Bas Wijnhoven - Academia.edu (original) (raw)

Papers by Bas Wijnhoven

Annals of Surgical Oncology, Nov 15, 2007

Background: Most studies addressing the volume-outcome relationship in complex surgical procedure... more Background: Most studies addressing the volume-outcome relationship in complex surgical procedures use hospital mortality as the sole outcome measure and are rarely based on detailed clinical data. The lack of reliable information about comorbidities and tumor stages makes the conclusions of these studies debatable. The purpose of this study was to compare outcomes for esophageal resections for cancer in low-versus high-volume hospitals, using an extensive set of variables concerning case-mix and outcome measures, including long-term survival. Methods: Clinical data, from 903 esophageal resections performed between January 1990 and December 1999, were retrieved from the original patientsÕ files. Three hundred and fortytwo patients were operated on in 11 low-volume hospitals (<7 resections/year) and 561 in a single high-volume center. Results: Mortality and morbidity rates were significantly lower in the high-volume center, which had an in-hospital mortality of 5 vs 13% (P < .001). On multivariate analysis, hospital volume, but also the presence of comorbidity proved to be strong prognostic factors predicting in-hospital mortality (ORs 3.05 and 2.34). For stage I and II disease, there was a significantly better 5-year survival in the high-volume center. (P = .04). Conclusions: Hospital volume and comorbidity patterns are important determinants of outcome in esophageal cancer surgery. Strong clinical endpoints such as in-hospital mortality and survival can be used as performance indicators, only if they are joined by reliable case-mix information.

BMC Cancer, Mar 6, 2020

Background: After neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer, high pathologically... more Background: After neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer, high pathologically complete response (pCR) rates are being achieved especially in patients with squamous cell carcinoma (SCC). An active surveillance strategy has been proposed for SCC patients with clinically complete response (cCR) after nCRT. To justify omitting surgical resection, patients with residual disease should be accurately identified. The aim of this study is to assess the accuracy of response evaluations after nCRT based on the preSANO trial, including positron emission tomography with computed tomography (PET-CT), endoscopy with bite-on-bite biopsies and endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) in patients with potentially curable esophageal SCC. Methods: Operable esophageal SCC patients who are planned to undergo nCRT according to the CROSS regimen and are planned to undergo surgery will be recruited from four Asian centers. Four to 6 weeks after completion of nCRT, patients will undergo a first clinical response evaluation (CRE-1) consisting of endoscopy with bite-on-bite biopsies. In patients without histological evidence of residual tumor (i.e. without positive biopsies), surgery will be postponed another 6 weeks. A second clinical response evaluation (CRE-2) will be performed 10-12 weeks after completion of nCRT, consisting of PET-CT, endoscopy with bite-on-bite biopsies and EUS with FNA. Immediately after CRE-2 all patients without evidence of distant metastases will undergo esophagectomy. Results of CRE-1 and CRE-2 as well as results of the three single diagnostic modalities will be correlated to pathological response in the resection specimen (gold standard) for calculation of sensitivity, specificity, negative predictive value and positive predictive value.

British Journal of Cancer, Feb 1, 2004

Up to 60% of gastro-oesophageal junction (GEJ) adenocarcinomas show nuclear b-catenin expression,... more Up to 60% of gastro-oesophageal junction (GEJ) adenocarcinomas show nuclear b-catenin expression, pointing to activated T-cell factor (TCF)/b-catenin-driven gene transcription. We demonstrate in five human GEJ adenocarcinoma cell lines that nuclear bcatenin expression indeed correlates with enhanced TCF-mediated transcription of a reporter gene. In several tumour types, TCF/bcatenin activation is caused by mutations in either adenomatous polyposis coli (APC), b-catenin exon 3, AXIN1, AXIN2 or b-transducin repeat-containing protein (b-TrCP). In GEJ adenocarcinomas, very few APC and b-catenin mutations have been found. Therefore, the mechanism of Wnt pathway activation remains unclear. In the present study, we did not find AXIN1 gene mutations in 17 GEJ tumours with nuclear b-catenin expression (without b-catenin exon 3 mutations). Six intragenic single nucleotide polymorphisms (SNPs) were identified. One of these, the AXIN1 gene T1942C SNP, has a frequency of 21% but is only very recently described despite numerous AXIN1 gene mutational studies. We provide evidence why this SNP was missed in single strand conformation polymorphism analyses. The AXIN1 gene G2063A variation was previously described as a gene mutation but we demonstrate that this is a polymorphism. With these six SNPs loss of heterozygosity (LOH) was found in 11 of 15 (73%) informative tumours. To investigate a possible AXIN1 gene dosage effect in GEJ tumours expressing nuclear b-catenin, AXIN1 locus LOH was determined in 20 tumours expressing membranous and no nuclear b-catenin. LOH was found in 10 of 13 (77%) informative cases. AXIN1 protein immunohistochemistry revealed cytoplasmic expression in all tumours irrespective of the presence of AXIN1 locus LOH. These data indicate that nuclear b-catenin expression is indicative for activated Wnt signalling and that neither AXIN1 gene mutations nor AXIN1 locus LOH are involved in Wnt pathway activation in GEJ adenocarcinomas.

