Loss of SRY-box2 (SOX2) expression and its impact on survival of patients with oesophageal adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma (OAC) is a highly aggressive malignancy with poor survival, which is highly variable amongst patients with comparable conventional prognosticators. Therefore molecular biomarkers are urgently needed to improve the prediction of survival in these patients. SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor involved in embryonal development of the gastrointestinal tract as well as in carcinogenesis. The purpose of this study was to see whether SOX2 expression is associated with survival in patients with OAC. METHODS: SOX2 was studied by immunohistochemistry in patients who had undergone potentially curative oesophagectomy for adenocarcinoma. Protein expression of SOX2 was evaluated using tissue microarrays from resection specimens, and results were analysed in relation to the clinical data by Cox regression analysis. SOX2 was evaluated in two independent OAC cohorts (Rotterdam cohort and a multicentre UK cohort). RESULTS: Loss of SOX2 expression was independently predictive of adverse overall survival in the multivariable analysis, adjusted for known factors influencing survival, in both cohorts (Rotterdam cohort: hazard ratio (HR) 1·42, 95 per cent c.i. 1·07 to 1·89, P = 0·016; UK cohort: HR 1·54, 1·08 to 2·19, P = 0·017). When combined with clinicopathological staging, loss of SOX2 showed an increased effect in patients with pT1-2 tumours (P = 0·010) and node-negative OAC (P = 0·038), with an incrementally adverse effect on overall survival for stage I OAC with SOX2 loss (HR 3·18, 1·18 to 8·56; P = 0·022). CONCLUSION: SOX2 is an independent prognostic factor for long-term survival in OAC, especially in patients with stage I OAC

Alterations of E-cadherin and β-catenin in gastric cancer

BACKGROUND: The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression. METHODS: We studied the alterations of E-cadherin and β-catenin in a set of 50 primary gastric tumours by using loss of heterozygosity (LOH) analysis, gene mutation screening, detection of aberrant transcripts and immunohistochemistry (IHC). RESULTS: A high frequency (75%) of LOH was detected at 16q22.1 containing E-cadherin locus. Three cases (6%) showed the identical missense mutation, A592T. This mutation is not likely to contribute strongly to the carcinogenesis of gastric cancer, because a low frequency (1.6%) of this mutation was also found in 187 normal individuals. We also detected a low frequency (0.36%, 0%) of this mutation in 280 breast tumours and 444 other tumours, including colon and rectum, lung, endometrium, ovary, testis, kidney, thyroid carcinomas and sarcomas, respectively. We also analyzed the aberrant E-cadherin mRNAs in the gastric tumours and found that 7 tumours (18%) had aberrant mRNAs in addition to the normal mRNA. These aberrant mRNAs may produce abnormal E-cadherin molecules, resulting in weak cell-cell adhesion and invasive behaviour of carcinoma cells. Reduced expression of E-cadherin and β-catenin was identified at the frequency of 42% and 28%, respectively. Specially, 11 tumours (22%) exhibited positive cytoplasmic staining for β-catenin IHC. An association was found between reduced expression of E-cadherin and β-catenin. Moreover, an association was detected between reduced expression of E-cadherin and diffuse histotype. CONCLUSION: Our results support the hypothesis that alterations of E-cadherin and β-catenin play a role in the initiation and progression of gastric cancer

Worldwide Esophageal Cancer Collaboration : clinical staging data

Peer reviewe

Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS)

textabstractBackground. A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial. Methods/design. The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm. The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up. Discussion. This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen. Trial registration. ISRCTN80832026

Prospective randomized trial of laparoscopic Nissen fundoplication with anterior versus posterior hiatal repair: Late outcomes

BackgroundThe technique used for hiatal closure in laparoscopic Nissen fundoplication might have an impact on the risk of postfundoplication dysphagia and hiatal herniation. In 1997, we commenced a randomized trial to evaluate the impact of anterior versus posterior hiatal repair techniques on these outcomes. In the present study, we evaluated the 10-year outcomes from this trial.MethodsA total of 102 patients were randomized to undergo laparoscopic Nissen fundoplication with either anterior (47 patients) or posterior (55 patients) repair of the diaphragmatic hiatus. Outcomes were assessed using standardized clinical assessment scores that evaluated reflux symptoms, dysphagia, and satisfaction with the outcome following surgery.ResultsClinical outcomes 10 years after surgery were available for 93% of patients, and outcome scores were obtained for 43 patients in each group. Patients undergoing anterior hiatal repair were less likely to report dysphagia for lumpy solid foods (14.0% vs. 39.5%, p = 0.01), although there were no significant differences in dysphagia outcomes for six other dysphagia assessment scores. There were no differences between the two groups for reflux symptoms, medication use, and overall satisfaction with the outcome of surgery.ConclusionsAt the 10-year follow-up, the outcomes for the two groups were similar. Anterior hiatal repair is an acceptable technique for hiatal closure during laparoscopic Nissen fundoplication.Carolyn R. Chew, Glyn G. Jamieson, Peter G. Devitt, David I. Watso

