Clonal Transitions and Phenotypic Evolution in Barrett's Esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression. METHODS: Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome. RESULTS: We identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0-2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time. CONCLUSIONS: We showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE.

Acute Kidney Injury After Esophageal Cancer Surgery: Incidence, Risk Factors, and Impact on Oncologic Outcomes.

OBJECTIVE: To determine the incidence, risk factors, and consequences of AKI in patients undergoing surgery for esophageal cancer. SUMMARY OF BACKGROUND DATA: Esophageal cancer surgery is an exemplar of major operative trauma, with well-defined risks of respiratory, cardiac, anastomotic, and septic complications. However, there is a paucity of literature regarding AKI. METHODS: consecutive patients undergoing curative-intent surgery for esophageal cancer from 2011 to 2017 in 3 high-volume centers were studied. AKI was defined according to the AKI Network criteria. AKI occurred if, within 48 hours postoperatively, serum creatinine rose by 50% or by 0.3 mg/dL (26.5 µmol/L) from preoperative baseline. Complications were recorded prospectively. Multivariable logistic regression determined factors independently predictive of AKI. RESULTS: A total of 1135 patients (24.7%:75.3% female:male, with a mean age of 64, a baseline BMI of 27 kg m-2, and dyslipidemia in 10.2%), underwent esophageal cancer surgery, 85% having an open thoracotomy. Overall in-hospital mortality was 2.1%. Postoperative AKI was observed in 208 (18.3%) patients, with AKI Network 1, 2, and 3 in 173 (15.2%), 28 (2.5%), and 7 (0.6%), respectively. Of these, 70.3% experienced improved renal function within 48 hours. Preoperative factors independently predictive of AKI were age [P = 0.027, odds ratio (OR) 1.02 (1.00-1.04)], male sex [P = 0.015, OR 1.77 (1.10-2.81)], BMI at diagnosis [P < 0.001, OR 1.10 (1.07-1.14)], and dyslipidemia [P = 0.002, OR 2.14 (1.34-3.44)]. Postoperatively, AKI was associated with atrial fibrillation (P = 0.013) and pneumonia (P = 0.005). Postoperative AKI did not impact survival outcomes. CONCLUSION: AKI is common but mostly self-limiting after esophageal cancer surgery. It is associated with age, male sex, increased BMI, dyslipidemia, and postoperative morbidity.

Insulin and the insulin receptor collaborate to promote human gastric cancer.

BACKGROUND: Gastric adenocarcinoma is common and consequent mortality high. Presentation and mortality are increased in obese individuals, many of whom have elevated circulating insulin concentrations. High plasma insulin concentrations may promote, and increase mortality from, gastric adenocarcinoma. Tumour promotion activities of insulin and its receptor are untested in gastric cancer cells. METHODS: Tumour gene amplification and expression were computed from sequencing and microarray data. Associations with patient survival were assessed. Insulin-dependent signal transduction, growth, apoptosis and anoikis were analysed in metastatic cells from gastric adenocarcinoma patients and in cell lines. Receptor involvement was tested by pharmacological inhibition and genetic knockdown. RNA was analysed by RT-PCR and proteins by western transfer and immunofluorescence. RESULTS: INSR expression was higher in tumour than in normal gastric tissue. High tumour expression was associated with worse patient survival. Insulin receptor was detected readily in metastatic gastric adenocarcinoma cells and cell lines. Isoforms B and A were expressed. Pharmacological inhibition prevented cell growth and division, and induced caspase-dependent cell death. Rare tumour INS expression indicated tumours would be responsive to pancreatic or therapeutic insulins. Insulin stimulated gastric adenocarcinoma cell PI3-kinase/Akt signal transduction, proliferation, and survival. Insulin receptor knockdown inhibited proliferation and induced programmed cell death. Type I IGF receptor knockdown did not induce cell death. CONCLUSIONS: The insulin and IGF signal transduction pathway is dominant in gastric adenocarcinoma. Gastric adenocarcinoma cell survival depends upon insulin receptor. That insulin has direct cancer-promoting effects on tumour cells has implications for clinical management of obese and diabetic cancer patients.

Evolution of Esophagectomy for Cancer Over 30 Years: Changes in Presentation, Management and Outcomes.

