Need for objective and reproducible criteria in histopathological assessment of total mesorectal excision specimens: lessons from a national improvement project.

AIM: Data on quality control of the pathologic evaluation of total mesorectal excision (TME) specimens are scarce. We aimed to assess differences between evaluation by local pathologists participating in PROject on CAncer of the REctum (PROCARE; a Belgian improvement project on rectal cancer) and by a review panel of experts. METHOD: Based on photographic material and histopathology slides, a Review Committee of gastrointestinal expert pathologists re-evaluated the mesorectal plane, the tumour differentiation grade, the (y)pT stage and the tumour regression grade in 444 patients previously routinely assessed by local pathologists. RESULTS: The surgical plane was reported in 89% of patients and the circumferential resection margin in 88% of patients by the local pathologist. The median number of lymph nodes harvested in patients undergoing neoadjuvant radiochemotherapy was 11 and 14 in the other patients. The Review Committee downgraded the surgical plane from (intra)mesorectal to intramuscular in 17% of patients, and upgraded it from intramuscular to (intra)mesorectal in 27%. Tumour differentiation grade, T stage and tumour regression grade differed between local pathologists and the Review Committee in 15%, 10% and 38%, respectively, of patients. T stage was upgraded, mainly from T2 to T3, in 8% of patients. Tumour regression was judged by the Review Committee to be less advanced in 15% of patients. CONCLUSION: Acknowledging some shortcomings, this study gives a realistic view of clinical practice. There are differences in interpretation with regard to both macroscopic and microscopic analysis of TME specimens. These findings indicate a need for more objective and reproducible criteria in histopathology. Being aware of this is a first step for improvement.

Cleanrooms and tissue banking how happy I could be with either GMP or GTP?

The regulatory framework of tissue banking introduces a number of requirements for monitoring cleanrooms for processing tissue or cell grafts. Although a number of requirements were clearly defined, some requirements are open for interpretation. This study aims to contribute to the interpretation of GMP or GTP guidelines for tissue banking. Based on the experience of the participating centers, the results of the monitoring program were evaluated to determine the feasibility of a cleanroom in tissue banking and the monitoring program. Also the microbial efficacy of a laminar airflow cabinet and an incubator in a cleanroom environment was evaluated. This study indicated that a monitoring program of a cleanroom at rest in combination with (final) product testing is a feasible approach. Although no statistical significance (0.90 < p < 0.95) was found there is a strong indication that a Grade D environment is not the ideal background environment for a Grade A obtained through a laminar airflow cabinet. The microbial contamination of an incubator in a cleanroom is limited but requires closed containers for tissue and cell products.

The prognostic relevance of tumor hypoxia markers in resected carcinoma of the gallbladder.

BACKGROUND: Intratumoral hypoxia has been suggested to drive more aggressive tumor behavior. Our aim was to define whether markers of tumor hypoxia are predictors of outcome in patients with gallbladder carcinoma. PATIENTS AND METHODS: From 1996 to 2006, 34 patients underwent resection for gallbladder carcinoma. The median follow-up was 12.6 months. Immunohistochemical stains for VEGF, HIF1α, GLUT1, GLUT3, CA9 and EGFR were performed on archival tissue. Immunohistochemical results were correlated with clinical and histopathological parameters. Cumulative overall survival (OS) rates were estimated using the Kaplan-Meier method. Multivariable Cox regression models were used to identify predictors of OS. RESULTS: The median OS was 11.9 (IQR: 3.4-22.0) months. Ubiquitous VEGF staining was observed in all gallbladder carcinomas. High (>50% of tumor cells) EGFR expression was associated with worse OS (p0.03). CA9 expression was less prevalent in poorly differentiated tumors (p0.02). GLUT3, GLUT1 and HIF1α expression were not associated with survival, but did correlate with the presence of lymph node metastasis (p0.02), tumor differentiation (p0.04) and tumor stage (p0.03) respectively. High EGFR expression, TNM stage and preoperative serum CA19.9 were retained as independent predictors of OS in multivariable analysis. CONCLUSION: In gallbladder cancer high expression of EGFR is an independent predictor of survival.

International and national initiatives in biobanking.

