficacy of computed tomography (CT) to identify these patients before esophagectomy.METHODS: Ninety-seven patients with locally advanced EC treated with Carboplatin/Paclitaxel and 41.4 Gy neoadjuvantly were restaged with CT. Two radiologists reviewed pre- and post-CRT CT images. The primary outcome was detection of clinically relevant progressive disease. Missed metastases were defined as metastatic disease found during surgery or within 3 months after post-CRT CT.RESULTS: Progressive disease was detected in 9 patients (9%). Both radiologists detected 5 patients with distant metastases (liver, n = 4; lung metastasis, n = 1), but missed progressive disease in 4 cases. One radiologist falsely assessed 2 metastatic lesions, but after agreement progressive disease was detected with sensitivity and specificity of 56% and 100%, respectively.CONCLUSION: CT is effective in detecting clinically relevant progressive disease in EC patients, after neoadjuvant treatment. (C) 2014 Elsevier Inc. All rights reserved.

Purpose/Objective(s): The aim of this study was to analyze the accuracy of gross tumor volume (GTV) delineation and clinical target volume (CTV) margins for neoadjuvant chemoradiation therapy (neo-CRT) in esophageal carcinoma at pathologic examination and to determine the impact on survival.Methods and Materials: The study population consisted of 63 esophageal cancer patients treated with neo-CRT. GTV and CTV borders were demarcated in situ during surgery on the esophagus, using anatomical reference points to provide accurate information regarding tumor location at pathologic evaluation. To identify prognostic factors for disease-free survival (DFS) and overall survival (OS), a Cox regression analysis was performed.Results: After resection, macroscopic residual tumor was found outside the GTV in 7 patients (11%). Microscopic residual tumor was located outside the CTV in 9 patients (14%). The median follow-up was 15.6 months. With multivariate analysis, only microscopic tumor outside the CTV (hazard ratio [HR], 4.96; 95% confidence interval [CI], 1.03-15.36), and perineural growth (HR, 5.77; 95% CI, 1.27-26.13) were identified as independent prognostic factors for OS. The 1-year OS was 20% for patients with tumor outside the CTV and 86% for those without (PConclusions: Microscopic tumor outside the CTV is associated with markedly worse OS after neo-CRT. This may either stress the importance of accurate tumor delineation or reflect aggressive tumor behavior requiring new adjuvant treatment modalities. (C) 2014 Elsevier Inc.

BACKGROUND: We evaluated the impact of neoadjuvant chemoradiotherapy (CRT) on nodal micro-metastases (NMMs) in esophageal adenocarcinoma (EAC) patients with histologically negative nodes ([y]pN0).METHODS: Of 48 consecutively treated patients with neoadjuvant CRT, we selected 20 EAC ypN0 patients (group 1). These patients were matched with 20 pN0 EAC patients who had surgery alone (group 2). Harvested (y) pN0 lymph nodes were examined immunohistochemically (anti-CK8/18 [CAM 5.2]) according to a validated sentinel node protocol. A 3rd group (n = 11) staged as ypN1 after neoadjuvant CRT was used as the control group.RESULTS: Upstaging to NMM+ occurred in 2 patients (10%) in group 1 and in 8 patients (40%) in group 2 (P = .028). Disease-free and overall survival rates in NMM+ patients in group 1 were worse compared with NMM- patients (P = .014 and P = .003, respectively) but comparable with ypN1 patients (n = 11).CONCLUSIONS: A 30% reduction of NMM+ was obtained after neoadjuvant treatment in (y) pN0 patients. NMM+ after CRT had a negative impact on survival in ypN1 patients. These data warrant further investigation in larger prospective datasets. (C) 2013 Elsevier Inc. All rights reserved.