BACKGROUND: Esophageal cancer has seen a considerable change in management and outcomes over the last 30 years. Historically, the overall prognosis has been regarded as poor; however, the use of multimodal treatment and the integration of enhanced recovery pathways have improved short- and long-term outcomes. OBJECTIVE: The aim of this study was to evaluate the changing trends in presentation, management, and outcomes for patients undergoing surgical treatment for esophageal cancer over 30 years from a single-center, high-volume unit in the UK. PATIENTS AND METHODS: Data from consecutive patients undergoing esophagectomy for cancer (adenocarcinoma or squamous cell carcinoma) between 1989 and 2018 from a single-center, high-volume unit were reviewed. Presentation method, management strategies, and outcomes were evaluated. Patients were grouped into successive 5-year cohorts for comparison and evaluation of changing trends. RESULTS: Between 1989 and 2018, 1486 patients underwent esophagectomy for cancer. Median age was 65 years (interquartile range [IQR] 59-71) and 1105 (75%) patients were male. Adenocarcinoma constituted 1105 (75%) patients, and overall median survival was 29 months (IQR 15-68). Patient presentation changed, with epigastric discomfort now the most common presentation (70%). An improvement in mortality from 5 to 2% (p < 0.001) was seen over the time period, and overall survival improved from 22 to 56 months (p < 0.001); however, morbidity increased from 54 to 68% (p = 0.004). CONCLUSIONS: Long-term outcomes have significantly improved over the 30-year study period. In addition, mortality and length of stay have improved despite an increase in complications. The reasons for this are multifactorial and include the use of perioperative chemo(radio)therapy, the introduction of an enhanced recovery pathway, and improved patient selection.

Impact of Smoking Status on Perioperative Morbidity, Mortality, and Long-Term Survival Following Transthoracic Esophagectomy for Esophageal Cancer.

INTRODUCTION: Esophagectomy is a key component in the curative treatment of esophageal cancer. Little is understood about the impact of smoking status on perioperative morbidity and mortality and the long-term outcome of patients following esophagectomy. OBJECTIVE: This study aimed to evaluate morbidity and mortality according to smoking status in patients undergoing esophagectomy for esophageal cancer. METHODS: Consecutive patients undergoing two-stage transthoracic esophagectomy (TTE) for esophageal cancers (adenocarcinoma or squamous cell carcinoma) between January 1997 and December 2016 at the Northern Oesophagogastric Unit were included from a prospectively maintained database. The main explanatory variable was smoking status, defined as current smoker, ex-smoker, and non-smoker. The primary outcome was overall survival (OS), while secondary outcomes included perioperative complications (overall, anastomotic leaks, and pulmonary complications) and survival (cancer-specific survival [CSS], recurrence-free survival [RFS]). RESULTS: During the study period, 1168 patients underwent esophagectomy for cancer. Of these, 24% (n = 282) were current smokers and only 30% (n = 356) had never smoked. The median OS of current smokers was significantly shorter than ex-smokers and non-smokers (median 36 vs. 42 vs. 48 months; p = 0.015). However, on adjusted analysis, there was no significant difference in long-term OS between smoking status in the entire cohort. The overall complication rates were significantly higher with current smokers compared with ex-smokers or non-smokers (73% vs. 66% vs. 62%; p = 0.018), and there were no significant differences in anastomotic leaks and pulmonary complications between the groups. On subgroup analysis by receipt of neoadjuvant therapy and tumor histology, smoking status did not impact long-term survival in adjusted multivariable analyses. CONCLUSION: Although smoking is associated with higher rates of short-term perioperative morbidity, it does not affect long-term OS, CSS, and RFS following esophagectomy for esophageal cancer. Therefore, implementation of perioperative pathways to optimize patients may help reduce the risk of complications.

Chyle Leak Following Radical En Bloc Esophagectomy with Two-Field Nodal Dissection: Predisposing Factors, Management, and Outcomes.