Translational research and biobanking are "in", also in Flanders and in Belgium. In Flanders the Advice report 120 from the Flemish Council for Science and innovation, entitled "Extension of translational research in Flanders" paved the way for the Center for Medical Innovation. The Center for Medical Innovation aims at promoting collaboration between Flemish Universities, university hospitals, pharma and biotech industry and the Flemish Government specifically in the domain of translational research. The Initiative # 27 of the Cancer plan from the Federal Government aims at financing a virtual interuniversity tumor bank in order to promote "cancer" translational research in a collaborative network between academic structures, general hospitals en different industrial partners (pharmacy, biotechnology, diagnostics, ...) active in research in Belgium. However, the scientific interest in the human tissues is not new, at all. This text aims at giving an overview of the development and evolutions of "biobanking" initiatives.

Living related intestinal transplantation for Churg-Strauss syndrome: a case report.

Exceptionally, gastrointestinal involvement of Churg-Strauss syndrome (CSS) may require extensive bowel resection resulting in a short bowel syndrome. Living related intestinal transplantation (IT) has emerged as an alternative to deceased-donor IT in the management of patients with irreversible short bowel syndrome. Herein, we have presented a 35-year-old patient with isolated intestinal involvement of CSS lesions refractory to steroids and azathioprine requiring multiple abdominal resections resulting in an ultrashort bowel syndrome. A living related IT (from the mother) was performed. She underwent several acute rejection episodes treated with additional immunosuppressive therapy. Despite higher doses of immunosuppression, these repeated acute rejection episodes eventually evolved into a syndrome of chronic allograft rejection. Eventually, owing to her poor general condition and to avoid life-threatening infections, transplantectomy was inevitable. Recent immunologic studies indicate that peripheral mononuclear cells from patients with CSS secrete large amounts of T-helper type 1 and 2 cytokines. It is likely that patients with CSS are at higher risk for acute and chronic rejection after transplantation.

Epidemiology of mucormycosis: review of 18 cases in a tertiary care hospital.

Mucormycosis is an angio-invasive mycosis with high morbidity and mortality rates which mainly affects immunocompromised patients. It is no longer an uncommon disease due to the increased incidence of diabetes and use of immunosuppressive agents in the current era. Our objective was to review all cases of proven and probable mucormycosis--according to EORTC criteria--diagnosed from 2000 until 2007 at the University Hospitals Leuven, a 1900-bed tertiary care hospital, to assess the changing epidemiology of the disease. In 45 patients there was microbiological or histopathological evidence for the presence of a member of Mucorales during the hospital stay of which 12 cases fulfilled the criteria for proven mucormycosis and 6 for probable mucormycosis. The overall incidence was 0.042 cases per 10,000 patient days. A slight although not statistically significant increase in incidence was noticeable during the study period. The major site of infection was the lungs (78% of the cases), with haematological malignancy the most common underlying disorder and Rhizopus species the most often suspected etiologic agent. Overall mortality was 55% and co-infections with Aspergillus species, proven or probable, noted in 44% of cases. The highest survival rate was achieved with surgery combined with antifungal therapy.

Effectiveness of antibiotics and antiseptics on coagulase-negative staphylococci for the decontamination of bone allografts.

Bone allografts retrieved from multi-organ donors can be decontaminated with minimally aggressive methods. Therefore, we evaluated the efficacy of antibiotics and antiseptics in the decontamination of bone fragments actively contaminated with coagulase-negative staphylococci. Gentamicin (512/1,024 microg/mL), rifampicin (400/1,000 microg/mL), chlorhexidine in alcohol and chlorhexidine soap were tested with different contact times and temperatures and a delay in starting decontamination. Gentamicin-susceptible strains dried on bone could be removed by gentamicin 512 microg/mL after 19 h of contact, while strains not dried on bone could be eliminated by soaking bone for 60 min in gentamicin 512 microg/mL. Rifampicin-susceptible strains could be eliminated by soaking bone for 60 min in rifampicin 1,000 microg/mL. In none of the experimental conditions could gentamicin/rifampicin-resistant staphylococci be eliminated. Antiseptics could not eliminate staphylococci from bone. Different antibiotics need different protocols in order to decontaminate bone allografts.

Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma.

