Fit-for-Discharge Criteria after Esophagectomy: An International Expert Delphi Consensus.

There are no internationally recognized criteria available to determine preparedness for hospital discharge after esophagectomy. This study aims to achieve international consensus using Delphi methodology. The expert panel consisted of 40 esophageal surgeons spanning 16 countries and 4 continents. During a 3-round, web-based Delphi process, experts voted for discharge criteria using 5-point Likert scales. Data were analyzed using descriptive statistics. Consensus was reached if agreement was ≥75% in round 3. Consensus was achieved for the following basic criteria: nutritional requirements are met by oral intake of at least liquids with optional supplementary nutrition via jejunal feeding tube. The patient should have passed flatus and does not require oxygen during mobilization or at rest. Central venous catheters should be removed. Adequate analgesia at rest and during mobilization is achieved using both oral opioid and non-opioid analgesics. All vital signs should be normal unless abnormal preoperatively. Inflammatory parameters should be trending down and close to normal (leucocyte count ≤12G/l and C-reactive protein ≤80 mg/dl). This multinational Delphi survey represents the first expert-led process for consensus criteria to determine 'fit-for-discharge' status after esophagectomy. Results of this Delphi survey may be applied to clinical outcomes research as an objective measure of short-term recovery. Furthermore, standardized endpoints identified through this process may be used in clinical practice to guide decisions regarding patient discharge and may help to reduce the risk of premature discharge or prolonged admission.

Cross validated serum small extracellular vesicle microRNAs for the detection of oropharyngeal squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is often diagnosed at an advanced stage because the disease often causes minimal symptoms other than metastasis to neck lymph nodes. Better tools are required to assist with the early detection of OPSCC. MicroRNAs (miRNAs, miRs) are potential biomarkers for early head and neck squamous cell cancer diagnosis, prognosis, recurrence, and presence of metastatic disease. However, there is no widespread agreement on a panel of miRNAs with clinically meaningful utility for head and neck squamous cell cancers. This could be due to variations in the collection, storage, pre-processing, and isolation of RNA, but several reports have indicated that the selection and reproducibility of biomarkers has been widely affected by the methods used for data analysis. The primary analysis issues appear to be model overfitting and the incorrect application of statistical techniques. The purpose of this study was to develop a robust statistical approach to identify a miRNA signature that can distinguish controls and patients with inflammatory disease from patients with human papilloma virus positive (HPV +) OPSCC. METHODS: Small extracellular vesicles were harvested from the serum of 20 control patients, 20 patients with gastroesophageal reflux disease (GORD), and 40 patients with locally advanced HPV + OPSCC. MicroRNAs were purified, and expression profiled on OpenArray™. A novel cross validation method, using lasso regression, was developed to stabilise selection of miRNAs for inclusion in a prediction model. The method, named StaVarSel (for Stable Variable Selection), was used to derive a diagnostic biomarker signature. RESULTS: A standard cross validation approach was unable to produce a biomarker signature with good cross validated predictive capacity. In contrast, StaVarSel produced a regression model containing 11 miRNA ratios with potential clinical utility. Sample permutations indicated that the estimated cross validated prediction accuracy of the 11-miR-ratio model was not due to chance alone. CONCLUSIONS: We developed a novel method, StaVarSel, that was able to identify a panel of miRNAs, present in small extracellular vesicles derived from blood serum, that robustly cross validated as a biomarker for the detection of HPV + OPSCC. This approach could be used to derive diagnostic biomarkers of other head and neck cancers.

Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Long-term follow-up of two randomized trials comparing laparoscopic Nissen 360° with anterior 90° partial fundoplication.

