http://repub.eur.nl/res/aut/3046/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/37349/ 2012-10-01T00:00:00Z http://repub.eur.nl/res/pub/30832/ 2011-09-01T00:00:00Z The following on the treatments of adenocarcinomas in Barrett's esophagus contains commentaries on endo mucosal resection; choice between other ablative therapies; the remaining genetic abnormalities following stepwise endoscopic mucosal resection and possible recurrences; the Fotelo-Fotesi PDT; the CT TNM classification of early stages of Barrett's carcinoma; the indications of lymphadenectomy in intramucosal cancer; the differences in lymph node yield in transthoracic versus transhiatal dissection; video-assisted lymphadenectomy; and the importance of the length of proximal esophageal resectipon; and indications of sentinel node dissection. http://repub.eur.nl/res/pub/25920/ 2011-07-01T00:00:00Z Background: Self-expandable metals stents (SEMSs) have increasingly been used as a temporary device to bridge chemoradiotherapy in patients with malignant esophageal disease or in patients with benign esophageal defects or stenosis. Objective: To evaluate the outcome of removal of SEMSs in a large cohort of patients with benign and malignant esophageal disease. Design: Observational study with standardized treatment and follow-up. Setting: Single university center. Patients: Between 2001 and 2010, 95 consecutive patients referred for endoscopic SEMS extraction were included. Interventions: Endoscopic stent removal. Main Outcome Measurements: Technical and functional outcome and complications. Results: A total of 124 stent extractions were undertaken in 95 patients; both partially covered (68%) and fully covered (32%) SEMSs were removed. Three patients had 2 overlapping SEMSs in place. Successful primary removal was achieved in 89%; the secondary removal rate was 96%. Uncomplicated primary removal rate was significantly higher for fully covered versus partially covered stents (P = .035) and for single versus overlapping stents (P = .033). Patients with a complicated stent removal had the stent in place significantly longer compared with patients with an uncomplicated primary stent removal (126 days vs 28 days; P = .01). Surgical removal was required in 3 patients (2.4%). Six moderate and severe complications (5%) related to the endoscopic extraction occurred. Limitations: Retrospective, nonrandomized study design. Conclusions: Primary endoscopic removal of an SEMS is feasible in the majority of patients with benign and malignant esophageal disease. A longer time that a stent is in place and the use of partially covered SEMSs both impede removal. Moreover, overlapping SEMSs should be avoided for temporary use because stent disintegration and subsequent complications may occur. http://repub.eur.nl/res/pub/25352/ 2011-05-19T00:00:00Z Background: This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed.Methods: This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test.Results: There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms.Conclusions: Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC. http://repub.eur.nl/res/pub/27421/ 2010-12-01T00:00:00Z Background: Both endoscopic and surgical treatments are recommended for m3- or sm1-adenocarcinomas of the esophagus, depending on patients' 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. Methods 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, <0.2 mm). Results 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. Conclusions 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. http://repub.eur.nl/res/pub/27592/ 2010-11-01T00:00:00Z Aims: According to the classification established by the Japanese Society for Oesophageal Disease, early oesophageal cancer can be subdivided into six successive layers of the mucosa or submucosa, which influences the treatment strategy and prognosis of the individual patient. However, the reproducibility of this classification in terms of inter- and intraobserver variability is unclear. Methods: Histological slides from 105 surgical resection specimens of patients who had undergone oesophagectomy for early oesophageal adenocarcinoma were reviewed independently by three gastrointestinal pathologists, andwere classified according to the Japanese criteria (m1/m2/m3/sm1/sm2/sm3 tumours). Inter- and intraobserver variation was determined by κ-statistics. Results: The interobserver reproducibility was good between pathologist 1 and 2 (κ=0.61, 95% CI 0.55 to 0.67), and moderate between pathologist 1 and 3 (κ=0.51, 95% CI 0.45 to 0.57) and between pathologist 2 and 3 (κ=0.50, 95% CI 0.38 to 0.61). The intraobserver agreement as assessed by the expert pathologist was good (κ=0.76), with a 95% CI that