Definitive (chemo)radiotherapy is employed in esophageal cancer patients as an alternative for patients considered medically unfit for surgery or having unresectable tumors. We evaluated a population-based cohort to improve the selection for intensified nonsurgical strategies and to identify prognostic factors.Patients who had squamous cell carcinoma (SCC) or adenocarcinoma (AC) were treated in four referral centers in the north-east Netherlands with definitive chemoradiotherapy (dCRT) or radiotherapy (dRT) between 1996 and 2008.Of the 287 included patients, 110 were treated with dCRT and 177 with dRT. Median overall survival (OS) was 11 months (95 % confidence interval: 10-12 months), with OS of 22 and 8 % and disease-free survival (DFS) of 16 and 5 % at 2 and 5 years, respectively. DFS at 2 and 5 years was 24 and 9 % for SCC versus 10 and 2 % for AC patients (P = 0.006). OS after 2 and 5 years was 29 and 14 % for SCC patients versus 17 and 3 % for AC patients (P = 0.044). On multivariate Cox regression, SCC was an independent prognostic factor for DFS [P = 0.020, hazard ratio (HR) = 0.71] and OS (P = 0.047, HR = 0.76). On matched cohort analysis, DFS was higher in the dCRT group compared with dRT patients (P = 0.016). The locoregional failure rate was lower in the dCRT group and in SCC patients (P = 0.001 and 0.046).Long-term results and the local control rate in SCC patients were better after definitive (chemo)radiotherapy compared with in AC patients. SCC was an independent prognostic factor for survival. Definitive chemoradiotherapy leads to improved local control rate and DFS.

147 Background: Involvement of the circumferential margin (CRM) is an important factor in esophageal cancer (EC) patients. CRM definitions are commonly based on the College of American Pathologists (CAP) at 0 mm and the Royal College of Pathologists (RCP) at >1 mm. We evaluated which CRM definition is useful in current practice with neoadjuvant chemoradiotherapy (CRT) and whether the CRM cut-off value differs after CRT. Methods: We prospectively included 209 patients (104 with CRT) with locally advanced EC (stage II-III), who underwent radical transthoracic esophagectomy. Patients were followed for at least 2 years after surgery or until death. Patients with 5cm), >0.2 L/N+ ratio, angioinvasion and CAP R0. In the surgery group; tumor length, >4 N+, angioinvasion and CAP R0 were independent prognostic factors (P

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.

The effects of intra-arterial injection of different doses of the selective histamine H-3-receptor agonist R-alpha-methylhistamine and the selective histamine H-3-receptor antagonist thioperamide on basal and electrically evoked noradrenaline overflow in the portal vein as well as on mean arterial pressure (MAP) and heart rate (HR) were investigated in permanently instrumented freely moving rats. R-alpha-Methylhistamine (0.01, 0.1 and 1 mu mol/kg) inhibited the evoked noradrenaline overflow up to 43%, the ED(50) value being 0.013 mu mol/kg. Thioperamide (0.1, 0.5 and 1.0 mu mol/kg) antagonized the effect of 1.0 mu mol/kg R-alpha-methylhistamine dose-dependently, evoked overflow returning to control values at 1.0 mu mol/kg of the antagonist; thioperamide alone had no effect on electrically evoked noradrenaline overflow. Basal noradrenaline levels, blood pressure and heart rate were not at all influenced by R-alpha-methylhistamine and thioperamide, alone or in combination. The results clearly show the presence of prejunctional histamine H-3-receptors inhibiting the electrically evoked noradrenaline overflow from vascular sympathetic nerve terminals in the portal vein of freely moving rats.

