Impact of sex and age on chemotherapy efficacy, toxicity and survival in localised oesophagogastric cancer: A pooled analysis of 3265 individual patient data from four large randomised trials (OE02, OE05, MAGIC and ST03).

BACKGROUND: There is a lack of large-scale randomised data evaluating the impact of sex and age in patients undergoing chemotherapy followed by potentially curative surgery for oesophagogastric cancer. PATIENTS AND METHODS: Individual patient data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival analysis, hazard ratios (HRs) were calculated for patients aged <70 and ≥ 70 years, as well as between males and females. Mandard tumour regression grade (TRG) and, ≥grade III toxicities were compared using logistic regression models to calculate odds ratios. All analyses were adjusted for the type of chemotherapy received. RESULTS: 3265 patients were included for survival analysis (2668 [82%] male, 597 [18%] female; 2627 (80%) <70 years, 638 (20%) ≥70 years). A significant improvement in overall survival (OS) (HR: 0.78; p < 0.001) and disease-specific survival (DSS) (HR: 0.78; p < 0.001) was observed in females compared with males. No significant differences in OS (HR: 1.11; p = 0.045) or DSS (HR: 1.01; p = 0.821) were observed in older patients compared with younger patients. For patients who underwent resection, older patients (15% vs 10%; p = 0.03) and female patients (14% vs 10%, p = 0.10) were more likely to achieve favourable Mandard TRG scores. Females experienced significantly more ≥grade III nausea (10% vs 5%; p≤0.001), vomiting (10% vs 4%; p≤0.001) and diarrhoea (9% vs 4%; p≤0.001) than males. CONCLUSIONS: In this large pooled analysis using prospective randomised trial data, females had significantly improved survival while experiencing more gastrointestinal toxicities. Older patients achieved comparable survival to younger patients and thus, dependent on fitness, should be offered the same treatment paradigm.

Surgical Innovation in the Era of Global Surgery: A Network Analysis.

OBJECTIVE: To present a novel network-based framework for the study of collaboration in surgery and demonstrate how this can be used in practice to help build and nurture collaborations that foster innovation. BACKGROUND: Surgical innovation is a social process that originates from complex interactions among diverse participants. This has led to the emergence of numerous surgical collaboration networks. What is still needed is a rigorous investigation of these networks and of the relative benefits of various collaboration structures for research and innovation. METHODS: Network analysis of the real-world innovation network in robotic surgery. Hierarchical mixed-effect models were estimated to assess associations between network measures, research impact and innovation, controlling for the geographical diversity of collaborators, institutional categories, and whether collaborators belonged to industry or academia. RESULTS: The network comprised of 1700 organizations and 6000 links. The ability to reach many others along few steps in the network (closeness centrality), forging a geographically diverse international profile (network entropy), and collaboration with industry were all shown to be positively associated with research impact and innovation. Closed structures (clustering coefficient), in which collaborators also collaborate with each other, were found to have a negative association with innovation (P < 0.05 for all associations). CONCLUSIONS: In the era of global surgery and increasing complexity of surgical innovation, this study highlights the importance of establishing open networks spanning geographical boundaries. Network analysis offers a valuable framework for assisting surgeons in their efforts to forge and sustain collaborations with the highest potential of maximizing innovation and patient care.

Safety and Efficacy of the Addition of Lapatinib to Perioperative Chemotherapy for Resectable HER2-Positive Gastroesophageal Adenocarcinoma: A Randomized Phase 2 Clinical Trial.

