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Objective: To test whether simvastatin improves physiological and biological outcomes in patients undergoing esophagectomy., Background: One-lung ventilation during esophagectomy is associated with inflammation, alveolar epithelial and systemic endothelial injury, and the development of acute lung injury (ALI). Statins that modify many of the underlying processes are a potential therapy to prevent ALI., Methods: We conducted a randomized double-blind placebo-controlled trial in patients undergoing esophagectomy. Patients received simvastatin 80 mg or placebo enterally for 4 days preoperatively and 7 days postoperatively. The primary end point was pulmonary dead space (Vd/Vt) at 6 hours after esophagectomy or before extubation. Inflammation was assessed by plasma cytokines and intraoperative exhaled breath condensate pH; alveolar type 1 epithelial injury was assessed by plasma receptor for advanced glycation end products and systemic endothelial injury by the urine albumin-creatinine ratio., Results: Thirty-nine patients were randomized; 8 patients did not undergo surgery and were excluded. Fifteen patients received simvastatin and 16 received placebo. There was no difference in Vd/Vt or other physiological outcomes. Simvastatin resulted in a significant decrease in plasma MCP-1 on day 3 and reduced exhaled breath condensate acidification. Plasma receptor for advanced glycation end products was significantly lower in the simvastatin-treated group, as was the urine albumin-creatinine ratio on day 7 postsurgery. ALI developed in 4 patients in the placebo group and no patients in the simvastatin group although this difference was not statistically significant (P=0.1)., Conclusions: In this proof of concept study, pretreatment with simvastatin in esophagectomy decreased biomarkers of inflammation as well as pulmonary epithelial and systemic endothelial injury.

Detection of bone marrow micrometastases (BMMs) in patients with esophageal carcinoma may indicate a metastatic phenotype. We assessed if the presence of BMMs had adverse prognostic significance in a 10-year follow-up study. Patients undergoing surgery for esophageal cancer were prospectively recruited between February 1999 and August 2000. Bone marrow aspirates were obtained from the iliac crest of patients under general anesthesia at the time of surgery. Immunocytochemical analysis using anticytokeratin antibodies CAM 5.2 and AE1/AE3 was undertaken to determine the presence of BMMs. Union International Contre le Cancer staging was recorded for all patients. Patient follow-up was completed over a 10-year period through analysis of the Northern Ireland Cancer Registry. Forty-two patients (male = 35) were included, with a mean age of 67.2 years (range 39-83). BMMs were detected in 19 patients (45.2%). International Contre le Cancer tumor staging was stage I = 6, stage II = 10, stage III = 24, and stage IV = 2. BMMs were associated with lymphovascular invasion (P= 0.02) and advanced T stage (P= 0.02). Overall, 10-year survival was 21.4% (n= 9), with a median follow-up of 877.5 days (interquartile range 391.5-2546.3). There was no statistically significant difference between the survival of patients with or without BMMs (1451.4 vs. 1431.6 days, P= 0.99). Univariate analysis demonstrated a trend toward decreased survival for patients with positive lymph nodes (P= 0.07), an increased T stage (P= 0.06), and lymphovascular invasion (P= 0.07). Multivariate analysis demonstrated that none of the variables were significant predictors of mortality. Although the presence of BMMs correlates with recognized adverse tumor characteristics in patients with esophageal cancer, micrometastases detected in the bone marrow at time of surgery does not influence long-term survival., (© 2012 Copyright the Authors. Journal compilation © 2012, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Vascular endothelial growth factor (VEGF) is an angiogenic cytokine that regulates tumour angiogenesis. The prognostic significance of VEGF expression remains incompletely investigated for patients with oesophagogastric cancer. This study assesses the significance of tumour VEGF (T-VEGF) and circulating VEGF (C-VEGF) expression in a 10-year follow-up of patients with oesophagogastric cancer. Patients undergoing surgical resection were prospectively recruited between February 1999 and August 2000. Circulating VEGF, derived both from plasma (P-VEGF) and serum (S-VEGF), and T-VEGF were assessed using a commercial enzyme-linked immunosorbent assay (ELISA). As platelet count may contribute to C-VEGF, pre-operative platelet levels were also recorded to exclude a confounding effect. Patients were followed up over a 10-year period using the Northern Ireland Cancer Registry. Sixty-one patients were recruited (men=45) with a mean age of 65.7 years. The 10-year survival was 19.7% (n=12) with a median follow-up of 808 days (inter-quartile range [IQR]: 349.5-2358.5). Union for International Cancer Control (UICC) tumour staging was Stage I=9 (14.8%), Stage II=15 (24.6%), Stage III=33 (54.1%) and Stage IV=4 (6.6%). The only significant relationship between clinicopathological features and the study variables was for S-VEGF, which was elevated in patients with advanced T-stage (P = 0.05). Circulating VEGF did not correlate with platelet count. Although a trend towards decreased survival was observed for patients who had positive lymph nodes (P = 0.08) and advanced UICC stage (P = 0.09) on univariate analysis, only lymphovascular invasion significantly predicted poor prognosis in this cohort (P = 0.05). Therefore, ELISA quantification of circulatory or tumour VEGF does not appear to be a significant predictor of mortality in patients with oesophagogastric cancer.