Annals of Surgical Oncology, Oct 16, 2019

Background. The course of health-related quality of life (HRQOL) during and after completion of n... more Background. The course of health-related quality of life (HRQOL) during and after completion of neoadjuvant chemoradiotherapy (nCRT) for esophageal or junctional carcinoma is unknown. Methods. This study was a multicenter prospective cohort investigation. Patients with esophageal or cancer to be treated with nCRT plus esophagectomy were eligible for inclusion in the study. The HRQOL of the patients was measured with European Organization for Research and Treatment of Cancer QLQ-C30, QLQ-OG25, and QLQ-CIPN20 questionnaires before and during nCRT, then 2, 4, 6, 8, 10, 12, 14, and 16 weeks after nCRT and before surgery. Predefined end points were based on the hypothesized impact of nCRT. The primary end points were physical functioning, odynophagia, and sensory symptoms. The secondary end points were global quality of life, fatigue, weight loss, and motor symptoms. Mixed modeling analysis was used to evaluate changes over time. Results. Of 106 eligible patients, 96 (91%) were included in the study. The rate of questionnaires returned ranged Electronic supplementary material The online version of this article (

Neoadjuvant Treatment of Esophageal and Gastro-Esophageal Cancer

The incidence of adenocarcinoma of the esophagus and gastroesophageal (GE) junction has increased... more The incidence of adenocarcinoma of the esophagus and gastroesophageal (GE) junction has increased rapidly in Western countries, while numbers of squamous cell carcinoma (SCC) have gradually declined. For locally advanced esophageal cancer, surgery remains the mainstay of treatment. However, esophagectomy is historically associated with relatively high rates of irradical resection margins and high numbers of patients presenting with recurrent disease within 2 years after surgery. Therefore, the last decades several multimodality treatment regimens have been developed. Numerous studies evaluated the value of neoadjuvant as well as adjuvant strategies, especially chemotherapy and chemoradiation. In most countries advanced esophageal cancers are treated nowadays by neoadjuvant multimodality treatment regimens. It is thought that neoadjuvant chemotherapy and neoadjuvant chemoradiation eliminate micrometastases and induce locoregional tumor regression which leads to a higher rate of radic...

Lasting Symptoms After Esophageal Resection (LASER)

Annals of Surgery, 2020

Objective: To identify the most prevalent symptoms and those with greatest impact upon health-rel... more Objective: To identify the most prevalent symptoms and those with greatest impact upon health-related quality of life (HRQOL) among esophageal cancer survivors. Background: Long-term symptom burden after esophagectomy, and associations with HRQOL, are poorly understood. Patients and Methods: Between 2010 and 2016, patients from 20 European Centers who underwent esophageal cancer surgery, and were disease-free at least 1 year postoperatively were asked to complete LASER, EORTC-QLQ-C30, and QLQ-OG25 questionnaires. Specific symptom questionnaire items that were associated with poor HRQOL as identified by EORTC QLQ-C30 and QLQ-OG25 were identified by multivariable regression analysis and combined to form a tool. Results: A total of 876 of 1081 invited patients responded to the questionnaire, giving a response rate of 81%. Of these, 66.9% stated in the last 6 months they had symptoms associated with their esophagectomy. Ongoing weight loss was reported by 10.4% of patients, and only 13....

Gastroenterology, 2020

'user' was defined as having at least two prescriptions in the same drug category on different da... more 'user' was defined as having at least two prescriptions in the same drug category on different days. Controls were matched on gender, race, and year of enrollment. Logistic regression was used to generate odds ratios (ORs) and 95% confidence intervals (95% CI). Wald Chisquare tests were used to assess the significance of variables included in the logistic regression models. Models were adjusted for age, history of gastroesophageal reflux disease, inflammatory bowel disease, and diabetes with complications. Results: 12,026 EAC cases and 120,260 controls were included in the analysis. EAC cases had a higher prevalence of BE (27.1%) than controls (3.1%). Among the cases, 34.1% of BE was diagnosed at least one year prior to EAC. Among all participants included in the study population, those with PPI, NSAID, or statin use had decreased risk of EAC (PPI: OR 0.23, 95% CI 0.21, 0.26; NSAID: OR 0.82, 95% CI 0.69, 0.96; statins: OR 0.35, 95% CI 0.35, 0.43). When only individuals with BE were evaluated, a similar reduction in EAC risk was observed. Those with pre-existing BE and PPI or statin use showed decreased risk of EAC (PPI: OR 0.30, 95% CI 0.20, 0.44; statins: OR 0.33, 95% CI 0.21, 0.51) compared to non-users. Conclusions: The results of this study suggest that use of PPIs or statins may confer substantial protection against the development of EAC for individuals with and without BE. Due to the rising incidence of EAC in the United States population, exploring opportunities for prevention using low-cost, minimal risk pharmaceuticals, such as PPIs or statins, may help alleviate this trend.

O161 Lasting Symptoms After Esophageal Resection (Laser) – European Multi-Center Cross-Sectional Study

Diseases of the Esophagus, 2019

Aim Long-term functional outcomes and the associations to health-related quality of life (HRQOL) ... more Aim Long-term functional outcomes and the associations to health-related quality of life (HRQOL) after esophagectomy is largely unknown. LASER is a multi-center European study aimed to identify the most prevalent symptoms, and those with the greatest impact upon HRQOL among patients surviving more than one-year after esophagectomy for cancer, and to develop a clinically relevant symptom-based tool to measure HRQOL. Background & Methods Between 2010 and 2016, patients from 20 European Centers who underwent esophagectomy for esophageal cancer, and were disease-free at least one year postoperatively were invited to complete the LASER questionnaire, EORTC-QLQ30 and OG25. Specific symptom questionnaire items that were associated with a poor HRQOL as identified by EORTC-QLQC30 and OG25 were identified by multivariable linear and logistic regression analysis and combined to form a tool, which was tested using receiver operating characteristics curve analysis. Results A total of 876 of 1081...