IMPORTANCE: Perioperative chemotherapy and surgery are a standard of care for operable gastroesophageal adenocarcinoma. Anti-HER2 therapy improves survival in patients with advanced HER2-positive disease. The safety and feasibility of adding lapatinib to perioperative chemotherapy should be assessed. OBJECTIVES: To assess the safety of adding lapatinib to epirubicin, cisplatin, and capecitabine (ECX) chemotherapy and to establish a recommended dose regimen for a phase 3 trial. DESIGN, SETTING, AND PARTICIPANTS: Phase 2 randomized, open-label trial comparing standard ECX (sECX: 3 preoperative and 3 postoperative cycles of ECX with modified ECX plus lapatinib (mECX+L). This multicenter national trial was conducted in 29 centers in the United Kingdom in patients with histologically proven, HER2-positive, operable gastroesophageal adenocarcinoma. Registration for ERBB/HER2 testing took place from February 25, 2013, to April 19, 2016, and randomization took place between May 24, 2013, and April 21, 2016. Data were analyzed May 10, 2017, to May 25, 2017. INTERVENTIONS: Patients were randomized 1:1 open-label to sECX (3 preoperative and 3 postoperative cycles of 50 mg/m2 of intravenous epirubicin on day 1, 60 mg/m2 intravenous cisplatin on day 1, 1250 mg/m2 of oral capecitabine on days 1 through 21) or mECX+L (ECX plus lapatinib days 1 through 21 in each cycle and as 6 maintenance doses). The first 10 patients in the mECX+L arm were treated with 1000 mg/m2 of capecitabine and 1250 mg of lapatinib per day, after which preoperative toxic effects were reviewed according to predefined criteria to determine doses for subsequent patients. MAIN OUTCOMES AND MEASURES: Proportion of patients experiencing grade 3 or 4 diarrhea with mECX+L. A rate of 20% or less was considered acceptable. No formal comparison between arms was planned. RESULTS: Between February 2013, and April 2016, 441 patients underwent central HER2 testing and 63 (14%) were classified as HER2 positive. Forty-six patients were randomized; 44 (24 sECX, 20 mECX+L) are included in this analysis. Two of the first 10 patients in the mECX+L arm reported preoperative grade 3 diarrhea; thus, no dose increase was made. The primary endpoint of preoperative grade 3 or 4 diarrhea rates were 0 of 24 in the sECX arm (0%) and 4 of 20 in the mECX+L arm (21%). One of 24 in the sECX arm and 3 of 20 in the mECX+L arm stopped preoperative treatment early, and for 4 of 19 in the mECX+L arm, lapatinib dose was reduced. Postoperative complication rates were similar in each arm. CONCLUSIONS AND RELEVANCE: Administration of 1250 mg of lapatinib per day in combination with ECX chemotherapy was feasible with some increase in toxic effects, which did not compromise operative management. TRIAL REGISTRATION: ISRCTN.org identifier: 46020948; clinicaltrialsregister.eu identifier: 2006-000811-12.

Benchmarking Complications Associated with Esophagectomy.

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

Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial.

BACKGROUND: Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen. METHODS: OE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 109 cells per L, platelet count at least 100 × 109 platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m2 intravenously on day 1] and fluorouracil [1 g/m2 per day intravenously on days 1-4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] intravenously on day 1, and capecitabine [1250 mg/m2] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4-6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed. FINDINGS: Between Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6-26·3) with CF and 26·1 months (22·5-29·7) with ECX (hazard ratio 0·90 (95% CI 0·77-1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis. INTERPRETATION: Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma. FUNDING: Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London.

Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial.

BACKGROUND: Peri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. METHODS: In this multicentre, randomised, open-label phase 2-3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1-21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203. FINDINGS: Between Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5-54·9) in the chemotherapy alone group and 48·1% (43·2-52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91-1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53). INTERPRETATION: The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing. FUNDING: Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.

Metabolomic Evidence for a Field Effect in Histologically Normal and Metaplastic Tissues in Patients with Esophageal Adenocarcinoma.