BACKGROUND: Chyle leak is an uncommon complication following esophagectomy, accounting for significant morbidity and mortality; however, the optimal treatment for the chylothorax is still controversial. OBJECTIVE: The aim of this study was to evaluate the incidence, management, and outcomes of chyle leaks within a specialist esophagogastric cancer center. METHODS: Consecutive patients undergoing esophagectomy for esophageal cancers (adenocarcinoma or squamous cell carcinoma) between 1997 and 2017 at the Northern Oesophagogastric Unit were included from a contemporaneously maintained database. Primary outcome was overall survival, while secondary outcomes were overall complications, anastomotic leaks, and pulmonary complications. RESULTS: During the study period, 992 patients underwent esophagectomy for esophageal cancers, and 5% (n = 50) of them developed chyle leaks. There was no significant difference in survival in patients who developed a chyle leak compared with those who did not (median: 40 vs. 45 months; p = 0.60). Patients developing chyle leaks had a significantly longer length of stay in critical care (median: 4 vs. 2 days; p = 0.002), but no difference in total length of hospital stay. CONCLUSION: Chyle leak remains a complication following esophagectomy, with limited understanding on its pathophysiology in postoperative recovery. However, these data indicate chyle leak does not have a long-term impact on patients and does not affect long-term survival.

The impact of age on patients undergoing transthoracic esophagectomy for cancer.

To compare long-term and short-term outcomes in patients <70 years old with those ≥ 70 years old, who underwent transthoracic esophagectomy for carcinoma. With an ageing population more patients, with increasing co-morbidities are being diagnosed with potentially curable esophageal cancer. Concerns exist regarding offering older patients esophagectomy, conversely undue prejudice may exists that may prevent surgery being offered. Consecutive patients from a single unit between January 2000 and July 2016 that underwent trans-thoracic esophagectomy with or without neoadjuvant treatment for carcinoma were included. Short-term outcomes including morbidity, mortality, length of stay and long-term survival were compared between those <70 and those ≥ 70. This study identified 992 patients who underwent esophagectomy during the study period, of which 302 (30%) ≥ 70 years old. Greater proportion ≥ 70 years old had SCC (squamous cell carcinoma) (23%) than <70 (18%) (p = 0.07). Patients ≥ 70 years old were noted to have higher ASA Grade 3 (34% vs 25%, p = 0.004) and were less likely to receive neoadjuvant treatment (64% vs 45% p<0.001). Length of stay was longer in ≥ 70 (14 vs 17 days p<0.001), and there were more complications (63% vs 75% p<0.001). In hospital mortality was higher in ≥ 70 (2% vs 5% p = 0.026). Overall survival was 50 months in <70 vs 36 months in ≥ 70 (p = <0.001). In <70s with adenocarcinoma, overall survival was 52 months vs 35 months in the ≥ 70 (p<0.001). No significant difference in survival in patients with SCC, 49 months in <70 vs 54 months in ≥ 70 (p = 0.711). Increased peri-operative morbidity and mortality combined with the reduction in the long term survival in the over 70s cohort should be addressed when counselling patients undergoing curative resection for oesophageal cancer.

Signet ring gastric and esophageal adenocarcinomas: characteristics and prognostic implications.

Controversy exists as to the relevance of the signet ring carcinoma (SRC) histological subtype of esophagogastric adenocarcinoma to long-term prognosis, with some studies reporting a worsened oncological outcome and others no clinically relevant impact. A retrospective analysis of outcomes of patients who underwent surgery with curative intent in two high-volume centers (2000-2015) was undertaken. Tumors were analyzed according to location (esophageal, junctional or gastric). Propensity score matching (PSM) analysis was used to match patients with signet ring histology to those without (195 SRC vs. 573 non-SRC), based on age, tumor location, use of neoadjuvant and adjuvant chemotherapy and pathological stage. A total of 2,500 patients with esophagogastric adenocarcinomas were treated, of whom 198 (7.9%) had signet ring histology. Signet ring tumors were more likely to have positive lymph nodes at pathological analysis (59% vs. 50%, P = 0.009). The 5-year survival rate for patients with early signet ring tumors (Stage 0/I/IIa) was 65% versus 85% for other early cancers (P < 0.003). Patients with esophageal signet ring tumors had a particularly poor prognosis with 23% 2-year survival and none alive at 5 years. With PSM, overall survival (OS) was significantly poorer in the signet ring group (44.3 ± 8.6 vs. 59.8 ± 8.5 months, 5-year OS 41% vs. 50%, P = 0.027). Signet ring cells within esophagogastric adenocarcinoma are associated with a poorer prognosis. Genomic studies to identify the composition of such tumors as well as identify strategies to improve treatment for this subtype are warranted.

