Influence of the surgical technique on survival in the treatment of carcinomas of the true cardia (Siewert Type II) - Right thoracoabdominal vs. transhiatal-abdominal approach.

INTRODUCTION: It is still a matter of debate whether subtotal esophagectomy via a right thoracoabdominal approach (RTA) or extended gastrectomy using a transhiatal-abdominal approach (TH) is the favorable technique in the treatment of Siewert type II esophago-gastric junction adenocarcinoma (EJA). MATERIALS AND METHODS: Patients undergoing RTA or TH for EJA at our institution between 2000 and 2013 were extracted from a prospective database. Of 270 patients 91 (33.7%) underwent RTA and 179 (66.3%) were treated by TH. Differences in baseline characteristics, 30d mortality and complications were investigated using the χ2-test or exact testing. Survival analysis was performed using the Kaplan-Meier method and log rank testing. Median survival and hazard ratios were calculated and multivariable analysis of predictors was performed using a Cox model. Confounders were balanced using propensity score matching (PSM). RESULTS: No significant difference between the two procedures was detected regarding overall-survival (OS) and disease-free survival (DFS). 30d mortality rates were 1.1% in the RTA group and 4.5% in the TH group (p = 0.134). Morbidity was 34.1% in the RTA and 24.6% in the TH group (p = 0.006). Cox regression analysis identified age, ASA class and UICC stage as independent prognostic factors for OS. After PSM survival curves (OS + PFS) showed no significant difference. CONCLUSION: The present study could not detect a difference between RTA and TH from the oncologic point of view; RTA was not associated with higher 30d mortality. RTA for Siewert Type II EJA is justified whenever the oral tumor margin cannot be safely reached via a transhiatal approach.

Influence of an elevated nutrition risk score (NRS) on survival in patients following gastrectomy for gastric cancer.

In the last years, the impact of weight loss in patients with malignant tumors has come more and more into the focus of clinical research, as the occurrence of weight loss is often associated with a reduced survival. Weight loss can be a hint for metastases in patients suffering from malignant tumors; furthermore, these patients are usually not able to be treated with chemotherapy. The aim of the study was to show the influence of weight loss and an elevated nutrition risk score on survival following tumor resection in patients suffering from gastric cancer. In 99 patients in whom a gastrectomy due to gastric cancer was performed, the nutrition risk score was calculated and its influence on mortality, morbidity and survival was analyzed. Of the included patients, 45 % of the patients gave a history of weight loss; they had significantly more often a NRS ≥ 3. In UICC stage 1a/b, a NRS ≥ 3 was associated with a significantly reduced survival compared to patients with a NRS < 3. In early tumor stages (UICC 1a/b), a NRS ≥ 3 was associated with a significantly reduced survival, while in progressed tumor stage, the influence of a poor NRS was not significant. This seems to show that in progressed stages in patients with gastric cancer, the influence of a reduced NRS is negligible.

Multi-colour FISH in oesophageal adenocarcinoma-predictors of prognosis independent of stage and grade.

BACKGROUND: Oesophageal adenocarcinoma or Barrett's adenocarcinoma (EAC) is increasing in incidence and stratification of prognosis might improve disease management. Multi-colour fluorescence in situ hybridisation (FISH) investigating ERBB2, MYC, CDKN2A and ZNF217 has recently shown promising results for the diagnosis of dysplasia and cancer using cytological samples. METHODS: To identify markers of prognosis we targeted four selected gene loci using multi-colour FISH applied to a tissue microarray containing 130 EAC samples. Prognostic predictors (P1, P2, P3) based on genomic copy numbers of the four loci were statistically assessed to stratify patients according to overall survival in combination with clinical data. RESULTS: The best stratification into favourable and unfavourable prognoses was shown by P1, percentage of cells with less than two ZNF217 signals; P2, percentage of cells with fewer ERBB2- than ZNF217 signals; and P3, overall ratio of ERBB2-/ZNF217 signals. Median survival times for P1 were 32 vs 73 months, 28 vs 73 months for P2; and 27 vs 65 months for P3. Regarding each tumour grade P2 subdivided patients into distinct prognostic groups independently within each grade, with different median survival times of at least 35 months. CONCLUSIONS: Cell signal number of the ERBB2 and ZNF217 loci showed independence from tumour stage and differentiation grade. The prognostic value of multi-colour FISH-assays is applicable to EAC and is superior to single markers.