was interpreted as good to very good (0.67 to 0.85). Most agreement was achieved at the lower (m1) and upper site (sm2, sm3) of the spectrum, whereas the m2 tumours reflected the most discrepant stage. The majority of the observed discrepancy included the variation in one substage only. Conclusions: The reproducibility of the Japanese classification is good in terms of inter- and intraobserver variability when grading early oesophageal adenocarcinoma on surgical resection specimens. The present data confirm that dedicated gastrointestinal pathologists with broad experience are preferred when grading the resection specimens of patients with early oesophageal adenocarcinoma. http://repub.eur.nl/res/pub/27285/ 2010-09-01T00:00:00Z Background: This study analyzes the outcome of esophageal resection in patients 70 or more years of age, compared with patients aged less than 70 years and identifies risk factors for worse outcome in the elderly. Methods: Comorbidity, postoperative morbidity, in-hospital mortality and survival rates were compared between 811 patients aged less than 70 years and 250 patients aged 70 years or more who underwent esophagectomy for esophageal cancer in a single high-volume center from 1985 to 2005. Results: Groups were similar regarding surgical approach, resectability, and tumor stage. More patients aged 70 years or more had cardiovascular and respiratory concomitant disease. Among patients aged 70 years or more, the prevalence of adenocarcinoma and Barrett's transformation was higher (67% versus 53% for patients aged less than 70 years, and 22% versus 15%, respectively). There were no differences in surgical complications (20% versus 17%). Nonsurgical complications occurred more in patients aged 70 years or more (35% versus 27%) and operative mortality was higher among elderly patients (8.4 versus 3.8%), as was in-hospital mortality (11.6% versus 5.4%). The disease-specific 5-year survival was lower for patients aged 70 years or more (27% versus 34%). The 1-year survival, reflecting the impact of operative morbidity and mortality, was 58% for patients aged 70 years or more and 68% for the patients aged less than 70 years (p = 0.002). Among patients aged 70 years or more, respiratory comorbidity and thoracoabdominal resection were risk factors for the occurrence of nonsurgical complications and respiratory comorbidity for in-hospital mortality. Conclusions: Older patients have increased operative and in-hospital mortality and decreased 5-year survival after esophageal resection for cancer. Our results indicate that especially thoracoabdominal resection for esophageal carcinoma should be carefully considered for patients older than 70 years who suffer from respiratory disease. http://repub.eur.nl/res/pub/27622/ 2010-09-01T00:00:00Z Background: A nomogram has been developed recently in order to predict the occurrence and severity of postoperative complications after esophagectomy for cancer. In the present study, we externally validated this nomogram in a new cohort of patients who underwent esophagectomy for cancer in a different high-volume center. Methods: An independent dataset of 777 patients who underwent esophagectomy for cancer was used for validation. The discriminatory capability of the nomogram was determined by using the concordance index (C statistic). Calibration was evaluated by comparing the observed with the expected number of patients with complications, as predicted by the original nomogram across patients with different risk profiles. We also examined whether adjusting the value of the original coefficients of the predictors or adding new predictors would improve the fit of the nomogram. Results: Discrimination of the original nomogram was similar in the validation cohort: the C statistic hardly decreased from 0.65 in the original cohort to 0.64 in the validation cohort. Observed and expected number of patients with complications were in close agreement, reflecting a good calibration (p = 0.84). Reestimation of the coefficients in the validation cohort did not lead to any significant changes of the original nomogram values. Conclusions: External validation of a nomogram predicting the occurrence and severity of complications after esophagectomy showed that the model is applicable in other high-volume hospitals. Nevertheless, preoperative prediction of complications in individual patients remains difficult, most likely due to the complexity of mechanisms causing these complications. http://repub.eur.nl/res/pub/20061/ 2010-07-05T00:00:00Z Introduction: Cachexia and obesity have been suggested to be risk factors for postoperative complications. However, high body mass index (BMI) might result in a higher R0-resection rate