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Neoadjuvant chemotherapy is established in the treatment of gastric adenocarcinoma. Histopathological regression may have important prognostic implications. There are little data comparing clinical outcomes of patients with gastric adenocarcinoma that received neoadjuvant treatment and those neoadjuvant naive. The aim of this study is to determine the impact of neoadjuvant chemotherapy upon prognosis of patients being treated for gastric adenocarcinoma.Consecutive patients with gastric cancer from a single center between 2007 and 2017 were evaluated. Patients were treated with either a subtotal or total gastrectomy with D2 lymphadenectomy. Stage-by-stage comparison of the extent of pathological downstaging was conducted for patients who received neoadjuvant treatment (ypTNM) and those who did not (pTNM) using the TNM eighth edition.Overall, 384 patients underwent gastrectomy, 141 patients received neoadjuvant chemotherapy, and 86 patients (58.1%) were downstaged. Downstaged patients had improved overall survival compared to patients who did not respond to neoadjuvant chemotherapy (not reported vs 66 months, P.001). Downstaging by3 stages was the strongest independent predictor of overall survival (hazard ratio: 0.17; 95% confidence interval 0.062-0.44). Overall survival was significantly better among patients in the ypTNM groups when a stage-by-stage comparison was performed with the pTNM group.Pathological stage is a more accurate predictor of prognosis compared clinical stage with downstaged patients benefiting from lower recurrence rates and improved overall survival. Patients downstaged due to neoadjuvant chemotherapy may potentially have more favorable clinical outcomes compared to stage-matched patients who did not receive this.

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.

Gastric cancer has seen a considerable change in management, and outcomes for the past 30 years. Historically, the overall prognosis has been regarded as poor. However, the use of multimodal treatment, and integration of enhanced recovery pathways have improved short and long-term outcomes. The aim of this study was to evaluate the changing trends in presentation, management, and outcomes for patients undergoing surgical treatment for gastric cancers over 30 years.Data from consecutive patients undergoing gastrectomy with curative intent for gastric adenocarcinoma between 1989 and 2018 from a single-center, high-volume unit were reviewed. Presentation method, management strategies and outcomes were reviewed. Patients were grouped into successive 5-year cohorts for comparison and evaluation of changing trends.Between 1989 and 2018, 1,162 patients underwent gastrectomy with curative intent for cancer. Median age was 71 years (interquartile range, 63-76 years) and 763 (66%) were male. Patient presentation changed with epigastric discomfort now the most common presentation (67%). An improvement in overall complications from 54% to 35% (P = .006) and mortality from 8% to 1% (P.001) was seen over the time period and overall survival improved from 28 months to 53 months (P.001).Both short-term and long-term outcomes have significantly improved over the 30 years studied. The reasons for this are multifactorial and include the use of perioperative chemotherapy, the introduction of an enhanced recovery pathway, and improved preoperative assessment of patients through a multidisciplinary input.

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.

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.

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 p 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.

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.

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, 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.

Summary To compare long-term and short-term outcomes in patients

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.

BackgroundCough 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.MethodsSingle-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.ResultsForty-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.ConclusionsA 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.

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.

ObjectiveEndoscopic 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.DesignPatients 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.Results11 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% (pConclusionsEMR 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.

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.

Objectives To explore how the concept of randomization is described by clinicians and understood by patients in randomized controlled trials (RCTs) and how it contributes to patient understanding and recruitment. Study Design and Setting Qualitative analysis of 73 audio recordings of recruitment consultations from five, multicenter, UK-based RCTs with identified or anticipated recruitment difficulties. Results One in 10 appointments did not include any mention of randomization. Most included a description of the method or process of allocation. Descriptions often made reference to gambling-related metaphors or similes, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was “best for them”. Descriptions of the rationale for randomization were rarely present and often only came about as a consequence of patients questioning the reason for a random allocation. Conclusions The methods and processes of randomization were usually described by recruiters, but often without clarity, which could lead to patient misunderstanding. The rationale for randomization was rarely mentioned. Recruiters should avoid problematic gambling metaphors and illusions of agency in their explanations and instead focus on clearer descriptions of the rationale and method of randomization to ensure patients are better informed about randomization and RCT participation., Highlights • Practices commonly used to describe randomisation in RCT recruitment could confuse patients. • Patients found it difficult to comprehend gambling-related metaphors of randomisation. • Computer-agency descriptions led to patients believing they would receive the best treatment.