Successful palliation of dysphagia in patients with inoperable esophageal carcinoma has a major effect on quality of life. Self-expanding metal stents (SEMS) are currently recommended for rapid symptomatic relief when life expectancy is less than 3 months. We assessed complication and reintervention rates along with survival outcomes in patients with inoperable esophageal carcinoma undergoing stent insertion. A retrospective audit was performed from April 2007 to June 2009 for all inoperable primary esophageal carcinoma patients who had an esophageal stent inserted for dysphagia. Case notes were reviewed for clinical, pathological, stent and complication details, while ICD-10 causes of death were obtained from the Department of Health and Social Services, Northern Ireland. Fifty-six stents were inserted into 53 patients (66.0% male, mean age of 70 years). Inoperability was defined by metastatic spread (n= 34, 64.2%), locally advanced disease (n= 7, 13.2%), and severe medical comorbidities (n= 12, 22.6%). The median time from diagnosis to stent insertion was 109 (interquartile range [IQR] 43-187) days. Fifty stents (94.3%) were successfully deployed, while three patients (5.7%) required an additional stent as the primary stent had not bridged the tumor (proximal deployment = 2, suboptimal stent length = 1). Post-SEMS dysphagia scores were significantly better than pre-SEMS scores (2.90 vs. 1.54, P < 0.001). There were 27 complications identified in 23 (43.4%) patients (major complications = 9, minor complications = 14). Twelve patients (22.6%) required additional endoscopic procedures. The 30-day mortality rate was 11.3% (n= 6). Only one patient (1.9%) remains alive with a cumulative median survival rate of 84 (IQR 38-156) days. Esophageal stent insertion in this group of patients still presents a clinical challenge, with complication and endoscopic reintervention rates of 43.4 and 22.6%, respectively. Our results are comparable with previously published series, and as a palliative modality stent insertion remains appropriate when expected survival is less than 3 months. A range of SEMS is currently available with broadly similar efficacy and safety profiles. Data regarding the newly available fully covered SEMS suggest that they should be avoided., (© 2011 Copyright the Authors. Journal compilation © 2011, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Purpose: The aim of the study was to compare the pre-operative metabolic tumour length on FDG PET/CT with the resected pathological specimen in patients with oesophageal cancer., Methods: All patients diagnosed with oesophageal carcinoma who had undergone staging PET/CT imaging between the period of June 2002 and May 2008 who were then suitable for curative surgery, either with or without neo-adjuvant chemotherapy, were included in this study. Metabolic tumour length was assessed using both visual analysis and a maximum standardised uptake value (SUV(max)) cutoff of 2.5., Results: Thirty-nine patients proceeded directly to curative surgical resection, whereas 48 patients received neo-adjuvant chemotherapy, followed by curative surgery. The 95% limits of agreement in the surgical arm were more accurate when the metabolic tumour length was visually assessed with a mean difference of -0.05 cm (SD 2.16 cm) compared to a mean difference of +2.42 cm (SD 3.46 cm) when assessed with an SUV(max) cutoff of 2.5. In the neo-adjuvant group, the 95% limits of agreement were once again more accurate when assessed visually with a mean difference of -0.6 cm (SD 1.84 cm) compared to a mean difference of +1.58 cm (SD 3.1 cm) when assessed with an SUV(max) cutoff of 2.5., Conclusion: This study confirms the high accuracy of PET/CT in measuring gross target volume (GTV) length. A visual method for GTV length measurement was demonstrated to be superior and more accurate than when using an SUV(max) cutoff of 2.5. This has the potential of reducing the planning target volume with dose escalation to the tumour with a corresponding reduction in normal tissue complication probability.

The aim of this study is to assess if individual case volume of oesophageal resections influences the operative mortality rate in a high volume hospital. Between June 1994 and June 2006, 252 total thoracic oesophageal resections (75% male, mean age 63 years) were performed by five surgeons in tertiary referral centre. Operative approach was standardised in all cases and consisted of left thoracolaparotomy, resection of all intrathoracic and abdominal oesophagus and left cervical incision for anastomosis. Operative mortality, defined as in-hospital death irrespective of length of stay, was compared among consultants and also trainees. A total of 207 operations were performed by five consultants with nine deaths (4.3%) compared to two deaths after 45 operations by 17 trainees (4.4%) [Fisher's exact test, P=0.61 (CI=0.84-1.26)]. Individual case volume for consultants ranged from 5 to 10.5 cases/years [chi2-test, P=0.34 (CI=0.89-1.29)] with 0-5.4% mortality rate [chi2-test, P=0.24 (CI=0.96-1.19)]. Overall hospital volume ranged from 17 to 57 cases/years. This study confirms that surgeons with appropriate training in oesophageal resection may get good results despite lower individual case volumes when a standardised approach is taken in an institution with a high case volume.