Patients with Barrett's esophagus (BO) are at increased risk of developing esophageal adenocarcinoma (EAC). Most Barrett's patients, however, do not develop EAC, and there is a need for markers that can identify those most at risk. This study aimed to see if a metabolic signature associated with the development of EAC existed. For this, tissue extracts from patients with EAC, BO, and normal esophagus were analyzed using 1H nuclear magnetic resonance. Where possible, adjacent histologically normal tissues were sampled in those with EAC and BO. The study included 46 patients with EAC, 7 patients with BO, and 68 controls who underwent endoscopy for dyspeptic symptoms with normal appearances. Within the cancer cohort, 9 patients had nonneoplastic Barrett's adjacent to the cancer suitable for biopsy. It was possible to distinguish between histologically normal, BO, and EAC tissue in EAC patients [area under the receiver operator curve (AUROC) 1.00, 0.86, and 0.91] and between histologically benign BO in the presence and absence of EAC (AUROC 0.79). In both these cases, sample numbers limited the power of the models. Comparison of histologically normal tissue proximal to EAC versus that from controls (AUROC 1.00) suggests a strong field effect which may develop prior to overt EAC and hence be useful for identifying patients at high risk of developing EAC. Excellent sensitivity and specificity were found for this model to distinguish histologically normal squamous esophageal mucosa in EAC patients and healthy controls, with 8 metabolites being very significantly altered. This may have potential diagnostic value if a molecular signature can detect tissue from which neoplasms subsequently arise.

Haemochromatosis and gastrointestinal cancer.

Iron overload in patients with haemochromatosis is a strong risk factor for liver cancer, but its influence on other gastrointestinal cancer risk is unclear. The aim was to assess the relative risk of luminal gastrointestinal cancer among patients diagnosed with haemochromatosis. This population-based, nationwide Swedish cohort study included patients with haemochromatosis in Sweden in 1965-2013. The incidence of gastrointestinal cancers was assessed through the Swedish Cancer Registry. The measure of relative risk was the standardised incidence ratio (SIR) with 95% confidence interval (CI), that is, the ratio of the observed number of gastrointestinal cancers in the haemochromatosis cohort divided by the expected number of such cancers, calculated from the entire corresponding background population of Sweden. Among 6,849 patients in the haemochromatosis cohort with up to 48 years of follow-up, the SIRs were 3-fold increased for oesophageal squamous cell carcinoma (SIR = 3.2, 95% CI 1.3-6.6; n = 7) and 40% increased for colon adenocarcinoma (SIR = 1.4, 95% CI 1.1-1.9; n = 54). No associations were found between haemochromatosis and the risk of adenocarcinoma of the oesophagus (SIR = 0.5, 95% CI 0.0-2.5; n = 1), stomach (SIR = 0.7, 95% CI 0.3-1.4; n = 8), small bowel (SIR = 1.2, 95% CI 0.0-6.7; n = 1) or rectum (SIR = 1.0, 95% CI 0.6-1.6; n = 21). These findings indicate that haemochromatosis increases the risk of oesophageal squamous cell carcinoma and colon adenocarcinoma, but might not influence the risk of other types of luminal gastrointestinal cancer. These findings should encourage further research examining the role of iron overload in cancer aetiology.

The lifetime cost to English students of borrowing to invest in a medical degree: a gender comparison using data from the Office for National Statistics.

OBJECTIVE: To evaluate this impact on male and female English medical graduates by estimating the total time and amount repaid on loans taken out with the UK's Student Loans Company (SLC). SETTING: UK. PARTICIPANTS: 4286 respondents with a medical degree in the Labour Force Surveys administered by the Office for National Statistics (ONS) between 1997 and 2014. OUTCOMES: Age-salary profiles were generated to estimate the repayment profiles for different levels of initial graduate debt. RESULTS: 2195 female and 2149 male medical graduates were interviewed by the ONS. Those working full-time (73.1% females and 96.1% males) were analysed in greater depth. Following standardisation to 2014 prices, average full-time male graduates earned up to 35% more than females by the age of 55. The initial graduate debt from tuition fees alone amounts to £39,945.69. Owing to interest charges on this debt the average full-time male graduate repays £57,303 over 20 years, while the average female earns less and so repays £61,809 over 26 years. When additional SLC loans are required for maintenance, the initial graduate debt can be as high as £81,916 and, as SLC debt is written off 30 years after graduation, the average female repays £75,786 while the average male repays £110,644. CONCLUSIONS: Medical graduates on an average salary are unlikely to repay their SLC debt in full. This is a consequence of higher university fees and as SLC debt is written off 30 years after graduation. This results in the average female graduate repaying more when debt is low, but a lower amount when debt is high compared to male graduates.