because of the presence of more fatty tissue surrounding the tumor. The purpose of this study was to investigate whether BMI is of prognostic value with regard to short-term and long-term outcome in patients who undergo esophagectomy for cancer. Methods: In 556 patients who underwent esophagectomy (1991-2007), clinical and pathological outcome were compared between different BMI classes (underweight, normal weight, overweight, obesity). Results: Overall morbidity, mortality, and reoperation rate did not differ in underweight and obese patients. However, severe complications seemed to occur more often in obese patients (p = 0.06), and the risk for anastomotic leakage increased with higher BMI (12.5% in underweight patients compared with 27.6% in obese patients, p = 0.04). Histopathological assessment showed comparable pTNM stages, although an advanced pT stage was seen more often in patients with low/normal BMI (p = 0.02). A linear association between BMI and R0-resection rate was detected (p = 0.02): 60% in underweight patients compared with 81% in obese patients. However, unlike pT-stage (p < 0.001), BMI was not an independent predictor for R0 resection (p = 0.12). There was no significant difference in overall or disease-free 5-year survival between the BMI classes (p = 0.25 and p = 0.6, respectively). Conclusions: BMI is not of prognostic value with regard to short-term and long-term outcome in patients who undergo esophagectomy for cancer and is not an independent predictor for radical R0 resection. Patients oncologically eligible for esophagectomy should not be denied surgery on the basis of their BMI class. http://repub.eur.nl/res/pub/27337/ 2010-06-01T00:00:00Z Background: The genetic changes that drive metaplastic progression from squamous oesophageal mucosa toward intestinal metaplasia and adenocarcinoma are unclear. The aberrant expression of microRNAs (miRNAs) is involved in the development of cancer. This study examined whether miRNAs play a role in the development of oesophageal adenocarcinoma. Methods: RNA was extracted from mucosa of normal oesophageal squamous epithelium, normal gastric epithelium, Barrett's oesophagus with intestinal metaplasia and oesophageal adenocarcinoma obtained from 16 individuals. Expression profiles of 377 human miRNAs were determined by microarray analysis and selected miRNAs were analysed further using real-time reverse transcription-polymerase chain reaction (RT-PCR) in tissues from 32 individuals. Results: Microarray analyses identified 44 miRNAs likely to have altered expression between various mucosal samples. Of these, miR-21, miR-143, miR-145, miR-194, miR-203, miR-205 and miR-215 were chosen for validation by real-time RT-PCR. Tissue-specific expression profiles were observed, with miR-21, miR-143, miR-145, miR-194 and miR-215 significantly upregulated in columnar tissues compared with normal squamous epithelium. Expression of miR-143, miR-145 and miR-215 was lower in oesophageal adenocarcinoma than in Barrett's oesophagus. Levels of miR-203 and miR-205 were high in normal squamous epithelium and low in columnar epithelia. MiR-205 levels were lower in gastric epithelium than in both Barrett's oesophagus and adenocarcinoma. Conclusion: Expression of miRNA might define disease states in oesophageal epithelium. Dysregulation of specific miRNAs could contribute to metaplastic and neoplastic processes in the oesophageal mucosa. Copyright http://repub.eur.nl/res/pub/27339/ 2010-06-01T00:00:00Z http://repub.eur.nl/res/pub/19215/ 2010-03-01T00:00:00Z 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. http://repub.eur.nl/res/pub/19480/ 2010-03-01T00:00:00Z Background: The fate of papers submitted and subsequently rejected by the British Journal of Surgery (BJS) is currently unknown. The present study was designed to investigate whether, when and where these papers are published following rejection. Methods: All rejected manuscripts in the year 2006 were identified from the Manuscript Central electronic database. Between December 2008 and February 2009, a PubMed search was conducted spanning the period 2006-2009 using the corresponding author's last name and initials to identify whether and when manuscripts had been published elsewhere. Results: From the 926 manuscripts rejected by BJS, 609 (65-8 per cent) were published in 198 different journals with a mean(s.d.) time lapse of 13-8(6-5) months. Some 165 manuscripts (27-1 per cent) were published in general surgical journals, 250 (41-1 per cent) in subspecialty surgical journals and 194 (31-9 per cent) in non-surgical journals. The mean(s.d.) impact factor of the journals was 2-0(1-1). Only 14 manuscripts (2-3 per cent) were published in journals with a higher