Objective: To examine the association between dietary glycemic index (GI), glycemic load (GL), total carbohydrate, sugars, starch, and fiber intakes and the risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma., Methods: In an all-Ireland study, dietary information was collected from patients with esophageal adenocarcinoma (n = 224), long-segment Barrett's esophagus (n = 220), reflux esophagitis (n = 219), and population-based controls (n = 256). Multiple logistic regression analysis examined the association between dietary variables and disease risk by tertiles of intake and as continuous variables, while adjusting for potential confounders., Results: Reflux esophagitis risk was positively associated with starch intake and negatively associated with sugar intake. Barrett's esophagus risk was significantly reduced in people in the highest versus the lowest tertile of fiber intake (OR 0.44 95%CI 0.25-0.80). Fiber intake was also associated with a reduced risk of esophageal adenocarcinoma, as was total carbohydrate intake (OR 0.45 95%CI 0.33-0.61 per 50 g/d increase). However, an increased esophageal adenocarcinoma risk was detected per 10 unit increase in GI intake (OR 1.42 95%CI 1.07-1.89)., Conclusions: Our findings suggest that fiber intake is inversely associated with Barrett's esophagus and esophageal adenocarcinoma risk. Esophageal adenocarcinoma risk is inversely associated with total carbohydrate consumption but positively associated with high GI intakes.

Background & Aims: Alcohol consumption may increase gastroesophageal reflux symptoms, cause damage to the esophageal mucosa, and/or promote carcinogenesis. However, reports about the association between alcohol and reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma are conflicting., Methods: Information relating to alcohol consumption, at age 21 and 5 years before the interview date, was collected from 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma patients and 260 frequency-matched population controls. Logistic regression analyses were used to compare alcohol consumption in the 3 case groups to controls with adjustment for potential confounders., Results: Population controls reporting gastroesophageal reflux symptoms were less likely than controls without symptoms to drink alcohol 5 years before the interview date (odds ratio [OR], 0.44, 0.20-0.99). No associations were observed between total alcohol consumption 5 years before the interview date and reflux esophagitis, Barrett's esophagus, or esophageal adenocarcinoma (OR, 1.26, 0.78-2.05; OR, 0.72, 0.43-1.21; and OR, 0.75, 0.46-1.22, respectively). Wine was inversely associated with reflux esophagitis (OR, 0.45, 0.27-0.75). Total alcohol consumption at age 21 years was significantly associated with reflux esophagitis (OR, 2.24, 1.35-3.74) but not with Barrett's esophagus or esophageal adenocarcinoma (OR, 1.06, 0.63-1.79 and OR, 1.27, 0.77-2.10, respectively)., Conclusions: Alcohol consumption in early adulthood may lead to the development of reflux esophagitis. More recent alcohol consumption does not appear to confer any increased risk of reflux esophagitis, Barrett's esophagus, or esophageal adenocarcinoma. In fact, wine consumption may reduce the risk of these 3 esophageal disorders.

Objective: To investigate strain and mental health among family caregivers of oesophageal cancer patients and possible factors associated with caregiver mental health and strain., Methods: Patients with oesophageal adenocarcinoma in Ireland were recruited into the FINBAR study (the main aim of which was to investigate factors influencing the Barrett's adenocarcinoma relationship). Carers completed the 13-item Caregiver Strain Index and the General Health Questionnaire-30 (GHQ) in the context of a brief interview with trained research staff that was undertaken separately from the interview with each cancer patient., Results: Two hundred and twenty-seven patients participated in the FINBAR study. A total of 39 patients did not have a family carer or the carer could not be identified. Fifty percent (94/188) of carers completed the questionnaires. Mean (SD) scores for strain (6.65, SD=3.63) and mental health status (10.21, SD=7.30) were high and 71% of carers scored >5 on the GHQ indicating psychological distress. There was a statistically significant positive relationship between level of strain experienced by caregivers and the severity of their mental health status and whether or not carers scored >5 on the GHQ. Relatives were 1.70 (95% CI 1.34-2.15) times more likely to be defined as high scorers with each unit increase in the CSI score., Conclusions: A significant proportion of caregivers experienced high levels of strain and psychological distress. There is a need to provide appropriate support and services targeted specifically at reducing the considerable strain of caring for patients with oesophageal cancer, particularly for carers of patients from lower socioeconomic groups., ((c) 2008 John Wiley & Sons, Ltd.)

Objective: A number of studies have shown an inverse association between infection with Helicobacter pylori and oesophageal adenocarcinoma (OAC). The mechanism of the apparent protection against OAC by H pylori infection and, in particular, the role of gastric atrophy is disputed. The relationship between all stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence and H pylori infection and gastric atrophy was explored., Methods: A case-control study involving 260 population controls, 227 OAC, 224 Barrett's oesophagus (BO) and 230 reflux oesophagitis (RO) patients recruited within Ireland was carried out. H pylori and CagA (cytotoxin-associated gene product A) infection was diagnosed serologically by western blot, and pepsinogen I and II levels were measured by enzyme immunoassay. Gastric atrophy was defined as a pepsinogen I/II ratio of <3., Results: H pylori seropositivity was inversely associated with OAC, BO and RO; adjusted ORs (95% CIs), 0.49 (0.31 to 0.76), 0.35 (0.22 to 0.56) and 0.42 (0.27 to 0.65), respectively. Gastric atrophy was uncommon (5.3% of all subjects), but was inversely associated with non-junctional OAC, BO and RO; adjusted ORs (95% CIs), 0.34 (0.10 to 1.24), 0.23 (0.05 to 0.96) and 0.27 (0.08 to 0.88), respectively. Inverse associations between H pylori and the disease states remained in gastric atrophy-negative patients., Conclusion: H pylori infection and gastric atrophy are associated with a reduced risk of OAC, BO and RO. While use of the pepsinogen I/II ratio as a marker for gastric atrophy has limitations, these data suggest that although gastric atrophy is involved it may not fully explain the inverse associations observed with H pylori infection.

