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OBJECTIVE: The aim was to develop a reliable surgical quality assurance system for 2-stage esophagectomy. This development was conducted during the pilot phase of the multicenter ROMIO trial, collaborating with international experts.SUMMARY OF BACKGROUND DATA: There is evidence that the quality of surgical performance in randomized controlled trials influences clinical outcomes, quality of lymphadenectomy and loco-regional recurrence.METHODS: Standardization of 2-stage esophagectomy was based on structured observations, semi-structured interviews, hierarchical task analysis, and a Delphi consensus process. This standardization provided the structure for the operation manual and video and photographic assessment tools. Reliability was examined using generalizability theory.RESULTS: Hierarchical task analysis for 2-stage esophagectomy comprised fifty-four steps. Consensus (75%) agreement was reached on thirty-nine steps, whereas fifteen steps had a majority decision. An operation manual and record were created. A thirty five-item video assessment tool was developed that assessed the process (safety and efficiency) and quality of the end product (anatomy exposed and lymphadenectomy performed) of the operation. The quality of the end product section was used as a twenty seven-item photographic assessment tool. Thirty-one videos and fifty-three photographic series were submitted from the ROMIO pilot phase for assessment. The overall G-coefficient for the video assessment tool was 0.744, and for the photographic assessment tool was 0.700.CONCLUSIONS: A reliable surgical quality assurance system for 2-stage esophagectomy has been developed for surgical oncology randomized controlled trials.ETHICAL APPROVAL: 11/NW/0895 and confirmed locally as appropriate, 12/SW/0161, 16/SW/0098.TRIAL REGISTRATION NUMBER: ISRCTN59036820, ISRCTN10386621.

Purpose Esophageal perforation is associated with high morbidity and mortality. In addition to surgical treatment, endoscopic endoluminal stent placement and endoscopic vacuum therapy (EVT) are established methods in the management of this emergency condition. Although health-related quality of life (HRQoL) is becoming a major issue in the evaluation of any therapeutic intervention, not much is known about HRQoL, particularly in the long-term follow-up of patients treated for non-neoplastic esophageal perforation with different treatment strategies. The aim of this study was to evaluate patients’ outcome after non-neoplastic esophageal perforation with focus on HRQoL in the long-term follow-up. Methods Patients treated for non-neoplastic esophageal perforation at the University Hospital Cologne from January 2003 to December 2014 were included. Primary outcome and management of esophageal perforation were documented. Long-term quality of life was assessed using the Gastrointestinal Quality of Life Index (GIQLI), the Health-Related Quality of Life Index (HRQL) for patients with gastroesophageal reflux disease (GERD), and the European Organization for Research and Treatment of Cancer (EORTC) questionnaires for general and esophageal specific QoL (QLQ-C30 and QLQ-OES18). Results Fifty-eight patients were included in the study. Based on primary treatment, patients were divided into an endoscopic (n = 27; 46.6%), surgical (n = 20; 34.5%), and a conservative group (n = 11; 19%). Short- and long-term outcome and quality of life were compared. HRQoL was measured after a median follow-up of 49 months. HRQoL was generally reduced in patients with non-neoplastic esophageal perforation. Endoscopically treated patients showed the highest GIQLI overall score and highest EORTC general health status, followed by the conservative and the surgical group. Conclusion HRQoL in patients with non-neoplastic esophageal perforation is reduced even in the long-term follow-up. Temporary stent or EVT is effective and provides a good alternative to surgery, not only in the short-term but also in the long-term follow-up.

Background/Aim: Esophagectomy and gastrectomy are procedures with considerable physical burden and intense post-operative care of which the patient’s physical condition seems to be a relevant predictor. The gold standard of the cardiorespiratory fitness is the peak oxygen consumption (VO(2)peak). This pilot study examined the prognostic value of VO(2)peak on post-surgery outcomes in esophageal and gastric cancer patients. Patients and Methods: In this prospective cross-sectional study, patients scheduled for esophagectomy or gastrectomy were examined 24 h before the surgery regarding their VO(2)peak. The post-operative complications according to Clavien-Dindo grade IIIb/IV/V, Intensive-Care-Unit days, and overall hospital stay were documented following surgery. In a subset, body weight changes from surgery until hospital discharge and first aftercare visit were recorded. Results: The functional capacity was significantly reduced in 34/35 of the included patients compared to matched norm-values (p

The incidence of esophagogastric junction (EGJ) cancer has been significantly increasing in Western countries. Appropriate planning for surgical therapy requires a reliable classification of EGJ cancers with respect to their exact location. Clinically, the most accepted classification of EGJ cancers is "adenocarcinoma of the EGJ" (AEG or "Siewert"), which divides tumor center localization into AEG type I (distal esophagus), AEG type II ("true junction"), and AEG type III (subcardial stomach). Treatment strategies in western countries routinely employ perioperative chemotherapy or neoadjuvant chemoradiation for cases of locally advanced cancers. The standard surgical treatment strategies are esophagectomy for AEG type I and gastrectomy for AEG type III cancers. For "true junctional cancers," i.e., AEG type II, whether the extension of resection in the oral or aboral direction represents the most effective surgical therapy remains debatable. This article reviews the history of surgical EGJ cancer treatment and current surgical strategies from a Western perspective.

Background Esophageal perforation is associated with high morbidity and mortality. In addition to surgical treatment, endoscopic endoluminal stent placement and endoscopic vacuum therapy (EVT) are established methods in the management of this emergency condition. As health-related quality of life (HRQoL) is becoming a major issue in the evaluation of any therapeutic intervention not much is known about HRQoL, particular in the long-term follow-up of patients treated for benign esophageal perforation with different treatment strategies. Methods Patients treated for benign esophageal perforation at the University Hospital Cologne from January 2003 to December 2014 were included. Primary outcome and management of esophageal perforation were documented and long-term quality of life was assessed using the Gastrointestinal Quality of Life Index (GIQLI), the Health-Related Quality of Life Index (HRQL) for patients with gastroesophageal reflux disease (GERD) and the European Organization for Research and Treatment of Cancer (EORTC) questionnaires for general and esophageal cancer specific QoL (QLQ-C30 and QLQ-OES18). . Results 58 patients were included in the study. Based on primary treatment patients were divided into an endoscopic (n = 27; 46.6%), surgical (n = 20; 34.5%) and conservative group (n = 11; 19%). Short- and long-term outcome, as well as quality of life were compared. HRQoL was measured after a median follow-up of 49 months HRQoL was generally reduced in patients with benign esophageal perforation. Endoscopically treated patients showed the highest GIQLI overall score and highest EORTC general health status, followed by the conservative and the surgical group. Conclusion HRQoL in patients with benign esophageal perforation is reduced even in the long-term follow-up. Temporary stent or EVT is effective and provides a good alternative to surgery not only in the short-term but also in the long-term follow-up.