BACKGROUND: The side-effects of Nissen fundoplication have led to modifications, including partial fundoplications such as an anterior 90° wrap. Five-year follow-up of two randomized trials suggested fewer side-effects following anterior 90° partial fundoplication, but better reflux control after Nissen fundoplication. However, longer-term outcomes have not been reported. This study combined data from previous trials to determine 10-year outcomes. METHODS: From 1999 to 2003, 191 patients were enrolled in two randomized trials comparing anterior 90° partial versus Nissen fundoplication. Trial protocols were similar, and data were combined to determine long-term clinical outcomes. Patients completed annual questionnaires assessing dysphagia, heartburn, medications, satisfaction and other symptoms. Visual analogue scales (0-10), a composite dysphagia score (0-45) and yes/no responses were used. RESULTS: Of the 191 patients, 152 (79·6 per cent) were available for 10-year follow-up. After anterior 90° fundoplication, patients reported less dysphagia to solids (score 2·03 versus 3·18 for the Nissen procedure; P = 0·037). Heartburn scores were lower after Nissen fundoplication (1·90 versus 2·83 for anterior 90° fundoplication; P = 0·035) and fewer patients required proton pump inhibitors (PPIs) (22 versus 39 per cent respectively; P = 0·035). Satisfaction scores were similar for both anterior 90° and Nissen groups (7·45 versus 7·36 respectively; P = 0·566), and the majority considered their original decision for surgery to be correct (86 versus 84 per cent; P = 0·818). CONCLUSION: After 10 years, both procedures achieved similar success as measured by global satisfaction measures. Patients who had a Nissen fundoplication reported more dysphagia, whereas more heartburn and PPI consumption were reported after anterior 90° fundoplication. Registration numbers: ACTRN12607000298415 and ACTRN12607000304437 (http://www.anzctr.org.au/).

ANTECEDENTES: Para evitar los efectos secundarios de la fundoplicatura de Nissen se han propuesto modificaciones técnicas, incluyendo las fundoplicaturas parciales como la plicatura anterior de 90°. El seguimiento a 5 años de dos ensayos aleatorizados sugiere menos efectos secundarios tras la fundoplicatura anterior de 90°, pero mejor control del reflujo con la fundoplicatura de Nissen. Sin embargo, no se han descrito los resultados a largo plazo. Este estudio combinó datos de dos ensayos previos para determinar los resultados a 10 años. MÉTODOS: Entre 1999 y 2003, se reclutaron 191 pacientes en dos ensayos aleatorizados que comparaban la fundoplicatura parcial anterior 90° versus fundoplicatura de Nissen. Los protocolos de ambos ensayos fueron similares, y los datos se combinaron para determinar los resultados clínicos a largo plazo. Los pacientes completaron cuestionarios anuales que evaluaban disfagia, pirosis, medicaciones, satisfacción y otros síntomas. Se utilizaron escalas analógicas visuales (0-10), una variable compuesta para la puntuación de disfagia (0-45) y respuestas sí/no. RESULTADOS: De los 191 pacientes, 152 (79,6%) pudieron seguirse a los 10 años. Tras la fundoplicatura anterior de 90°, los pacientes refirieron menos disfagia a sólidos (2,03 versus 3,18, P = 0,037). Las puntuaciones de pirosis fueron inferiores tras fundoplicatura de Nissen (2,83 versus 1,90, P = 0,035) y menos pacientes tomaban inhibidores de la bomba de protones (proton pump inhibitors, PPIs; 22% versus 39%, P = 0,035). Las puntuaciones de satisfacción fueron similares para ambos grupos de fundoplicatura anterior 90° y Nissen (7,45 versus 7,36, P = 0,566), y la mayoría consideró su decisión original para la cirugía como correcta (86,1% versus. 83,8%, P = 0,818). Las tasas de reoperación fueron similares (10,0% versus 8,8%). CONCLUSIÓN: Después de 10 años, ambos procedimientos lograron un éxito similar medido con medidas de satisfacción global. Los pacientes con fundoplicatura de Nissen referían más disfagia mientras que los pacientes con fundoplicatura anterior 900 describieron más pirosis y consumo de PPIs.

Flatulence After Anti-reflux Treatment (FAART) Study.

