High expression of Cathepsin E in tissues but not blood of patients with Barrett’s esophagus and adenocarcinoma

Background Cathepsin E (CTSE), an aspartic proteinase, is differentially expressed in the metaplasia–dysplasia–neoplasia sequence of gastric and colon cancer. We evaluated CTSE in Barrett’s esophagus (BE) and cancer because increased CTSE levels are linked to improved survival in several cancers, and other cathepsins are up-regulated in BE and esophageal adenocarcinoma (EAC). Methods A total of 273 pretreatment tissues from 199 patients were analyzed [31 normal squamous esophagus (NE), 29 BE intestinal metaplasia, 31 BE with dysplasia (BE/D), 108 EAC]. CTSE relative mRNA expression was measured by real-time polymerase chain reaction, and protein expression was measured by immunohistochemistry. CTSE serum levels were determined by enzyme-linked immunosorbent assay. Results Median CTSE mRNA expression levels were ≥1,000-fold higher in BE/intestinal metaplasia and BE/D compared to NE. CTSE levels were significantly lower in EAC compared to BE/intestinal metaplasia and BE/D, but significantly higher than NE levels. A similar expression pattern was present in immunohistochemistry, with absent staining in NE, intense staining in intestinal metaplasia and dysplasia, and less intense EAC staining. CTSE serum analysis did not discriminate patient groups. In a uni- and multivariable Cox proportional hazards model, CTSE expression was not significantly associated with survival in patients with EAC, although CTSE expression above the 25th percentile was associated with a 41 % relative risk reduction for death (hazard ratio 0.59, 95 % confidence interval 0.27–1.26, p = 0.17). Conclusions CTSE mRNA expression is up-regulated more than any known gene in Barrett intestinal metaplasia and dysplasia tissues. Protein expression is similarly highly intense in intestinal metaplasia and dysplasia tissues

Prognostic Impact of Array-based Genomic Profiles in Esophageal Squamous Cell Cancer

Background: Esophageal squamous cell carcinoma (ESCC) is a genetically complex tumor type and a major cause of cancer related mortality. Although distinct genetic alterations have been linked to ESCC development and prognosis, the genetic alterations have not gained clinical applicability. We applied array-based comparative genomic hybridization (aCGH) to obtain a whole genome copy number profile relevant for identifying deranged pathways and clinically applicable markers. Methods: A 32 k aCGH platform was used for high resolution mapping of copy number changes in 30 stage I-IV ESCC. Potential interdependent alterations and deranged pathways were identified and copy number changes were correlated to stage, differentiation and survival. Results: Copy number alterations affected median 19% of the genome and included recurrent gains of chromosome regions 5p, 7p, 7q, 8q, 10q, 11q, 12p, 14q, 16p, 17p, 19p, 19q, and 20q and losses of 3p, 5q, 8p, 9p and 11q. High-level amplifications were observed in 30 regions and recurrently involved 7p11 (EGFR), 11q13 (MYEOV, CCND1, FGF4, FGF3, PPFIA, FAD, TMEM16A, CTTS and SHANK2) and 11q22 (PDFG). Gain of 7p22.3 predicted nodal metastases and gains of 1p36.32 and 19p13.3 independently predicted poor survival in multivariate analysis. Conclusion: aCGH profiling verified genetic complexity in ESCC and herein identified imbalances of multiple central tumorigenic pathways. Distinct gains correlate with clinicopathological variables and independently predict survival, suggesting clinical applicability of genomic profiling in ESCC

Gastroesophageal reflux disease - complications and prognostic aspects

This thesis investigates several aspects on gastroesophageal reflux disease (GERD) and associated complications as Barrett’s esophagus and esophageal adenocarcinoma. I. To clarify the natural course of GERD, a pH-metry verified cohort was re-evaluated after 20 years. The course of GERD may well be progressive. A statement based on the evidence that reflux induced complications as esophagitis and Barrett’s esophagus increased significantly. II. A myotomised achalasia with an abolished antireflux barrier (upon an aperistaltic esophagus), creates an unrestrained gastroesophageal reflux and can therefore be regarded as an end-stage reflux disease. This clinical trial was to compare the long-term outcome for patients with an end-stage reflux disease (achalasia) who underwent Heller’s esophagomyotomy with or without an additional Nissen fundoplication. Heller’s esophagomyotomy induces advanced reflux. The complications induced by reflux and the need for acid suppressants can successfully be eliminated by an additional antireflux repair. III. Defective mismatch repair (MMR) is the cause of microsatellite instability pathway and specifically associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. MMR expression was evaluated in Barrett’s adenocarcinomas. An association between HNPCC and Barrett’s adenocarcinoma may exist, although probably without clinical significance. IV. Increased understanding of the molecular processes associated with Barrett’s carcinogenesis may be beneficial for early tumor detection, refined diagnosis and for improved prognostication. Immunohistochemical staining was applied for tumor markers in order to evaluate their prognostic importance in Barrett’s adenocarcinomas. Reduced expression of E-cadherin was significantly associated with a more advanced tumor stage and was also shown to independently predict a poor prognosis