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.

Randomised, double-blind, placebo-controlled pilot trial of omeprazole in idiopathic pulmonary fibrosis.

BACKGROUND: Cough is a common, disabling symptom of idiopathic pulmonary fibrosis (IPF), which may be exacerbated by acid reflux. Inhibiting gastric acid secretion could potentially reduce cough. This study aimed to determine the feasibility of a larger, multicentre trial of omeprazole for cough in IPF, to assess safety and to quantify cough. METHODS: Single-centre, double-blind, randomised, placebo-controlled pilot trial of the proton pump inhibitor (PPI) omeprazole (20 mg twice daily for 3 months) in patients with IPF. Primary objectives were to assess feasibility and acceptability of trial procedures. The primary clinical outcome was cough frequency. RESULTS: Forty-five participants were randomised (23 to omeprazole, 22 to placebo), with 40 (20 in each group) having cough monitoring before and after treatment. 280 patients were screened to yield these numbers, with barriers to discontinuing antacids the single biggest reason for non-recruitment. Recruitment averaged 1.5 participants per month. Geometric mean cough frequency at the end of treatment, adjusted for baseline, was 39.1% lower (95% CI 66.0% lower to 9.3% higher) in the omeprazole group compared with placebo. Omeprazole was well tolerated and adverse event profiles were similar in both groups, although there was a small excess of lower respiratory tract infection and a small fall in forced expiratory volume and forced vital capacity associated with omeprazole. CONCLUSIONS: A large randomised controlled trial of PPIs for cough in IPF appears feasible and justified but should address barriers to randomisation and incorporate safety assessments in relation to respiratory infection and changes in lung function.

The influence of procedural volume and proficiency gain on mortality from upper GI endoscopic mucosal resection.

OBJECTIVE: Endoscopic mucosal resection (EMR) is established for the management of benign and early malignant upper GI disease. The aim of this observational study was to establish the effect of endoscopist procedural volume on mortality. DESIGN: Patients undergoing upper GI EMR between 1997 and 2012 were identified from the Hospital Episode Statistics database. The primary outcome was 30-day mortality and secondary outcomes were 90-day mortality, requirement for emergency intervention and elective cancer re-intervention. Risk-adjusted cumulative sum (RA-CUSUM) analysis was used to assess patient mortality risk during initial stage of endoscopist proficiency gain and the effect of endoscopist and hospital volume. Mortality was compared before and after the change point or threshold in the RA-CUSUM curve. RESULTS: 11 051 patients underwent upper GI EMR. Endoscopist procedure volume was an independent predictor of 30-day mortality. Fifty-eight per cent of EMR procedures were performed by endoscopists with annual volume of 2 cases or less, and had a higher 30-day and 90-day mortality rate for patients with cancer, 6.1% vs 0.4% (p<0.001) and 12% vs 2.1% (p<0.001), respectively. The requirement for emergency intervention after EMR for cancer was also greater with low volume endoscopists (1.8% vs 0.1%, p=0.002). In patients with cancer, the RA-CUSUM curve change points for 30-day mortality and elective re-intervention were 4 cases and 43 cases, respectively. CONCLUSIONS: EMR performed by high volume endoscopists is associated with reduced adverse outcomes. In order to reach proficiency, appropriate training and procedural volume accreditation training programmes are needed nationally.

Trainee Involvement in Ivor Lewis Esophagectomy Does Not Negatively Impact Outcomes.