Background Gastric cancer is one of the deadliest cancer entities worldwide. While surgery is the only curative treatment option in early tumors, for locally advanced and metastatic patients further therapeutic targets are needed. Several studies not only reported mutations but also amplifications of the KRAS locus in different cancer entities. More recently, KRAS amplification was discussed as a new therapeutic target. Little is known about the (prognostic) relevance and (heterogenic) distribution of KRAS amplification in gastric adenocarcinomas, especially in Non-Asian patients. Methods Amplification of the KRAS locus and corresponding protein expression was analyzed in 582 gastric adenocarcinomas employing fluorescence in-situ hybridization (FISH) and immunohistochemistry. Amplification status was correlated with clinico-pathological features, clinical outcome and molecular tumor data including a correlation to the TCGA subtypes of gastric carcinoma. Results KRAS amplification was detected in 27 out of 470 analysable tumors (5.7%) and correlated with protein expression of KRAS in all amplified tumors. Within the KRAS amplified gastric tumors 14/27 (51.9%) showed a heterogeneous distribution with also KRAS non-amplified tumor parts. According to TCGA 24 tumors (88.8%) were related to chromosomal instable tumors (CIN). The survival analysis of the entire patient cohort did not show any difference in overall survival in dependence on the KRAS status. However, a significant survival difference with a worse outcome for patients with KRAS amplified tumors was identified when analysing patients without neoadjuvant pre-treatment. Conclusions We confirm the unfavorable prognosis of KRAS amplified tumors reported by other studies in (Asian) patient groups, at least in patients without neoadjuvant pre-treatment. Within KRAS amplified tumors we revealed intratumoral heterogeneity that may define a (more aggressive) tumor cell population which is more frequently observed in patients with lymph node metastases. Despite the heterogeneous distribution of KRAS amplified tumor clones, KRAS amplified locally advanced or metastasized gastric adenocarcinomas represent a therapeutically highly relevant tumor subgroup.

Background. Indoleamine 2,3-dioxygenase (IDO) is an interferon-inducible immune checkpoint expressed on tumor-infiltrating lymphocytes (TILs). IDO is known as a poor prognostic marker in esophageal squamous cell cancer, while a positive effect was shown for breast cancer. A comprehensive analysis of IDO expression in a well-defined cohort of esophageal adenocarcinoma (EAC) is missing. Methods. We analyzed 551 patients with EAC using single-protein and multiplex immunohistochemistry as well as mRNA in situ technology for the expression and distribution of IDO on subtypes of TILs (INF-γ mRNA and CD4- and CD8-positive T lymphocytes). Results. IDO expression on TILs was seen in up to 59.6% of tumors, and expression on tumor cells was seen in 9.2%. We found a strong positive correlation of IDO-positive TILs, CD3-positive T lymphocytes, and INF-γ mRNA-producing TILs in the tumor microenvironment of EACs showing significantly better overall survival (47.7 vs. 22.7 months, p<0.001) with emphasis on early tumor stages (pT1/2: 142.1 vs. 37.1 months, p<0.001). In multivariate analysis, IDO is identified as an independent prognostic marker. Conclusions. Our study emphasizes the importance of immunomodulation in EAC marking IDO as a potential biomarker. Beyond this, IDO might indicate a subgroup of EAC with an explicit survival benefit.

Background Total minimally-invasive transthoracic esophagectomy (ttMIE) faces increasing application in surgical treatment of esophageal cancer. For esophago-gastric reconstruction, different anastomotic techniques are currently used, but their impact on postoperative anastomotic leakage and morbidity has not been investigated. The aim of this retrospective multicenter analysis was to describe anastomotic techniques used for ttMIE and to analyze the associated morbidity. Patients and Methods Patients were selected from a basic dataset, collected over a 5-year period from 13 international surgical high-volume centers. Endpoints were anastomotic leakage rate and postoperative morbidity in correlation to anastomotic techniques, measured by the CD classification and the Comprehensive Complication Index® (CCI). Results Five anastomotic techniques were identified in 966 patients after ttMIE: Intrathoracic end-to-side circular-stapled technique in 427 patients (double-stapling n=90, purse-string n=337), intrathoracic (n=109) or cervical (n=255) side-to-side linear-stapled, and cervical end-to-side hand-sewn (n=175). Leakage rates were similar in intrathoracic and cervical anastomoses (15.9% vs. 17.2%, P=0.601), but overall complications (56.7%% vs. 63.7%, P=0.029) and median 90-day CCI (21 (IQR 0-36) vs. 29 (IQR 0-40), P=0.019) favored intrathoracic reconstructions. Leakage rates after intrathoracic end-to-side double-stapling (23.3%) and cervical end-to-side hand-sewn (25.1%) techniques were significantly higher compared with intrathoracic side-to-side linear (15.6%), end-to-side purse-string (13.9%) and cervical side-to-side linear-stapled esophago-gastrostomies (11.8%) (P Conclusion Results of this analysis present the current status of the technical evolution of ttMIE with anastomotic leakage as predominant surgical complication. However, technique-related morbidity requires cautious interpretation considering the long learning curve of this complex surgical procedure.

BackgroundComplications after surgery for esophageal cancer are associated with significant resource utilization. The aim of this study was to analyze the economic burden of two frequently used endoscopic treatments for anastomotic leak management after esophageal surgery: Treatment with a Self-expanding Metal Stent (SEMS) and Endoscopic Vacuum Therapy (EVT).Materials and methodsBetween January 2012 and December 2016, we identified 60 German-Diagnosis Related Group (G-DRG) cases of patients who received a SEMS and / or EVT for esophageal anastomotic leaks. Direct costs per case were analyzed according to the Institute for Remuneration System in Hospitals (InEK) cost-accounting approach by comparing DRG payments on the case level, including all extra fees per DRG catalogue.ResultsIn total, 60 DRG cases were identified. Of these, 15 patients were excluded because they received a combination of SEMS and EVT. Another 6 cases could not be included due to incomplete DRG data. Finally, N = 39 DRG cases were analyzed from a profit-center perspective. A further analysis of the most frequent DRG code -G03- including InEK cost accounting, revealed almost twice the deficit for the EVT group (N = 13 cases, € - 9.282 per average case) compared to that for the SEMS group (N = 9 cases, € - 5.156 per average case).ConclusionEndoscopic treatments with SEMS and EVT for anastomotic leaks following oncological Ivor Lewis esophagectomies are not cost-efficient for German hospitals. Due to longer hospitalization and insufficient reimbursements, EVT is twice as costly as SEMS treatment. An adequate DRG cost compensation is needed for SEMS and EVT.

Immune checkpoint modulation in cancer has been demonstrated as a high-value therapeutic strategy in many tumor entities. VISTA is an immune checkpoint receptor regulating T-cell function. To the best of our knowledge, nothing is known about the expression and prognostic impact of VISTA on tumor infiltrating lymphocytes (TILs) in the tumor microenvironment of esophageal adenocarcinoma (EAC). We analyzed in total 393 EACs within a test-cohort (n = 165) and a validation-cohort (n = 228) using a monoclonal antibody (clone D1L2G). These data were statistically correlated with clinical as well as molecular data. 22.2% of the tumor cohort presented with a VISTA expression on TILs. These patients demonstrated an improved median overall survival compared to patients without VISTA expression (202.2 months vs. 21.6 months; p

