Grotenhuis, B.A.

Early morbidity encountered in the dietary-related mouse model of Barrett's esophagus: A question of zinc? (Article)

2011-07-01T00:00:00Z

Recently, a mouse model for Barrett's esophagus based on a zinc-deficient diet supplemented with deoxycholic bile acids has been published. The aim of this study was to attempt to reproduce these data and extend them by employing genetically modified mice and intraperitoneal iron supplementation. The study design encompassed six experimental groups (wild type, Apc-mutant and Smad4-mutant mice, with or without iron injections), with all animals fed with the zinc-deficient diet supplemented with deoxycholic bile acids. All treatments were started at 3-5 weeks of age (the majority [78%] at 5 weeks). Animals were scheduled for euthanasia at two distinct time points, namely at 3 and 6 months of age. All mice showed signs of considerable distress already 4 weeks after the start of the modified diets, and had to be euthanized before the first evaluation time point (mean age 9.3 weeks, range 5-15 weeks). No differences were observed between wild type and genetically modified mice, or between animals with or without iron supplementation. On histological examination, we could not detect any lesions (Barrett's esophagus-like or tumors) other than esophagitis. In the currently presented experimental settings, we were not able to reproduce the mouse model according to which Barrett's-like lesions could be detected in animals fed with the zinc-deficient diet supplemented with deoxycholic bile acids. © 2010 Copyright the Authors. Journal compilation

The Miscellaneous Mystery of Esophageal Cancer: New pathogenetic and clinical insights (Doctoral Thesis)

2010-12-01T00:00:00Z

Esophageal cancer is the 8th most common type of malignancy and the 6th most common cause of cancer mortality in the world. Worldwide more than 400,000 patients are newly diagnosed with esophageal cancer each year. The majority of patients (>90%) is diagnosed with the two most common histological subtypes: squamous cell carcinoma or adenocarcinoma of the esophagus. Esophageal squamous cell carcinoma arises from dysplastic squamous epithelium, usually as a result of chronic irritation. Substantial alcohol intake, especially in combination with smoking, greatly increases the risk of squamous cell carcinoma and accounts for more than 90 percent of all cases of squamous cell carcinoma of the esophagus in the developed world. Patients with recurring symptoms of reflux have an eightfold increase in the risk of developing esophageal adenocarcinoma. Ongoing gastroesophageal reflux results in the replacement of normal squamous epithelium by a columnar-lined esophagus, which is characterized by the presence of intestinal metaplasia. This so-called Barrett’s esophagus is the precursor lesion of esophageal adenocarcinoma, that develops through a metaplasia – dysplasia – carcinoma sequence.

Lymphatic micrometastases in patients with early esophageal adenocarcinoma (Article)

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.

Inter- and intraobserver variation in the histopathological evaluation of early oesophageal adenocarcinoma (Article)

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.

Validation of a nomogram predicting complications after esophagectomy for cancer (Article)

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.

Prognostic Value of Body Mass Index on Short-Term and Long-Term Outcome after Resection of Esophageal Cancer (Article)

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.

Reply to the Editor (Article)

2010-06-01T00:00:00Z

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

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.

Delay in diagnostic workup and treatment of esophageal cancer (Article)

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.

The sentinel node concept in adenocarcinomas of the distal esophagus and gastroesophageal junction (Article)

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.