Transhiatal Esophagectomy

(With CD-ROM), 2009

Gastroenterology, 2015

Objective Preoperative chemoradiotherapy has recently become common practice in treatment of esop... more Objective Preoperative chemoradiotherapy has recently become common practice in treatment of esophageal cancer with a gain in 5-year survival of 10-15%. However, a significant proportion of patients do not respond well and experiencing unnecessary severe side-effects. Accurate risk-stratification of patients using informative biomarkers before therapy may help to avoid unnecessary morbidity due to ineffective treatment. The aim of this study was to investigate the correlation between the expression of SOX2 and P53 in pre-treatment tumor biopsies and grade of pathological tumor response in resected specimen of patients with esophageal adenocarcinoma (EAC) treated with neoadjuvant chemoradiotherapy (nCRT). Methods All EAC patients who received nCRT according to the CROSS regimen followed by esophagectomy, between January 2003 and July 2011 at the Erasmus University Medical Center, were included. SOX2 and P53 protein expression was visualized by immunohistochemistry on all pre-treatment tumor biopsies and scored independently by two investigators who were blinded for clinical outcome. Aberrant expression was defined as negative expression of SOX2 and overexpression or complete loss of P53 expression. The overall Tumor Regression Grade (TRG) was evaluated using the modified Mandard scoring system. Patients with TRG 1 or TRG 2 were classified as major responders (ie, < 10% of tumor cells remaining), whereas patients with TRG 3 or TRG 4 were classified as minor responders (ie, > 10% of tumor cells remaining). Results In total 77 patients were included. Forty (53%) patients had a major pathological response (TRG 1-2) and 37 (47%) a minor response (TRG 3-4). In pre-treatment biopsies aberrant SOX2 and P53 expression was seen in 40% (31/77) and 83% (64/77), respectively. A major response was significantly associated with an aberrant SOX2 expression (OR 3.9, 95% CI: 1.5-10.2, p=0.005) and aberrant p53 expression (OR 4.5, 95% CI: 1.15-18.2, p=0.031). Aberrant expression of both biomarkers increased the probability of a major response in the individual patient (OR of 5.6; 95% CI: 2.1-14.9, p= 0.001), with a sensitivity of 68%, specificity of 73% and a positive predictive value of 73%. Conclusion SOX2 and P53 expression in the pre-treatment biopsies predict response to nCRT in patients with EAC. These biomarkers might help to identify patients who are likely to benefit most from this multimodality treatment.

Lymph Node Retrieval During Esophagectomy With and Without Neoadjuvant Chemoradiotherapy

Annals of Surgery, 2014

We aimed to examine the association between total number of resected nodes and survival in patien... more We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT. Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;sterilize&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful. Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups. One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12-27) and 14 (9-21), with 2 (1-6) and 0 (0-1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P=0.007), but not in the multimodality arm (hazard ratio 1.00; P=0.98). The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

World Journal of Surgery, 2012

Background The incidence of esophageal cancer has risen among all age groups. Controversy exists ... more Background The incidence of esophageal cancer has risen among all age groups. Controversy exists about the clinical presentation and prognosis of young patients. The aim of this study was to compare the clinicopathologic characteristics and outcomes after surgery between patients with esophageal cancer who were \50 years of age and those C50 years of age. Methods Patients diagnosed with esophageal carcinoma who underwent esophagectomy between January 1990 and December 2010 in a single institution were selected from a prospective database. Patients aged \50 years at diagnosis (n = 163) were compared with those C50 years (n = 1151) with respect to clinicopathologic stage and oncologic outcome. Results Younger patients had less co-morbidity (p \ 0.001). There were no significantly differences in tumor localization, histology, differentiation, or TNM stage in the two groups. In both groups, 37 % of the patients underwent neoadjuvant chemo(radio)therapy. One or more nonsurgical complications developed in 53 % of the older group versus 42 % in the younger group (p = 0.012). In-hospital mortality was 6.3 % for patients C50 years compared to 1.8 % for younger patients (p = 0.021). The 5 year overall survival was significantly better for the younger patients than for those C50 years (41 vs. 31 %, p \ 0.001), but median disease-specific and disease-free survival did not differ between the groups (37 vs. 30 months, p = 0.140 and 49 vs. 28 months, p = 0.079, respectively). Multivariate analysis identified moderate, poorly, and undifferentiated tumors; tumor-positive resection margins (pR1-2); and TNM stage IIB-IV as independent predictors of disease-specific survival. Conclusions A considerable proportion (12 %) of patients diagnosed with resectable esophageal carcinoma were \50 years. Phenotypic tumor characteristics and diseasespecific survival were comparable for the two age groups. The study was conducted for the Rotterdam Esophageal Tumor Study Group. The members of Rotterdam Esophageal Cancer Study Group are given in the Appendix.