OBJECTIVE: Utilizing a standardized dataset with specific definitions to prospectively collect international data to provide a benchmark for complications and outcomes associated with esophagectomy. SUMMARY OF BACKGROUND DATA: Outcome reporting in oncologic surgery has suffered from the lack of a standardized system for reporting operative results particularly complications. This is particularly the case for esophagectomy affecting the accuracy and relevance of international outcome assessments, clinical trial results, and quality improvement projects. METHODS: The Esophageal Complications Consensus Group (ECCG) involving 24 high-volume esophageal surgical centers in 14 countries developed a standardized platform for recording complications and quality measures associated with esophagectomy. Using a secure online database (ESODATA.org), ECCG centers prospectively recorded data on all resections according to the ECCG platform from these centers over a 2-year period. RESULTS: Between January 2015 and December 2016, 2704 resections were entered into the database. All demographic and follow-up data fields were 100% complete. The majority of operations were for cancer (95.6%) and typically located in the distal esophagus (56.2%). Some 1192 patients received neoadjuvant chemoradiation (46.1%) and 763 neoadjuvant chemotherapy (29.5%). Surgical approach involved open procedures in 52.1% and minimally invasive operations in 47.9%. Chest anastomoses were done most commonly (60.7%) and R0 resections were accomplished in 93.4% of patients. The overall incidence of complications was 59% with the most common individual complications being pneumonia (14.6%) and atrial dysrhythmia (14.5%). Anastomotic leak, conduit necrosis, chyle leaks, recurrent nerve injury occurred in 11.4%, 1.3%, 4.7%, and 4.2% of cases, respectively. Clavien-Dindo complications ≥ IIIb occurred in 17.2% of patients. Readmissions occurred in 11.2% of cases and 30- and 90-day mortality was 2.4% and 4.5%, respectively. CONCLUSION: Standardized methods provide contemporary international benchmarks for reporting outcomes after esophagectomy.

Background: Percutaneous endoscopic gastrostomy (PEG) placed in the pull through (PT) technique is a common procedure to restore enteral feeding in patients with swallowing disorders. Limitations of this technique are patients with obstruction of the pharynx or esophagus or with an esophageal stent. We report our experience with the direct puncture (DP) PEG device. Methods: We included 154 patients (55 women). One hundred forty patients had cancer. After passing the endoscope into the stomach, 4 gastropexies were performed with a gastropexy device and the PEG was placed with the introducer method. After 1 month, the sutures were removed and a constant gastrocutaneous fistula had been created and the new catheter could be placed safely. Results: The DP PEG was successfully placed in all patients. Overall complication rate was 11% (minor: 6%, major: 5%). The most common event was tube dislocation (40 cases). In 5 cases of dislocation, this resulted in a major complication with injuring the gastric wall and the necessity for surgical treatment. Conclusions: The DP PEG system is safe, and can be used in cases in which a standard PT PEG is not feasible. To avoid dislocation, strict adherence to a post-interventional protocol is highly recommended.

De-Hua Chang,1,* Sebastian Brinkmann,2,* Lucy Smith,3 Ingrid Becker,4 Wolfgang Schroeder,2 Arnulf H Hoelscher,5 Stefan Haneder,1 David Maintz,1 Judith Eva Spiro6 1Department of Radiology, University Hospital of Cologne, Cologne, Germany; 2Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany; 3Faculty of Medicine, Memorial University of Newfoundland, St John’s, Canada; 4Institute of Medical Statistics and Computational Biology, University of Cologne, Cologne, Germany; 5Agaplesion Markus Hospital, Frankfurt am Main, Germany; 6Department of Radiology, University Hospital, LMU Munich, Munich, Germany *These authors contributed equally to this work Purpose: Anastomotic leakage is a major surgical complication following esophagectomy and gastric pull-up. Specific risk factors such as celiac trunk (TC) stenosis and high calcification score of the aorta have been identified, but no data are available on their relative prognostic values. This retrospective study aimed to compare and evaluate calcification score versus stenosis quantification with regards to prognostic impact on anastomotic leakage.Patients and methods: Preoperative contrast-enhanced computed tomography scans of 164 consecutive patients with primary esophageal cancer were evaluated by two radiologists to apply a calcification score (0–3 scale) assessing the aorta, the celiac axis and the right and left postceliac arteries. Concurrently, the presence and degree of stenosis of TC and superior mesenteric artery were recorded for stenosis quantification.Results: Anastomotic leakage was noted in 14/164 patients and 12/14 showed stenosis of TC (n=11). The presence of TC stenosis was found to have a significant impact on anastomotic healing (p=0.004). The odds ratio for the prediction of anastomotic leakage by the degree of stenosis was 1.04 (95% CI, 1.02–1.07). Ten of 14 patients had aortic calcification scores of 1 or 2, but calcification scores of the aorta, the celiac axis and the right and left postceliac arteries did not correlate with the corresponding TC stenosis values and showed no influence on patient outcome as defined by the occurrence of anastomotic insufficiency (p=0.565, 0.855, 0.518 and 1.000, respectively). Inter-reader reliability of computed tomography analysis and absolute agreement on calcium scoring was mostly over 90%. No significant differences in preoperative comorbidities and patient characteristics were found between those with and without anastomotic leakage.Conclusion: Measurement of TC stenosis in preoperative contrast-enhanced computed tomography scans proved to be more reliable than calcification scores in predicting anastomotic leakage and should, therefore, be used in the risk assessment of patients undergoing esophagectomy and gastric pull-up. Keywords: TC stenosis, calcification score, anastomotic leakage, stenosis quantification, Ivor Lewis esophagectomy, graft perfusion

Esophageal cancer is the eighth most common malignant tumor worldwide, and the number of incidences of esophageal adenocarcinoma is increasing in the Western world. Despite improvements in perioperative treatment, the overall survival rate of patients with esophageal adenocarcinoma remains poor. Breast cancer type 1 susceptibility protein (BRCA1)-associated protein (BAP1) is located on chromosome 3p21, and it is an enzyme with ubiquitin carboxyl hydrolase activity that regulates cell growth. It interacts with BRCA1, and the nuclear localization of BAP1 is required for its tumor suppressor function. BAP1 is frequently mutated in uveal melanomas, malignant mesothelioma and several carcinomas, including a subtype of renal cell carcinoma, intrahepatic cholangiocarcinoma and squamous cell carcinoma of the esophagus. Furthermore, several germline-associated mutations of tumors have been described (BAP1 hereditary cancer syndrome). However, the importance and frequency of BAP1 alterations in adenocarcinoma of the esophagus remain to be elucidated. In the present study, tissue microarrays of 332 resected adenocarcinomas (including a few cases of concomitant Barrett dysplasia) of the esophagus were constructed. The tumor tissue was analyzed using immunohistochemistry to investigate the levels of BAP1 expression. Fibroblasts or inflammatory cells served as an internal positive control. Three adenocarcinomas revealed nuclear loss of BAP1 (0.9%). One case with concomitant Barrett dysplasia also exhibited a loss of BAP1. Of the resected adenocarcinomas, 329 of them exhibited an intact and uniform strong nuclear staining pattern. To the best of our knowledge, this is the first description of BAP1 deficiency in adenocarcinomas of the esophagus. Furthermore, it has been demonstrated that BAP1 loss is possibly an early event in esophageal adenocarcinoma. These results warrant further functional and clinical evaluation.

Epidemiologically, around 15,500 persons per year contract gastric cancer with continuously decreasing incidence and a 5-year survival rate of only 30% to 35%. Contrary to the Asian countries, there are no prevention programs for gastric cancer in Germany, which leads to the disease frequently being diagnosed in locally advanced stages and predominantly being treated with multimodal therapy concepts. Complete (R0) resection is the therapy of choice for resectable gastric cancer. Special forms of gastric cancer that are limited to the mucosa can be endoscopically resected with a curative intent. Systematic D2 lymphadenectomy (LAD) plays a decisive role in the management of local advanced tumors because it significantly contributes to the reduction of tumor-related death and both local and regional relapse rates. Perioperative chemotherapy improves prognosis in the advanced stages, whereas palliative chemotherapy is normally indicated for metastatic diseases. Standardized resection procedures and the use of individualized multimodal therapy concepts have led to improvement in the 5-year survival rate.