BACKGROUND: Flatulence is known to be a common side effect of laparoscopic fundoplication, yet the true incidence is unclear and its impact on patients' quality of life not well understood. This study aimed to assess the long-term incidence of flatulence, and its effect on quality of life, following fundoplication. METHODS: All patients who underwent primary laparoscopic fundoplication between 1999 and 2009 were identified from a prospectively maintained institutional database. A cross-sectional analysis of post-operative gastrointestinal symptoms and quality of life was performed using a symptom-specific questionnaire. Statistical analysis of outcomes stratified by sex and type of fundoplication was performed. RESULTS: 462 eligible patients were identified from the database, with follow-up obtained in 265 (57%). Median age at surgery was 53 (22-78) years. 137 patients (52%) were female. 138 (52%) underwent a 360° fundoplication, the remainder a partial fundoplication. At median follow-up of 11 (8-15) years, excessive flatulence was reported by 85%. Only 12% reported an adverse impact on social life, and 11% an adverse impact on quality of life. Flatulence was worse following a total than partial fundoplication, women reported more gas-related symptoms than men, yet neither sex nor wrap type had a significant impact on social life or quality of life. CONCLUSIONS: The majority of patients report excessive flatulence at long-term follow-up after anti-reflux surgery, yet the impact on social life and quality life was small. There was no evidence to support tailoring of wrap type by sex to avoid gas-related symptoms. The authors advocate that all patients understand the inevitable side effects of fundoplication to help manage expectations from surgery.

Cytokine Response in the Pleural Fluid and Blood in Minimally Invasive and Open Esophagectomy.

BACKGROUND: Transthoracic esophagectomy for cancer triggers a massive inflammatory reaction. The data whether a minimally invasive esophagectomy (MIE) leads to less pronounced inflammatory response compared to open right-sided transthoracic esophagectomy (OE) are scarce. The aim of this study was to evaluate the extent of the inflammatory reaction, represented by levels of the pro-inflammatory interleukins IL-6 and IL-8, the anti-inflammatory IL-1 RA and the chemokines CINC-1 and MCP-1 in the right pleural fluid and the blood from patients undergoing standard OE or MIE. METHODS: Pleural drainage fluid and blood was collected at five different time points during the first 72 h following surgery, and the concentrations of IL-6, IL-8, IL-1 RA, CINC-1 and MCP-1 were analyzed using enzyme-linked immune-sorbent assays in 24 patients undergoing MIE or OE. RESULTS: The groups were matched for cancer stage and comorbidities. Pro- and anti-inflammatory mediator levels in the pleural fluid were markedly increased at the end of surgery and on postoperative days 1-3. The pleural inflammatory response of all cyto- and chemokines was lower in the MIE group, reaching significance at some time points. Cyto- and chemokine response levels measured in the blood were overall lower compared to those in the pleural fluid. The chemokines CINC-1 and MCP-1 reacted less pronounced or not at all. Preoperative pulmonary comorbidity, postoperative pulmonary morbidity and length of surgery were associated with an increased reaction in selected mediators. CONCLUSIONS: The minimally invasive technique attenuates the inflammatory response, especially locally in the thoracic compartment. Length of procedure, preoperative pulmonary comorbidity and postoperative pulmonary complications are mirrored in an increase in individual inflammatory markers in the pleural fluid. The value of the chemokines CINC-1 and MCP-1 as markers of inflammation in the setting of esophagectomy is unclear.

The 2018 ISDE achalasia guidelines.

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

Multicentre factorial randomized clinical trial of perioperative immunonutrition versus standard nutrition for patients undergoing surgical resection of oesophageal cancer.

BACKGROUND: Preoperative immunonutrition has been proposed to reduce the duration of hospital stay and infective complications following major elective surgery in patients with gastrointestinal malignancy. A multicentre 2 × 2 factorial RCT was conducted to determine the impact of preoperative and postoperative immunonutrition versus standard nutrition in patients with oesophageal cancer. METHODS: Patients were randomized before oesophagectomy to immunonutrition (IMPACT® ) versus standard isocaloric/isonitrogenous nutrition, then further randomized after operation to immunonutrition versus standard nutrition. Clinical and quality-of-life outcomes were assessed at 14 and 42 days after operation on an intention-to-treat basis. The primary outcome was the occurrence of infective complications. Secondary outcomes were other complications, duration of hospital stay, mortality, nutritional and quality-of-life outcomes (EuroQol EQ-5D-3 L™, European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-OES18). Patients and investigators were blinded until the completion of data analysis. RESULTS: Some 278 patients from 11 Australian sites were randomized; two were excluded and data from 276 were analysed. The incidence of infective complications was similar for all groups (37 per cent in perioperative standard nutrition group, 51 per cent in perioperative immunonutrition group, 34 per cent in preoperative immunonutrition group and 40 per cent in postoperative immunonutrition group; P = 0·187). There were no significant differences in any other clinical or quality-of-life outcomes. CONCLUSION: Use of immunonutrition before and/or after surgery provided no benefit over standard nutrition in patients undergoing oesophagectomy. Registration number: ACTRN12611000178943 ( https://www.anzctr.org.au).