Reflux of gastric contents can lead to development of reflux esophagitis and Barrett's esophagus. Barrett's esophagus is a risk factor for esophageal adenocarcinoma. Damage to DNA may lead to carcinogenesis but is repaired through activation of pathways involving polymorphic enzymes, including human 8-oxoguanine glycosylase 1 (hOGG1), X-ray repair cross-complementing 1 (XRCC1), and xeroderma pigmentosum group D (XPD). Of the single nucleotide polymorphisms identified in these genes, hOGG1 Ser 326 Cys, XRCC1 Arg 399 Gln, and XPD Lys 751 Gln are particularly common in Caucasians and have been associated with lower DNA repair capacity. Small studies have reported associations with XPD Lys 751 Gln and esophageal adenocarcinoma. XRCC1 Arg 399 Gln has been linked to Barrett's esophagus and reflux esophagitis. In a population-based case-control study, we examined associations of the hOGG1 Ser 326 Cys, XRCC1 Arg 399 Gln, and XPD Lys 751 Gln polymorphisms with risk of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barrett's esophagus (n = 212), reflux esophagitis (n = 230), and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. There were no statistically significant associations between these polymorphisms and risk of esophageal adenocarcinoma, Barrett's esophagus, or reflux esophagitis.

The incidence of esophageal adenocarcinoma has increased in recent years, and Barrett's esophagus is a recognized risk factor. Gastroesophageal reflux of acid and/or bile is linked to these conditions and to reflux esophagitis. Inflammatory disorders can lead to carcinogenesis through activation of "prosurvival genes," including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Increased expression of these enzymes has been found in esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Polymorphic variants in COX-2 and iNOS genes may be modifiers of risk of these conditions. In a population-based case-control study, we examined associations of the COX-2 8473 T>C and iNOS Ser(608) Leu (C>T) polymorphisms with risk of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barrett's esophagus (n = 212), and reflux esophagitis (n = 230) and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. The presence of at least one COX-2 8473 C allele was associated with a significantly increased risk of esophageal adenocarcinoma (adjusted odds ratio, 1.58; 95% confidence interval, 1.04-2.40). There was no significant association between this polymorphism and risk of Barrett's esophagus or reflux esophagitis or between the iNOS Ser 608 Leu polymorphism and risk of these esophageal conditions. Our study suggests that the COX-2 8473 C allele is a potential genetic marker for susceptibility to esophageal adenocarcinoma.

Oxidative stress appears to be important in the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Single-nucleotide polymorphisms (SNPs) of antioxidant enzyme genes may play a part in determining individual susceptibility to these diseases. The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study is a population-based, case-control study of BE and EAC in Ireland. DNA from EAC (n = 207), BE (> or =3 cm BE at endoscopy with specialized intestinal metaplasia on biopsy, n = 189) and normal population controls (n = 223) were analyzed. Several SNPs spanning the genes for glutathione S-transferase P1 (GSTP1), manganese superoxide dismutase (MnSOD) and glutathione peroxidase 2 (GPX2) were genotyped using multiplex polymerase chain reaction and SNaPshottrade mark. The chi(2) test was used to compare genotype and allele frequencies between case and control subjects. Linkage disequilibrium between SNPs was quantified using Lewontin's D' value and haplotype frequency estimates obtained using Haploview. Eleven SNPs were genotyped (six for GSTP1, three for MnSOD and two for GPX2); all were in Hardy-Weinberg equilibrium. None was significantly associated with EAC or BE even before Bonferroni correction. Odds ratios for EAC for individual SNPs ranged from 0.68 [95% confidence interval (CI) 0.43-1.08] to 1.25 (95% CI 0.73-2.16), and for BE from 0.84 (95% CI 0.52-1.30) to 1.30 (95% CI 0.85-1.97). SNPs in all three genes were in strong linkage disequilibrium (D' > 0.887) but haplotype analysis did not show any significant association with EAC or BE. SNPs involving the GSTP1, MnSOD and GPX2 genes were not associated with BE or EAC. Further studies aimed at identifying susceptibility genes should focus on different antioxidant genes or different pathways.

Observational studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of esophageal adenocarcinoma, but it is not known at what stage they may act in the esophageal inflammation-metaplasia-adenocarcinoma sequence. In an all-Ireland case-control study, we investigated the relationship between the use of NSAIDs and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Patients with esophageal adenocarcinoma, long-segment Barrett's esophagus and population controls were recruited from throughout Ireland. Esophagitis patients were recruited from Northern Ireland only. Data were collected on known and potential risk factors for esophageal adenocarcinoma and on the use of NSAIDs, including aspirin, at least 1 year before interview. Associations between use of NSAIDs and the stages of the esophageal inflammation-metaplasia-adenocarcinoma sequence were estimated by multiple logistic regression. In total, 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma and 260 population controls were recruited. Use of aspirin and NSAIDs was associated with a reduced risk of Barrett's esophagus [odds ratio [OR; 95% confidence interval (95% CI)], 0.53 (0.31-0.90) and 0.40 (0.19-0.81), respectively] and esophageal adenocarcinoma [OR (95% CI), 0.57 (0.36-0.93) and 0.58 (0.31-1.08), respectively]. Barrett's esophagus and esophageal adenocarcinoma patients were less likely than controls to have used NSAIDs. Selection or recall bias may explain these results and the results of previous observational studies indicating a protective effect of NSAIDs against esophageal adenocarcinoma. If NSAIDs have a true protective effect on the esophageal inflammation-metaplasia-adenocarcinoma sequence, they may act early in the sequence.