For the planning and performance of surgical treatment, the exact topographic assignment of carcinomas of the stomach and the esophagogastric junction is of central importance. In distal gastric adenocarcinoma of the antrum or the pylorus especially of category cT1 or cT2 with intestinal type of Lauren, a subtotal gastric resection can be performed. However in more proximally located carcinomas of the corpus or fundus especially those of the diffuse type, a total gastrectomy is necessary.

In 2012 the European Union Network of Excellence on gastric and esophagogastric junction cancer (EUNE) held its third conference in Cologne, Germany. The main themes discussed included translational research, standard and audit, early diagnosis, development of surgical treatment, adequate surgery for EGJ cancer, adjuvant and neoadjuvant treatment, prevention of peritoneal carcinomatosis and finally education and training. The meeting was attended by 150 experts from 18 different countries.

Esophagogastric junction (EGJ) cancer is a solid tumor entity with rapidly increasing incidence in the Western countries. Given the high proportion of advanced cancers in the West, treatment strategies routinely employed include surgery and chemotherapy perioperatively, and chemoradiation in neoadjuvant settings. Neoadjuvant chemoradiation and perioperative chemotherapy are mostly performed in esophageal cancer that extends to the EGJ and gastric as well as EGJ cancers, respectively. Recent trials have tried to combine both strategies in a perioperative context, which might have beneficial outcomes, especially in patients with EGJ cancer. However, it is difficult to recruit patients for trials, exclusively for EGJ cancers; therefore, the results have to be carefully reviewed before establishing a standard protocol. Trastuzumab was the first drug for targeted therapy that was positively evaluated for this tumor entity, and there are several ongoing trials investigating more targeted drugs in order to customize effective therapies based on tissue characteristics. The current study reviews the multimodal treatment concept for EGJ cancers in the West and summarizes the latest reports.

Objective Chylothorax is a major complication after esophagectomy. As recent studies refer to heterogeneous patient cohorts and surgical procedures, this study was conducted to report the incidence and evaluate the optimal management of chylous fistula in patients treated with transthoracic esophagectomy and 2-field lymphadenectomy for esophageal cancer. Methods From January 2005 to December 2013, a total of 906 patients underwent transthoracic esophageal resection for esophageal carcinoma at our institution. En bloc esophagectomy was performed with routine supradiaphragmatic ligation of the thoracic duct. The incidence of chylothorax, and associated morbidity and mortality, were analyzed, and subsequent therapeutic management was reviewed. Results Chylothorax after Ivor Lewis esophagectomy was observed in 17 (1.9%) patients. Fifteen patients required surgical intervention with rethoracotomy and repeat duct ligation. Thoracic duct ligation was successful in all patients. Two patients died within 90 days after primary esophageal resection. The median time between initial tumor resection and rethoracotomy was 13 days. Average daily chest-tube output at time of reoperation was 1900 mL. In 2 patients, pleural effusion did not exceed 1000 mL per day. In these cases, conservative management with additional thoracic drainage and total parenteral nutrition led to complete resolution of chylous fistula. Conclusions Occurrence of chylothorax after prophylactic thoracic duct ligation during transthoracic esophagectomy for esophageal cancer is rare. In patients with high-output chylous fistula, an early rethoracotomy with repeat ligation of the thoracic duct is safe and helps to shorten recovery time. In cases of low-volume drainage, a conservative approach is feasible.

Presently, there is no scientific evidence supporting a definite role for follow-up after gastrectomy for cancer, and clinical practices are quite different around the globe. The aim of this consensus conference was to present an ideal prototype of follow-up after gastrectomy for cancer, based on shared experiences and taking into account the need to rationalize the diagnostic course without losing the possibility of detecting local recurrence at a potentially curable stage. On June 19–22, 2013 in Verona (Italy), during the 10th International Gastric Cancer Congress (IGCC) of the International Gastric Cancer Association, a consensus meeting was held, concluding a 6-month, Web-based, consensus conference entitled “Rationale of oncological follow-up after gastrectomy for cancer.” Forty-eight experts, with a geographical distribution reflecting different health cultures worldwide, participated in the consensus conference, and 39 attended the consensus meeting. Six statements were finally approved, displayed in a plenary session and signed by the vast majority of the 10th IGCC participants. These statements are attached as an annex to the Charter Scaligero on Gastric Cancer. After gastrectomy for cancer, oncological follow-up should be offered to patients; it should be tailored to the stage of the disease, mainly based on cross-sectional imaging, and should be discontinued after 5 years.

Aims: Survivin (SVV) mRNA expression levels in peripheral blood of patients with gastrointestinal malignancies change significantly during the course of treatment. We wanted to scrutinize these findings in patients with esophageal carcinoma and furthermore evaluate whether the detection of mRNA and the change in detecting ability have an association with overall survival. Materials & methods: Whole blood was drawn 1 day pre- and 10 days post-operatively from 62 patients with esophageal carcinoma. Tumor cells were enriched from whole blood by density-gradient centrifugation prior to extraction of total cellular RNA and subsequent direct quantitative reverse transcriptase-PCR assays. Results: SVV was detectable in 48 out of 62 patients (77%). Stepwise multivariate Cox linear regression models demonstrated a significant and independent association of measured SVV with overall survival (6.6 exp[b]; 95% CI: 1.97–22.12; p = 0.002). Increased SVV levels after the operation were linked to shorter overall survival (p = 0.04). Conclusion: Preoperative SVV expression levels appear to be associated with overall survival in patients with esophageal cancers. Increasing levels could potentially indicate a higher risk for shorter overall survival and therefore demand adapted treatment modalities.

The oxygen-regulated transcription factor subunit hypoxia inducible factor-1alpha (HIF-1alpha) is involved in angiogenesis, energy metabolism, cell survival, and inflammation. We examined the protein expression of HIF-1alpha within the progression of Barrett's sequence as well as the type and degree of the environmental inflammatory reaction. Squamous epithelium (SE), metaplastic, low- and high-grade dysplastic lesions, and tumor tissue of 57 resection specimens from patients with Barrett's adenocarcinoma were immunohistochemically analyzed. Active and chronic inflammatory reactions were classified according to the Updated Sydney System. HIF-1alpha protein expression increased significantly from SE to Barrett's metaplasia (BM) (P < 0.0001). From metaplasia through low- and high-grade dysplasia to cancer, no further increase could be detected. Active and chronic inflammation were also significantly different between SE and BM (P < 0.0001) but not during further progression in the sequence. HIF-1alpha protein expression did not correlate with histopathologic parameters or survival. HIF-1alpha protein expression pattern resembles the active and chronic environmental inflammatory reaction. All were significantly increased in metaplasia compared to SE without further change in tumor development. HIF-1alpha protein expression appears to be associated with inflammatory processes in the development of BM.