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.

Purpose The progressive loss of skeletal muscle and function (known as sarcopenia) has been shown to be associated with various adverse outcome measures. Sophisticated measurements of body composition are increasingly being incorporated into research studies to stratify patients into those with or without sarcopenia, monitor treatment effects, and predict complications. A typical approach is to select axial image(s) at the mid-lumbar level and use semi-automated software to identify and quantify the skeletal muscle area. This area is then used to estimate whole-body parameters. This approach is somewhat subjective, and in this study we investigate its reproducibility, both within and between observers. Materials and methods Repeated muscle measurements were performed on a cohort of 29 patients by 3 radiologists, to examine their intra- and interobserver reproducibility. Results and discussion Mean muscle area for the cohort was 156 cm2, with a wide range (98 – 261 cm2). There was good intraobserver agreement between measurements, with a mean absolute difference between repeated measurements on the same patient of 0.98 cm2, and a measurement variability of 2.92 cm2. Much of the variability was shown to be due to the choice of a different slice when performing the repeated measurement. Averaging two slices provided a small but non-significant improvement in comparison to the single slice approach. Interobserver results showed good agreement, though there was a small bias for one observer, who measured slightly larger volumes compared to the other two. We conclude that the approach described provides reproducible skeletal muscle area measurements, and offer three specific recommendations to minimise variability.

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. 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. 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. 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). 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.

The aim of the present study was to determine whether trainee involvement in esophageal cancer resection is associated with adverse patient outcomes. 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. 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. 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). 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.

Amplification of seven oncogenes: HER2, EGFR, FGFR1, FGFR2, MET, KRAS and IGF1R has been identified in gastric cancer. The first five are targeted therapeutically in patients with HER2-positivity, FGFR2- or MET-amplification but the majority of patients are triple-negative and require alternative strategies. Our aim was to evaluate the importance of the IGF1R tyrosine kinase in triple-negative gastric cancer with and without oncogenic KRAS, BRAF or PI3K3CA mutations. Cell lines and metastatic tumor cells isolated from patients expressed IGF1R, and insulin-like growth factor-1 (IGF-1) activated the PI3-kinase/Akt and Ras/Raf/MAP-kinase pathways. IGF-1 protected triple-negative cells from caspase-dependent apoptosis and anoikis. Protection was mediated via the PI3-kinase/Akt pathway. Remarkably, IGF-1-dependent cell survival was greater in patient samples. IGF-1 stimulated triple-negative gastric cancer cell growth was prevented by IGF1R knockdown and Ras/Raf/MAP-kinase pathway inhibition. The importance of the receptor in cell line and metastatic tumor cell growth in serum-containing medium was demonstrated by knockdown and pharmacological inhibition with figitumumab. The proportions of cells in S-phase and mitotic-phase, and Ras/Raf/MAP-kinase pathway activity, were reduced concomitantly. KRAS-addicted and BRAF-impaired gastric cancer cells were particularly susceptible. In conclusion, IGF1R and the IGF signal transduction pathway merit consideration as potential therapeutic targets in patients with triple-negative gastric cancer.