Protocol for a multicentre, prospective, population-based cohort study of variation in practice of cholecystectomy and surgical outcomes (The CholeS study).

INTRODUCTION: Cholecystectomy is one of the most common general surgical operations performed. Despite level one evidence supporting the role of cholecystectomy in the management of specific gallbladder diseases, practice varies between surgeons and hospitals. It is unknown whether these variations account for the differences in surgical outcomes seen in population-level retrospective data sets. This study aims to investigate surgical outcomes following acute, elective and delayed cholecystectomies in a multicentre, contemporary, prospective, population-based cohort. METHODS AND ANALYSIS: UK and Irish hospitals performing cholecystectomies will be recruited utilising trainee-led research collaboratives. Two months of consecutive, adult patient data will be included. The primary outcome measure of all-cause 30-day readmission rate will be used in this study. Thirty-day complication rates, bile leak rate, common bile duct injury, conversion to open surgery, duration of surgery and length of stay will be measured as secondary outcomes. Prospective data on over 8000 procedures is anticipated. Individual hospitals will be surveyed to determine local policies and service provision. Variations in outcomes will be investigated using regression modelling to adjust for confounders. ETHICS AND DISSEMINATION: Research ethics approval is not required for this study and has been confirmed by the online National Research Ethics Service (NRES) decision tool. This novel study will investigate how hospital-level surgical provision can affect patient outcomes, using a cross-sectional methodology. The results are essential to inform commissioning groups and implement changes within the National Health Service (NHS). Dissemination of the study protocol is primarily through the trainee-led research collaboratives and the Association of Upper Gastrointestinal Surgeons (AUGIS). Individual centres will have access to their own results and the collective results of the study will be published in peer-reviewed journals and presented at relevant surgical conferences.

International Consensus on Standardization of Data Collection for Complications Associated With Esophagectomy: Esophagectomy Complications Consensus Group (ECCG).

INTRODUCTION: Perioperative complications influence long- and short-term outcomes after esophagectomy. The absence of a standardized system for defining and recording complications and quality measures after esophageal resection has meant that there is wide variation in evaluating their impact on these outcomes. METHODS: The Esophageal Complications Consensus Group comprised 21 high-volume esophageal surgeons from 14 countries, supported by all the major thoracic and upper gastrointestinal professional societies. Delphi surveys and group meetings were used to achieve a consensus on standardized methods for defining complications and quality measures that could be collected in institutional databases and national audits. RESULTS: A standardized list of complications was created to provide a template for recording individual complications associated with esophagectomy. Where possible, these were linked to preexisting international definitions. A Delphi survey facilitated production of specific definitions for anastomotic leak, conduit necrosis, chyle leak, and recurrent nerve palsy. An additional Delphi survey documented consensus regarding critical quality parameters recommended for routine inclusion in databases. These quality parameters were documentation on mortality, comorbidities, completeness of data collection, blood transfusion, grading of complication severity, changes in level of care, discharge location, and readmission rates. CONCLUSIONS: The proposed system for defining and recording perioperative complications associated with esophagectomy provides an infrastructure to standardize international data collection and facilitate future comparative studies and quality improvement projects.

Strategies to improve clinical research in surgery through international collaboration.

More than 235 million patients undergo surgery every year worldwide, but less than 1% are enrolled in surgical clinical trials--few of which are international collaborations. Several levels of action are needed to improve this situation. International research collaborations in surgery between developed and developing countries could encourage capacity building and quality improvement, and mutually enhance care for patients with surgical disorders. Low-income and middle-income countries increasingly report much the same range of surgical diseases as do high-income countries (eg, cancer, cardiovascular disease, and the surgical sequelae of metabolic syndrome); collaboration is therefore of mutual interest. Large multinational trials that cross cultures and levels of socioeconomic development might have faster results and wider applicability than do single-country trials. Surgeons educated in research methods, and aided by research networks and trial centres, are needed to foster these international collaborations. Barriers to collaboration could be overcome by adoption of global strategies for regulation, health insurance, ethical approval, and indemnity coverage for doctors.