Perioperative transfusion of allogeneic blood has been hypothesized to have an immunomodulatory effect and influence survival in several cancer types. This study evaluates the association between receipt of leucocyte-depleted and non-depleted allogeneic blood and survival following esophagectomy for cancer. A retrospective analysis was performed including 291 patients with esophageal cancers who underwent transthoracic en bloc esophagectomy and extended mediastinal lymphadenectomy. Neoadjuvant chemoradiation was administered in 152 (52.2%) patients. Perioperative blood transfusions were quantified and the potential prognostic cutoff for transfused units was calculated according to LeBlanc. The median number of perioperative blood transfusions was 2 (0–24), and 106 patients (36.4%) received no transfusions. Patients with one or less blood transfusion showed a significantly improved survival compared to patients receiving more than one unit (p

Pancreatic cancer still has one of the worst prognoses of all cancers with a 5-year survival rate of 5%, making it necessary to find markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens. Especially heparanase (HPSE) has recently been discussed as a key factor in pancreatic cancer.Paraffin-embedded tissue samples were obtained from 41 patients with pancreatic adenocarcinoma who were scheduled for primary surgical resection. Direct quantitative real-time reverse transcriptase polymerase chain reaction (TaqMan) assays were performed in triplicates to determine HPSE, hypoxia inducible factor-1 alpha (HIF1a), platelet-derived growth factor alpha (PDGFA), heparin-binding EGF-like growth factor (HB-EGF), and basic fibroblast growth factor (bFGF) gene expression levels.HPSE was significantly correlated to PDGFA (p = 0.04) and HIF1a (p = 0.04). The correlation of HIF1a to bFGF and HB-EGF was significant (p = 0.04, p = 0.02). Stepwise multiple linear regression models showed a significant independent association of HPSE with lymph node metastasis (p = 0.025) and with dedifferentiation (p = 0.042).Heparanase seems to be significantly associated with lymph node metastasis (p = 0.025) as well as dedifferentiation (p = 0.042). We assume that HPSE plays a crucial role for the aggressiveness of pancreatic cancer. Larger studies including more patients seem to be warranted.

OBJECTIVES We examined mRNA expression of the urokinase-type plasminogen activator (uPA), its receptor (uPAR), and the plasminogen activator inhibitor 1 (PAI-1) in a panel of adenocarcinomas of the pancreas (PC) and cancers of the papilla of Vater (CPV). Expression profiles were compared with paired uninvolved normal tissues to define a possible differential role of these genes in tumorigenesis of both tumor types. METHODS Urokinase-type plasminogen activator, uPAR, and PAI-1 mRNA expression was analyzed by real-time quantitative reverse-transcriptase polymerase chain reaction (TaqMan) in 25 PC, 7 CPV, and in the paired uninvolved normal tissues. RESULTS Uninvolved normal tissue probes from PC and CPV showed similar mRNA expression profiles of uPA, uPAR, and PAI-1. Whereas expression levels of uPA (P = 0.81) and uPAR (P = 0.75) were not statistically significant different between tumor and paired normal tissues, PAI-1 levels were significantly down-regulated in tumor compared with paired normal tissue samples (Wilcoxon test; P < 0.006). No differences in mRNA expression of uPA, uPAR, and PAI-1 between PC and CPV were observed. Expression levels of the 3 genes were not associated with tumor stage, grading, or survival. CONCLUSIONS Increased mRNA expression of uPA and uPAR could not be detected in PC and CPV; however, PAI-1 mRNA expression levels are significantly down-regulated in PC, which might lead to higher activity levels of uPA components. Our data are merely hypothesis generating and should be validated in larger translational studies.

Objective: Severe obesity is a clear indication for appropriate, effective weight loss therapy. One option is operative intervention, e.g., gastric banding. Risks of the operation and therapeutic alternatives need to be comprehensibly presented to the patient. The literature has shown that better informed consent is obtained using information presented in a multimedia/video-based format. The current study developed and evaluated a multimedia program aimed at obtaining informed consent from obese patients before gastric banding. Research Methods and Procedure: An interactive multimedia program was developed with information about preoperative examinations, the operation itself, hospital stay, operative risks, alternative therapies, and the pathophysiology and health risks of obesity. Two groups (Group 1, n = 20, mean age 38 years, informed consent attained with conventional document information; Group 2, n = 20, mean age 37 years, informed consent attained with additional multimedia information) were interviewed regarding comprehensibility of the information presented, personal satisfaction, and anxiety levels during the informed consent process. Results: Group 2 showed significantly better (p < 0.05) understanding of the presented information and higher levels of satisfaction with the informed consent process. Anxiety levels did not significantly differ between the two groups. Discussion: Because patient satisfaction with the informed consent process and understanding of the presented information significantly improved, the multimedia program clearly benefits both surgeons and patients. Personal contact from the surgeon remains essential. High volumes of information presented in multimedia format do not alleviate patient anxiety, and personal contact may be beneficial.

Aims: Risk reduction for Barrett's cancer in individuals taking non-steroidal anti-inflammatory drugs has been reported. Cyclooxygenase (COX)-2, one of the inhibited enzymes, is putatively involved in Barrett's cancer pathogenesis. The aim of this study was to examine a possible association between COX-2 protein expression and the development and progression of the Barrett's metaplasia–dysplasia–carcinoma sequence and the type and degree of associated inflammatory reaction. Methods and results: Squamous epithelium, metaplastic, low-grade, high-grade dysplastic lesions and tumour tissue of 49 resection specimens from patients with Barrett's adenocarcinoma were immunohistochemically analysed. Active and chronic inflammatory reactions were classified according to the Updated Sydney System. Within the Barrett's sequence, a significant progressive increase in COX-2 expression was identified (P

Aim: The aim of this prospective study was to evaluate the clinical and prognostic impact of immunohisto-chemically assessed uPA and PAI-1 in patients with gastric cancer. Methods: This prospective study analyzed specimens obtained from 105 gastric cancer patients who underwent gastrectomy with extended lymphadenectomy. The immunohistochemical expression of uPA and PAI-1 was studied semiquantitatively in the tumor epithelium and was correlated with the clinicopathological features of each patient. Results: Univariate analysis revealed no statistically significant association of uPA levels with pT and pN category (p=0.655 and 0.053, respectively), grading (p=0.374), depth of tumor invasion (p=0.665), UICC classification (p=0.21) and the Lauren classification (p=0.578). PAI-1 expression showed no statistically significant correlation with pT, pN and M category (p=0.589, 0.414, and 0.167, respectively), grading (p=0.273), and the Lauren classification (p=0.368). Only the UICC classification was significantly correlated with PAI-1 (p=0.016). Kaplan-Meier analysis revealed no significant association of uPA and PAI-1 with overall survival (p=0.0929 and 0.0870, respectively). Conclusions: Our results could not verify any prognostic value of uPA and PAI-1 levels in patients with gastric carcinoma. Therefore, the uPA-system as a biologically defined prognostic marker to identify high-risk gastric cancers should be applied with caution. However, considering the number of patients involved and the borderline level of significance observed in this study, a larger number of events may have resulted in significant differences.