Objective This review summarizes reporting of complications of esophageal cancer surgery. Background Accurate assessment of morbidity and mortality after surgery for cancer is essential to compare centers, allow data synthesis, and inform clinical decision-making. A lack of defined standards may distort clinically relevant treatment effects. Methods Systematic literature searches identified articles published between 2005 and 2009 reporting morbidity and mortality after esophagectomy for cancer. Data were analyzed for frequency of complication reporting and to check whether outcomes were defined and classified for severity and whether a validated system for grading complications was used. Information about reporting outcomes adjusting for baseline risk factors was collated, and a descriptive summary of the results of included outcomes was undertaken. Results Of 3458 abstracts, 224 full papers were reviewed and 122 were included (17 randomized trials and 105 observational studies), reporting outcomes of 57,299 esophagectomies. No single complication was reported in all papers, and 60 (60.6%) did not define any of the measured complications. Anastomotic leak was the most commonly reported morbidity, assessed in 80 (80.1%) articles, defined in 28 (28.3%), but 22 different descriptions were used. Five papers (5.1%) categorized morbidity with a validated grading system. One hundred fifteen papers reported postoperative mortality rates, 25 defining the term using 10 different definitions. In-hospital mortality was the most commonly used term for postoperative death, with 6 different interpretations of this phrase. Eighteen papers adjusted outcomes for baseline risk factors and 60 presented baseline measures of comorbidity. Conclusions Outcome reporting after esophageal cancer surgery is heterogeneous and inconsistent, and it lacks methodological rigor. A consensus approach to reporting clinical outcomes should be considered, and at the minimum it is recommended that a "core outcome set" is defined and used in all studies reporting outcomes of esophageal cancer surgery. This will allow meaningful cross study comparisons and analyses to evaluate surgery.

A dramatic rise in incidence, an aging population, and expensive palliative treatments have led to an escalating burden on clinicians managing inoperable esophageal cancer with only limited evidence of effectiveness. This study compares the clinical effectiveness and cost-effectiveness of self-expanding metal stents (SEMSs) with other palliative therapies to aid clinicians in making an evidence-based treatment choice.We conducted a prospective, multicenter, randomized, controlled, clinical trial with 215 patients followed until death or study closure. The primary outcome measures were dysphagia, quality of life (QL) 6 weeks following treatment, and total cost of treatment. Secondary outcome measures included treatment-associated morbidity, mortality, survival, and cost-effectiveness. An intention-to-treat analysis was carried out.There was a significant difference in mean dysphagia grade between treatment arms 6 weeks following treatment (P=0.046), with worse swallowing reported by rigid stent-treated patients (mean dysphagia score difference=-0.49; 95% confidence interval (CI) -0.10 to -0.89, P=0.014). Global QL scores were lower at both 1 and 6 weeks following treatment for patients treated by SEMSs (mean difference QL index week 1=-0.66; 95% CI: -0.02 to -1.30, P=0.04; mean difference QL index week 6=-1.01; 95% CI -0.30 to -1.72, P=0.006). These findings were associated with higher post-procedure pain scores in the SEMS patient group (mean difference of the European Organisation for Research and Treatment of Cancer QLQ C-30 pain symptom score at week 1=11.13; 95% CI: 2.89-19.4; P=0.01). Although mean EQ-5D QL values differed between the treatments (P0.001), this difference dissipated following generation of quality-adjusted life year values. Total costs varied between treatment arms but these findings canceled out when SEMSs were compared with non-SEMS therapies (95% CI -845.15-1,332.62). These results were robust to sensitivity analysis. There were no differences in the in-hospital mortality or early complication rates, but late complications were more frequent after rigid stenting (risk ratio=2.47; 95% CI 1.88-3.04). There was a survival advantage for non-stent-treated patients (log-rank statistic=4.21, P=0.04).The treatment choice for patients with inoperable esophageal cancer should be between a SEMS or a non-stent treatment after consideration has been given to both patient and tumor characteristics and clinician and patient preferences.