Development of a risk prediction model for Barrett's esophagus in an Australian population.

Esophageal adenocarcinoma has poor 5-year survival rates. Increased survival might be achieved with earlier treatment, but requires earlier identification of the precursor, Barrett's esophagus. Population screening is not cost effective, this may be improved by targeted screening directed at individuals more likely to have Barrett's esophagus. To develop a risk prediction tool for Barrett's esophagus, this study compared individuals with Barrett's esophagus against population controls. Participants completed a questionnaire comprising 35 questions addressing medical history, symptom history, lifestyle factors, anthropomorphic measures, and demographic details. Statistical analysis addressed differences between cases and controls, and entailed initial variable selection, checking of model assumptions, and establishing calibration and discrimination. The area under the curve (AUC) was used to assess overall accuracy. One hundred and twenty individuals with Barrett's esophagus and 235 population controls completed the questionnaire. Significant differences were identified for age, gender, reflux history, family reflux history, history of hypertension, alcoholic drinks per week, and body mass index. These were used to develop a risk prediction model. The AUC was 0.82 (95% CI 0.78-0.87). Good calibration between predicted and observed risk was noted (Hosmer-Lemeshow test P = 0.67). At the point minimizing false positives and false negatives, the model achieved a sensitivity of 84.96% and a specificity of 66%. A well-calibrated risk prediction model with good discrimination has been developed to identify patients with Barrett's esophagus. The model needs to be externally validated before consideration for clinical practice.

Risk factors for delayed gastric emptying following laparoscopic repair of very large hiatus hernias.

BACKGROUND: Delayed gastric emptying can complicate surgery for hiatus hernia. The aim of this study was to quantify its incidence following laparoscopic repair of very large hiatus hernias, identify key risk factors for its occurrence and determine its impact on clinical outcomes. METHODS: Data collected from a randomized trial of patients who underwent laparoscopic mesh versus sutured repair of very large hiatus hernias (more than 50 per cent of stomach in chest) were analysed retrospectively. Delayed gastric emptying was defined as endoscopic evidence of solid food in the stomach after fasting for 6 h at 6 months after surgery. RESULTS: Delayed gastric emptying occurred in 19 of 102 patients (18·6 per cent). In univariable analysis, type 2 paraoesophageal hernia (relative risk (RR) 3·15, 95 per cent c.i. 1·41 to 7·06), concurrent anterior and posterior hiatal repair (RR 2·66, 1·14 to 6·18), hernia sac excision (RR 4·85, 1·65 to 14·24), 270°/360° fundoplication (RR 3·64, 1·72 to 7·68), division of short gastric vessels (RR 6·82, 2·12 to 21·90) and revisional surgery (RR 3·69, 1·73 to 7·87) correlated with delayed gastric emptying. In multivariable analysis, division of short gastric vessels (RR 6·27, 1·85 to 21·26) and revisional surgery (RR 6·19, 1·32 to 28·96) were independently associated with delayed gastric emptying. Delayed gastric emptying correlated with adverse gastrointestinal symptomatology, including higher rates of bloating, nausea, vomiting and anorexia, as well as reduced patient satisfaction with the operation and recovery. CONCLUSION: Delayed gastric emptying following large hiatus hernia repair is common and associated with adverse symptoms and reduced patient satisfaction. Division of short gastric vessels and revisional surgery were independently associated with its occurrence.

Venous thromboembolism in patients with esophageal or gastric cancer undergoing neoadjuvant chemotherapy.