impact factor than that of BJS. Conclusion: Rejection of a manuscript by BJS does not preclude publication, but rejected manuscripts are published more often in surgical subspecialty journals and journals with a lower impact factor, although the occasional exception exists. http://repub.eur.nl/res/pub/28375/ 2010-03-01T00:00:00Z Introduction: Esophageal cancer should preferably be detected and treated at an early stage, but this may be prohibited by late onset of symptoms and delays in referral, diagnostic workup, and treatment. The aim of this study was to investigate the impact of these delays on outcome in patients with esophageal cancer. Methods: For 491 patients undergoing esophagectomy for cancer between 1991 and 2007, patients' short- and long-term outcome were analyzed according to different time intervals between onset of symptoms, diagnosis, and surgical treatment. Results: Length of prehospital delay (from onset of symptoms until endoscopic diagnosis) did not affect patient's short- or long-term outcome. A shorter hospital delay between establishing the diagnosis of esophageal cancer on endoscopy and surgery was associated with lower overall morbidity and in-hospital mortality. Patients of ASA classes I and II experienced a shorter hospital delay than patients of ASA classes III and IV. Length of hospital delay between endoscopic diagnosis and surgery did not affect pathological tumor-node-metastasis stage or R0-resection rate. Longer hospital delay did not result in worse survival: Overall survival after esophagectomy for cancer was not significantly different between patients with hospital delay <5, 5-8, or >8 weeks (24. 7%, 21. 7%, and 32. 3%, respectively; p = 0. 12). Conclusion: A longer hospital delay (between endoscopic diagnosis and surgery) resulted in worse patient's short-term outcome (higher overall morbidity and mortality rates) but not in a worse long-term outcome (overall survival). This may be explained by a more time-consuming diagnostic workup in patients with a poorer physical status and not by tumor progression. http://repub.eur.nl/res/pub/17488/ 2009-12-01T00:00:00Z Background: Most randomized controlled trials (RCTs) that have compared neoadjuvant chemoradiation followed by surgery with surgery alone for locally advanced esophageal cancer have shown no difference in survival between the two treatments. Meta-analyses on neoadjuvant chemoradiation in esophageal cancer, however, are discordant. Methods: For the present study, published meta-analyses on neoadjuvant chemoradiation for esophageal cancer were identified from the PubMed database and critically appraised in order to make a judgment on the applicability of neoadjuvant chemoradiation in clinical practice and decision making. Results: Two of the six meta-analyses examined did not show a significant survival benefit in patients with resectable esophageal cancer. Differences in the studies included and statistical methods applied might account for this. Moreover, there was heterogeneity between the RCTs included in the meta-analyses with regard to the patients included, tumor histology, and radiotherapy and chemotherapy regimes. Also, surgical technique was not uniform. No data on individual patients were available for most meta-analyses. The RCTs included in the meta-analyses were of inadequate sample size. All were started in the nineties, and hence methods for diagnosis, staging, treatment delivery, and outcome measurement reflect clinical practice during that decade. Conclusions: The current data on neoadjuvant chemoradiation for esophageal cancer strongly indicate the need for designing future high-quality trials that will contribute to a better understanding of the role of neoadjuvant treatment for resectable cancer of the esophagus and help to identify patient subgroups that would benefit most. http://repub.eur.nl/res/pub/17955/ 2009-10-01T00:00:00Z BACKGROUND: Patients with carcinoma of the distal esophagus and metastatic celiac lymph nodes (M1a) have a poor prognosis and are often denied surgery. In this study, we evaluated our treatment strategy of chemotherapy followed by surgery in patients with M1a disease. METHODS: Thirty-eight patients who received chemotherapy for carcinoma of the distal esophagus with celiac lymph node involvement between 2000 and 2007 were identified from a prospective database. Clinical and histopathological responses to chemotherapy were analyzed and follow-up comprised review of medical charts. RESULTS: Twelve non-responding patients were not eligible for surgery. Twenty-six patients with partial responses or stable disease were operated on. The resectability rate was 96% (25/26) and tumor-free resection margins (R0) were achieved in 