OBJECTIVE: The aim of the present study was to determine whether trainee involvement in esophageal cancer resection is associated with adverse patient outcomes. BACKGROUND: Operative experience for surgical trainees is under threat. A number of factors have been implicated in this leading to fewer hours for training. Esophagogastric cancer training is particularly vulnerable due to the publication of individual surgeon results and a perception that dual consultant operating improves patient outcomes. Resectional surgery is increasingly viewed as a subspeciality to be developed after completion of the normal training pathway. METHODS: Data from a prospectively maintained database of consecutive patients undergoing trans-thoracic esophagectomy for potentially curable carcinoma of the esophagus or gastroesophageal junction were reviewed. Patients were divided into 4 cohorts, according to whether a consultant or trainee was the primary surgeon in either the abdominal or thoracic phase. Outcomes including operative time, lymph node yield, blood loss, complications graded by Accordion score, and mortality were recorded. RESULTS: A total of 323 patients underwent esophagectomy during 4 years. The overall in-hospital mortality rate was 1.5%. At least 1 phase of the surgery was performed by a trainee in 75% of cases. There was no significant difference in baseline demographics of age, stage, neoadjuvant treatment, and histology between cohorts. There was no significant difference in blood loss (P = 0.8), lymph node yield (P = 0.26), length of stay (P = 0.24), mortality, and complication rate according to Accordion scores (P = 0.21) between cohorts. Chest operating time was a median 25 minutes shorter when performed by a consultant (P < 0.001). CONCLUSIONS: These findings demonstrate that patient outcomes are not compromised by supervised trainee involvement in transthoracic esophagectomy. Training is an essential role of all surgical units and training data should be more widely reported especially in areas of high-risk surgery.

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.

Impact of Extent of Lymphadenectomy on Survival, Post Neoadjuvant Chemotherapy and Transthoracic Esophagectomy.

OBJECTIVE: The aim of this study was to evaluate the influence of lymph node yield and the location of nodes on prognosis in patients with distal esophageal or gastroesophageal junction adenocarcinoma who have received neoadjuvant chemotherapy followed by transthoracic esophagectomy. BACKGROUND: Debate continues regarding the extent of lymphadenectomy required when carrying out an esophagectomy. Lymph node yield has been used as a surrogate for extent of lymphadenectomy. Node location must, however, be reviewed to determine the true extent of lymphadenectomy. METHODS: Data from consecutive patients with potentially curable adenocarcinoma of the lower esophagus or gastroesophageal junction were reviewed. Patients were treated with neoadjuvant chemotherapy, transthoracic esophagectomy, and 2-field lymphadenectomy. Outcomes according to lymph node yield were determined. Projected prognosis of carrying out less radical lymphadenectomies was calculated according to 3 groups: group 1-exclusion of proximal thoracic nodes, group 2-a minimal abdominal lymphadenectomy, and group 3-a minimal abdominal and thoracic lymphadenectomy. RESULTS: Three hundred five patients were included. Median cancer-related survival was 37.7 months (confidence interval 29-46 mo). Absolute lymph node retrieval was not related to survival (P = 0.520). An estimated additional 4 (2-6) cancer-related deaths were projected if group 1 nodes were omitted, 2 (1-4) additional deaths if group 2 nodes were omitted, and 9 (6-12) extra deaths if group 3 nodes were omitted. A minimal lymphadenectomy (groups 1, 2, and 3) was projected to lead to a 23% reduction in survival in patients with N1 or N2. CONCLUSIONS: The present study demonstrates high lymph node yields are possible after transthoracic esophagectomy with en bloc 2-field lymphadenectomy in patients post neoadjuvant chemotherapy. This allows excellent postoperative staging. Furthermore, the extent of lymphadenectomy must be correlated with node location, which may have important implications in patients who have a less extensive lymphadenectomy.

Columnar Metaplasia in the Esophageal Remnant After Esophagectomy: A Common Occurrence and a Valuable Insight Into the Development of Barrett Esophagus.