Lymphatic micrometastases in patients with early esophageal adenocarcinoma

Journal of Surgical Oncology, 2010

Both endoscopic and surgical treatments are recommended for m3- or sm1-adenocarcinomas of the eso... more Both endoscopic and surgical treatments are recommended for m3- or sm1-adenocarcinomas of the esophagus, depending on patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; lymph nodal status. Lymphatic dissemination is related to tumor infiltration depth, but varying incidences have been reported in m3- and sm1-adenocarcinomas. The study aim was to investigate whether the presence of occult tumor cells in lymph nodes could explain this variation. Sixty-three node-negative (N0) patients with early esophageal adenocarcinoma (m2/m3/sm1-tumors) were included. Multilevel-sectioning of lymph nodes was performed; sections were stained by means of immunohistochemistry with cytokeratin marker CAM5.2. Two pathologists searched for micrometastases (0.2-2.0 mm) and isolated tumor cells (ITCs, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.2 mm). Positive CAM5.2 staining in lymph nodes was not seen in any of the 18 m2-patients. In 2/25 m3-tumors (8.0%) an ITC was found, but no micrometastases. Tumor cells were identified in 4/20 sm1-tumors (20.0%): three micrometastases and one ITC. Median follow-up was 121 months. Two m3-patients (3.2%) died due to disease recurrence, including one patient in whom an ITC was detected. Lymphatic migration of tumor cells was found in node-negative m3- and sm1-adenocarcinomas of the esophagus (8.0% and 20.0%, respectively). However, the clinical relevance of these occult tumor cells should become apparent from large series of endoscopically treated patients.

The molecular biology of esophageal adenocarcinoma

Journal of Surgical Oncology, 2005

BackgroundBarrett's esophagus is an acquired metaplastic change that occurs in the distal eso... more BackgroundBarrett's esophagus is an acquired metaplastic change that occurs in the distal esophagus secondary to chronic gastroesophageal reflux. This premalignant condition forms the most important risk factor for developing esophageal adenocarcinoma, which is an extremely aggressive tumor with a 5‐year survival rate of less than 25%. Carcinomas that arise in the setting of Barrett's esophagus are thought to develop as part of the metaplasia–dysplasia–carcinoma sequence.ObjectiveTo review the current knowledge on the genomic alterations involved in the development of Barrett's esophagus and its progression to dysplasia and/or cancer.ResultsSeveral changes in gene structure, gene expression, and protein structure are associated with the progression of Barrett's esophagus to adenocarcinoma. Accumulation of these changes seems to be essential, rather than the exact sequence of these changes. Multiple molecular pathways are involved and interact with each other. Alterat...

Preoperative risk assessment and prevention of complications in patients with esophageal cancer

Journal of Surgical Oncology, 2010

In this review the preoperative risk assessment and prevention of complications in patients under... more In this review the preoperative risk assessment and prevention of complications in patients undergoing esophagectomy for cancer is discussed. Age, pulmonary and cardiovascular condition, nutritional status, and neoadjuvant chemo(radio)therapy are known predictive factors. None of these factors is a valid exclusion criterion for esophagectomy, but may help in careful patient selection. Both anesthetists and surgeons play an important role in intraoperative risk reduction by means of appropriate fluid management and application of optimal surgical techniques.

Reduced p120ctn expression correlates with poor survival in patients with adenocarcinoma of the gastroesophageal junction

Journal of Surgical Oncology, 2005

P120-catenin (p120ctn) is a member of the E-cadherin-catenin cell-cell adhesion complex. Impairme... more P120-catenin (p120ctn) is a member of the E-cadherin-catenin cell-cell adhesion complex. Impairment of one or more of the components of this complex is associated with tumorigenesis. The role of p120ctn in malignancy is not clear yet. We studied the in vivo expression and cellular localization of p120ctn in adenocarcinomas of the gastroesophageal junction. Immunohistochemical staining for p120ctn was performed on 96 tumor samples, 20 cases of Barretts metaplasia and 13 lymph node metastases. The relationship with pathological characteristics and patient survival was also assessed. Loss of normal surface p120ctn expression was found in 4/20 (20%) Barretts metaplasia, in 65/96 (68%) tumors, and 11/13 (85%) lymph node metastases. Nuclear immunoreactivity for p120ctn was seen in five tumors. Loss of normal expression of p120ctn was associated with a higher tumor grade (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) but not with pTNM-stage. Reduced expression of p120ctn was correlated with poor survival (P = 0.0002). Cox regression analysis showed that p120ctn is an independent prognostic marker. Abnormal p120ctn expression is frequently seen in adenocarcinomas of the gastroesophageal junction, and may be a useful as a prognostic marker in these tumors.

The Journal of Pathology, 2010

Accumulating evidence has suggested that tumours have a hierarchical organization in which only t... more Accumulating evidence has suggested that tumours have a hierarchical organization in which only the cancer stem cells (CSCs) have tumour-initiating properties. Several surface antigens have been employed to isolate CSCs from various malignancies, although not from oesophageal adenocarcinoma (EA). We tested whether Barrett's oesophagus (BE) and EA might serve as a model for the CSC concept. In vivo assays were performed by transplantation of serially diluted bulk EA cells into NOD-SCID mice to establish the presence and frequency of tumour-initiating cells. These were found to be present as ca. 1 in 64 000 cells. The transplanted tumours fully recapitulated the primary lesions. Subsequently, a panel of previously established CSC markers was employed for immunohistochemistry. CD24, CD29 and CD44 showed heterogeneous staining in EA. Nuclear β-catenin accumulation increased during progression from metaplasia to dysplasia and was often observed in the basal compartment with CD24 and CD29 staining. However, the overall staining patterns were not such to clearly point out specific candidate markers. Accordingly, all markers were employed to sort the corresponding subpopulations of cancer cells and transplant them at low multiplicities in NOD-SCID mice. No increased tumour-initiating capacity of sorted EA cells was observed upon transplantation. These results indicate that tumour-initiating cells are present in EA, thus reflecting a hierarchical organization. However, antibodies directed against novel surface antigens are needed to detect subpopulations enriched for CSCs in EA by transplantation assays.