A specific expression profile of heat-shock proteins and glucose-regulated proteins is associated with response to neoadjuvant chemotherapy in oesophageal adenocarcinomas.

BACKGROUND: Oesophageal adenocarcinomas often show resistances to chemotherapy (CTX), therefore, it would be of high interest to better understand the mechanisms of resistance. We examined the expression of heat-shock proteins (HSPs) and glucose-regulated proteins (GRPs) in pretherapeutic biopsies of oesophageal adenocarcinomas to assess their potential role in CTX response. METHODS: Ninety biopsies of locally advanced adenocarcinomas before platin/5-fluorouracil (FU)-based CTX were investigated by reverse phase protein arrays (RPPAs), immunohistochemistry (IHC) and quantitative RT-PCR. RESULTS: CTX response strongly correlated with survival (P=0.001). Two groups of tumours with specific protein expression patterns were identified by RPPA: Group A was characterised by low expression of HSP90, HSP27 and p-HSP27((Ser15, Ser78, Ser82)) and high expression of GRP78, GRP94, HSP70 and HSP60; Group B exhibited the inverse pattern. Tumours of Group A were more likely to respond to CTX, resulting in histopathological tumour regression (P=0.041) and post-therapeutic down-categorisation from cT3 to ypT0-T2 (P=0.040). High HSP60 protein (IHC) and mRNA expression were also associated with tumour down-categorisation (P=0.016 and P=0.004). CONCLUSION: Our findings may enhance the understanding of CTX response mechanisms, might be helpful to predict CTX response and might have translational relevance as they highlight the role of potentially targetable cellular stress proteins in the context of CTX response.

[The new TNM classification of tumors of the esophagogastric junction. Surgical consequences]. / Die neue TNM-Klassifikation der Tumoren des ösophagogastralen Übergangs. Chirurgische Konsequenzen.

The new International Union Against Cancer (UICC) classification in its seventh version has been out since January 2010. It included some important changes for the classification of esophageal and gastric carcinomas compared to the sixth version. For esophageal carcinomas this means a more detailed subdivision of the T and N stages which should, together with the newly introduced prognostic grouping (separate for squamous cell carcinoma and adenocarcinoma) enable a more precise and individualized prediction of prognosis. Another innovation is that positive lymph nodes in the esophageal drainage area, including celiac axis nodes and paraesophageal lymph nodes in the neck, are classified as regional lymph node metastases rather than distant metastatic spread, irrespective of tumor location. Hereby the lymphadenectomy specimen should include ≥ 6 lymph nodes (LN). The most controversial improvement is that adenocarcinomas of the esophagogastric junction (AEG) are all classified as esophageal carcinomas. This should acknowledge the similar prognosis of AEGs and esophageal carcinomas, which is worse compared to gastric carcinomas in other locations. Regarding the classification of gastric carcinomas the T-stages were redefined and lymph node staging (N-stage) was refined to allow for a better prediction of prognosis. The lymphadenectomy specimen after gastrectomy should hereby include ≥ 16 LNs. As the primary aim of the UICC classification is a preferably accurate prognosis prediction, the impact on a surgeon's therapeutic decision is low. For decisions regarding the type of resection the endoscopic AEG classification with the aim of R0 resections is still the instrument of choice. The value of the UICC classification is that it enables sophisticated comparisons between different treatment regimens and strategies.

Training of a standardized natural orifice transluminal endoscopic surgery cholecystectomy using an ex vivo training unit.