To evaluate the rate and pattern of recurrences after neoadjuvant chemoradiotherapy (CRT) in esophageal cancer patients.We described survival and differences in recurrences from a single center between neoadjuvant CRT (carboplatin/paclitaxel and 41.4 Gy) and surgery alone for the period 2000-2011. To reduce bias, we performed a propensity score matched analysis.A total of 204 patients were analyzed, 75 treated with neoadjuvant CRT and 129 with surgery alone. The pathologic response to neoadjuvant CRT was 69 % with a complete response rate of 25 %. After matching, baseline characteristics between the groups (both n = 75) were equally distributed. The 3- and 5-year disease-free survival was 53 and 42 % in the neoadjuvant CRT group compared with 24 and 18 % in the surgery-alone group (P = 0.011). After 3 and 5 years' CRT, patients had an estimated locoregional recurrence-free survival of 83 and 73 % compared with 52 and 49 % in the surgery-alone group (P = 0.015). The distant recurrence-free survival was comparable in both groups. Locoregional recurrences were located less in the paraesophageal lymph nodes in the CRT group than in the surgery-alone group, 9 versus 21 %, respectively (P = 0.041). With respect to differences in distant recurrences, we observed more skeletal recurrences in the surgery-alone group compared to CRT, 12 versus 1 % (P = 0.009).The neoadjuvant CRT regimen we used offers a significant improvement in outcome, with a different recurrence pattern compared with surgery alone. This effect is probably due to both the pathologic complete response and eradication of micrometastases in CRT group.

136 Background: The main objective of this study was to develop and validate a method to reconstruct the gross and clinical tumor volume (GTV and CTV) on the esophageal specimen in order to facilitate a good pathologic examination of the original tumor area after neo-adjuvant chemoradiation (CRT). Methods: The GTV and CTV borders of 25 patients were defined by a radiation oncologist on the planning CT in relation to 5 anatomical reference points. After CRT, the GTV and CTV borders were marked in vivo on the esophagus during surgical resection. Finally, the pathologist evaluated the presence of macroscopic and microscopic tumor in- and outside the GTV and CTV. The radiation tumor response was scored according to the standardized 5-tier Mandard classification. Radiation induced side effects were scored as well. Results: The Mandard classification could be scored on basis of the GTV alone in 68% of the cases (N=17). For the other patients (N=8), the GTV and the CTV should both be incorporated for correct evaluation of the tumor response. Five patients (20%) showed complete tumor response (Mandard 1), 68% (N=17) showed partial response (Mandard 2-3) and 12% (N=3) showed hardly any response (Mandard 4-5). In the partial responders, macroscopic tumor was found within the delineated GTV and microscopic tumor remained within the CTV both in 100% of the cases. In two patients (40%) with hardly any response, microscopic tumor was also found outside the CTV. This might be caused by tumor growth during the neo-adjuvant treatment or by geographical miss. Nine patients turned out to have positive lymph nodes. On average 18 (range 8-30) lymph nodes were evaluated per patients. Giant cell reactions, lymphocyte infiltration, and fibrosis, which indicate tumor regression were seen in the CTV and GTV, and were most pronounced in the GTV. Conclusions: This study suggested that demarcation of the GTV and CTV on the esophagus in vivo is important for standardized pathologic evaluation of the esophagus after neo-adjuvant chemoradiation. Furthermore using this method we determined microscopic tumor outside the CTV in 40% of the cases (N=2) of the bad responders (Mandard 4-5), illustrating the importance of our method in this patient category.

BACKGROUND: High recurrence rates determine the dismal outcome in esophageal cancer. We reviewed our experiences and defined prognostic factors and patterns of recurrences after curatively, intended transthoracic esophagectomy.METHODS: Between January 1991 and December 2005, 212 consecutive patients underwent a radical transthoracic esophagectomy with extended 2-field lymphadenectomy. Recurrence rates, survival, and prognostic factors were analyzed (minimal follow-up period, 2 y).RESULTS: Radicality was obtained in 85.6%. The median follow-up period was 26.6 months. The overall recurrence rate at I, 3, and 5 years was 28%, 44%, and 64%, respectively, and locoregional recurrence rate was 17%, 27%, and 43%, respectively. Overall survival rates, including postoperative deaths, were 45% and 34% at 3 and 5 years, respectively. pT stage and lymph node (LN) ratio greater than .20 were independent prognostic factors for survival and recurrences. Radicality was most prognostic for survival, and for N+ greater than 4 positive LN for recurrences.CONCLUSIONS: Radicality and LN ratio are strong prognostic factors. High radicality and adequate nodal assessment are guaranteed by an extended transthoracic approach. (C) 2010 Elsevier Inc. All rights reserved.