33 ORAL Centralization of oesophageal resections for cancer: does it actually improve clinical outcome?

European Journal of Surgical Oncology (EJSO), 2006

European Journal of Gastroenterology & Hepatology, 1998

European Journal of Gastroenterology & Hepatology, 1999

Annals of Surgical Oncology, Nov 15, 2007

Background: Most studies addressing the volume-outcome relationship in complex surgical procedure... more Background: Most studies addressing the volume-outcome relationship in complex surgical procedures use hospital mortality as the sole outcome measure and are rarely based on detailed clinical data. The lack of reliable information about comorbidities and tumor stages makes the conclusions of these studies debatable. The purpose of this study was to compare outcomes for esophageal resections for cancer in low-versus high-volume hospitals, using an extensive set of variables concerning case-mix and outcome measures, including long-term survival. Methods: Clinical data, from 903 esophageal resections performed between January 1990 and December 1999, were retrieved from the original patientsÕ files. Three hundred and fortytwo patients were operated on in 11 low-volume hospitals (<7 resections/year) and 561 in a single high-volume center. Results: Mortality and morbidity rates were significantly lower in the high-volume center, which had an in-hospital mortality of 5 vs 13% (P < .001). On multivariate analysis, hospital volume, but also the presence of comorbidity proved to be strong prognostic factors predicting in-hospital mortality (ORs 3.05 and 2.34). For stage I and II disease, there was a significantly better 5-year survival in the high-volume center. (P = .04). Conclusions: Hospital volume and comorbidity patterns are important determinants of outcome in esophageal cancer surgery. Strong clinical endpoints such as in-hospital mortality and survival can be used as performance indicators, only if they are joined by reliable case-mix information.

BMC Cancer, Mar 6, 2020

Background: After neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer, high pathologically... more Background: After neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer, high pathologically complete response (pCR) rates are being achieved especially in patients with squamous cell carcinoma (SCC). An active surveillance strategy has been proposed for SCC patients with clinically complete response (cCR) after nCRT. To justify omitting surgical resection, patients with residual disease should be accurately identified. The aim of this study is to assess the accuracy of response evaluations after nCRT based on the preSANO trial, including positron emission tomography with computed tomography (PET-CT), endoscopy with bite-on-bite biopsies and endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) in patients with potentially curable esophageal SCC. Methods: Operable esophageal SCC patients who are planned to undergo nCRT according to the CROSS regimen and are planned to undergo surgery will be recruited from four Asian centers. Four to 6 weeks after completion of nCRT, patients will undergo a first clinical response evaluation (CRE-1) consisting of endoscopy with bite-on-bite biopsies. In patients without histological evidence of residual tumor (i.e. without positive biopsies), surgery will be postponed another 6 weeks. A second clinical response evaluation (CRE-2) will be performed 10-12 weeks after completion of nCRT, consisting of PET-CT, endoscopy with bite-on-bite biopsies and EUS with FNA. Immediately after CRE-2 all patients without evidence of distant metastases will undergo esophagectomy. Results of CRE-1 and CRE-2 as well as results of the three single diagnostic modalities will be correlated to pathological response in the resection specimen (gold standard) for calculation of sensitivity, specificity, negative predictive value and positive predictive value.

British Journal of Cancer, Feb 1, 2004

Up to 60% of gastro-oesophageal junction (GEJ) adenocarcinomas show nuclear b-catenin expression,... more Up to 60% of gastro-oesophageal junction (GEJ) adenocarcinomas show nuclear b-catenin expression, pointing to activated T-cell factor (TCF)/b-catenin-driven gene transcription. We demonstrate in five human GEJ adenocarcinoma cell lines that nuclear bcatenin expression indeed correlates with enhanced TCF-mediated transcription of a reporter gene. In several tumour types, TCF/bcatenin activation is caused by mutations in either adenomatous polyposis coli (APC), b-catenin exon 3, AXIN1, AXIN2 or b-transducin repeat-containing protein (b-TrCP). In GEJ adenocarcinomas, very few APC and b-catenin mutations have been found. Therefore, the mechanism of Wnt pathway activation remains unclear. In the present study, we did not find AXIN1 gene mutations in 17 GEJ tumours with nuclear b-catenin expression (without b-catenin exon 3 mutations). Six intragenic single nucleotide polymorphisms (SNPs) were identified. One of these, the AXIN1 gene T1942C SNP, has a frequency of 21% but is only very recently described despite numerous AXIN1 gene mutational studies. We provide evidence why this SNP was missed in single strand conformation polymorphism analyses. The AXIN1 gene G2063A variation was previously described as a gene mutation but we demonstrate that this is a polymorphism. With these six SNPs loss of heterozygosity (LOH) was found in 11 of 15 (73%) informative tumours. To investigate a possible AXIN1 gene dosage effect in GEJ tumours expressing nuclear b-catenin, AXIN1 locus LOH was determined in 20 tumours expressing membranous and no nuclear b-catenin. LOH was found in 10 of 13 (77%) informative cases. AXIN1 protein immunohistochemistry revealed cytoplasmic expression in all tumours irrespective of the presence of AXIN1 locus LOH. These data indicate that nuclear b-catenin expression is indicative for activated Wnt signalling and that neither AXIN1 gene mutations nor AXIN1 locus LOH are involved in Wnt pathway activation in GEJ adenocarcinomas.