BACKGROUND AND STUDY AIMS: The endoscopic-laparoscopic interdisciplinary training entity (ELITE) is one of the first training models for the training of natural orifice transluminal endoscopic surgery (NOTES) and conventional laparoscopic and endoscopic skills. The current study was designed to assess whether the effect of surgical simulation with an ex vivo training unit is relevant to surgical practice in the operating room and who, in particular, might benefit from this training. PATIENTS AND METHODS: A group of 30 participants (gastroenterologists, laparoscopists, and novices) performed a standardized NOTES cholecystectomy via a trans-sigmoidal approach. Fifteen participants performed the cholecystectomy following training with ELITE and 15 participants performed the procedures without previous training. The parameters studied were task times, quality and safety of the surgical procedure, and subjective evaluation of the ELITE trainer as a teaching model. RESULTS: During the training courses all participants showed a significant learning curve, with a total time needed on the first pass of 32 minutes vs. 18 minutes for the fourth pass ( P < 0.001). For the cholecystectomy in the pig model, participants with prior training needed less time to complete the procedure than participants without training. In the group without training, more complications/difficulties occurred than in the group with prior training (16 vs. 8). The video analyses by two independent NOTES experts showed an inter-rater validity of 1.0. Subjective evaluation showed that participants considered ELITE to be a suitable and recommendable simulator for NOTES. CONCLUSIONS: The ELITE model is suitable for training in the NOTES cholecystectomy procedure. This type of simulator training leads to fewer intraoperative complications.

[Neoadjuvant therapy in the upper gastro-intestinal tract. Modern strategies for Barrett's cancer]. / Neoadjuvante Therapie im oberen Gastrointestinaltrakt. Aktuelle Konzepte beim Barrett-Karzinom.

While primary surgical resection with systematic lymphadenectomy remains the treatment of choice for locoregional Barrett's cancer, neoadjuvant chemotherapy is an increasingly accepted treatment modality for patients with locally advanced tumors and patients with extensive lymphatic spread. In contrast to neoadjuvant radiochemotherapy preoperative chemotherapy alone does not seem to increase peri-operative complications and mortality. Responders to pre-operative treatment clearly have a survival advantage as compared to those who do not respond. The use of positron emission tomography to measure changes in glucose metabolism of the primary tumor can predict response early after initiation of neoadjuvant chemotherapy and thus help to select patients who will or will not benefit from this approach. The best treatment strategy for non-responders to neoadjuvant therapy remains to be defined.

Management of early esophageal cancer.

In early esophageal cancer, squamous cell cancer and early adenocarcinoma must be managed differently because they have different origins, pathogenesis. and clinical characteristics. The current treatment options vary widely, from extended resection with lymphadenectomy to endoscopic mucosectomy or ablation. None of these treatment options can be recommended universally. Instead, an individualized strategy should be based on the depth of tumor infiltration into the mucosa or submucosa, the presence or absence of lymph node metastases, the multicentricity of tumor growth, the length of the segment of intestinal metaplasia, and comorbidities of the patient. Endoscopic mucosectomy may be sufficient in a subset of patients who have m1 or m2 squamous cell carcinoma and in patients who have isolated foci of high-grade intraepithelial neoplasia or mucosal cancer. Surgical resection is the treatment of choice for carcinomas invading the submucosal and multicentric tumors. Limited resection with jejunal interposition provides an effective treatment option for patients who have early esophageal adenocarcinoma. The onset of lymph node involvement is later in patients who have early adenocarcinoma than in patients who have squamous cell cancer, probably because chronic injury and repair mechanisms obliterate the otherwise abundant lymph vessels.

[Lymphadenectomy with tumors of the upper gastrointestinal tract]. / Lymphadenektomie bei Tumoren des oberen Gastrointestinaltraktes.

In surgical therapy for upper gastrointestinal cancer, adequate lymphadenectomy together with R0 resection of the primary tumour is one of the most important prognostic factors which can be influenced by the surgeon. Recommendations for localization- and stage-adapted lymphadenectomy can be made according to histopathologic and anatomic investigations of the patient collectives of large centres. After neoadjuvant radiochemotherapy in cancer of the cervical oesophagus, the absence of lymph nodes on the resected specimen seems to be of less prognostic value. In squamous cell cancer of the suprabifurcal oesophagus, radical lymphadenectomy is recommended. Despite significant morbidity, in specialized centres this procedure yields good results with low mortality. For infrabifurcal oesophageal cancer, two-field lymphadenectomy during the so-called Ivor-Lewis operation is the method of choice. Locally advanced Barrett carcinoma is also an indication for classic two-field lymphadenectomy together with abdominothoracic oesophagectomy and creation of a stomach tube with intrathoracic anastomosis. The lymphadenectomy should however include the area of retroperitoneal lymphatic drainage at the pedicle of the left kidney. Submucosal cancer in this area can be treated with luminal limited resection of the oesophagogastric junction with adequate lymphadenectomy. Adenocarcinoma of the cardia and subcardial gastric cancer including the cardia both require lymphadenectomy analogous to that performed in gastric cancer, with special attention paid to the retroperitoneal lymphatic drainage towards the left kidney pedicle. For therapy of gastric cancer, a systematic D2 lymphadenectomy should always be performed.