AIMS: Despite curative surgery for pancreatic ductal adenocarcinoma (PDAC), most patients develop cancer recurrence and die from metastatic disease. Understanding of the patterns of failure after surgery can lead to new insights for novel therapeutic modalities. The aim of the present study is to describe the patterns of recurrence after curative resection of PDAC. METHODS: A retrospective analysis was performed of 145 consecutive resections for PDAC between 1998 and 2005 (M/F 75/70; median (range) age 67 years (32-85 y)). The location of the first and consecutive recurrences, and the time interval to cancer recurrence after surgical resection was studied. The magnitude of tumour-free margin was less than a millimetre in 48 patients, whereas a positive surgical margin was observed in 27 patients. The median duration of follow-up was 18.5 (range 0.3-116.8) months. RESULTS: Cancer recurrence was observed in 110 patients. The first location of recurrence was locoregional in 19, extra-pancreatic in 66, and combined locoregional and extra-pancreatic in 25 patients. Extra-pancreatic recurrence developed in the liver in 57, peritoneal in 35, pulmonary in 15, and retroperitoneal in 5 patients. The median (95% CI) overall (OS) and disease-free (DFS) survival was 18.7 (15.7-23.5) and 9.8 (7.5-12.4) months, respectively. The type of cancer recurrence did not significantly influence OS, while the resection margin status had a prognostic effect. CONCLUSION: The vast majority of patients who undergo potentially curative surgery for PDAC develop cancer recurrence located in the abdominal cavity. Surgical resection margins with tumour involvement and tumour-free margins of less then 1mm are negative prognostic factors. Further research on better local surgical control, peri-operative locoregional treatment, and more effective adjuvant systemic therapy is necessary to improve long-term survival of patients with curable PDAC.

Influence of postmortem time on the outcome of blood cultures among cadaveric tissue donors.

Tissue banks provide tissues of human cadaver donors for transplantation. The maximal time limit for tissue retrieval has been set at 24 h postmortem. This study aimed at evaluating the evidence for this limit from a microbiological point of view. The delay of growth in postmortem blood cultures, the identification of the species isolated and clinical/environmental factors were investigated among 100 potential tissue donors. No significant difference was found in the rate of donors with grown blood cultures within (25/65=38%) compared with after (24/65=37%) 24 h of death. Coagulase-negative staphylococci and gastro-intestinal microorganisms were isolated within and after 24 h of death. Two factors--antimicrobial therapy and "delay before body cooling"--were significantly inversely related with donors' blood culture results. From a microbiological point of view, there is no evidence for avoiding tissue retrieval among donors after 24 h of death.

Bacteriostasis testing on allograft tissue inoculated in Wilkins-Chalgren broth.

Tissue banks culture tissue specimens to confirm the absence of viable micro-organisms after decontamination with antibiotics. It is possible that antibiotic residues attached to decontaminated tissue are introduced into enrichment culture media. These could have an inhibitory effect on the culture results and generate false-negative results. Our aim was to detect bacteriostasis in Wilkins-Chalgren broth inoculated with bone and tendon remnants. These remnants had been soaked in a solution containing gentamicin as part of the tissue-processing procedure. We used the United States Pharmacopeia method for bacteriostasis testing with gentamicin-susceptible Pseudomonas aeruginosa American Type Culture Collection (ATCC) 15442, Staphylococcus aureus ATCC 6538, Bacillus subtilis ATCC 6633 as test strains, and gentamicin-resistant Candida albicans ATCC 90029 as control. The residual gentamicin concentration in the broths was determined and gentamicin-soaked tissue was placed on Mueller-Hinton agar inoculated with a staphylococcal suspension. Bacteriostasis was present in 53-75% of the reference test strains. Tendon remnants had a significantly higher rate of bacteriostasis (85%) than bone remnants (28%). Broths inoculated with tendon remnants had the highest residual gentamicin concentrations.

Determinants of complications and adequacy of surgical resection in laparoscopic versus open total gastrectomy for adenocarcinoma.