In patients with cancer circulating vascular endothelial growth factor (VEGF) may be tumor-derived and have prognostic significance. Activated platelets may also be a source of VEGF, releasing it in serum formation. Debate exists as to whether serum or plasma VEGF (S-VEGF, P-VEGF) is the most appropriate surrogate marker of tumor angiogenesis. As healing wounds produce VEGF that can spill over into the circulation, we aimed to investigate the potential confounding effects of cancer surgery on both perioperative S-VEGF and P-VEGF levels and to evaluate their relationship with platelet count. S-VEGF, P-VEGF and platelet counts were measured in 23 patients undergoing esophageal cancer resection. Samples were taken preoperatively and six weeks following surgery. Seven patients were also sampled on postoperative days 1, 5 and 10. VEGF was assayed using a commercial enzyme linked immunosorbent assay. S-VEGF and P-VEGF both rose after surgery (S-VEGF; day 5: 1017 [446-1224] pg/mL and day 10: 1231 [626-2046] pg/mL versus pre-op: 329 [189-599] pg/mL. P-VEGF; day 1: 55 [46-104] pg/mL and day 10: 58 [20-154] pg/mL versus pre-op: 23 [13-46] pg/mL), falling towards preoperative levels by six weeks. Platelet count correlated with S-VEGF (rho=0.281; p<0.05, Spearman's rank) and P-VEGF (rho=0.330; p<0.01, Spearman's rank). Platelets may contribute to VEGF levels in plasma as well as in serum. The effects of surgery on S-VEGF or P-VEGF levels are mainly transient. Care must be exercised when interpreting circulating VEGF levels in the early postoperative period.

Background and Study Aims: Self-expanding metal stents have become accepted palliation for inoperable malignant oesophageal obstruction, the cost of the devices being offset against the ease of insertion and the reduced complication rate. However, re-intervention is often required for obstruction, malposition, migration and tumour progression. The marginal cost of re-stenting is generally higher than other modalities. This study aims to determine the rate of re-intervention and the effectiveness of the various intervention modalities., Patients and Methods: A population of 165 patients, treated in a tertiary referral oesophageal centre, (132 with oesophageal cancer, 31 with mediastinal metastases from other tumours, two with benign conditions) whose initial stent placement was performed between January 1994 and December 1998 was followed-up through July 1999 or till death., Results: A total of 75 re-interventions were required in 44 patients and were successful in 51 (68%). Rigid oesophagoscopy and removal of food bolus was successful in three out of three, dilation in one of 11, rigid oesophagoscopy and physical debridement in 12 of 17 and laser debridement in 12 of 20. Re-stenting was the primary re-intervention in 10 cases and was ultimately necessary in 14 patients (with 11 self-expanding metal stents, three Celestin) who had previously undergone other forms of re-intervention. It was not successful in one case. The median survival following first re-intervention was 9.8 weeks (compared with 14.3 weeks for initial stenting) and was longer in those receiving radiotherapy (23.6 weeks) or chemotherapy (14.4 weeks)., Conclusions: While repeated stenting is usually successful, debridement and laser vaporization are viable alternatives for proximal tumour overgrowth or ingrowth in the upper or middle third of the oesophagus. Distal tumour growth or ingrowth at the oesophagogastric junction are best treated with a second stent. Repeated treatment is justified, as survival following first re-intervention is comparable to that after initial stenting, particularly in those patients who are able to undergo chemotherapy or radiotherapy.

It has been suggested that the high prevalence of short segments of specialised intestinal metaplasia (SIM) at the gastro-oesophageal junction is associated with the rising incidence of oesophageal adenocarcinoma. Our aims were to document the prevalence of short segments of SIM at the gastro-oesophageal junction in patients attending for routine endoscopy and to determine if there was molecular evidence of neoplastic transformation in those with SIM. Patients (n = 101) were recruited from randomly selected upper gastro-intestinal endoscopy lists. Biopsy specimens were taken at the squamo-columnar junction to assess the prevalence of SIM. Frozen sections were assessed for molecular evidence of neoplastic transformation using microsatellite analysis. Squamo-columnar biopsies were suitable for analysis in 95 patients, of whom 20 (21%) had oesophagitis and 2 (2%) had Barrett's oesophagus (>3 cm of endoscopically apparent columnar-lined oesophagus). Twenty patients had SIM at the gastro-oesophageal junction, including 2 with Barrett's oesophagus and 18 with short segments of SIM, one of whom had an associated intramucosal adenocarcinoma detected incidentally by histology. Three of the 20 cases with SIM exhibited novel microsatellite alleles, 2 with Barrett's oesophagus and 1 with short segment SIM and an associated adenocarcinoma. The 18 patients with short segments of SIM at the gastro-oesophageal junction were significantly older than those without SIM., (Copyright 2000 Wiley-Liss, Inc.)