Is the course of gastroesophageal reflux disease progressive? A 21-year follow-up.

OBJECTIVE. We re-evaluated a cohort of patients referred for reflux symptoms and objectively diagnosed with pathological reflux, with the purpose of clarifying the course of conservatively treated gastroesophageal reflux disease (GERD). MATERIAL AND METHODS. All consecutive patients with GERD diagnosed between 1984 and 1988 showing pathologic 24-h pH-metry in the interval 3.8-10% and without any previous surgery in the gastroesophageal tract were assessed for further follow-up. A total of 40 evaluable patients were followed in the years 2007-08 with endoscopy, manometry, 24-h pH-metry, Helicobacter pylori assessment and the self-administered questionnaires the GERD Impact Scale, the Reflux Disease Questionnaire, the Quality of Life in Reflux and Dyspepsia and the Medical Outcome Study Short Form-36 Health Survey. Baseline data from the 1980s were retrieved and compared with the evaluations conducted at follow-up. RESULTS. At follow-up 20.7 years (range 18.8-23.5 years) after referral, the study population showed more use of acid suppressants (p = 0.007) and increasing prevalences of esophagitis (p = 0.001) and Barrett's esophagus (p = 0.002). Esophagitis was seen in 16/40 patients (40%) at baseline and in 29/40 (72.5%) at follow-up. No significant deterioration was seen at follow-up in manometry data and in most pH data. Patients with esophagitis (ERD) were less likely to have a positive H. pylori test (hazard ratio 0.054; p = 0.002) than non-erosive (NERD) patients. Symptom evaluations showed significantly lower quality of life in the ERD group. CONCLUSIONS. After 20 years a considerable part of the cohort still experienced symptoms of reflux and showed endoscopic progression, although no significant deteriorations were seen in manometry data and in most pH-metry data. H. pylori infection was inversely associated with erosive esophagitis and this supports the hypothesis that H. pylori colonization is a protective factor against GERD

Prognostic value of cell adhesion in esophageal adenocarcinomas.

Increased understanding of the molecular processes associated with the dysplasia-adenocarcinoma sequence linked to Barrett's esophagus may be beneficial for early tumor detection and refined diagnosis as well as for improved prognostication. We applied immunohistochemical staining for the markers Ki-67, p53, beta-catenin and E-cadherin in order to evaluate their prognostic importance in 59 Barrett's esophagus-associated adenocarcinomas. Reduced or absent membranous E-cadherin staining was identified in 75% of the tumors and predicted poor prognosis in manova (hazard ratio [HR] 3.3, P = 0.05). The small subset of tumors with low levels (< 10%) of Ki-67 staining showed a worse prognosis (HR 3.2, P < 0.01), whereas immunostaining for p53 and beta-catenin showed no correlation with prognosis. Deranged cell adhesion has been demonstrated to be an early event in tumor development. The down-regulation of E-cadherin and its prognostic importance indicate that cell adhesion may be a prime area for targeted therapies in esophageal adenocarcinoma

Surface Microdialysis Detects Ischemia After Esophageal Resection—An Experimental Animal Study