Background and Objectives We evaluated if mRNA expression of survivin, an inhibitor of apoptosis, can be used to detect circulating tumor cells in peripheral blood of patients with various gastrointestinal cancers and if they decrease following complete surgical resection. Methods Blood samples from 40 gastrointestinal cancer patients were analyzed prior and following surgical resection by direct quantitative real-time reverse transcriptase-PCR (RT-PCR) assays. Results Survivin mRNA expression was pre-operatively detected in 35 of 40 cancer patients (88%). Post-operative survivin levels were significantly lower than pre-operative levels in 59% of resected patients and were non-detectable in 38% (Wilcoxon rank test: P

Esophageal cancer ranks among the 10 most frequent malignancies worldwide. Once diagnosed, the 5-year survival rate for these patients is about 10%.1 Surgery is the treatment of choice for most localized esophageal cancers. However, despite complete tumor resection and extensive lymphadenectomy, systemic and local recurrences are common and the 5-year survival rate ranges from 15% to 39%.2 Surgical results have improved in recent decades; however, most of this can be attributed to advances in preoperative staging, patient selection, refinement of surgical techniques, and postoperative care.3,4 The particularly poor prognosis associated with locally advanced esophageal cancer prompted an evaluation of combined modality treatments using neoadjuvant chemotherapy, radiotherapy, or radiochemotherapy in combination with surgery.5 The purported advantage of preoperative administration of chemotherapy, radiotherapy, or combined chemoradiation is that it may downstage the primary tumor, increase the resectability rate, eliminate micrometastases, and prolong survival.6 Results of larger randomized phase III trials using preoperative chemotherapy7–9 or radiochemotherapy10–12 were inconclusive; only 2 studies demonstrated a survival advantage for neoadjuvant treatment.9,10 Two recent meta-analyses of randomized trials showed modest but significant survival advantages for patients that received neoadjuvant chemotherapy13 or radiochemotherapy.14 In these trials, patients with a pathologic complete response have been consistently found to have impressive survival rates around 60%.2 According to the World Health Organization (WHO), clinical response is graded as complete, partial (>50% tumor regression), minor/no change (≤50% tumor regression), or progressive disease.15 Clinical response evaluations using endoscopic ultrasound and computed tomography (CT), however, have been shown to be highly inaccurate.16 In an effort to objectively evaluate response to neoadjuvant therapy, morphologic criteria have been defined for several cancers, including lung,17 stomach,18 and esophagus.19,20 Classification of regression based on the estimated percentage of vital residual tumor cells (VRTCs) was reported in non-small cell lung cancer patients following neoadjuvant radiochemotherapy.17 In a prospective trial, the presence of

The aim of this prospective study was to analyze Ming's classification in correlation with other currently used classification systems of gastric cancer. In addition, we wanted to define the prognostic significance of the Ming classification system. The present study analyzed material of 117 patients with gastric carcinoma who underwent D2-gastrectomy with curative intent. All specimens were categorized according to International Union Against Cancer (UICC) classification, World Health Organization (WHO) classification, Borrmann classification, Lauren classification, Goseki classification, Ming classification, and tumor differentiation. For analysis of correlation between the classification systems, the correlation coefficient according to Spearman was calculated. The survival curves have been calculated according to the Kaplan-Meier method. According to the Ming classification, 38.5% of the carcinomas exhibited an expanding growth pattern, and 61.5% of specimens showed an infiltrating growth pattern. The subtypes according to the Ming and Lauren classification correlated significantly (P < 0.001). WHO classification (P < 0.001), tumor differentiation (P < 0.001), and Goseki classification (P < 0.001), as well as the macroscopic classification of Borrmann (P < 0.001) and the pT and pN categories of the UICC classification exhibited a highly significant correlation with the Ming classification (P < 0.001 and 0.001, respectively). Median overall survival was 31.3 months. In Kaplan-Meier analysis, the 3-year survival rates were lower in the infiltrative tumor type when compared to the expansive tumor type according to Ming (P = 0.0847). In multivariate analysis, only the UICC system presented as an independent prognostic factor in multivariate analysis (P < 0.001). This study shows that the Ming classification correlates significantly with the currently used classification systems for gastric cancer and with the UICC staging system, especially, the pT and pN category. The 3-year survival rates were lower in the infiltrative tumor type than in the expansive tumor type according to Ming. However, the Ming classification is not an independent prognostic factor.

Purpose: The excision repair cross-complementing 1 (ERCC1) gene is coding for a nucleotide excision repair protein involved in the repair of radiation- and chemotherapy-induced DNA damage. We examined the potential of quantitative ERCC1 mRNA expression to predict minor or major histopathological response to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, and 36 Gy of radiation) followed by transthoracic en bloc esophagectomy in patients with locally advanced esophageal cancer (cT2–4, Nx, M0). Experimental Design: Tissue samples were collected by endoscopic biopsy before treatment. RNA was isolated from biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression. Relative mRNA levels (tumor/normal ratios) were calculated as (ERCC1/β-actin in tumor)/(ERCC1/β-actin in paired normal tissue). ERCC1 expression levels were correlated with the objective histopathological response in resected specimens. Histomorphological regression was defined as major response when resected specimens contained Results: Twelve of 36 tumors showed a major histopathological response, and 24 of 36 showed a minor histopathological response. Relative expression levels of ERCC1 of >1.09 were not associated with a major histopathological response (sensitivity, 62.5%; specificity, 100%) and 15 of 24 patients with minor histopathological response to the delivered neoadjuvant radiochemotherapy could be unequivocally identified. This association of dichotomized relative ERCC1 mRNA expression and histopathological response was statistically significant (P < 0.001). Conclusions: Relative expression levels of ERCC1 mRNA determined by quantitative real-time reverse transcriptase-PCR appear highly specific to predict minor response to our neoadjuvant radiochemotherapy protocol in patients with locally advanced esophageal cancer and could be applied to prevent expensive, noneffective, and potentially harmful therapies in a substantial number (42%) of patients.

Epigastrische Schmerzen, Ubelkeit, Erbrechen und eine obere gastrointestinale Blutung werden gelegentlich durch heterotopes Pankreasgewebe der Magenwand verursacht. Trotz moderner diagnostischer Verfahren gestaltet sich die Diagnose heterotopen Pankreasgewebes oftmals schwierig. Daher wird von vielen Autoren die Magenwandresektion und Schnellschnittuntersuchung als diagnostische und therapeutische Masnahme befurwortet. Zwei typische Kasuistiken werden im Folgenden mit einer Literaturubersicht vorgestellt.

$('.header-date').hide();$('#titleAuthors').hide(); $('#abstractHeader').hide(); Alexander Shimabukuro-Vornhagen 1 , 2 , * , Hans A. Schloser 1 , 3 , * , Luise Gryschok 1 , Joke Malcher 1 , Kerstin Wennhold 1 , Maria Garcia-Marquez 1 , Till Herbold 1 , 3 , Laura S. Neuhaus 1 , Hans J. Becker 1 , Anne Fiedler 1 , Pascal Scherwitz 4 , Thomas Koslowsky 5 , Roland Hake 6 , Dirk L. Stippel 3 , Arnulf H. Holscher 3 , Sebastian Eidt 6 , Michael Hallek 2 , Sebastian Theurich 1 , 2 , Michael S. von Bergwelt-Baildon 1 , 2 1 Cologne Interventional Immunology, University of Cologne, Germany. 2 Department I of Internal Medicine, University of Cologne, Cologne, Germany. 3 Department of General, Visceral and Cancer Surgery, University of Cologne, Germany. 4 Department of Surgery, Marien Hospital, Bruhl, Germany. 5 Department of Surgery, St. Elisabeth Hospital, Cologne, Germany. 6 Institute of Pathology, St. Elisabeth Hospital, Cologne, Germany. * This authors contributed equally to this work. Correspondence to: Michael S. von Bergwelt-Baildon, e-mail: michael.von-bergwelt-baildon@uk-koeln.de Received: December 14, 2013 Accepted: April 28, 2014 Published: May 09, 2014 ABSTRACT Purpose: A precise understanding of the mechanisms by which human immune cell subsets affect tumor biology will be critical for successful treatment of cancer using immunotherapeutic approaches. Recent evidence suggests that B cells can both promote and inhibit the development and progression of tumors. The aim of this study was to characterize the composition of the B-cell infiltrates in colorectal cancers (CRC) in order to gain further insight into the role of B cells in CRC. Experimental Design: In this study we characterized B-cell subsets in primary tumors (n=38), metastases (n=6) and blood (n=46) of 51 patients with a diagnosis of CRC and blood of 10 healthy controls. B-cell subsets were analyzed by flow cytometry or immunohistochemistry. Results: Peripheral blood of CRC patients contained a higher percentage of memory B cells than that of age-matched healthy controls. Furthermore, the percentage of B cells within tumors was higher than that in the peripheral blood of CRC patients while metastases were typically devoid of tumor-infiltrating B cells. Tumor-associated B cells were enriched for activated and terminally differentiated B cells. Relevant proportions of regulatory B cells could only be detected in advanced cancer and metastases. Conclusion: B cells constitute a significant proportion of the immune infiltrate in CRC. The B-cell infiltrate of primary CRC is characterized by an accumulation of terminally differentiated memory B cells or plasma cells suggestive of a specific immune response against the tumor. However advanced tumors and metastases are also infiltrated by a considerable number of regulatory B cells.