Annals of Surgical Oncology, Oct 16, 2019

Background. The course of health-related quality of life (HRQOL) during and after completion of n... more Background. The course of health-related quality of life (HRQOL) during and after completion of neoadjuvant chemoradiotherapy (nCRT) for esophageal or junctional carcinoma is unknown. Methods. This study was a multicenter prospective cohort investigation. Patients with esophageal or cancer to be treated with nCRT plus esophagectomy were eligible for inclusion in the study. The HRQOL of the patients was measured with European Organization for Research and Treatment of Cancer QLQ-C30, QLQ-OG25, and QLQ-CIPN20 questionnaires before and during nCRT, then 2, 4, 6, 8, 10, 12, 14, and 16 weeks after nCRT and before surgery. Predefined end points were based on the hypothesized impact of nCRT. The primary end points were physical functioning, odynophagia, and sensory symptoms. The secondary end points were global quality of life, fatigue, weight loss, and motor symptoms. Mixed modeling analysis was used to evaluate changes over time. Results. Of 106 eligible patients, 96 (91%) were included in the study. The rate of questionnaires returned ranged Electronic supplementary material The online version of this article (

Neoadjuvant Treatment of Esophageal and Gastro-Esophageal Cancer

The incidence of adenocarcinoma of the esophagus and gastroesophageal (GE) junction has increased... more The incidence of adenocarcinoma of the esophagus and gastroesophageal (GE) junction has increased rapidly in Western countries, while numbers of squamous cell carcinoma (SCC) have gradually declined. For locally advanced esophageal cancer, surgery remains the mainstay of treatment. However, esophagectomy is historically associated with relatively high rates of irradical resection margins and high numbers of patients presenting with recurrent disease within 2 years after surgery. Therefore, the last decades several multimodality treatment regimens have been developed. Numerous studies evaluated the value of neoadjuvant as well as adjuvant strategies, especially chemotherapy and chemoradiation. In most countries advanced esophageal cancers are treated nowadays by neoadjuvant multimodality treatment regimens. It is thought that neoadjuvant chemotherapy and neoadjuvant chemoradiation eliminate micrometastases and induce locoregional tumor regression which leads to a higher rate of radic...

Lasting Symptoms After Esophageal Resection (LASER)

Annals of Surgery, 2020

Objective: To identify the most prevalent symptoms and those with greatest impact upon health-rel... more Objective: To identify the most prevalent symptoms and those with greatest impact upon health-related quality of life (HRQOL) among esophageal cancer survivors. Background: Long-term symptom burden after esophagectomy, and associations with HRQOL, are poorly understood. Patients and Methods: Between 2010 and 2016, patients from 20 European Centers who underwent esophageal cancer surgery, and were disease-free at least 1 year postoperatively were asked to complete LASER, EORTC-QLQ-C30, and QLQ-OG25 questionnaires. Specific symptom questionnaire items that were associated with poor HRQOL as identified by EORTC QLQ-C30 and QLQ-OG25 were identified by multivariable regression analysis and combined to form a tool. Results: A total of 876 of 1081 invited patients responded to the questionnaire, giving a response rate of 81%. Of these, 66.9% stated in the last 6 months they had symptoms associated with their esophagectomy. Ongoing weight loss was reported by 10.4% of patients, and only 13....

Gastroenterology, 2020

'user' was defined as having at least two prescriptions in the same drug category on different da... more 'user' was defined as having at least two prescriptions in the same drug category on different days. Controls were matched on gender, race, and year of enrollment. Logistic regression was used to generate odds ratios (ORs) and 95% confidence intervals (95% CI). Wald Chisquare tests were used to assess the significance of variables included in the logistic regression models. Models were adjusted for age, history of gastroesophageal reflux disease, inflammatory bowel disease, and diabetes with complications. Results: 12,026 EAC cases and 120,260 controls were included in the analysis. EAC cases had a higher prevalence of BE (27.1%) than controls (3.1%). Among the cases, 34.1% of BE was diagnosed at least one year prior to EAC. Among all participants included in the study population, those with PPI, NSAID, or statin use had decreased risk of EAC (PPI: OR 0.23, 95% CI 0.21, 0.26; NSAID: OR 0.82, 95% CI 0.69, 0.96; statins: OR 0.35, 95% CI 0.35, 0.43). When only individuals with BE were evaluated, a similar reduction in EAC risk was observed. Those with pre-existing BE and PPI or statin use showed decreased risk of EAC (PPI: OR 0.30, 95% CI 0.20, 0.44; statins: OR 0.33, 95% CI 0.21, 0.51) compared to non-users. Conclusions: The results of this study suggest that use of PPIs or statins may confer substantial protection against the development of EAC for individuals with and without BE. Due to the rising incidence of EAC in the United States population, exploring opportunities for prevention using low-cost, minimal risk pharmaceuticals, such as PPIs or statins, may help alleviate this trend.

O161 Lasting Symptoms After Esophageal Resection (Laser) – European Multi-Center Cross-Sectional Study

Diseases of the Esophagus, 2019

Aim Long-term functional outcomes and the associations to health-related quality of life (HRQOL) ... more Aim Long-term functional outcomes and the associations to health-related quality of life (HRQOL) after esophagectomy is largely unknown. LASER is a multi-center European study aimed to identify the most prevalent symptoms, and those with the greatest impact upon HRQOL among patients surviving more than one-year after esophagectomy for cancer, and to develop a clinically relevant symptom-based tool to measure HRQOL. Background & Methods Between 2010 and 2016, patients from 20 European Centers who underwent esophagectomy for esophageal cancer, and were disease-free at least one year postoperatively were invited to complete the LASER questionnaire, EORTC-QLQ30 and OG25. Specific symptom questionnaire items that were associated with a poor HRQOL as identified by EORTC-QLQC30 and OG25 were identified by multivariable linear and logistic regression analysis and combined to form a tool, which was tested using receiver operating characteristics curve analysis. Results A total of 876 of 1081...