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.

83 Background: Definitive (chemo)radiation as primary treatment modality is offered to esophageal cancer (EC) patients, as an alternative for patients considered medically unfit for surgery or having irresectable tumors. We evaluated the results in our cohort to improve selection of patients for intensified non-surgical strategies and to identify which clinical factors have a prognostic impact on the overall (OS) and disease free survival (DFS). Methods: EC patients treated with definitive radiotherapy (RT) or chemoradiotherapy (CRT) from 4 radiotherapy referral centers between 1996 and 2008 were used. Only patients with squamouscellcarcinoma (SCC) or adenocarcinoma (AC) were included in the analyses. Results: In total 278 patients were identified of whom 106 (38.1%) were treated with CRT (platinum based, median 50.4 (46.8 – 70)Gy) and 172 (61.9%) with RT alone (median 60 (40-70)Gy). T- stage was cT1=5.6%;cT2=15.3%;cT3=60.9% and cT4=18.2%. Nodal stage consisted of cN0=35%;cN1=65%, including cM1a=5.8%. The male/female ratio was 78.3% to 21.7%. AC occurred in 57.6% and 42.4% had a SCC. The median age was 69 years. Median OS time was 11 (1-166) months with an OS of 45%, 22% and 6% and a DFS of 32%, 18% and 6% at 1, 2 and 5 years, respectively. There was no significant difference between the CRT and RT group in OS (p=0.09) and DFS (p=0.17). The DFS after 2 and 5 year was 25% and 12% for SCC patients versus 11% and 0% for AC patients (p=0.007). The OS at 2 and 5 year was 28% and 11% for SCC versus 14% and 0% for AC patients (p=0.020). Initial recurrence was seen locoregionally in 66.7% and distant metastases occurred in 33.3%. Common sites for distant recurrence were the liver with 52.4%, 17.5% bones and 15.5% lungs. Patients with SCC had a better response to (chemo)radiotherapy considering the OS (p=0.02, HR=0.7) and DFS (p=0.01, HR=0.69) in a multivariate analysis. Conclusions: Patients with a SCC esophageal tumor have better long-term results then AC patients after definitive (chemo)radiation. In this patient group SCC seems to be a strong prognostic factor for both OS and DFS. Furthermore the difference between RT and CRT is still small.

1 The duration of the facilitatory effect of adrenaline on the electrically evoked overflow of noradrenaline was studied in the portal vein of permanently adreno-demedullated freely moving rats.2 Rats were infused with adrenaline (20 or 100 ng min(-1)) for 2 h. After an interval of 1 h, when plasma adrenaline had returned to undetectable levels, electrical stimulation resulted in an enhanced catecholamine overflow amounting to 219% (noradrenaline) and 241% (noradrenaline plus adrenaline) of control (saline infusion), respectively.3 When stimulation was applied again, in the same animal, at 24, 48 and 72 h after the first stimulation episode, the evoked noradrenaline overflow was 150, 111 and 102% (after 20 ng ml(-1) adrenaline) and 158, 134 and 105% (after 100 ng min(-1) adrenaline) of control.4 The B-2-adrenoceptor antagonist, ICI 118,551 (0.3 mg kg(-1)), blocked the facilitatory effect obtained after the 100 ng min(-1) adrenaline infusion on all days.5 The results show that adrenaline, after being taken up by and released from sympathetic nerve terminals, is able to facilitate the evoked noradrenaline overflow through activation of prejunctional B-2-adrenoceptors for at least 48 h after administration.