There is a well-established link between cancer and venous thromboembolism (VTE), and patients receiving chemotherapy for esophageal or gastric cancer appear at high risk of developing VTE. The incidence of VTE in the neoadjuvant setting in these patients is poorly understood, as is the role for thromboprophylaxis during neoadjuvant chemotherapy. A PubMed search was conducted using a combination of terms including; esophageal & gastric cancer, deep venous thrombosis (DVT), VTE, neoadjuvant, chemotherapy and chemoradiotherapy. One hundred and fifty-four articles were retrieved and a narrative review was conducted. For patients with esophageal and gastric cancer the incidence of VTE ranged from 4 to 19%. Gastric cancer (Odds Ratio [OR] 6.38, [95% CI: 1.96-20.80]) and Stage III/IV disease, (OR 5.16 [95% CI: 1.29-20.73]) were identified as risk factors for developing VTE. Neoadjuvant chemotherapy was identified as an independent risk factor for developing VTE. Symptomatic and asymptomatic VTE have a similar effect on mortality. Median overall survival for asymptomatic VTE was 13.9 months (95% CI: 5.0-∞) versus 12.8 months (95% CI: 4.7-30.3) if the VTE was symptomatic. Neoadjuvant chemotherapy is a significant risk factor for VTE in patients with esophageal and gastric cancer. Intervention to minimize the risk using pharmacological and mechanical thromboprophylaxis should be considered, and this should start in the neoadjuvant period.

Tamoxifen enhances the cytotoxicity of conventional chemotherapy in esophageal adenocarcinoma cells.

INTRODUCTION: Esophageal adenocarcinoma is a lethal malignancy which is increasing in incidence, and many patients receive chemotherapy as part of their treatment. We have previously demonstrated that esophageal adenocarcinoma-derived cell lines respond to treatment with estrogen receptor modulators, such as tamoxifen. Reports from breast cancer suggest that tamoxifen may attenuate the efficacy of other chemotherapeutic agents. We have therefore assessed the response of esophageal adenocarcinoma cell lines to tamoxifen therapy when given in combination with conventional agents. METHODS: Two estrogen receptor (ER)-positive esophageal adenocarcinoma cell lines (OE-19 and OE-33) were treated with combinations of tamoxifen, cisplatin and 5-fluorouracil (5-FU). Effects on cell viability were measured using an MTS assay, and cell death was detected with annexin V/propidium iodide flow cytometry. To assess whether the efficacy of tamoxifen in these cell lines might be relevant to the clinical setting, we analyzed ER status in 10 esophageal adenocarcinoma tissue specimens by immunohistochemistry. RESULTS: IC50 values (µM) for OE-19 and OE-33 were 11.2 and 7.1 for tamoxifen, 19.6 and 4.7 for cisplatin, and 1.7 and 5.9 for 5-FU, respectively. Cell death was detected in 11.9% and 15.8% of cells treated with tamoxifen, 7.9% and 8.7% cells treated with cisplatin, and 3.6% and 8.6% cells treated with 5-FU at their IC50s. The addition of tamoxifen to cisplatin increased cell death by 11.4% in OE-19 (p < 0.0001) and 16.3% in OE-33 (p < 0.0001). Similarly, the addition of tamoxifen to 5-FU increased cell death by 11.6% in OE-19 (p < 0.0001) and 15.9% in OE-33 (p < 0.0001). Eight of 10 tissue specimens showed positive staining for ERα and 7 of 10 for ERß. CONCLUSIONS: In a cell culture model the addition of tamoxifen to conventional chemotherapy appears to be both feasible and beneficial. Expression of ERα and ERß was also confirmed in esophageal adenocarcinoma tissues.

Effects of chemotherapy agents on Sphingosine-1-Phosphate receptors expression in MCF-7 mammary cancer cells.

Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid involved in the regulation of cell proliferation and cancer progression. Increased expression of S1P receptors has been detected in advanced breast tumours with poor prognosis suggesting that S1P receptors might control tumour response to chemotherapy. However, it remains unclear how the levels of S1P receptor expression are influenced by chemotherapy agents. Western immunoblotting, PCR analysis and fluorescent microscopy techniques were used in this study to analyze expression patterns of S1P receptors 2 and 3 (S1P2/S1P3) in MCF-7 breast adenocarcinoma cells treated by Tamoxifen (TAM) and/or Medroxyprogesterone acetate (MPA). We found that TAM/MPA induce downregulation of S1P3 receptors, but stimulate expression of S1P2. According to cell viability and caspase activity analyses, as expected, TAM activated apoptosis. We also detected TAM/MPA-induced autophagy marked by formation of macroautophagosomes and increased level of Beclin 1. Combined application of TAM and MPA resulted in synergistic apoptosis- and autophagy-stimulating effects. Assessed by fluorescent microscopy with autophagosome marker LAMP-2, changes in S1P receptor expression coincided with activation of autophagy, suggestively, directing breast cancer cells towards death. Further studies are warranted to explore the utility of manipulation of S1P2 and S1P3 receptor expression as a novel treatment approach.