Objective: Anastomotic recurrence is a major cause of late mortality following oesophago-gastrectomy (OG) for carcinoma of the oesophagus and oesophago-gastric junction using either the Ivor Lewis or left thoraco-abdominal approach with intra-thoracic anastomosis. The aim of this study was to determine whether the more extensive total thoracic oesophagectomy (TTO) with cervical anastomosis would reduce the anastomotic recurrence rate while maintaining acceptable operative morbidity and mortality., Methods: From January 1988 to December 1996, 108 total thoracic oesophagectomies and 66 oesophago-gastrectomies were performed with curative intent in 174 patients (125 males, mean age 62.4 years) with carcinoma (squamous cell carcinoma in 34 and adenocarcinoma in 140) of the middle (31 patients) and lower (44 patients) oesophagus and oesophago-gastric junction (99 patients)., Results: Minor complications occurred in 37 (34%) total thoracic oesophagectomy and 18 (27%) oesophago-gastrectomy patients, major complications in 15 (14%) and 5 (8%) and peri-operative death in 5 (4.6%) and 7 (11%) patients, respectively. Anastomotic leakage occurred in 10 (9%) total thoracic oesophagectomy and 5 (8%) oesophago-gastrectomy patients, and was fatal in 1 (1%) and 4 (6%). There was no incidence of tumour at or within 5 mm of the proximal limit in the total thoracic oesophagectomy group and this was reflected in the complete absence of anastomotic recurrence. In the oesophago-gastrectomy group there was a positive proximal resection margin in 13 (20%) and 13 anastomotic recurrences (22% of peri-operative survivors). The 5-year survival (including operative mortality) was 29% for total thoracic oesophagectomy compared with 21% for the other techniques (P = 0.028 log rank test). Median survival was 25.2 months after total thoracic oesophagectomy and 15.8 after oesophago-gastrectomy., Conclusions: Total thoracic oesophagectomy can be performed in oesophageal cancer patients with comparable morbidity to that of lesser resections. Incomplete proximal resection and anastomotic recurrence did not occur in this series of 108 total thoracic oesophagectomies and this is reflected in an increased medium term survival. The improved survival is most apparent for tumours of the oesophago-gastric junction.

From 1988 to 1994 year extirpation of thoracic part of the esophagus with the use of left lateral thoracoabdominal and cervical approach was carried out in 81 patients with cancer of middle (27) and lower (25) thirds of the esophagus and cardia (29). Tumor was removed en bloc with regional lymph nodes, dissected stomach was fixed to the esophageal stump and transferred to the neck, where esophago-gastral anastomosis was created by uninterrupted one-layer suture. 5 patients (6.2%) died after the operation, insufficiency of sutures of the anastomosis was detected in 5 (6.2%) patients, the fistula being spontaneously closed up. Mean duration of the operation made up 309 +/- 48 min, hospitalization 18.4 + 10.9 days. Cumulative actuarial survival rate made up: 1- years--58.9 +/- 5.7%, 3 years--26.9 +/- 6.3%, 5 years-- 20.8 +/- 6.2%. Mean duration of life after the operation was 27.8 +/- 3.4 months.

The development of adenocarcinoma in Barrett's oesophagus is proposed to occur via a stepwise progression recognised histologically as a metaplasia-dysplasia-carcinoma sequence. In order to identify chromosomal loci involved in the malignant transformation of Barrett's epithelium and the development of oesophageal adenocarcinoma, microsatellite analysis was carried out on 17 cases of Barrett's-associated oesophageal adenocarcinoma. Samples of premalignant Barrett's epithelium adjacent to adenocarcinoma were obtained from seven of these cases. Allelic imbalance was detected in > 45% of informative cases of oesophageal adenocarcinoma on chromosome arms 3q (65%), 4q (71%), 5q (59%), 6q (59%), 9p (50%), 9q (47%), 12p (47%), 12q (65%), 17p (76%), and 18q (75%). Allelic imbalance at 4q, 17p, and 18q was significantly higher than the upper 95% confidence interval for background allelic imbalance. Allelic imbalance was detected at several loci in the premalignant epithelium from five of the seven cases studied. These loci included several chromosomal arms that had demonstrated high levels of allelic imbalance in oesophageal adenocarcinoma, namely, 4q (one case), 5q (two cases), 9 (three cases), 12q (five cases), 17p (four cases), and 18q (two cases). Novel microsatellite alleles were detected in both premalignant and malignant Barrett's epithelium. In three cases, dysplastic Barrett's epithelium and adjacent adenocarcinoma demonstrated the same pattern of novel microsatellite alleles at a number of loci. In conclusion, these data indicate chromosomal loci which may be specifically involved in the histological progression of Barrett's epithelium. The detection of shared novel microsatellite alleles in premalignant and malignant Barrett's epithelium is consistent with a process of clonal expansion underlying this progression.