Transhiatal Esophagectomy

(With CD-ROM), 2009

Gastroenterology, 2015

Objective Preoperative chemoradiotherapy has recently become common practice in treatment of esop... more Objective Preoperative chemoradiotherapy has recently become common practice in treatment of esophageal cancer with a gain in 5-year survival of 10-15%. However, a significant proportion of patients do not respond well and experiencing unnecessary severe side-effects. Accurate risk-stratification of patients using informative biomarkers before therapy may help to avoid unnecessary morbidity due to ineffective treatment. The aim of this study was to investigate the correlation between the expression of SOX2 and P53 in pre-treatment tumor biopsies and grade of pathological tumor response in resected specimen of patients with esophageal adenocarcinoma (EAC) treated with neoadjuvant chemoradiotherapy (nCRT). Methods All EAC patients who received nCRT according to the CROSS regimen followed by esophagectomy, between January 2003 and July 2011 at the Erasmus University Medical Center, were included. SOX2 and P53 protein expression was visualized by immunohistochemistry on all pre-treatment tumor biopsies and scored independently by two investigators who were blinded for clinical outcome. Aberrant expression was defined as negative expression of SOX2 and overexpression or complete loss of P53 expression. The overall Tumor Regression Grade (TRG) was evaluated using the modified Mandard scoring system. Patients with TRG 1 or TRG 2 were classified as major responders (ie, < 10% of tumor cells remaining), whereas patients with TRG 3 or TRG 4 were classified as minor responders (ie, > 10% of tumor cells remaining). Results In total 77 patients were included. Forty (53%) patients had a major pathological response (TRG 1-2) and 37 (47%) a minor response (TRG 3-4). In pre-treatment biopsies aberrant SOX2 and P53 expression was seen in 40% (31/77) and 83% (64/77), respectively. A major response was significantly associated with an aberrant SOX2 expression (OR 3.9, 95% CI: 1.5-10.2, p=0.005) and aberrant p53 expression (OR 4.5, 95% CI: 1.15-18.2, p=0.031). Aberrant expression of both biomarkers increased the probability of a major response in the individual patient (OR of 5.6; 95% CI: 2.1-14.9, p= 0.001), with a sensitivity of 68%, specificity of 73% and a positive predictive value of 73%. Conclusion SOX2 and P53 expression in the pre-treatment biopsies predict response to nCRT in patients with EAC. These biomarkers might help to identify patients who are likely to benefit most from this multimodality treatment.

Lymph Node Retrieval During Esophagectomy With and Without Neoadjuvant Chemoradiotherapy

Annals of Surgery, 2014

We aimed to examine the association between total number of resected nodes and survival in patien... more We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT. Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;sterilize&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful. Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups. One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12-27) and 14 (9-21), with 2 (1-6) and 0 (0-1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P=0.007), but not in the multimodality arm (hazard ratio 1.00; P=0.98). The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

World Journal of Surgery, 2012

Background The incidence of esophageal cancer has risen among all age groups. Controversy exists ... more Background The incidence of esophageal cancer has risen among all age groups. Controversy exists about the clinical presentation and prognosis of young patients. The aim of this study was to compare the clinicopathologic characteristics and outcomes after surgery between patients with esophageal cancer who were \50 years of age and those C50 years of age. Methods Patients diagnosed with esophageal carcinoma who underwent esophagectomy between January 1990 and December 2010 in a single institution were selected from a prospective database. Patients aged \50 years at diagnosis (n = 163) were compared with those C50 years (n = 1151) with respect to clinicopathologic stage and oncologic outcome. Results Younger patients had less co-morbidity (p \ 0.001). There were no significantly differences in tumor localization, histology, differentiation, or TNM stage in the two groups. In both groups, 37 % of the patients underwent neoadjuvant chemo(radio)therapy. One or more nonsurgical complications developed in 53 % of the older group versus 42 % in the younger group (p = 0.012). In-hospital mortality was 6.3 % for patients C50 years compared to 1.8 % for younger patients (p = 0.021). The 5 year overall survival was significantly better for the younger patients than for those C50 years (41 vs. 31 %, p \ 0.001), but median disease-specific and disease-free survival did not differ between the groups (37 vs. 30 months, p = 0.140 and 49 vs. 28 months, p = 0.079, respectively). Multivariate analysis identified moderate, poorly, and undifferentiated tumors; tumor-positive resection margins (pR1-2); and TNM stage IIB-IV as independent predictors of disease-specific survival. Conclusions A considerable proportion (12 %) of patients diagnosed with resectable esophageal carcinoma were \50 years. Phenotypic tumor characteristics and diseasespecific survival were comparable for the two age groups. The study was conducted for the Rotterdam Esophageal Tumor Study Group. The members of Rotterdam Esophageal Cancer Study Group are given in the Appendix.

Lymphatic micrometastases in patients with early esophageal adenocarcinoma

Journal of Surgical Oncology, 2010

Both endoscopic and surgical treatments are recommended for m3- or sm1-adenocarcinomas of the eso... more Both endoscopic and surgical treatments are recommended for m3- or sm1-adenocarcinomas of the esophagus, depending on patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; lymph nodal status. Lymphatic dissemination is related to tumor infiltration depth, but varying incidences have been reported in m3- and sm1-adenocarcinomas. The study aim was to investigate whether the presence of occult tumor cells in lymph nodes could explain this variation. Sixty-three node-negative (N0) patients with early esophageal adenocarcinoma (m2/m3/sm1-tumors) were included. Multilevel-sectioning of lymph nodes was performed; sections were stained by means of immunohistochemistry with cytokeratin marker CAM5.2. Two pathologists searched for micrometastases (0.2-2.0 mm) and isolated tumor cells (ITCs, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.2 mm). Positive CAM5.2 staining in lymph nodes was not seen in any of the 18 m2-patients. In 2/25 m3-tumors (8.0%) an ITC was found, but no micrometastases. Tumor cells were identified in 4/20 sm1-tumors (20.0%): three micrometastases and one ITC. Median follow-up was 121 months. Two m3-patients (3.2%) died due to disease recurrence, including one patient in whom an ITC was detected. Lymphatic migration of tumor cells was found in node-negative m3- and sm1-adenocarcinomas of the esophagus (8.0% and 20.0%, respectively). However, the clinical relevance of these occult tumor cells should become apparent from large series of endoscopically treated patients.