Pre-therapy mRNA expression of TNF is associated with regimen-related gastrointestinal toxicity in patients with esophageal cancer: a pilot study.

PURPOSE: Esophageal cancer has a high mortality rate, and its multimodality treatment is often associated with significant rates of severe toxicity. Effort is needed to uncover ways to maximize effectiveness of therapy through identification of predictive markers of response and toxicity. As such, the aim of this study was to identify genes predictive of chemoradiotherapy-induced gastrointestinal toxicity using an immune pathway-targeted approach. METHODS: Adults with esophageal cancer treated with chemotherapy consisting of 5-fluorouracil and cisplatin and 45-50 Gy radiation were recruited to the study. Pre-therapy-collected whole blood was analyzed for relative expression of immune genes using real-time polymerase chain reaction (RT-PCR). Gene expression was compared between patients who experienced severe regimen-related gastrointestinal toxicity vs. those experiencing mild to moderate toxicity. RESULTS: Blood from 31 patients were analyzed by RT-PCR. Out of 84 immune genes investigated, TNF was significantly elevated (2.05-fold, p = 0.025) in the toxic group (n = 12) compared to the non-toxic group (n = 19). Nausea and vomiting was the most commonly documented severe toxicity. No associations between toxicity and response, age, sex, histology, or treatment were evident. CONCLUSIONS: This study supports evidence of TNF as a predictive biomarker in regimen-related gastrointestinal toxicity. Confirming these findings in a larger cohort is warranted.

Effect of estrogen on growth and apoptosis in esophageal adenocarcinoma cells.

The epidemiology of esophageal adenocarcinoma demonstrates a strong gender bias with a sex ratio of 8-9:1 in favor of males. A potential explanation for this is that estrogen might protect against esophageal adenocarcinoma. Estrogen has previously been shown to stimulate apoptosis in esophageal squamous cancer cells. However, the effect of estrogen on esophageal adenocarcinoma cells has not been determined. We used immunoblotting analysis to determine the expression of estrogen receptors, cell adhesion marker E-cadherin, and proliferation marker Ki-67 in cell lines derived from esophageal adenocarcinoma (OE-19, OE-33) and Barrett's esophagus (QhTRT, ChTRT, GihTRT). Estrogen and selective estrogen receptor modulator (SERM)-dependent effects on cell growth were determined by the CellTiter-96 Aqueous Proliferation Assay. Apoptosis was determined by Annexin V/Propidium Iodide cell labeling and flow cytometry. We detected that physiological and supra-physiological concentrations of 17ß-estradiol and SERM decreased cell growth in esophageal adenocarcinoma cells. In Barrett's esophagus cells (QhTRT, ChTRT), decreased growth was also detected in response to estrogen/SERM. The level of estrogen receptor expression in the cell lines correlated with the level of anti-growth effects induced by the receptor agonists. Flow cytometry analysis confirmed estrogen/SERM stimulated apoptosis in esophageal adenocarcinoma cells. Estrogen/SERM treatments were associated with a decrease in the expression of Ki-67 and an increase in E-cadherin expression in esophageal adenocarcinoma cells. This study suggests that esophageal adenocarcinoma and Barrett's esophagus cells respond to treatment with selective estrogen receptor ligands, resulting in decreased cell growth and apoptosis. Further research to explore potential therapeutic applications is warranted.

Twenty years of experience with laparoscopic antireflux surgery.