Background: After an esophageal resection, continuity is commonly restored by a gastric tube reconstruction and an intrathoracic anastomosis to the remaining proximal esophagus. Ischemia of the anastomotic region is considered to play a pivotal role in anastomotic leakage. Microdialysis (μD) is an excellent method to measure local biochemical substances and parameters in a specific organ or compartment aiming at early detection of ischemia. This animal study evaluates ischemia of the gastric tube reconstruction using a novel method—μD on organ surfaces. This promising method may have the potential to detect an anastomotic leakage before clinical symptoms develop. Methods: Anesthetized normoventilated pigs were used. Surface microdialysis (S-μD) catheters and an intraparenchymal oxygen tension catheter were placed on the stomach. A gastric tube was made and the gastroepiploic artery was divided halfway along the greater curvature to produce severe ischemia at the top of the gastric tube. μD data from four locations (gastric tube, ileum and peritoneal cavity) were recorded every 20 min during the experiment. Tissue samples from all catheter sites underwent histopathological analysis. Intraparenchymal oxygen partial pressure, systemic blood tests, and hemodynamic parameters were recorded. Results: S-μD data showed values indicating severe ischemia at the top of the gastric tube and intermediate ischemia at the level of transection of the gastroepiploic artery. Ischemia was verified by histopathological analysis of tissue samples and intraparenchymal oxygen tension data. Conclusions: S-μD can detect and grade severity of local ischemia in real time, in an animal model

The impact of initial treatment strategy and survival time on quality of end-of-life care among patients with oesophageal and gastric cancer : A population-based cohort study

BACKGROUND: Oesophageal and gastric cancer are highly lethal malignancies with a 5-year survival rate of 15-29%. More knowledge is needed about the quality of end-of-life care in order to understand the burden of the illness and the ability of the current health care system to deliver timely and appropriate end-of-life care. The aim of this study was to describe the impact of initial treatment strategy and survival time on the quality of end-of-life care among patients with oesophageal and gastric cancer. METHODS: This register-based cohort study included patients who died from oesophageal and gastric cancer in Sweden during 2014-2016. Through linking data from the National Register for Esophageal and Gastric Cancer, the National Cause of Death Register, and the Swedish Register of Palliative Care, 2156 individuals were included. Associations between initial treatment strategy and survival time and end-of-life care quality indicators were investigated. Adjusted risk ratios (RRs) with 95% confidence intervals were calculated using modified Poisson regression. RESULTS: Patients with a survival of ≤3 months and 4-7 months had higher RRs for hospital death compared to patients with a survival ≥17 months. Patients with a survival of ≤3 months also had a lower RR for end-of-life information and bereavement support compared to patients with a survival ≥17 months, while the risks of pain assessment and oral assessment were not associated with survival time. Compared to patients with curative treatment, patients with no tumour-directed treatment had a lower RR for pain assessment. No significant differences were shown between the treatment groups regarding hospital death, end-of-life information, oral health assessment, and bereavement support. CONCLUSIONS: Short survival time is associated with several indicators of low quality end-of-life care among patients with oesophageal and gastric cancer, suggesting that a proactive palliative care approach is imperative to ensure quality end-of-life care

Health care utilization among patients with oesophageal and gastric cancer : the impact of initial treatment strategy and assignment of a contact nurse

Background: Patients diagnosed with oesophageal and gastric cancer face a poor prognosis and numerous challenges of symptom management, lifestyle adjustments and complex treatment regimens. The multifaceted care needs and rapid disease progression reinforce the need for proactive and coherent health care. According to the national cancer strategy, providing coherent health care and palliative support is an area of priority. More knowledge is needed about health care utilization and the characteristics of the health care service in order to understand the readiness, accessibility and quality of current health care. The aim of this study was to describe individuals’ health care use from the time of treatment decision until death, and investigate the impact of the initial treatment strategy and assignment of a contact nurse (CN) on health care use among patients with oesophageal and gastric cancer. Methods: This population-based cohort study included patients who died from oesophageal and gastric cancer in Sweden during 2014–2016. Through linking data from the National Register for Oesophageal and Gastric Cancer, the National Cause of Death Register, and the National Patient Register, 2614 individuals were identified. Associations between the initial treatment strategy and CN assignment, and health care use were investigated. Adjusted incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were calculated using Poisson regression. Results: Patients receiving palliative treatment and those receiving no tumour-directed treatment had a higher IRR for unplanned hospital stays and unplanned outpatient care visits compared with patients who received curative treatment. Patients receiving no tumour-directed treatment also had a lower IRR for planned hospital stays and planned outpatient care visits compared with patients given curative treatment. Compared with this latter group, patients with palliative treatment had a higher IRR for planned outpatient care visits. Patients assigned a CN had a higher IRR for unplanned hospital stays, unplanned outpatient care visits and planned outpatient care visits, compared with patients not assigned a CN. Conclusions: A palliative treatment strategy and no tumour-directed treatment were associated with higher rates of unplanned health care compared with a curative treatment strategy, suggesting that a proactive approach is imperative to ensure quality palliative care