The influence of anastomotic techniques on postoperative anastomotic complications: Results of the Oesophago-Gastric Anastomosis Audit

Background: The optimal anastomotic techniques in esophagectomy to minimize rates of anastomotic leakage and conduit necrosis are not known. The aim of this study was to assess whether the anastomotic technique was associated with anastomotic failure after esophagectomy in the international Oesophago-Gastric Anastomosis Audit cohort. Methods: This prospective observational multicenter cohort study included patients undergoing esophagectomy for esophageal cancer over 9 months during 2018. The primary exposure was the anastomotic technique, classified as handsewn, linear stapled, or circular stapled. The primary outcome was anastomotic failure, namely a composite of anastomotic leakage and conduit necrosis, as defined by the Esophageal Complications Consensus Group. Multivariable logistic regression modeling was used to identify the association between anastomotic techniques and anastomotic failure, after adjustment for confounders. Results: Of the 2238 esophagectomies, the anastomosis was handsewn in 27.1%, linear stapled in 21.0%, and circular stapled in 51.9%. Anastomotic techniques differed significantly by the anastomosis sites (P < .001), with the majority of neck anastomoses being handsewn (69.9%), whereas most chest anastomoses were stapled (66.3% circular stapled and 19.3% linear stapled). Rates of anastomotic failure differed significantly among the anastomotic techniques (P < .001), from 19.3% in handsewn anastomoses, to 14.0% in linear stapled anastomoses, and 12.1% in circular stapled anastomoses. This effect remained significant after adjustment for confounding factors on multivariable analysis, with an odds ratio of 0.63 (95% CI, 0.46-0.86; P = .004) for circular stapled versus handsewn anastomosis. However, subgroup analysis by anastomosis site suggested that this effect was predominantly present in neck anastomoses, with anastomotic failure rates of 23.2% versus 14.6% versus 5.9% for handsewn versus linear stapled anastomoses versus circular stapled neck anastomoses, compared with 13.7% versus 13.8% versus 12.2% for chest anastomoses. Conclusions: Handsewn anastomoses appear to be independently associated with higher rates of anastomotic failure compared with stapled anastomoses. However, this effect seems to be largely confined to neck anastomoses, with minimal differences between techniques observed for chest anastomoses. Further research into standardization of anastomotic approach and techniques may further improve outcomes

Anterior 90 degree(s) partial vs Nissen fundoplication-5 year follow-up of a single-centre randomised trial

INTRODUCTION: Nissen fundoplication can be followed by side effects, and this has driven modifications, including partial fundoplications. We previously reported early outcomes from a randomised trial of Nissen vs anterior 90 degrees partial fundoplication. This paper reports 5-year follow-up outcomes to determine whether anterior 90 degrees fundoplication achieves a satisfactory longer-term outcome. METHODS: From February 1999 to August 2003, 79 patients were randomised to Nissen vs anterior 90 degrees fundoplication. Patients were followed yearly using a standardized clinical questionnaire which included symptom scores to assess heartburn, dysphagia, other post-fundoplication side effects and overall satisfaction with the outcome. Five-year clinical outcomes were analysed. RESULTS: Seventy-four patients were available for follow-up at 5 years. There were no significant differences for heartburn or satisfaction, although more patients used antisecretory medication after anterior 90 degrees fundoplication (29.7 vs 8.1 %). Dysphagia was greater after Nissen fundoplication when measured by an analogue score for solid food and a composite dysphagia score. Symptoms of bloating were more common following Nissen fundoplication (80.0 vs 32.4 %), and less patients could eat a normal diet (78.4 vs 94.6 %). Re-operation was undertaken in four patients after Nissen fundoplication (dysphagia, three; hiatus hernia, one) vs three after anterior 90 degrees fundoplication (recurrent reflux, three). CONCLUSIONS: At 5 years, anterior 90 degrees partial fundoplication was associated with less side effects, offset by greater use of antisecretory medication. Reflux symptoms and overall satisfaction were similar to Nissen fundoplication. Laparoscopic anterior 90 degrees partial fundoplication is an effective treatment for gastro-esophageal reflux.David Ian Watson, Peter G. Devitt, Lorelle Smith and Glyn G. Jamieso