OBJECTIVE:: The aim of this study was to determine whether the risk of systemic disease after esophagectomy can be predicted by the number of involved lymph nodes. SUMMARY BACKGROUND DATA:: Primary esophagectomy is curative in some but not all patients with esophageal cancer. Identification of patients at high risk for systemic disease would allow selective use of additional systemic therapy. This study is a multinational, retrospective review of patients treated with resection alone to assess the impact of the number of involved lymph nodes on the probability of systemic disease. METHODS:: The study population included 1053 patients with esophageal cancer (700 adenocarcinoma, 353 squamous carcinoma) who underwent R0 esophagectomy with >/=15 lymph nodes resected at 9 international centers: Asia (1), Europe (5), and United States (3). To ensure a minimum potential follow-up of 5 years, only patients who had esophagectomy before October 2002 were included. Patients treated with neoadjuvant or adjuvant therapy were excluded. The impact of the number of involved lymph nodes on the risk of systemic disease recurrence was assessed using univariate and multivariate analyses. RESULTS:: Systemic disease occurred in 40%. The number of involved lymph nodes ranged from 0 to 26 with 55% of patients having at least 1 involved lymph node. The frequency of systemic disease after esophagectomy was 16% for those without nodal involvement and progressively increased to 93% in patients with 8 or more involved lymph nodes. CONCLUSIONS:: This study shows that the number of involved lymph nodes can be used to predict the likelihood of systemic disease in patients with esophageal cancer. The probability of systemic disease exceeds 50% when 3 or more nodes are involved and approaches 100% when the number of involved nodes is 8 or more. Additional therapy is warranted in these patients with a high probability of systemic disease

BACKGROUND: Esophageal resection represents a major surgical and physiologic insult carrying major morbidity and mortality. We present the results of esophagectomy in a specialist unit with emphasis on early complications and their management. STUDY DESIGN: From January 4, 1990 through January 6, 2000, 228 patients have undergone Ivor Lewis subtotal esophagectomy with two-field lymphadenectomy for malignancy under the care of one surgeon. The median age was 64 years (range 39 to 77 years), with a male to female ratio of 2.3:1 and a predominance of adenocarcinoma (n = 146) compared with squamous cell carcinoma (n = 75) and other tumors (n = 7). Detailed prospective data were collected on preoperative status, operative parameters, and postoperative complications. RESULTS: Median ICU stay was 1 day (range 1 to 47 days) and the median postoperative hospital stay in patients surviving surgery (n = 219) was 13 days (range 9 to 159 days). There were 119 separate postoperative complications occurring in 45% of patients (102 of 228), comprising predominantly pulmonary morbidity. Major respiratory complications (17%) were significantly associated with poor preoperative spirometry (p = 0.002) and a history of smoking (p = 0.03). Seven percent of patients (16 of 228) suffered cardiovascular or thromboembolic complications. Major surgical complications occurred in 10% of patients (22 of 228) including mediastinal leaks in 4%. Isolated anastomotic leaks (2%) were successfully treated conservatively in all cases; extensive leaks from ischemic gastric conduits (1%) or gastrotomy dehiscence (1%) underwent further exploration and either local repair or resection and exclusion. Reoperation for hemostasis was required in 3% (6 of 228) and only 1% of patients (2 of 228) developed chyle leaks. Thirty-day mortality was 2%, rising to 4% for in-hospital mortality. The nine fatalities were significantly older (p = 0.02) than those who survived and 67% (6 of 9) had suffered primary surgical complications. CONCLUSIONS: Overall morbidity after radical esophagectomy is high, but early recognition and aggressive management of complications can minimize subsequent mortality. Concentration of facilities and surgical expertise in specialist units together with more careful patient selection can decrease mortality further.