This study examined the association between 17p allelic loss, p53 gene mutation, p53 protein expression and DNA aneuploidy in a series of adenocarcinomas arising in the oesophagus and gastric cardia. 17p allelic loss was detected in 79% (15 of 19) of oesophageal and in 83% (29 of 35) of gastric adenocarcinomas. p53 mutations were detected in 70% (14 of 20) and 63% (26 of 41) of oesophageal and of gastric adenocarcinomas respectively. Both tumour types were associated with a predominance of base transitions at CpG dinucleotides. In five cases of oesophageal adenocarcinoma, the same mutation was detected both in tumour and in adjacent dysplastic Barrett's epithelium. Diffuse p53 protein expression was detected in 65% (13 of 20) and 59% (24 of 41) of oesophageal and of gastric tumours, respectively, and was associated with the presence of p53 missense mutation (Chi-squared, P < 0.0001). DNA aneuploidy was detected in 80% (16 of 20) of oesophageal and in 70% (28 of 40) of gastric tumours. No association was found between p53 or DNA content abnormalities and tumour stage or histological subtype. In conclusion, this study detected a similar pattern of p53 alterations in adenocarcinoma of the oesophagus and gastric cardia--molecular data consistent with the observation that these tumours demonstrate similar clinical and epidemiological features.

Background: Many current methods of esophageal resection have drawbacks that result in inadequate proximal resection, inadequate lymphadenectomy, and difficult gastric and splenic access. We describe a technique that allows reliable and safe access to the chest, abdomen, and neck., Study Design: From 1988 to 1995, 113 patients (82 men; mean age 65.3 +/- 4.5 years) with carcinoma of the esophagus or esophagogastric junction (middle third in 34, lower third in 41, and cardia in 38) underwent total thoracic esophagectomy. The histology was adenocarcinoma in 71 (62.8%), squamous cell carcinoma in 32 (28.3%), and undifferentiated carcinoma in 10 (8.9%) of the patients; 57 tumors (50.5%) were stage III. The esophagus and stomach were mobilized through a left thoracoabdominal incision. After completion of the esophageal resection, the fundus of the stomach was sutured to the esophageal stump to allow later delivery of the stomach into the neck. The esophagogastric anastomosis was performed with continuous single-layer absorbable suture through a left oblique cervical incision., Results: The mean duration of the operation was 309.2 +/- 47.9 minutes. Hospital stay ranged from 5 to 49 days (median, 12 days). The perioperative mortality rate was 4.4%. Anastomotic leak occurred in six patients (5.3%), one of whom died. The proximal resection margin was microscopically free of tumor in all cases, and with a minimum followup period of 18 months, there has been no anastomotic recurrence in any patient. Actuarial survival at 1 year was 63.4% +/- 4.9%, at 3 years 41.4% +/- 5.9%, and at 5 years 22.7% +/- 6.3%., Conclusions: Total thoracic esophagectomy through the left chest with a separate left cervical incision allows clear access to the esophagus and stomach and good tumor clearance. This procedure may be performed with a low rate of anastomotic leakage, a very low mortality rate, and no anastomotic tumor recurrence.

Self-expanding metallic stents have been employed successfully for vascular, urethral, and biliary strictures. In a prospective study we examined the efficacy of the 16 mm Wallstent for palliation of malignant dysphagia. Eight patients with severe dysphagia due to advanced primary (four) or secondary (four) oesophageal malignant disease were recruited and nine Wallstents were inserted (one patient required two). Dysphagia was reduced in all but one patient, who died after oesophageal perforation; a second patient had a self-limiting bout of haematemesis. Two patients required subsequent treatment for tumour ingrowth but five had no further palliative therapy from stent insertion to time of death. With careful patient selection and skillful application, a 16 mm self-expanding metal endoprosthesis affords effective palliation in malignant oesophageal obstruction.

Microsatellite alterations have been documented in a subset of sporadic tumors, including those of the colon, lung, bladder, stomach, and esophagus. This study documented the frequency of microsatellite alterations at 139 loci, comprising predominantly dinucleotide and tetranucleotide repeat units, in 17 cases of primary esophageal adenocarcinoma arising against a background of Barrett's metaplasia. Each tumor demonstrated alterations in at least one locus studied. Widespread microsatellite alterations, occurring at 45.3% (58 of 128) of loci tested, were detected in a single case. The remaining 16 tumors exhibited low levels of microsatellite instability, ranging from 0.8% (1 of 128) to 8.1% (10 of 123) of loci tested. The single case with ubiquitous somatic alterations showed no significant difference in the incidence of novel alleles at di- and tetranucleotide repeat loci. The 16 cases showing a low level of microsatellite alterations demonstrated a 3.3-fold higher incidence of novel alleles at tetranucleotide repeat loci compared to dinucleotide repeat loci. These data suggest that ubiquitous somatic alterations at microsatellite loci, considered a phenotypic expression of defective mismatch repair, occur infrequently in Barrett's-associated adenocarcinoma. However, the majority of these tumors demonstrate a low level of microsatellite alterations, perhaps reflecting the inherent instability of these markers.