The molecular biology of esophageal adenocarcinoma

Journal of Surgical Oncology, 2005

BackgroundBarrett's esophagus is an acquired metaplastic change that occurs in the distal eso... more BackgroundBarrett's esophagus is an acquired metaplastic change that occurs in the distal esophagus secondary to chronic gastroesophageal reflux. This premalignant condition forms the most important risk factor for developing esophageal adenocarcinoma, which is an extremely aggressive tumor with a 5‐year survival rate of less than 25%. Carcinomas that arise in the setting of Barrett's esophagus are thought to develop as part of the metaplasia–dysplasia–carcinoma sequence.ObjectiveTo review the current knowledge on the genomic alterations involved in the development of Barrett's esophagus and its progression to dysplasia and/or cancer.ResultsSeveral changes in gene structure, gene expression, and protein structure are associated with the progression of Barrett's esophagus to adenocarcinoma. Accumulation of these changes seems to be essential, rather than the exact sequence of these changes. Multiple molecular pathways are involved and interact with each other. Alterat...

Preoperative risk assessment and prevention of complications in patients with esophageal cancer

Journal of Surgical Oncology, 2010

In this review the preoperative risk assessment and prevention of complications in patients under... more In this review the preoperative risk assessment and prevention of complications in patients undergoing esophagectomy for cancer is discussed. Age, pulmonary and cardiovascular condition, nutritional status, and neoadjuvant chemo(radio)therapy are known predictive factors. None of these factors is a valid exclusion criterion for esophagectomy, but may help in careful patient selection. Both anesthetists and surgeons play an important role in intraoperative risk reduction by means of appropriate fluid management and application of optimal surgical techniques.

Reduced p120ctn expression correlates with poor survival in patients with adenocarcinoma of the gastroesophageal junction

Journal of Surgical Oncology, 2005

P120-catenin (p120ctn) is a member of the E-cadherin-catenin cell-cell adhesion complex. Impairme... more P120-catenin (p120ctn) is a member of the E-cadherin-catenin cell-cell adhesion complex. Impairment of one or more of the components of this complex is associated with tumorigenesis. The role of p120ctn in malignancy is not clear yet. We studied the in vivo expression and cellular localization of p120ctn in adenocarcinomas of the gastroesophageal junction. Immunohistochemical staining for p120ctn was performed on 96 tumor samples, 20 cases of Barretts metaplasia and 13 lymph node metastases. The relationship with pathological characteristics and patient survival was also assessed. Loss of normal surface p120ctn expression was found in 4/20 (20%) Barretts metaplasia, in 65/96 (68%) tumors, and 11/13 (85%) lymph node metastases. Nuclear immunoreactivity for p120ctn was seen in five tumors. Loss of normal expression of p120ctn was associated with a higher tumor grade (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) but not with pTNM-stage. Reduced expression of p120ctn was correlated with poor survival (P = 0.0002). Cox regression analysis showed that p120ctn is an independent prognostic marker. Abnormal p120ctn expression is frequently seen in adenocarcinomas of the gastroesophageal junction, and may be a useful as a prognostic marker in these tumors.

The Journal of Pathology, 2010

Accumulating evidence has suggested that tumours have a hierarchical organization in which only t... more Accumulating evidence has suggested that tumours have a hierarchical organization in which only the cancer stem cells (CSCs) have tumour-initiating properties. Several surface antigens have been employed to isolate CSCs from various malignancies, although not from oesophageal adenocarcinoma (EA). We tested whether Barrett's oesophagus (BE) and EA might serve as a model for the CSC concept. In vivo assays were performed by transplantation of serially diluted bulk EA cells into NOD-SCID mice to establish the presence and frequency of tumour-initiating cells. These were found to be present as ca. 1 in 64 000 cells. The transplanted tumours fully recapitulated the primary lesions. Subsequently, a panel of previously established CSC markers was employed for immunohistochemistry. CD24, CD29 and CD44 showed heterogeneous staining in EA. Nuclear β-catenin accumulation increased during progression from metaplasia to dysplasia and was often observed in the basal compartment with CD24 and CD29 staining. However, the overall staining patterns were not such to clearly point out specific candidate markers. Accordingly, all markers were employed to sort the corresponding subpopulations of cancer cells and transplant them at low multiplicities in NOD-SCID mice. No increased tumour-initiating capacity of sorted EA cells was observed upon transplantation. These results indicate that tumour-initiating cells are present in EA, thus reflecting a hierarchical organization. However, antibodies directed against novel surface antigens are needed to detect subpopulations enriched for CSCs in EA by transplantation assays.

33 ORAL Centralization of oesophageal resections for cancer: does it actually improve clinical outcome?

European Journal of Surgical Oncology (EJSO), 2006

European Journal of Gastroenterology & Hepatology, 1998

European Journal of Gastroenterology & Hepatology, 1999