The association between extraesophageal reflux (EER) and symptoms of gastroesophageal reflux disease (GERD) is inadequately understood. We used the Comprehensive Reflux Symptom Scale (CReSS) to evaluate EER and reflux-symptom prevalence in gastroenterology and otolaryngology outpatients and symptom awareness among UK gastroenterologists.Cross-sectional cohort survey.Six hundred thirty-nine participants were surveyed: 103 controls, 359 patients undergoing esophagogastroduodenoscopy (EGD), and 177 otolaryngology clinic patients with throat symptoms. Participants completed the CReSS questionnaire. The study was undertaken in the Endoscopy Unit and the Department of Otolaryngology-Head and Neck Surgery, Newcastle upon Tyne Hospitals, Newcastle-upon-Tyne, United Kingdom. Registered members of the British Gastroenterology Society were asked to rate how frequently reflux patients might complain of each CReSS item.The median CReSS total in volunteers (4) was significantly lower (P .002) than in ear, nose, and throat (ENT) patients (26) or EGD patients with (42) or without (32) esophageal inflammation. All items were scored as ≥1 by15% of ENT patients and 28% of EGD patients. Three major, robust CReSS factors: esophageal, pharyngeal, and upper airway emerged. Of 259 gastroenterologists,20% scored 8 of the 34 symptoms as never being reported by reflux patients.Endorsement of each EER CReSS item by 28% to 58% of patients with endoscopic evidence of GERD supports the Montreal consensus on an EER-GERD continuum. Gastroenterologists vary considerably in their appreciation of EER symptom relevance. The advantages of CReSS include standardized, comprehensive capture of patient experience; discriminant validity of ENT and GERD patients from volunteers; and discrete esophageal, pharyngeal, and upper airway subscales.4.

Background: Argon plasma coagulation is a diathermy-based non-contact therapeutic endoscopic modality that may have a lower risk of perforation than other tissue ablation techniques. Methods: Its effect was studied on three fresh esophageal and three fresh gastric resection specimens using power settings from 40 to 99 Watts at 90 degrees, with 1 mm separation using pulse durations of 1 and 3 seconds. A scoring system for depth of tissue damage was created and samples were analyzed blindly by a gastrointestinal histopathologist. Results: There was significantly greater damage to gastric tissue using a 3-second (compared with 1-second) pulse ( p = 0.003) and marginally significantly greater damage to esophageal tissue using the 3-second pulse ( p = 0.053). Tissue damage was related to power setting for gastric ( p = 0.031) but not for esophageal tissue ( p = 0.065). Only 1 of 42 esophageal samples and 2 of 42 gastric samples examined showed damage extending into the muscularis propria. Conclusions: Deep tissue damage that could lead to perforation was rare with argon plasma coagulation. The depth of gastric mucosal damage increased with increased pulse duration and increasing power settings, and, although the depth of esophageal mucosal damage was marginally related to pulse duration, it was not related to the power setting. (Gastrointest Endosc 2000;52:342–5).

To provide novel pilot data to quantify reflux, aspiration, and allograft injury immediately post-lung transplantation. Asymptomatic reflux/aspiration, associated with allograft dysfunction, occurs in lung transplant recipients. Early fundoplication has been advocated. Indications for surgery include elevated biomarkers of aspiration (bile salts) in bronchoalveolar lavage fluid (BALF). Measurements have been mostly documented after the immediate posttransplant period. We report the first prospective study of reflux/aspiration immediately posttransplantation to date. Lung transplant recipients were recruited over 12 months. At 1 month posttransplantation, patients completed a Reflux Symptom Index questionnaire and underwent objective assessment for reflux (manometry and pH/impedance). Testing was performed on maintenance proton pump inhibitor. BALF was assessed for pepsin, bile salts, interleukin-8 and neutrophils. Eighteen lung transplant recipients, median age of 46 years (range: 22-59 years), were recruited. Eight of 18 patients had abnormal esophageal peristalsis. Five of 17 patients were positive on Reflux Symptom Index questionnaire. Twelve of 17 patients had reflux. Three patients exclusively had weakly acid reflux. Median acid exposure was 4.8% (range: 1%-79.9%) and median esophageal volume exposure was 1.6% (range: 0.7-5.5). There was a median of 72 reflux events (range: 27-147) per 24 hours. A correlation existed between Reflux Symptom Index score and proximal reflux (r = 0.533, P = 0.006). Pepsin was detected in 11 of 15 BALF samples signifying aspiration (median: 18 ng/mL; range: 0-43). Bile salts were undetectable, using spectrophotometry and rarely detectable using dual mass spectrometry (2/15) (levels 0.2 and 1.2 μmol/L). Lavage interleukin-8 and neutrophil levels were elevated. A correlation existed between proximal reflux events and neutrophilia (r = 0.52, P = 0.03). Lung transplant recipients should be routinely assessed for reflux/aspiration within the first month posttransplant. Reflux/aspiration can be present early postoperatively. Pepsin was detected suggesting aspiration. Bile salts were rarely detected. Proximal reflux events correlated with neutrophilia, linked to allograft dysfunction and mortality. These results support the need for early assessment of reflux/aspiration, which may inform fundoplication