68% (17/25). The overall survival of patients with M1a disease was 16 months. Patients who received chemotherapy alone had a median survival of 10 months; patients who underwent additional surgery had a median survival of 26 months (log-rank P < 0.001). CONCLUSION: The overall survival of patients with carcinoma of the distal esophagus and clinical celiac lymph node involvement is poor. Tumor-free resection margins (R0) in M1a patients with clinical response to chemotherapy are likely to be achieved and contributes to prolonged survival. (c) 2009 Wiley-Liss, Inc. http://repub.eur.nl/res/pub/24450/ 2009-09-01T00:00:00Z Objective: The sentinel node concept is of great value in the treatment of various malignancies. In this study we investigated whether the application of the sentinel node procedure is feasible in esophageal adenocarcinoma and whether it can tailor surgical treatment of the individual patient. Methods: In 40 patients with an adenocarcinoma of the distal esophagus or gastroesophageal junction, blue dye was injected around the tumor intraoperatively. Sentinel nodes (blue-stained) and nonsentinel nodes were identified and dissected during transhiatal esophagectomy. In sentinel nodes negative for tumor cells on routine hematoxylin-eosin examination, multilevel sectioning and immunohistochemical staining were performed to search for micrometastases. Results: The sentinel node procedure was technically successful in 39 of 40 patients (98%). The median number of sentinel nodes identified was 4. Sentinel nodes were present in more than 1 nodal station in 8 patients (21%). In 6 patients in whom the sentinel node was negative for metastasis, nonsentinel nodes were positive for tumor cells (false-negative rate 6/39 = 15%). Micrometastases and isolated tumor cells were detected in 7 of 19 patients (37%) with sentinel nodes, but this finding did not affect the false-negative rate. Conclusion: Detection of sentinel nodes is technically feasible during esophagectomy for cancer. However, given the relatively high false-negative rate of 15% and the high frequency of sentinel nodes in more than 1 nodal station, the clinical relevance of the sentinel node concept (through application of the blue dye technique) in the current treatment of patients with an adenocarcinoma of the distal esophagus or gastroesophageal junction seems limited. http://repub.eur.nl/res/pub/16072/ 2009-07-01T00:00:00Z Background: The volume-outcome relationship for complex surgical procedures has been extensively studied. Most studies are based on administrative data and use in-hospital mortality as the sole outcome measure. It is still unknown if concentration of these procedures leads to improvement of clinical outcome. The aim of our study was to audit the process and effect of centralizing oesophageal resections for cancer by using detailed clinical data. Methods: From January 1990 until December 2004, 555 esophagectomies for cancer were performed in 11 hospitals in the region of the Comprehensive Cancer Center West (CCCW); 342 patients were operated on before and 213 patients after the introduction of a centralization project. In this project patients were referred to the hospitals which showed superior outcomes in a regional audit. In this audit patient, tumor, and operative details as well as clinical outcome were compared between hospitals. The outcome of both cohorts, patients operated on before and after the start of the project, were evaluated. Results: Despite the more severe comorbidity of the patient group, outcome improved after centralizing esophageal resections. Along with a reduction in postoperative morbidity and length of stay, mortality fell from 12% to 4% and survival improved significantly (P = 0.001). The hospitals with the highest procedural volume showed the biggest improvement in outcome. Conclusion: Volume is an important determinant of quality of care in esophageal cancer surgery. Referral of patients with esophageal cancer to surgical units with adequate experience and superior outcomes (outcome-based referral) improves quality of care. http://repub.eur.nl/res/pub/24233/ 2009-04-01T00:00:00Z Background: Different prediction models for operative mortality after esophagectomy have been developed. The aim of this study is to independently validate prediction models from Philadelphia, Rotterdam, Munich, and the ASA. Methods: The scores were validated using logistic regression models in two cohorts of patients undergoing esophagectomy for cancer from Switzerland (n∈=∈170) and Australia (n∈=∈176). Results: All scores except ASA were significantly higher in the Australian cohort. There was no significant difference in 30-day mortality or in-hospital death between