BACKGROUND: There are few reports of large patient cohorts with long-term follow-up after laparoscopic antireflux surgery. This study was undertaken to evaluate changes in surgical practice and outcomes for laparoscopic antireflux surgery over a 20-year period. METHODS: A standardized questionnaire, prospectively applied annually, was used to determine outcome for all patients undergoing laparoscopic fundoplication in two centres since commencing this procedure in 1991. Visual analogue scales ranging from 0 to 10 were used to assess symptoms of heartburn, dysphagia and satisfaction with overall outcome. Data were analysed to determine outcome across 20 years. RESULTS: From 1991 to 2010, 2261 consecutive patients underwent laparoscopic fundoplication at the authors' institutions. Follow-up ranged from 1 to 19 (mean 7.6) years. Conversion to open surgery occurred in 73 operations (3.2 per cent). Revisional surgery was performed in 216 patients (9.6 per cent), within 12 months of the original operation in 116. There was a shift from Nissen to partial fundoplication across 20 years, and a recent decline in operations for reflux, offset by an increase in surgery for large hiatus hernia. Dysphagia and satisfaction scores were stable, and heartburn scores rose slightly across 15 years of follow-up. Heartburn scores were slightly higher and reoperation for reflux was more common after anterior partial fundoplication (P = 0.005), whereas dysphagia scores were lower and reoperation for dysphagia was less common (P < 0.001). At 10 years, satisfaction with outcome was similar for all fundoplication types. CONCLUSION: Laparoscopic Nissen and partial fundoplications proved to be durable and achieved good long-term outcomes. At earlier follow-up, dysphagia was less common but reflux more common after anterior partial fundoplication, although differences had largely disappeared by 10 years.

Impact of participation in randomized trials on outcome following surgery for gastro-oesophageal reflux.

BACKGROUND: Patients may be unwilling to participate in clinical trials if they perceive risks. Outcomes were evaluated following surgery for gastro-oesophageal reflux in patients recruited to randomized trials compared with patients not in trials. METHODS: This study compared outcomes of patients who had surgery for reflux within or outside randomized trials between 1994 and 2009. The choice of procedure outside each trial was according to surgeon or patient preference. Clinical outcomes were determined 1 and 5 years after surgery using a standardized questionnaire, with analogue scales to assess heartburn, dysphagia and overall satisfaction. Subgroup analysis was undertaken for those aged less than 75 years undergoing laparoscopic Nissen fundoplication. RESULTS: Some 417 patients entered six randomized trials evaluating surgery for reflux and 981 underwent surgery outside the trials. The trial group contained a higher proportion of men and younger patients, and patients in trials were more likely to have undergone Nissen fundoplication. At 1 year, patients in the trials had slightly lower heartburn scores and less abdominal bloating, but otherwise similar outcomes to those not in the trials. At 5 years there were no differences, except for a slightly higher dysphagia score for liquids in the trial group. For the subgroup analysis, demographic data were similar for both groups. There were no differences at 1 year, but at 5 years patients enrolled in the trials had higher scores for dysphagia for liquids and heartburn. All of the statistically significant differences were thought unlikely to be clinically relevant. CONCLUSION: Participation in a randomized trial assessing surgery for reflux did not influence outcomes.

Healthcare resource use and medical costs for the management of oesophageal cancer.

BACKGROUND: This study examined the interaction between natural history, current practice patterns in diagnosis, monitoring and treatment of oesophageal cancer, and associated health resource utilization and costs. METHODS: A cost analysis of a prospective population-based cohort of 1100 patients with a primary diagnosis of oesophageal cancer was performed using chart review from the Australian Cancer Study Clinical Follow-Up Study. The analysis enabled estimation of healthcare resources and associated costs in 2009 euros by stage of disease and treatment pathway. RESULTS: Most patients (88·5 per cent) presented with stage II, III or IV cancer; 61·1 per cent (672 of 1100) were treated surgically. Overall mean costs were €37,195 (median €29,114) for patients undergoing surgery and €17,281 (median €13,066) for those treated without surgery. Surgery contributed 66·4 per cent of the total costs (mean €24,697 per patient) in the surgical group. In the non-surgical group, use of chemotherapy was more prevalent (81·9 per cent of patients) and contributed 61·1 per cent of the total costs. Other important cost determinants were gastro-oesophageal junction tumours, treatment location and tumour stage. Mean costs of those monitored for Barrett's oesophagus (7·3 per cent of patients) were lower, although about one-third still presented with advanced-stage cancer. CONCLUSION: Overall costs for managing oesophageal cancer were high and dominated by surgery costs in patients treated surgically and by chemotherapy costs in patients treated without surgery. Radiotherapy, treatment location and cancer subtype were also important. Monitoring for Barrett's oesophagus and earlier-stage detection were associated with lower management costs, but the potential net benefit from surveillance strategies needs further investigation.