Background & Aims Esophageal adenocarcinoma (EA) is increasingly common among patients with Barrett's esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. Methods We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. Results Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. Conclusions We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Over the past decade the Improving Outcomes Guidance (IOG) document has led to service re-configuration in the NHS and there are now 41 specialist centres providing oesophageal and gastric cancer care in England and Wales. The National Oesophago-Gastric Cancer Audit, which was supported by the British Society of Gastroenterology, the Association of Upper Gastrointestinal Surgeons (AUGIS) and the Royal College of Surgeons of England Clinical Effectiveness Unit, and sponsored by the Department of Health, has been completed and has established benchmarks for the service as well as identifying areas for future improvements.1–3 The past decade has also seen changes in the epidemiology of oesophageal and gastric cancer. The incidence of lower third and oesophago-gastric junctional adenocarcinomas has increased further, and these tumours form the most common oesophago-gastric tumour, probably reflecting the effect of chronic gastro-oesophageal reflux disease (GORD) and the epidemic of obesity. The increase in the elderly population with significant co-morbidities is presenting significant clinical management challenges. Advances in understanding of the natural history of the disease have increased interest in primary and secondary prevention strategies. Technology has improved the options for diagnostic and therapeutic endoscopy and staging with cross-sectional imaging. Results from medical and clinical oncology trials have established new standards of practice for both curative and palliative interventions. The quality of patient experience has become a significant component of patient care, and the role of the specialist nurse is fully intergrated. These many changes in practice and patient management are now routinely controlled by established multidisciplinary teams (MDTs) which are based in all hospitals managing these patients. The original guidelines described the management of oesophageal and gastric cancer within existing practice. This paper updates the guidance to include new evidence and to embed it within the framework of the current UK National Health Service (NHS) Cancer …

Surgery has been the mainstay of treatment for spontaneous full-thickness rupture of the esophagus for the last 50 years. In an acute presentation with contamination of the mediastinal or pleural cavities, this remains the definitive course of action. However, the management when diagnosis has been delayed is more contentious. This is a description of a novel approach with a combined percutaneousendoscopic technique that was used in 2 such cases.

OBJECTIVE: Surveillance, Epidemiology and End Results (SEER) data indicate that number of lymph nodes removed impacts survival in gastric cancer. Our aim was to study this relationship in esophageal cancer. METHODS: The study population included 2303 esophageal cancer patients (1381 adenocarcinoma, 922 squamous) from 9 international centers that had R0 esophagectomy prior to 2002 and were followed at regular intervals for 5 years or until death. Patients treated with neoadjuvant or adjuvant therapy were excluded. RESULTS: Operations consisted of esophagectomy with (1700) and without (603) thoracotomy. Median number of nodes removed was 17 (IQR10-29). There were 508 patients with stage I, 853 stage II, and 942 stage III. Five-year survival was 40%. Cox regression analysis showed that the number of lymph nodes removed was an independent predictor of survival (P < 0.0001). The optimal threshold predicted by Cox regression for this survival benefit was removal of a minimum of 23 nodes. Other independent predictors of survival were the number of involved nodes, depth of invasion, presence of nodal metastasis, and cell type. CONCLUSIONS: The number of lymph nodes removed is an independent predictor of survival after esophagectomy for cancer. To maximize this survival benefit a minimum of 23 regional lymph nodes must be removed