groups. The Philadelphia and Rotterdam scores had a significant predictive value for 30-day mortality (p∈=∈0.001) and in-hospital death (p∈=∈0.003) in the pooled cohort, but only the Philadelphia score had a significant prediction value for 30-day mortality in both cohorts. Neither score showed any predictive value for in-hospital death in Australians but were highly significant in the Swiss cohort. ASA showed only a significant predictive value for 30-day mortality in the Swiss. For in-hospital death, ASA was a significant predictor in the pooled and Swiss cohorts. The Munich score did not have any significant predictive value whatsoever. Conclusion: None of the scores can be applied generally. A better overall predictive score or specific prediction scores for each country should be developed. http://repub.eur.nl/res/pub/30339/ 2008-12-01T00:00:00Z Background. A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial. Methods/design. The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm. The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up. Discussion. This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen. Trial registration. ISRCTN80832026. http://repub.eur.nl/res/pub/30205/ 2008-01-01T00:00:00Z 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 patients' files. Three hundred and forty-two 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. http://repub.eur.nl/res/pub/35423/ 2007-05-01T00:00:00Z OBJECTIVE: To evaluate prognostic factors and tumor staging in patients after esophagectomy for cancer. SUMMARY BACKGROUND DATA: Several reports have questioned the appropriateness of the sixth edition of the International Union Against Cancer (UICC) TNM guidelines for staging esophageal cancer. Additional pathologic characteristics, besides the 3 basic facets of anatomic spread (tumor, node, metastases), might also have prognostic value. METHODS: All patients who underwent resection of the esophagus for carcinoma between January 1995 and March 2003 were extracted from a prospective database. Univariate and multivariate analysis was performed to identify prognostic factors for survival. The goodness of fit and accuracy of 3 staging models (UICC-TNM, Korst classification, Rice classification) predicting survival were assessed. RESULTS: A total of 292 patients (mean age, 63 years) underwent esophagectomy. The 5-year overall survival rate was 29% (median, 21 months). pT-, pN-, pm-stage, and radicality of the resection were independent prognostic factors. Subdivision of T1 tumors into mucosal and submucosal showed significant differences in 5-year survival between both groups: 90% versus 47%, respectively (P = 0.01). Subdivision of pN-stage into 3 groups based on the number of positive nodes (0, 1-2, and >3 nodes positive) or the lymph node ratio (0, 0.01-0.2, and >0.2) also refined staging (P = 0.001 and P < 0.001, respectively). The current subclassification of M1 (M1a and M1b) is not warranted (P = 0.41). The staging model of Rice was more accurate than the UICC-TNM classification in predicting survival. CONCLUSION: This study supports the view that the current (6th edition) UICC-TNM staging model for esophageal cancer needs to be revised. http://repub.eur.nl/res/pub/23407/ 2001-06-06T00:00:00Z Adenocarcinomas of the gastro-oesophageal junction are thought to arise from premalignant Barretr's epithelium. Barrett's epithelium is columnar epithelium that has replaced the normal squamous cell lining of the oesopha",ous. This metaplastic change is driven by duodeno-gastro-oesophageal reflu.'(, which leads to oesophagitis and ultimately, in some patients, to Barrett's epithelium. The development of Barrett's carcinoma involves multiple genetic changes. In PART I, the general introduction of this thesis, CHAPTER 1 reviews our current knowledge on these genetic changes involved in the progression from Barrett's oesophagus to adenocarcinoma. Over the past decades, many researchers focused on the role of cell-cell adhesion in carcinogenesis. The E-cadherin-catenin complex is thought to be the most important regulator of tight cell-cell adhesion in normal tissues, and perturbation of this complex is associated with malignancy. There is evidence that dysfunction of the E-cadherin-catenin complex also plays an important role in the pathogenesis of adenocarcinomas of the gastro-oesophageal junction. In CHAPTER 2, the literature on the role of the E-cadherin-catenin complex in human cancer and the possible clinical implications are discussed. This chapter serves as an introduction to Part IV (chapters 7-10). PART II of the thesis deals ",~th epidemiological and clinical aspects of adenocarcinomas of the gastro-oesophageal junction. http://repub.eur.nl/res/pub/9597/ 