This study examined the association between 17p allelic loss and p53 gene mutation in a series of 16 esophageal adenocarcinomas arising on a background of Barrett's esophagus. Two highly polymorphic dinucleotide repeat polymorphisms mapping to 17p13 were analyzed to assess the frequency of 17p allelic loss in these tumors. Mutations in the p53 gene were detected by direct DNA sequencing. Ninety-four % (15 of 16) of samples were informative at one or both polymorphic loci. Allelic loss at one or both loci was detected in 80% (12 of 15) of samples. Mutations were detected in 69% (11 of 16) esophageal adenocarcinomas, and there was a close association between 17p allelic loss and p53 gene mutation (P = 0.00879; Fisher's Exact Test). The tumors that were analyzed demonstrated a specific p53 mutation spectrum, with G:C to A:T base transitions at CpG dinucleotides accounting for 80% (8 of 10) of single-base substitutions. In three cases, the same p53 mutation was detected in both high-grade dysplasia and adjacent tumor. These results indicate that p53 gene alterations contribute to the development of esophageal adenocarcinoma and precede the development of invasive carcinoma in patients with Barrett's esophagus.

In the late 1970's the options for treatment of oesophageal cancer were limited. When cure was thought possible, resection was performed by the Ivor Lewis or oesophagogastrectomy techniques. Mortality was high, local recurrence rates disappointing, and long-term survival poor. For those patients whose tumours could not be resected, palliative intubation required open operation with high morbidity, and gave poor quality of life. In 1994, selective screening is diagnosing cancers early, more extensive resections are possible with lower mortality, and fewer local recurrences. Adjuvant therapy is increasing the operability rates. Gradually the facade of poor prognosis is being etched away, so that more patients are being given better quality of life, and cure is a distinct possibility. Palliation can be achieved endoscopically by dilatation, intubation or laser ablation combined with local external beam radiation. Mortality for palliative procedures is now considerably reduced.

Background: Flexible oesophagoscopy is regarded as superior to rigid oesophagoscopy on the basis of perforation rates as an end point. This advantage may be more apparent than real because no comparison has been made in a diagnostic setting in patients with carcinoma of the oesophagus with both perforation rate and diagnostic efficacy as indices., Methods: A retrospective analysis was carried out on data on 336 diagnostic oesophagoscopies in patients with carcinoma of the oesophagus, comparing rigid with flexible oesophagoscopy., Results: Both rigid and flexible oesophagoscopies were performed without perforation when they were used for diagnosis only. Rigid biopsy achieved a diagnostic success rate of 99.3%, compared with 80.5% for flexible oesophagoscopy., Conclusions: Diagnostic oesophagoscopy can be achieved without perforation with either instrument, but the chance of diagnosing carcinoma was significantly greater with the rigid instrument.

A prospective, controlled, randomized study of 80 patients undergoing esophageal operations was undertaken, in which one group of patients was given digoxin and the other was not. The incidence of cardiac dysrhythmia was compared in each group. Twenty-six patients underwent operation for benign disease. Equal numbers were digitalized or not and no dysrhythmias occurred. Fifty-four patients underwent operation for malignant disease. Of 26 in the group digitalized, 12 suffered dysrhythmia (46%). Of 28 not digitalized, 9 suffered dysrhythmia (32%). Overall, 39% of patients with malignant disease suffered a dysrhythmia compared with none with benign disease (p < 0.002 by chi 2).

The efficacy and safety of rigid oesophagoscopy in diagnostic and therapeutic settings in a consecutive series of 404 patients with oesophageal carcinoma were studied and compared to that for flexible oesophagoscopy in the same group. In addition, we examined the same parameters in a smaller group who had undergone radiotherapy with subsequent malignant stricturing. We performed 328 rigid procedures and 118 flexible procedures in a single regional surgical referral unit over a 7 year period. The combined perforation rate was 1.3%, with an overall mortality of 1% from 446 procedures. We conclude that rigid oesophagoscopy in the presence of carcinoma retains an important diagnostic and therapeutic role which can be achieved with low incidence of perforation in high-risk patients.

Leakage from an oesophagogastric anastomosis has a high morbidity and mortality. Recent evidence suggests that mechanical tissue stapling devices can decrease the rate of anastomotic breakdown but at the expense of an increase in the occurrence of fibrotic strictures at the anastomosis site. This study examines the rate of leakage and stricture in hand sutured and stapled anastomoses. A retrospective study was made of 221 oesophagogastric anastomoses following resection for carcinoma between 1977 and 1986. There were 122 sutured and 99 stapled anastomoses. Leak occurred in 21 sutured (17.2%) and 7 stapled (7.1%), P less than 0.05. If the stapled anastomosis was completely satisfactory and required no reinforcing sutures, the breakdown rate was in fact only 3% (2/69), P less than 0.01. A stapled anastomosis which required reinforcement had a similar chance of breakdown as a sutured anastomosis (16.7%). There was little difference in the performance of registrars in training and consultants at hand-sewn anastomoses with leakage rates of 13.7% and 18%, respectively; P greater than 0.05. The registrars, however, did not improve with the use of the stapler with a leakage rate of 14.3% compared to the consultants' rate of 1.75%, P less than 0.05. Involvement of the limits of resection with tumour slightly favoured breakdown--15.5% compared to 11.6% if the limits were free from tumour, P greater than 0.05. The incidence of malignant strictures was similar in both groups but benign stricture was more common in the stapled group--13% (13/99) compared to 1.6% (2/122), P less than 0.01. The mechanical stapler brings uniformity to the anastomosis but cannot compensate for deficiencies in surgical technique.