BACKGROUND: The role of laparoscopic total gastrectomy (LTG) in the treatment of gastric cancer is controversial. The present study analyzed the morbidity and adequacy of resection in LTG versus open total gastrectomy (OTG) for gastric adenocarcinoma. METHODS: Between 2003 and 2006, clinical data of 38 consecutive patients who underwent LTG for gastric adenocarcinoma were collected prospectively. The same data-entry form was used for retrospective data collection from 22 consecutive patients who underwent OTG within the same time period. Logistic regression models were used in univariate and multivariate analyses to identify the optimally combined factors related to the occurrence of postoperative complications and to the number of harvested lymph nodes. RESULTS: Postoperative complications occurred in 24 patients with subsequent mortality in two. Median (range) length of hospital stay was 11 (6-73) days and comparable after LTG versus OTG (p = 0.847). The occurrence of postoperative complications was related (p = 0.004) to the first year of surgery and patients' medical condition before surgery [American Society of Anaesthesiologists (ASA) physical status III]. Microscopic tumor-free margins were obtained in all but two patients. The number of harvested lymph nodes was 17 (0-90), and determined by tumor wall penetration (p = 0.001). CONCLUSIONS: The occurrence of complications after total gastrectomy is determined by the patients' medical condition before surgery and the surgical expertise, but not by the approach. LTG and OTG can result in adequate tumor-free resection margins and lymph node yield, which is related to the tumor wall penetration. The role of LTG in gastric cancer needs further evaluation in randomized controlled trials with large patient series.

Nonfunctioning neuroendocrine tumor of the pancreas in an 8-year-old girl.

We report a case of a nonfunctioning neuroendocrine pancreatic tumor in the pediatric age group. An 8-year-old child complains of vague abdominal pain and radiological investigations detect a tumoral mass in the pancreatic tail. Abdominal ultrasound, contrast enhanced computed tomography and magnetic resonance imaging demonstrate a round intrapancreatic solid moderately vascularized lesion of approximately 5 cm in diameter, with a smooth contour and well demarcated from the surrounding tissues. After surgical resection, the diagnosis of a hormonally inactive benign neuroendocrine tumor is histologically diagnosed. Patient's follow-up is uneventful.

The effect of polyethylene glycol and butyrate on anastomotic healing in the rat colon.

BACKGROUND: The use of mechanical bowel preparation is much debated. METHODS: We evaluated the effects of polyethylene glycol (PEG), with or without a single dose of 3.0 mmol butyrate (BUT), on the bursting pressure (BP) of an intact colon segment and a colon anastomosis in rats. Also, histopathologic damage was studied. RESULTS: In rats without colectomy, the mean BP was 159.2 mmHg (SD=18.9) after PEG treatment and 116.7 mmHg (SD=27.5) in controls (p=0.001). In rats with colectomy, the mean BP was 90.4 mmHg (SD=45.9) in the PEG group, 108.0 mmHg (SD=31.9) in the BUT group, and 102.7 mmHg (SD=44.7) in controls (p=0.44). No significant differences in histopathologic scores were observed between rats treated with PEG and controls. CONCLUSIONS: PEG does not interfere with anastomotic healing in rats as measured by BP. No benefit of a single dose of butyrate was observed.

Review article: the nature of oesophageal injury in gastro-oesophageal reflux disease.

The purpose of this review was to explore issues relating to the nature of oesophageal injury in gastro-oesophageal reflux disease. Several structural and functional elements of the oesophageal epithelium provide for an inherent resistance against refluxed material. It is only when this defence is overcome that reflux-induced damage ensues. The light microscopic changes in reflux oesophagitis are manifold. Early changes are confined to the epithelium and consist of reactive changes and inflammatory cell infiltration. When the epithelial integrity can no longer be maintained, erosions and ulcers develop. Recently, dilatation of the intercellular spaces was described as a sensitive early marker for gastro-oesophageal reflux disease. This parameter was first identified by electron microscopy but can also be assessed by light microscopy in routinely stained tissue sections. Some of the changes occurring in early gastro-oesophageal reflux disease can be reproduced by incubating oesophageal mucosal biopsies in gastrointestinal fluids or their components. Activated pepsin, trypsin and conjugated bile acids at an acidic pH have been identified as probable causes of reflux-induced damage.

Validation of 16S rDNA sequencing in microdissected bowel biopsies from Crohn's disease patients to assess bacterial flora diversity.