2001-01-01T00:00:00Z OBJECTIVE: To review the current knowledge on the genetic alterations involved in the development and progression of Barrett's esophagus-associated neoplastic lesions. SUMMARY BACKGROUND DATA: Barrett's esophagus (BE) is a premalignant condition in which the normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. BE predisposes patients to the development of esophageal adenocarcinoma. Endoscopic surveillance can detect esophageal adenocarcinomas when they are early and curable, but most of the adenocarcinomas are detected at an advanced stage. Despite advances in multimodal therapy, the prognosis for invasive esophageal adenocarcinoma is poor. A better understanding of the molecular evolution of the Barrett's metaplasia to dysplasia to adenocarcinoma sequence may allow improved diagnosis, therapy, and prognosis. METHODS: The authors reviewed data from the published literature to address what is known about the molecular changes thought to be important in the pathogenesis of BE-associated neoplastic lesions. RESULTS: The progression of Barrett's metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure. Some of the molecular alterations already showed promise as markers for early cancer detection or prognostication. Among these, alterations in the p53 and p16 genes and cell cycle abnormalities or aneuploidy appear to be the most important and well-characterized molecular changes. However, the exact sequence of events is not known, and probably multiple molecular pathways interact and are involved in the progression of BE to adenocarcinoma. CONCLUSIONS: Further research into the molecular biology of BE-associated adenocarcinoma will enhance our understanding of the genetic events critical for the initiation and progression of Barrett's adenocarcinoma, leading to more effective surveillance and treatment. http://repub.eur.nl/res/pub/9011/ 1999-01-01T00:00:00Z Incidence rates have risen rapidly for esophageal and gastric cardia adenocarcinomas. These cancers, arising at and around the gastroesophageal junction (GEJ), share a poor prognosis. In contrast, there is no consensus with respect to clinical staging resulting in possible adverse effects on treatment and survival. The goal of this study was to provide more insight into the genetic changes underlying esophageal and gastric cardia adenocarcinomas. We have used comparative genomic hybridization for a genetic analysis of 28 adenocarcinomas of the GEJ. Eleven tumors were localized in the distal esophagus and related to Barrett's esophagus, and 10 tumors were situated in the gastric cardia. The remaining seven tumors were located at the junction and could not be classified as either Barrett-related, or gastric cardia. We found alterations in all 28 neoplasms. Gains and losses were distinguished in comparable numbers. Frequent loss (> or = 25% of all tumors) was detected, in decreasing order of frequency, on 4pq (54%), 14q (46%), 18q (43%), 5q (36%), 16q (36%), 9p (29%), 17p (29%), and 21q (29%). Frequent gain (> or = 25% of all tumors) was observed, in decreasing order of frequency, on 20pq (86%), 8q (79%), 7p (61%), 13q (46%), 12q (39%), 15q (39%), 1q (36%), 3q (32%), 5p (32%), 6p (32%), 19q (32%), Xpq (32%), 17q (29%), and 18p (25%). Nearly all patients were male, and loss of chromosome Y was frequently noted (64%). Recurrent high-level amplifications (> 10% of all tumors) were seen at 8q23-24.1, 15q25, 17q12-21, and 19q13.1. Minimal overlapping regions could be determined at multiple locations (candidate genes are in parentheses): minimal regions of overlap for deletions were assigned to 3p14 (FHIT, RCA1), 5q14-21 (APC, MCC), 9p21 (MTS1/CDKN2), 14q31-32.1 (TSHR), 16q23, 18q21 (DCC, P15) and 21q21. Minimal overlapping amplified sites could be seen at 5p14 (MLVI2), 6p12-21.1 (NRASL3), 7p12 (EGFR), 8q23-24.1 (MYC), 12q21.1, 15q25 (IGF1R), 17q12-21 (ERBB2/HER2-neu), 19q13.1 (TGFB1, BCL3, AKT2), 20p12 (PCNA), 20q12-13 (MYBL2, PTPN1), and Xq25. The distribution of the imbalances revealed similar genetic patterns in the three GEJ tumor groups. However, loss of 14q31-32.1 occurred significantly more frequent in Barrett-related adenocarcinomas of the distal esophagus, than in gastric cardia cancers (P = 0.02). The unclassified, "pure junction" group displayed an intermediate position, suggesting that these may be in part gastric cardia tumors, whereas the others may be related to (short-segment) Barrett's esophagus. In conclusion, this study has, fist, provided a detailed comparative genomic hybridization-map of GEJ adenocarcinomas documenting new genetic changes, as well as candidate genes involved. Second, genetic divergence was revealed in this poorly understood group of cancers.