The effect of acetyl - tyrosyl-valyl-alanyl-aspartyl - chloromethylketone (ac-YVAD-cmk), an irreversible caspase-1 (IL-1beta converting enzyme, ICE) inhibitor on mortality, leukocyte and platelet counts and cytokine levels was investigated in a double-blind rat model of endotoxaemia. Intravenous (i.v.) bolus administration of lipopolysaccharide (LPS) (25-75 mg kg(-1), n=12 per group) to anaesthetized rats induced a dose dependent increase in mortality over 8 h (LD(50)=48 mg kg(-1)). During this period, animals became leukopenic and thrombocytopenic. Serum levels of IL-beta, IL-6, and TNF-alpha were highly elevated. Pretreatment of rats with ac-YVAD-cmk at a dose of 12.5 micromol kg(-1) significantly reduced mortality from 83 to 33% using Log Rank analysis. However, ac-YVAD-cmk did not modify blood cell counts or cytokine profiles as compared with the LPS-drug vehicle group. These data lay credence to the potential importance of caspase-1-inhibition in modifying the inflammatory response to endotoxin. Further investigations are warranted in understanding the relationship between caspase-1 inhibition, cytokine production and animal survival in different experimental paradigms of sepsis.

A prospective study was performed in patients with non-small cell lung cancer (NSCLC) to evaluate the prognostic importance of multiple molecular marker (p53, c-Ki-ras, c-erbB-2) testing. 103 patients with potentially curative resections (RO resection) for NSCLC in histopathological stages I–IIIA were included. SSCP analysis and DNA sequencing for p53 and c-Ki-ras genes were performed on paired tumour and normal lung tissue samples and immunohistochemistry (c-erbB-2) was done on frozen tissue sections with a specific anti-c-erbB-2 monoclonal antibody. 46/103 (44.6%) NSCLC showed p53 mutations and 17/103 (16.5%) c-Ki-ras mutations including 12/37 (32.4%) adenocarcinomas. Overexpression of c-erbB-2 (p185) was detected in 56/103 (54.4%) tumours. 24/103 (23.3%) NSCLC were negative for alterations in all 3 parameters (c-Ki-ras, p53 and p185) whereas 79/103 (76.7%) were positive for at least one of the 3 parameters. In a regression model including a multiple molecular marker parameter (negative for all 3 markers versus positive for at least one marker), histopathological stage (P< 0.00001), respectively the pT (P< 0.01) and pN (P< 0.00001) categories and the multiple molecular marker parameter (P< 0.01) were of significant prognostic importance. This study demonstrates that testing 3 molecular markers (c-Ki-ras, p53 and c-erbB-2) improves estimation of prognosis compared to single marker testing and appears to define low (82.6% ± 7.9% 5-year survival) and high risk (40.2% ± 5.5% 5-year survival) groups for treatment failure in potentially curative (RO) resected NSCLC. © 2000 Cancer Research Campaign

In addition to the tumor suppressor gene p53, Cyclin Dependent Kinases (CDK) are well known to influence the cell cycle in normal human tissues and various neoplasias as well. The purpose of our present study was to evaluate the expression of the CDK-inhibitor p21/waf1/cip1 in colorectal cancer with special emphasis on the prognostic impact. Between 1985 and 1991, 294 patients (median age, 65 years) underwent surgical operative therapy for colorectal cancer. Formalin-fixed and paraffin-embedded tumor specimens were investigated. For immunohistochemistry the Catalysed Reporter Deposition (CARD) technique was performed. The survival probability was calculated and possible prognostic risk factors were tested using multivariate analysis. The p21/ waf1/cip1 staining pattern was positive in 197 (67%) specimens and negative in 97 (33%) samples. No significant correlation could been calculated between p21/waf1/cip1 expression and other variables such as age, sex, WHO-Classification, localisation, grading, TNM-classification or UICC-stage. Patients with a positive staining reaction had a significantly better survival (p < 0.0052). Moreover, p21/waf1/cip1 was shown to be an independent prognostic parameter by multivariate analysis (p < 0.022). In contrast with these findings, the p53 tumor status had no impact on survival. P21/ waf1/cip1 appears to be an independent prognostic parameter in colorectal cancer and is associated with a favorable survival. This feature may be related to a cell cycle arrest in the G1 phase induced by p21/waf1/cip1, resulting in lower tumor cell proliferative activity.

Several pathohistological classification systems exist for the diagnosis of gastric cancer. Many studies have investigated the correlation between the pathohistological characteristics in gastric cancer and patient characteristics, disease specific criteria and overall outcome. It is still controversial as to which classification system imparts the most reliable information, and therefore, the choice of system may vary in clinical routine. In addition to the most common classification systems, such as the Lauren and the World Health Organization (WHO) classifications, other authors have tried to characterize and classify gastric cancer based on the microscopic morphology and in reference to the clinical outcome of the patients. In more than 50 years of systematic classification of the pathohistological characteristics of gastric cancer, there is no sole classification system that is consistently used worldwide in diagnostics and research. However, several national guidelines for the treatment of gastric cancer refer to the Lauren or the WHO classifications regarding therapeutic decision-making, which underlines the importance of a reliable classification system for gastric cancer. The latest results from gastric cancer studies indicate that it might be useful to integrate DNA- and RNA-based features of gastric cancer into the classification systems to establish prognostic relevance. This article reviews the diagnostic relevance and the prognostic value of different pathohistological classification systems in gastric cancer.