[Oesophageal tumours--what does the surgeon need from the radiologist?]. / Tumoren des Osophagus--was benötigt der Chirurg vom Radiologen?

Surgery is the most important therapeutic discipline for oesophageal cancers and the surgeon has specific questions for the radiologist which can require various imaging procedures. The radiological presentation is, for example, necessary for the topographic imaging of larger space occupying processes, the localization and axial spread of which are important for the surgical procedure chosen. Imaging diagnostics helps with the identification of R0 resectable patients. High resolution computed tomography (CT) of the mediastinum is used to clarify the spatial relationship between oesophageal cancer and the tracheobronchial system. This method also helps demonstrate the presence of fistulas in the tracheobronchial system or mediastinum. Using a neck or thorax CT, or a PET-CT distant metastases can be documented and a second tumour excluded. Imaging procedures gain additional significance for the evaluation of the T stage of the oesophageal tumour or the response to neoadjuvant therapy concepts, for which an earliest possible response evaluation is of great importance. Imaging procedures are also of importance in aftercare as it is sometimes possible and valuable to carry out surgery for local relapses.

Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study.

AIMS: To correlate immunohistochemical expression patterns and prognosis in oesophageal adenocarcinoma. METHODS: The expression of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor (EGFR) was studied in a series of 137 primarily resected oesophageal adenocarcinoma samples. The expression analysis on protein level was performed on routine paraffin wax-embedded material, with immunohistochemical staining of the samples, assembled on a tissue microarray. The results were correlated with clinicopathological features (pT, pN and G) and survival. RESULTS: 22 (16%) tumours showed an overexpression of the c-erbB-2 oncoprotein. Expression of EGFR was observed in 72 (55%) cases, accumulation of p53 in 68 (52%) cases and of cyclin D1 in 102 (77%) cases. Loss of p16INK4A expression was observed in 101 (76%) cases and low expression of p27KIP1 in 91 (71%) cases. Expression of these proteins did not correlate with tumour stage, grade, Lauren's or World Health Organization classification or lymph node status. On univariate survival analysis, more advanced tumour stage (p = 0.002), lymph node involvement (p = 0.003), high tumour grade (p = 0.017) and lack of EGFR expression (p = 0.034) were found to be associated with poorer survival. On multiple regression analysis, only tumour stage (p = 0.03) and lymph node involvement (p = 0.004) were shown to have an association with the survival of the patient. CONCLUSION: The immunohistochemical expression of c-erbB-2 oncoprotein, cylin D1, p16INK4A, p27KIP1, p53 and EGFR in most oesophageal adenocarcinomas suggests their implication in the pathogenesis of this entity. None of the molecular markers assessed, however, was of prognostic value. Identification of any marker superior to or even approaching the prognostic value of conventional histopathological markers (pT and pN) was therefore not possible.

[Limited surgical resection versus local endoscopic therapy of early cancers of the esophagogastric junction]. / Limitierte chirurgische Resektion versus lokale endoskopische Therapie beim Frühkarzinom des ösophagogastralen Ubergangs.