The incremental benefit of two quadrant lavage for peritoneal cytology at staging laparoscopy for oesophagogastric adenocarcinoma.

BACKGROUND: Patients with positive peritoneal cytology from oesophagogastric cancer have a poor prognosis. The purpose of this study was to compare lavage cytology from the pelvis alone with the pelvis and subphrenic areas at staging laparoscopy in patients with potentially resectable oesophagogastric adenocarcinoma. METHODS: Between November 2006 and November 2010, all patients with operable oesophagogastric adenocarcinoma on spiral CT considered fit for surgical resection underwent staging laparoscopy. Subphrenic and pelvic peritoneal lavage for cytology was performed followed by laparoscopic biopsy of any visible peritoneal disease. Patients were divided into groups: macroscopic peritoneal metastases (P+), no macroscopic peritoneal disease with negative cytology (P-C-), no macroscopic peritoneal disease with positive pelvic cytology (P-PC+), no macroscopic peritoneal disease with positive subphrenic cytology (P-SC+), or both (P-PSC+). RESULTS: A total of 316 staging laparoscopy procedures were performed; 245 patients (78 %) were P-C-, 28 (9 %) were P+, and 43 (14 %) were P-C+, of whom 29 (9 %) were P-PSC+, 10 (3 %) were P-SC+, and 4 (1 %) were P-PC+. Pelvic cytology alone had 76.7 % sensitivity for peritoneal disease, and subphrenic cytology alone had 90.7 % sensitivity. CONCLUSIONS: Peritoneal lavage for cytology at staging laparoscopy has an incremental benefit for staging oesophagogastric adenocarcinoma in the absence of macroscopic metastatic disease. Subphrenic washings have the highest yield of positive results. Performing isolated pelvic washings for cytology will understage 23.3 % of patients with microscopic peritoneal disease. The routine use of subphrenic in combination with pelvic lavage for cytology at staging laparoscopy in patients with oesophagogastric adenocarcinoma has an incremental benefit in detecting cytology-positive disease over either pelvic or subphrenic cytology alone.

Vitamin D to prevent acute lung injury following oesophagectomy (VINDALOO): study protocol for a randomised placebo controlled trial.

BACKGROUND: Acute lung injury occurs in approximately 25% to 30% of subjects undergoing oesophagectomy. Experimental studies suggest that treatment with vitamin D may prevent the development of acute lung injury by decreasing inflammatory cytokine release, enhancing lung epithelial repair and protecting alveolar capillary barrier function. METHODS/DESIGN: The 'Vitamin D to prevent lung injury following oesophagectomy trial' is a multi-centre, randomised, double-blind, placebo-controlled trial. The aim of the trial is to determine in patients undergoing elective transthoracic oesophagectomy, if pre-treatment with a single oral dose of vitamin D3 (300,000 IU (7.5 mg) cholecalciferol in oily solution administered seven days pre-operatively) compared to placebo affects biomarkers of early acute lung injury and other clinical outcomes. The primary outcome will be change in extravascular lung water index measured by PiCCO® transpulmonary thermodilution catheter at the end of the oesophagectomy. The trial secondary outcomes are clinical markers indicative of lung injury: PaO2:FiO2 ratio, oxygenation index; development of acute lung injury to day 28; duration of ventilation and organ failure; survival; safety and tolerability of vitamin D supplementation; plasma indices of endothelial and alveolar epithelial function/injury, plasma inflammatory response and plasma vitamin D status. The study aims to recruit 80 patients from three UK centres. DISCUSSION: This study will ascertain whether vitamin D replacement alters biomarkers of lung damage following oesophagectomy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27673620.