The bowel flora is implicated in Crohn's disease (CD) pathogenesis but its precise role is still unclear. Several non-mutually exclusive hypotheses have been proposed: an unidentified persistent pathogen; excessive bacterial translocation; an immune system abnormality in response to normal bacteria; or a breakdown in the balance between protective and harmful bacteria. These hypotheses can be tested by identifying bacteria in specific microscopic bowel structures or lesions. The present paper describes a novel technique to assess bacterial flora diversity in bowel biopsies, by combining laser capture microdissection with broad-range 16S rDNA sequencing. Fifty-four samples comprising histologically normal and pathological mucosa, MALT, ulcers, submucosal lymphangiectasias, epithelioid granulomas, and lymph nodes were microdissected out of 30 bowel biopsies from five CD patients. Bacterial 16S rDNA was successfully amplified by PCR in all samples, and PCR products from 15 samples were selected for cloning and sequence analysis. A total of 729 bacterial DNA sequences were analysed, which could be attributed to six different phyla (Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria, and Planctomycetes). DNA from typical bowel bacteria (Enterobacteriaceae, Clostridiales, Bacteroidetes, Fusobacteria) was detected in all microdissected areas. It was thus convincingly demonstrated that 16S rDNA sequencing can be combined with microdissection to study the bowel flora. However, no specific persistent pathogen causal for CD was identified. The results suggest that Enterobacteriaceae may initiate or colonize ulcers in CD. Translocation of bacteria through established mucosal lesions or as a result of increased permeability may be involved in the evolution towards chronic inflammation and in the establishment of persistent lesions. Further study is needed to confirm these preliminary findings.

A new approach to the validation of tissue microarrays.

Although tissue microarrays (TMA) have been widely used for a number of years, it is still not clear how many core biopsies should be taken to determine a reliable value for percentage positivity or how much heterogeneity in marker expression influences this number. The first aim of this study was to validate the human visual semi-quantitative scoring system for positive staining of tumour tissue with the exact values determined from computer-generated images. The second aim was to determine the minimum number of core biopsies needed to estimate percentage positivity reliably when the immunohistochemical staining pattern is heterogeneous and scored in a non-binary way. Tissue sections from ten colorectal cancer specimens were stained for carbonic anhydrase IX (CA IX). The staining patterns were digitized and 400 artificial computer-generated images were generated to test the accuracy of the human scoring system. To determine the minimal number of core biopsies needed to account for tumour heterogeneity, 50 (artificial) core biopsies per section were taken from the tumoural region of the ten digitally recorded full tissue sections. Based on the semi-quantitative scores from the 50 core biopsies per section, 2500 x n (n = 1-10 core biopsies) experimental core biopsies were then generated and scores recorded. After comparison with field-by-field analysis from the tumoural region of the whole tissue section, the number of core biopsies that need to be taken to minimize the influence of heterogeneity could be determined. In conclusion, visual scoring accurately estimated the percentage positivity and the percentage tumour present in a section, as judged by comparison with the artificial images. The exact number of core biopsies that has to be examined to determine tumour marker positivity using TMAs is affected by the degree of heterogeneity in the expression pattern of the protein, but for most purposes at least four is recommended.

Chemo-radiotherapy versus radiotherapy alone in the pre-operative treatment of resectable rectal cancer.

AIM: To determine the differences in downstaging, local control (LC), disease free survival (DFS) and overall survival (OS) between combined pre-operative chemoradiation and pre-operative radiotherapy alone in the treatment of resectable rectal cancer. METHODS: One hundred and ten patients who underwent pre-operative radiotherapy or chemo-radiotherapy were reviewed. Fifty-seven patients were treated with radiotherapy (30 Gy/3 Gy) alone and 53 patients with chemo-radiotherapy (bolus 5FU+45 Gy/1.8 Gy). The median interval between the end of neo-adjuvant treatment and surgery was 28 and 46 days for the patients treated with radiotherapy alone and chemo-radiotherapy. RESULTS: The groups were homogeneously distributed for all characteristics except for cN-stage with more clinically node positive patients in the combined modality treatment group (47 vs 73%). A significant downstaging for tumour and/or lymph node status was observed in both groups. More ypT0-x-is were observed after chemoradiation than after radiotherapy alone (26 vs 7%; p=0.02). The local control rate at 3 years was 94% for both groups. DFS after radiation and chemoradiation was comparable with a 3-year DFS of 83 and 88%, respectively. CONCLUSION: Both pre-operative schemes have similar outcomes concerning DFS, OS and LC. Tumour downstaging is associated with improved survival.

What is the role of celiac disease in enteropathy-type intestinal lymphoma? A retrospective study of nine cases.