OBJECTIVE: This study aimed to establish the incidence of postesophagectomy columnar metaplasia and dysplasia, and the timescale over which it develops. It also aimed to assess if this epithelium is molecularly similar to sporadic Barrett esophagus, thereby confirming suitability as a research model. BACKGROUND: Metaplasia in the esophageal remnant after esophagectomy is well described, but incidence and the potential for dysplasia are uncertain, and the clinical relevance unclear. Although proposed as a model for Barrett esophagus, no large studies have examined the molecular phenotype of postesophagectomy metaplasia. METHODS: Patients underwent prospective endoscopic evaluation having previously undergone esophagectomy. The macroscopic appearance of the esophageal remnant was noted and biopsies taken. Specimens were stained using hematoxylin and eosin and by immunohistochemistry for cytokeratins 7 and 20, and Chromogranin A-proteins which have a well described expression pattern in sporadic Barrett esophagus. RESULTS: Of the 126 eligible patients, 45 (36%) had evidence of metaplasia. There were no cases of dysplasia. Nonintestinalized columnar epithelium occurred earlier than specialized intestinal metaplasia (median 4.8 vs 8.1 yr; P = 0.025). Thirty-seven samples underwent immunohistochemical analysis. A classic cytokeratin 7/20 staining pattern was present in 23 cases (62%), within the prevalence range reported for sporadic Barrett. CONCLUSIONS: Columnar metaplasia is common following esophagectomy, but the absence of dysplasia in this large cohort is reassuring. Presence of specialized intestinal metaplasia is associated with increased time from surgery, suggesting this represents later disease. Immunohistochemistry staining is similar to sporadic Barrett, suggesting that this group of patients represent an accurate human model for the development of Barrett.

Prognostic Significance of the Location of Lymph Node Metastases in Patients With Adenocarcinoma of the Distal Esophagus or Gastroesophageal Junction.

OBJECTIVE: To identify the prognostic significance of the location of lymph node metastases in patients with esophageal or gastroesophageal junction (GEJ) adenocarcinoma treated with neoadjuvant therapy followed by esophagectomy. BACKGROUND: Detection of lymph node metastases in the upper mediastinum and around the celiac trunk after neoadjuvant therapy and resection does not alter the TNM classification of esophageal carcinoma. The impact of these distant lymph node metastases on survival remains unclear. METHODS: Between March 2003 and September 2013, 479 consecutive patients with adenocarcinoma of the distal esophagus or GEJ who underwent transthoracic esophagectomy with en bloc 2-field lymphadenectomy after neoadjuvant therapy were included, and survival was analyzed according to the location of positive lymph nodes in the resection specimen. RESULTS: Two hundred fifty-three patients had nodal metastases in the resection specimen. Of these patients, 92 patients had metastases in locoregional nodes, 114 patients in truncal nodes, 21 patients in the proximal field of the chest, and 26 patients had both positive truncal and proximal field nodes. Median disease-free survival was 170 months in the absence of nodal metastases, 35 months for metastases limited to locoregional nodes, 16 months for positive truncal nodes, 15 months for positive nodes in the proximal field, and 8 months for nodal metastases in both truncal and the proximal field. On multivariate analysis, location of lymph node metastases was independently associated with survival. CONCLUSIONS: Location of lymph node metastases is an independent predictor for survival. Relatively distant lymph node metastases along the celiac axis and/or the proximal field have a negative impact on survival. Location of lymph node metastases should therefore be considered in future staging systems of esophageal and GEJ adenocarcinoma.

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.

Trefoil Factor Expression in a Human Model of the Early Stages of Barrett's Esophagus.

BACKGROUND: Trefoil proteins are believed to have an important role in mucosal protection and repair in the gastrointestinal tract. They are well recognized in Barrett's esophagus and considered a potential biomarker for the condition. Metaplasia occurring in the esophageal remnant after esophagectomy is a human model for the early stages of development of Barrett's esophagus. AIMS: To assess expression of trefoil proteins in post-esophagectomy columnar epithelium and to use trefoils as a molecular tool to understand regenerative mucosa in the esophagus. METHODS: Patients with columnar metaplasia in the esophageal remnant were recruited from a large esophago-gastric cancer center. Trefoil factor expression was determined using immunohistochemical techniques. RESULTS: Samples were obtained from 37 patients. TFF1 and TFF2 were expressed by all samples in a similar pattern to that described in studies of sporadic Barrett's esophagus. TFF3 was less widely expressed and was significantly associated with time elapsed between surgery and endoscopy. Median time from surgery to endoscopy was 8.1 years for patients with TFF3 expression versus 3.4 years for those without (p = 0.004). CONCLUSIONS: Widespread expression of trefoils in this environment suggests that these proteins have an important role in development of Barrett's metaplasia. TFF3 expression may be absent in the early stages of metaplasia and may represent more established columnar epithelium. Biopsy samples from post-esophagectomy patients provide a valuable resource to study the early stages of Barrett's esophagus.