BACKGROUND: Adenocarcinomas of the esophagogastric junction (especially Barrett's cancers) are increasingly diagnosed at early stages. The current standard treatment - radical resection with extensive lymphadenectomy - has been challenged. Limited resection or endoscopic mucosal ablation have been proposed as less invasive alternatives. METHODS: Available data regarding limited surgical resections and endoscopic interventional procedures are evaluated with respect to short- and long-term results (mortality, morbidity, oncologic adequacy, quality of life). RESULTS: Limited resection of the esophagogastric junction has been proven as safe (low morbidity and mortality) and oncologically adequate procedure (low rate of recurrence/excellent long-term survival) with good quality of life. The procedure meets the oncological requirements (R0-resection, complete resection of potentially tumor-infiltrated lymph nodes and the entire precancerous Barrett's esophagus). Reconstruction with interposition of a pedicled isoperistaltic jejunal loop prevents reflux and is crucial for achieving good postoperative quality of life. In contrast, endoscopic mucosal resection (EMR) carries the risk of high recurrence rates (at least 30 %). This has to be regarded as an effect of the frequent incomplete resection, multicentric tumor growth, the persistence of precancerous Barrett's mucosa and persistence of gastroesophageal reflux. Consequently, from the oncological view point, EMR is only suited for unicentric mucosal tumors (T1a) in short segments of Barrett's esophagus. Reliable preoperative identification of such tumors is, however, currently not possible. CONCLUSION: For adequately selected patients with early Barrett's cancer, limited resection of the esophagogastric junction is an appropriate procedure. Endoscopic mucosa resection (EMR) might gain importance as staging tool.

The prognostic impact of O6-Methylguanine-DNA Methyltransferase (MGMT) promotor hypermethylation in esophageal adenocarcinoma.

Promotor hypermethylation is a common event in human cancer. O6-Methylguanine-DNA Methyltransferase (MGMT) is a gene involved in DNA repair, which is methylated in a variety of cancer types. In colorectal cancer and lung cancer, hypermethylation of MGMT has been correlated with p53 mutation. In the present study, 132 samples of esophageal adenocarcinoma and 58 samples of normal esophageal tissue were investigated for MGMT hypermethylation status by methylation-specific real-time PCR and results were correlated to clinicopathological parameters, patient's survival, p53 mutation and expression of p53 protein and MGMT protein. In the carcinomas, hypermethylation of MGMT was found in 63.6% of cases and loss of MGMT protein expression in 48.5% of cases. Furthermore, MGMT hypermethylation was found in 5.7% of normal esophageal smooth muscle tissue, in 20.0% of esophageal squamous epithelium and in 61.5% of nonneoplastic Barrett's mucosa. In the carcinomas, hypermethylation of the MGMT gene was correlated with loss MGMT protein expression (p < 0.0001) and with high tumor differentiation (p = 0.0079). In contrast, no correlation between MGMT hypermethylation, Lauren's classification, WHO classification, tumor size, gender, age, pT category and pN category, and p53 status was found. Neither MGMT hypermethylation nor loss of MGMT protein expression was correlated with patient's survival. In conclusion, MGMT hypermethylation in esophageal adenocarcinoma is a frequent event that is associated with loss of MGMT protein expression but not with patient's outcome.

Preferred location for the development of esophageal adenocarcinoma within a segment of intestinal metaplasia.

BACKGROUND: Barrett's metaplasia is the predominant precursor for the development of esophageal adenocarcinoma. This precancerous lesion has become the focus of various surveillance programs aimed at detecting earlier and therefore potentially curable lesions. However, sampling error by missing invasive cancer lesions is a common problem. This study aimed to identify preferred locations within a segment of Barrett's mucosa for the development of esophageal adenocarcinoma. METHODS: The study group consisted of 213 patients with histologically proven esophageal adenocarcinoma. Of those, there were 134 cases of early cancer and 79 cases of locally advanced lesions. These patients received neoadjuvant chemotherapy. The frequency of intestinal metaplasia and the location of the tumor occurrence within the segment of intestinal metaplasia were assessed. RESULTS: Intestinal metaplasia was found in 83% of the early lesions and in 98% of the advanced tumors after neoadjuvant chemotherapy. In 82.2% of the cases, the tumor was located at the distal margin of the intestinal metaplasia in patients with early tumor manifestations. The remaining tumor mass after neoadjuvant therapy also was located predominantly at the distal margin of the segment of intestinal metaplasia (85% of the cases). CONCLUSIONS: The results demonstrate that almost all adenocarcinomas of the esophagus are based on the development of a segment of intestinal metaplasia. The distal margin of Barrett's mucosa seems to be the most vulnerable location for the development of invasive cancer.

Adenocarcinoma of the esophago-gastric junction.