BACKGROUND AND AIMS: It is generally accepted that enteropathy-type intestinal lymphoma (EATL) arises against a background of gluten enteropathy. We investigate whether patients with this diagnosis had celiac disease or pre-existing celiac disease, based on gliadin and endomysium antibodies, as well as duodenal biopsies, HLA typing and response to gluten-free diet. METHODS AND RESULTS: Retrospective study of patients with the diagnosis of peripheral T cell lymphoma of the intestine between January 1990 and January 2002 at the university hospital Gasthuisberg Leuven (n = 14). Patients in whom serologic testing was performed or patients known with pre-existing celiac disease (CD) were included (n = 9). Six of these nine patients were tested for endomysium antibodies (AEM), none of them were positive. Of the six patients with biopsies of mucosa uninvolved by lymphoma, all of them had villous atrophy; five had increased intraepithelial lymphocytes (IEL). In the four patients were HLA typing was performed, the results were compatible with CD. The three patients with initially diagnosed celiac disease all improved on gluten free diet (control biopsies improved as well, but failed to normalise). Of the six other patients, one patient never started GFD, two didn't get better, one initially went better after GFD, and one went better with the concomitantly started chemotherapy. CONCLUSION: There are two possible explanations: Either these patients with EATL have indeed gluten intolerance but the sensitivity of AEM is overestimated in this patient population; or these patients don't have gluten intolerance and EATL itself can mimic CD or other factors mimicking CD are at risk for developing EATL.

Three-field lymphadenectomy for carcinoma of the esophagus and gastroesophageal junction in 174 R0 resections: impact on staging, disease-free survival, and outcome: a plea for adaptation of TNM classification in upper-half esophageal carcinoma.

OBJECTIVE: To determine the impact of esophagectomy with 3-field lymphadenectomy on staging, disease-free survival, and 5-year survival in patients with carcinoma of the esophagus and gastroesophageal junction (GEJ). BACKGROUND: Esophagectomy with 3-field lymphadenectomy is mainly performed in Japan. Data from Western experience with 3-field lymphadenectomy are scarce and dealing with relatively small numbers. As a result, its role in the surgical practice of cancer of the esophagus and GEJ remains controversial. METHODS: Between 1991 and 1999, primary surgery with 3-field lymphadenectomy was performed in 192 patients, of whom a cohort of 174 R0 resections was used for further analysis. RESULTS: Hospital mortality of the whole series was 1.2%. Overall morbidity was 58%. Pulmonary complications occurred in 32.8%, cardiac dysrhythmias in 10.9%, and persistent recurrent nerve problems in 2.6%. pTNM staging was as follows: stage 0, 0.6%; stage I, 9.2%; stage II, 27.6%; stage III, 28.7%; and stage IV, 33.9%. Overall 3- and 5-year survival was 51% and 41.9%, respectively. The 3- and 5-year disease-free survival was 51.4% and 46.3%, respectively. Locoregional lymph node recurrence was 5.2%; no patient developed an isolated cervical lymph node recurrence. Five-year survival for node-negative patients was 80.2% versus 24.5% for node-positive patients. Five-year survival by stage was 100% in stages 0 and I, 59.1% in stage II, 36.8% in stage III, and 13.3% in stage IV. Twenty-three percent of the patients with adenocarcinoma (25.8% distal third and 17.6% GEJ) and 25% of the patients with squamous cell carcinoma (26.2% middle third) had positive cervical nodes resulting in a change of pTNM staging specifically related to the unforeseen cervical lymph node involvement in 12%. Cervical lymph node involvement was unforeseen in 75.6% of patients with cervical nodes at pathologic examinations. Five-year survival for patients with positive cervical nodes was 27.7% for middle third squamous cell carcinoma. For distal third adenocarcinomas, 4-year survival was 35.7% and 5-year survival 11.9%. No GEJ adenocarcinoma with positive cervical nodes survived for 5 years. CONCLUSIONS: Esophagectomy with 3-field lymph node dissection can be performed with low mortality and acceptable morbidity. The prevalence of involved cervical nodes is high, regardless of the type and location of tumor resulting in a change of final staging specifically related to the cervical field in 12% of this series. Overall 5-year and disease-free survival after R0 resection of 41.9% and 46.3%, respectively, may indicate a real survival benefit. A 5-year survival of 27.2% in patients with positive cervical nodes in middle third carcinomas indicates that these nodes should be considered as regional (N1) rather than distant metastasis (M1b) in middle third carcinomas. These patients seem to benefit from a 3-field lymphadenectomy. The role of 3-field lymphadenectomy in distal third adenocarcinoma remains investigational.