Background Context Osteomyelitis secondary to perforation of the esophagus is a rare condition. Thoracic osteomyelitis after chronic esophageal perforation has never been described in the literature. Purpose We report a case of vertebral osteomyelitis resulting from a chronic esophageal perforation. Study Design/Setting Case report/University hospital. Methods A 52-year-old woman presented with dysphagia, severe mid back, and epigastric pain over a 6-week period. Endoscopic and radiological investigations revealed the presence of a paraspinal inflammatory mass protruding into the posterior esophageal wall. Two weeks after admission, the patient developed septic complications which required surgical intervention. This revealed the presence of an esophageal perforation and osteomyelitis of the T4–T5 and T7–T8 vertebrae. After T-tube closure of the esophageal perforation along with surgical debridement of the vertebrae and a 6-week course of antibiotics, the patient made a sound recovery. However, there was persistence of back pain with exaggerated thoracic spine kyphosis at T7–T8 which needed thoracic spine stabilization with pedicle screw instrumentation and fusion. Results This treatment led to complete recovery with no recurrence of symptoms at 8-months' follow-up. Conclusions To date this is the first case of thoracic osteomyelitis secondary to a chronic esophageal perforation to be reported in the literature. A high index of suspicion of this diagnosis is warranted in patients who present with similar clinical and radiological findings to enable prompt diagnosis and avoid the high mortality of esophageal perforation.

Oesophageal perforation is a rare but catastrophic event which can occur through a variety of insults. The risks of external trauma are low because of the mediastinal position of the oesophagus but the escalating availability of upper gastrointestinal endoscopy and associated instrumentation has resulted in an increase in iatrogenic damage which now accounts for the majority of injuries. Oesophageal perforation carries a high morbidity and mortality because of the difficulty of access to the oesophagus, the unusual blood supply, the lack of a strong serosal layer and the proximity of vital structures. Added to this, clinicians gain limited exposure to these cases because of their rarity.

It may be difficult to value palliative health states using health state valuation methods such as the time trade-off (TTO) and standard gamble (SG) where health states are traditionally valued relative to perfect/good health and death. Chained methods have been developed to help in this context. However, few studies have compared the values produced by chained TTO and SG methods. To address this issue, a study was conducted to measure the health state values associated with oesophageal cancer using chained TTO and SG techniques. The methods were found to be acceptable amongst the sample respondents, who had previously been treated for oesophageal cancer. There were no significant differences between the health state values produced by the TTO and the SG methods. Within each method, however, there were significant differences between the health states valued. It is concluded that the use of health state valuation techniques such as the TTO and SG is feasible amongst people with a history of oesophageal cancer.

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The gastric tumour suppressor trefoil protein TFF1 is present as a covalently bound heterodimer with a previously uncharacterised protein, TFIZ1, in normal human gastric mucosa. The purpose of this research was firstly to examine the molecular forms of TFIZ1 present, secondly to determine if TFIZ1 binds other proteins apart form TFF1 in vivo, thirdly to investigate if TFIZ1 and TFF1 are co-regulated in normal gastric mucosa and fourthly to determine if their co-regulation is maintained or disrupted in gastric cancer. We demonstrate that almost all human TFIZ1 is present as a heterodimer with TFF1 and that TFIZ1 is not bound to either of the other two trefoil proteins, TFF2 and TFF3. TFIZ1 and TFF1 are co-expressed by the surface mucus secretory cells throughout the stomach and the molecular forms of each protein are affected by the relative abundance of the other. TFIZ1 expression is lost consistently, early and permanently in gastric tumour cells. In contrast, TFF1 is sometimes expressed in the absence of TFIZ1 in gastric cancer cells and this expression is associated with metastasis (lymph node involvement: p=0.007). In conclusion, formation of the heterodimer between TFIZ1 and TFF1 is a specific interaction that occurs uniquely in the mucus secretory cells of the stomach, co-expression of the two proteins is disrupted in gastric cancer and expression of TFF1 in the absence of TFIZ1 is associated with a more invasive and metastatic phenotype. This indicates that TFF1 expression in the absence of TFIZ1 expression has potentially deleterious consequences in gastric cancer.