BACKGROUND: The border between the esophagus and stomach gives rise to many discrepancies in the current literature regarding the etiology, classification and surgical treatment of adenocarcinoma arising at the esophago-gastric junction. We have consequently used the AEG-criteria (adenocarcinoma of the esophago-gastric junction) for classification and have based the selection of the surgical approach on the anatomic topographic subclassification. METHODS: In the following we report an analysis of a large and homogeneously classified population of 1602 consecutive patients with adenocarcinoma of the esophago-gastric junction, with an emphasis on the surgical approach, the pattern of lymphatic spread, the outcome after surgical treatment and the prognostic factors. Demographic data, morphologic and histopathologic tumor characteristics, and long-term survival rates were compared among the three tumor subclassifiations. RESULTS: The study confirms the marked differences in sex distribution, associated specialized intestinal metaplasia in the esophagus, tumor grading, tumor growth pattern, lymphatic spread, and stage between the three tumor entities. The degree of resection and lymph node status were the dominating independent prognostic factors by multivariate analysis. The data show no significant differences of long-term survival after abdomino-thoracic esophagectomy and extended total gastrectomy in these patients. CONCLUSION: The classification of adenocarcinomas of the esophago-gastric junction in three types, AEG type I, type II and type III shows marked differences between the tumor entities and is recommended for selection of a proper surgical approach. Complete tumor resection and adequate lymphadenectomy are associated with good long-term prognosis. Better surgical management and standardized procedures will improve the outcome also of patients who need to undergo more radical surgery, i.e. abdomino-thoracic esophagectomy.

Surgical strategies for early esophageal adenocarcinoma.

The need for extensive surgical resection for early-stage esophageal adenocarcinoma has been challenged by the increasing frequency of early detection in patients with Barrett's esophagus undergoing surveillance endoscopy. Limited endoscopic or surgical procedures are promoted as alternatives to radical esophagectomy and lymphadenectomy in such patients. Currently available data show that limited surgical resection of the distal esophagus with regional lymphadenectomy and interposition of an isoperistaltic jejunal segment is a safe and oncologically adequate procedure in this situation and provides good quality of life. This is in contrast to endoscopic ablation or endoscopic mucosal resection, which are associated with high tumour recurrence rates and persistence of premalignant Barrett esophagus. New technologies for accurate prediction of the presence and pattern of lymphatic spread-e.g. sentinel node techniques and artificial neural networks-may allow a further reduction of the invasiveness of surgical resection without compromising cure rates.

Surgery for early stage esophageal adenocarcinoma.

Current treatment recommendations for early esophageal adenocarcinoma range from radical esophagectomy with extensive lymphadenectomy, limited surgical resection with/without regional lymphadenectomy to endoscopic mucosectomy or ablation. A comparison of treatment associated morbidity, tumor recurrence rates, and functional outcome suggests that none of these alternatives can be universally recommended. Rather, an individualized strategy should be employed based on depth of tumor penetration into the mucosa/submucosa, presence of lymph node metastases, multicentricity of tumor growth, length of the underlying Barrett mucosa and comorbidity of the affected patient. Endoscopic mucosectomy may suffice for an isolated focus of high-grade neoplasia or mucosal cancer, provided the neoplasia and underlying Barrett mucosa can be removed completely. Surgical resection is the treatment of choice for tumors invading the submucosa, multicentric tumors and recurrence after endoscopic mucosectomy. The extent of surgical resection must be guided by the length of the Barrett mucosa. In most instances a complete tumor resection and removal of the entire Barrett mucosa can be achieved by a limited transabdominal approach, and therefore subtotal esophagectomy may not be necessary. Application of the sentinel node technology may in the future allow to limit systematic lymphadenectomy to the rather small subgroup of patients who in fact have lymph node metastases.

[Esophagectomy as therapeutic principle for squamous cell esophageal cancer]. / Osophagektomie als chirurgisches Therapieprinzip beim Plattenepithelkarzinom des Osophagus.