73 Background: Neoadjuvant chemoradiation (CRT) is important in the treatment ofesophageal cancer. Rationales are tumor-downstaging and elimination of micrometastases improving resectability and curability rate. In this study we evaluated the effect of neo-adjuvant CRT on nodal micrometastases (NMM) in pN0 esophageal cancer patients. Methods: From a prospective database, we selected a matched group of patients on cT-stage, histological type and treatment without (group 1) or with neo-adjuvant CRT (group 2). Patients were staged by EUS, PET-scan, CT-scan and EUS guided cytology. CRT was given in a randomized clinical trial and consisted of paclitaxel 50 mg/m2 and carboplatin AUC = 2 for 5 weeks and concurrent radiotherapy (41.4 Gy/23 frs). All patients (n = 19) underwent a curative intended transthoracic esophagectomy with extended 2-field nodal dissection. After reviewing routine pathological examination all tumors were confirmed as stage pN0. Four sections of every examined lymph node (n = 261) were made at different levels according to a sentinel node protocol and further analyzed immunohistochemically with anti-CK8/18 (CAM 5.2) to detect NMM. Results: Patients characteristics were equally distributed. All patients had a microscopically radical (R0) resection. In group 2 (n = 9) the response rate was 55% which was complete (CR) in 33%. The median number of resected nodes was comparable: 15 ± 6.5 and 15 ± 5.6 in both groups. Thirtheen of the 261 (5%) pN0 nodes in these 19 pts contained NMM. In group 1 (n = 10); 12 of the 136 (9%) examined pN0 lymph nodes were positive and in group 2 only one of the 125 (0.8%) examined pN0 nodes was positive (p = 0.003). NMM were found in 7 pts (70%) in group 1 and in only one patient (11%) in group 2 (p = 0.02). Interestingly, this last patient had responded well to CRT. Conclusions: Neo-adjuvant CRT seems to have a significant impact on the numbers of NMMs in esophageal cancer. Based on the presence of NMM even in patients with good responses, we still advocate a curatively intended nodal dissection. No significant financial relationships to disclose.

36 Background: Neo-adjuvant chemoradiation is considered as standard treatment in esophageal cancer (EC). However, a significant proportion of these tumors do not respond well to radiotherapy. Here, we investigated the presence of radioresistant cells in EC with cancer stem cell characteristics. Methods: EC OE-33 adenotype and OE-21 squamous cell carcinoma cell-lines and fresh tumor material of EC patients were analyzed for common CSC-markers with Fluorecence Activated Cell Sorting (FACS) and immunohistochemistry. Subpopulations were tested for clonogenic survival to determine radioresistance. Non-adherent 3D sphere-cultures and xenograft tumors generated in NOD/SCID mice were performed to investigate stem cell properties. Results: Both cell lines lacked expression of CD133 and CD90, whereas the expression of EpCam overlapped with CD44 in OE-33. In sub-confluent cultures the expression of CD44+/CD24- was 5.6% SD ± 2.3 and 35.1% SD ± 1.3 in OE-33 and OE-21, respectively. In a clonogenic survival assay the CD44+/CD24- cells showed up to a 2-fold lower radiosensitivity compared to CD44+/CD24+ cells in both the OE-33 (p = 0.02) and the OE-21 cell line (p = 0.01). The CD44+/CD24- subpopulation had a 2.2-fold higher sphere-forming capacity compared to the CD44+/CD24+ subset (p = 0.01) in OE-33. Analysis of the spheres showed an enrichment in the CD44+/CD24- phenotype from 5.6% to 56.4% (p = 0.01) after 4 days of culturing as measured by FACS, but differentiated to a higher percentage of CD44+/CD24+ in time. Furthermore, CD44+/CD24- cells exhibited a greater in vivo tumor initiating capacity, shorter latency time and faster growth speed compared with unsorted or CD44+/CD24+ cells. Importantly, a clear CD44+/CD24- population could be identified in fresh EC biopsies of patients. Conclusions: EC appear to contain a radioresistant CD44+/CD24- subpopulation. This phenotype displays some CSC characteristics in vitro and in vivo and is present in human EC tumors. This marker could be used in future trials to predict tumor response. No significant financial relationships to disclose.

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.