Background. During the last two decades, a rising incidence of adenocarcinoma of the esophagus has been observed in the Western world. The prognostic relevance of tumor-biological factors, such as DNA ploidy or c-erbB-2 overexpression, for overall survival following complete resection is still unknown. Methods. In a retrospective study of 80 patients with adenocarcinoma of Barrett's esophagus, the prognostic significance of flow cytometric DNA ploidy determination was investigated. Overexpression of c-erbB-2 oncoprotein was studied by immunohistochemical alkaline phosphatase-antialkaline phosphatase staining of formalin fixed, paraffin embedded tissue sections of the primary tumor. Results. The rate of aneuploidy was 86%. Aneuploidy was significantly correlated with lymph node metastases only. c-erbB-2 oncoprotein overexpression of the primary tumor was detected in 15 patients (19%). A significant correlation was seen between c-erbB-2 overexpression and depth of tumor invasion, lymph node involvement, distant metastases, and status of residual tumor after resection (R category, International Union Against Cancer [UICC], 1987). All primary tumors with c-erbB-2 oncoprotein overexpression were aneuploid. In a multivariate Cox regression analysis for overall survival of those 62 patients (78%) whose tumor resection was macroscopically and microscopically complete (RO-UICC), depth of invasion, distant metastases, and c-erbB-2 over-expression were independent prognostic factors. The relative risk of death due to recurrence was nearly identical for patients with either c-erbB-2 oncoprotein overexpression or distant metastases: 4.06 (1.4–11.8) and 3.94 (1.6–9.5). In a multivariate Cox regression analysis of the subgroup of lymph node-negative patients (n = 26), the ploidy status of the primary tumor (defined as neardiploid plus tetraploid versus aneuploid plus multiploid) was the only independent prognostic factor for overall survival. Conclusions. These findings demonstrate that DNA ploidy as well as c-erbB-2 oncoprotein overexpression are valuable prognostic factors in patients with adenocarcinoma of Barrett's esophagus after complete tumor resection.

Background In intestinal epithelium, tyrosine kinase receptor Ephrin B3 (Eph B3) maintains the architecture of the crypt-villus axis by repulsive interaction with its ligand ephrin-B1. While loss of Eph B3 is linked to colorectal cancer initiation, overexpression of Eph B3 in cancer cell lines inhibits growth and induces functional changes with decreased mesenchymal and increased epithelial markers. In order to study this tumor suppressor activity of Eph B3 in esophageal adenocarcinoma we analyzed the simultaneous expression of Eph B3 and E-cadherin in both the healthy esophagus and in Barrett’s carcinoma. Methods Simultaneous expression of Eph B3 and E-cadherin was investigated in samples from 141 patients with Barrett’s carcinoma and from 20 healthy esophagi using immunhistology and quantitative PCR. Results from healthy squamous epithelium, Barrett’s metaplasia and staging-specific esophageal adenocarcinoma were correlated. Results A significantly reduced E-cadherin mRNA expression could be detected in adenocarcinoma compared to dysplasia. The immunhistological activity of E-cadherin and Eph B3 was reduced in adenocarcinoma compared to dysplasia or healthy esophageal mucosa. The intracellular E-cadherin distribution changed significantly from the cytoplasm to the membrane, when the Eph receptor was simultaneously expressed. Simultaneous expression of E-cadherin and Eph B3 showed a significant inverse correlation to tumor stage. Conclusions We present novel evidence of the tumor suppressor activity of Eph B3 in esophageal adenocarcinoma possibly due to the impact on redistribution of cellular E-cadherin to the membrane. Our results suggest that this effect might play a role in the dysplasia-adenocarcinoma sequence, the infiltrative growth pattern and the development of lymph node metastases.

Background. Differing survival rates have been reported between patients having undergone surgical intervention for the treatment of gastric carcinoma in Japan and Western industrialized countries. Through the actual availability of the data compiled at a major Japanese medical center (National Cancer Center, Tokyo), it was possible, for the first time, to compare the patients and therapeutic results of a Japanese center (n = 1475) with that of a German center (Department of Surgery, Technical University of Munich, Munich; n = 453). Methods. The prognostic factors involving both groups were compared. Survival rates were analyzed in univariate and multivariate fashions. Results. Some of the examined prognostic factors, such as sex, histologic type, tumor size, and Borrmann classification, were similarly distributed. Differences in frequency were discovered concerning pathologic tumor (pT), node (pN), and metastasis (pM) categories, localization, and age groups. Univariate analysis showed a 2-year survival rate of 88% for all Japanese patients with gastric cancer compared with 58% for German patients. The 5-year survival rates were 77% and 44%, respectively. The difference in the 2-year and 5-year survival rates for both departments may be related to differences in frequencies of several characteristics. In performing the same analysis in a multivariate fashion for the patient populations at both centers, it became clear that an important prognostic factor was the center itself. The survival curves of patients from Tokyo and Munich with the same prognostic factors demonstrate this difference. These differences, however, were small in comparison with those of univariate analysis. Conclusions. Using a similar classification of the tumor stage and similar prognostic characteristics, the prognosis for gastric cancer in Japan and Germany may be the same.

Aims: Neoadjuvant treatment strategies have been developed to improve the survival of patients with locally advanced esophageal cancer. Since only patients with major histopathological response benefit from multimodality treatment, we profiled the genome of patients with esophageal cancer for markers indicating response or nonresponse. Patients and methods: Pretreatment biopsies of responding and nonresponding patients with locally advanced esophageal cancer, as well as the corresponding normal epithelium, were analyzed by human genome microarrays. Differential gene expression was associated with histomorphological tumor regression. Quantitative real-time reverse transcriptase-PCR was applied for verification of the predictive value of a panel of the identified marker genes, including 66 patients. Results: We detected differentially expressed candidate genes with regard to response and nonresponse to neoadjuvant radiochemotherapy. The response-predictive impact of the novel markers, CUL2 and STK11, was confirmed by the verification study including 66 patients. Whereas CUL2 mRNA expression levels of greater than 1.7 was predictive for major response (p = 0.02) in adeno- and squamous cell carcinoma, STK11 was predominantly response predictive for adenocarcinomas. Downregulation of CUL2 (p = 0.04) and STK11 (p = 0.02) mRNA also correlated with a more favorable prognosis. Conclusion: We identified two novel markers, CUL2 and STK11, for response prediction in esophageal cancer. They will be applied to complement our panel of response-predictive markers to further individualize therapy.

Background: We analyzed perioperative platelet counts as a potential clinical marker for survival after transthoracic en bloc resection for esophageal cancer. Recent data described preoperative thrombocytosis in malignancies to be associated with poor prognosis. Methods: A retrospective analysis from a prospective database (1997-2006) was performed for 291 consecutive patients with esophageal cancer who underwent transthoracic en bloc esophagectomy and extended lymphadenectomy. Squamous cell cancer was found in 47.0% and adenocarcinoma in 50.9% (2.1% had rare histologies). Neoadjuvant chemoradiation was performed in 152 (52%) patients. Platelet counts before surgery and on postoperative days (PODs) 1, 10, and 30 were evaluated. We used the published cutoff value of 293×109/l (mean of 80 healthy controls±standard deviation) for platelet counts. Results: High platelet counts before surgery missed significance for poorer survival (p=0.054). Following a perioperative fall in thrombocytes, a significant rise at POD 10 after surgery was evident. Platelet counts of more than 293×109/l at this time correlated with a significantly improved survival rate (p=0.027). Patients with no increase in thrombocytes until POD 10 had significantly poorer survival (p=0.012). Multivariate analysis confirmed that a thrombocyte increase between the preoperative count and that on POD 10 is an independent prognostic indicator (p=0.035) for patients with completely (R0) resected tumors. Conclusions: An increase in platelet counts measured on POD 10 following transthoracic en bloc esophagectomy and extended lymphadenectomy is an independent prognostic indicator for improved survival in patients with esophageal cancer