The fatalistic approach towards surgical therapy of esophageal squamous cell cancer has been replaced in recent years by a more differentiated view. This was triggered by the establishment of individualized therapeutic modalities based on tumor stage, tumor location, general patient status, and comorbidity. Despite advances in nonsurgical therapy of squamous cell esophageal cancer, esophagectomy remains the central therapeutic modality. Primary subtotal en-bloc esophagectomy with lymphadenectomy is the only curative option with a high likelihood of success for resectable tumors (uT1-3 categories) located below the level of the tracheal bifurcation and for early more proximal tumors. In patients with locally advanced tumors at or above the level of the tracheal bifurcation, surgical resection can still cure those who respond to neoadjuvant radiochemotherapy. Preoperative "conditioning" of risk patients, surgical safety strategies in risk situations, and standardization of both the operative procedure and the perioperative management have resulted in a marked reduction of the previously substantial postoperative mortality to below 3% in experienced centers. In our own experience of 900 esophagectomies for squamous cell esophageal cancer, the 5-year survival rate rose from about 20% to more than 50% in the last two decades. Esophagectomy thus has become a safe operation and remains the only therapeutic option offering cure for a substantial proportion of patients with squamous cell cancer of the esophagus.

COX2 expression, angiogenesis, proliferation and survival in Barrett's cancer.

OBJECTIVES: To examine COX2 expression and its relation to angiogenesis, Ki67 and Bcl2 expression in Barrett's cancer. METHODS: Specimens from 48 R0-resected Barrett's adenocarcinoma were immunostained for cyclooxygenase 2 (COX2), CD 31 and alpha-sm actin to discriminate between mature and immature vessels, Mib-1 and Bcl2. COX2 staining, angiogenesis, Ki67 expression and Bcl2 expression were also measured. RESULTS: COX2 expression was increased in 25 of 48 cases. There was no significant correlation between COX2 expression and age, sex and tumor differentiation. A significant association was found between lymph node positive cases and elevated COX2 expression (p=0.008). The percentage of Ki67 positive cancer cells was 43.8% (range 15.4-67.5%) in the low COX2 group and 57.8% (range 12.0-84.6%) in the high COX2 group. The difference was statistically significant (p=0.046). The median neovascularisation coefficient in the low COX2 group was 11.68 (range 8.22-43.64) and 25.47 (range 8-38.3) in the high COX2 group. The difference was statistically significant (p=0.012). A significant difference in survival was observed between patients in the COX2 low category when compared with the COX2 high category (log-rank test p=0.013). CONCLUSIONS: Elevated COX2 expression is associated with lymph-node metastases and reduced survival in Barrett's cancer. This appears to be related to the induction of angiogenesis and proliferation.

Malignant degeneration of Barrett's esophagus: the role of the Ki-67 proliferation fraction, expression of E-cadherin and p53.

Barrett's columnar epithelium with dysplasia is the most important risk factor for adenocarcinoma of the distal esophagus. The molecular mechanisms responsible for progression of columnar metaplasia to dysplasia and invasive carcinoma are mostly unknown. We investigated expression of the tumor suppressor gene p53, E-cadherin expression and cell proliferation in the metaplasia-dysplasia-carcinoma sequence of esophageal adenocarcinoma. In 24 patients with R0-resected adenocarcinomas of the distal esophagus we evaluated the expression of E-cadherin (antibody HECD-1), mutated p53 (antibody DO1) and cell proliferation (antibody MiB1) by immunohistochemistry in sections of adenocarcinoma, columnar metaplasia, with and without dysplasia, and in squamous epithelium of the esophagus. No p53 immunoreactivity was seen in sections of normal squamous epithelium or columnar metaplasia. Fifty per cent of invasive adenocarcinomas stained positive for mutated p53. The p53 expression correlated with the T-category (P = 0.048) and the N-category (P = 0.024). There was a significant decrease in the expression of E-cadherin from columnar metaplasia to dysplasia and to esophageal adenocarcinoma (P < 0.0001). Expression of E-cadherin in columnar metaplasia without dysplasia was similar to that seen in normal squamous epithelium of the esophagus. The Ki-67 proliferation fraction increased significantly from normal squamous epithelium to columnar metaplasia to dysplasia and to invasive carcinoma (P < 0.001), with a marked expansion of the proliferative component. There was no correlation between cell proliferation, E-cadherin expression and the tumor stage. In contrast to the alterations in the p53 expression, a decreased E-cadherin expression and the expansion of the proliferative component represent an early phenomenon in the malignant degeneration of Barrett's esophagus. This might aid in the early detection of esophageal adenocarcinoma.