Airway cellularity, lipid laden macrophages and microbiology of gastric juice and airways in children with reflux oesophagitis

Background: Gastroesophageal reflux disease (GORD) can cause respiratory disease in children from recurrent aspiration of gastric contents. GORD can be defined in several ways and one of the most common method is presence of reflux oesophagitis. In children with GORD and respiratory disease, airway neutrophilia has been described. However, there are no prospective studies that have examined airway cellularity in children with GORD but without respiratory disease. The aims of the study were to compare (1) BAL cellularity and lipid laden macrophage index (LLMI) and, (2) microbiology of BAL and gastric juices of children with GORD (G+) to those without (G-). Methods: In 150 children aged <14-years, gastric aspirates and bronchoscopic airway lavage (BAL) were obtained during elective flexible upper endoscopy. GORD was defined as presence of reflux oesophagitis on distal oesophageal biopsies. Results: BAL neutrophil% in G- group (n = 63) was marginally but significantly higher than that in the G+ group (n = 77), (median of 7.5 and 5 respectively, p = 0.002). Lipid laden macrophage index (LLMI), BAL percentages of lymphocyte, eosinophil and macrophage were similar between groups. Viral studies were negative in all, bacterial cultures positive in 20.7% of BALs and in 5.3% of gastric aspirates. BAL cultures did not reflect gastric aspirate cultures in all but one child. Conclusion: In children without respiratory disease, GORD defined by presence of reflux oesophagitis, is not associated with BAL cellular profile or LLMI abnormality. Abnormal microbiology of the airways, when present, is not related to reflux oesophagitis and does not reflect that of gastric juices. © 2005 Chang et al; licensee BioMed Central Ltd.

Relationship between Helicobacter pylori infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: Results from the FINBAR case-control study.

Objective: A number of studies have shown an inverse association between infection with Helicobacter pylori and oesophageal adenocarcinoma (OAC). The mechanism of the apparent protection against OAC by H pylori infection and, in particular, the role of gastric atrophy is disputed. The relationship between all stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence and H pylori infection and gastric atrophy was explored. Methods: A case-control study involving 260 population controls, 227 OAC, 224 Barrett's oesophagus (BO) and 230 reflux oesophagitis (RO) patients recruited within Ireland was carried out. H pylori and CagA (cytotoxin-associated gene product A) infection was diagnosed serologically by western blot, and pepsinogen I and II levels were measured by enzyme immunoassay. Gastric atrophy was defined as a pepsinogen I/II ratio of <3. Results: H pylori seropositive was inversely associated with OAC, BO and RO; adjusted ORs (95% CIs), 0.49 (0.31 to 0.76), 0.35 (0.22 to 0.56) and 0.42 (0.27 to 0.65), respectively. Gastric atrophy was uncommon (5.3% of all subjects), but was inversely associated with non-junctional OAC, BO and RO; adjusted ORs (95% CIs), 0.34 (0.10 to 1.24), 0.23 (0.05 to 0.96) and 0.27 (0.08 to 0.88), respectively. Inverse associations between H pylori and the disease states remained in gastric atrophy-negative patients. Conclusion: H pylori infection and gastric atrophy are associated with a reduced risk of OAC, BO and RO. While use of the pepsinogen I/II ratio as a marker for gastric atrophy has limitations, these data suggest that although gastric atrophy is involved it may not fully explain the inverse associations observed with H pylori infection.

The Association Between Alcohol and Reflux Esophagitis, Barrett's Esophagus, and Esophageal Adenocarcinoma

Background & Aims: Alcohol consumption may increase gastroesophageal reflux symptoms, cause damage to the esophageal mucosa, and/or promote carcinogenesis. However, reports about the association between alcohol and reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma are conflicting. Methods: Information relating to alcohol consumption, at age 21 and 5 years before the interview date, was collected from 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma patients and 260 frequency-matched population controls. Logistic regression analyses were used to compare alcohol consumption in the 3 case groups to controls with adjustment for potential confounders. Results: Population controls reporting gastroesophageal reflux symptoms were less likely than controls without symptoms to drink alcohol 5 years before the interview date (odds ratio [OR], 0.44, 0.20-0.99). No associations were observed between total alcohol consumption 5 years before the interview date and reflux esophagitis, Barrett's esophagus, or esophageal adenocarcinoma (OR, 1.26, 0.78-2.05; OR, 0.72, 0.43-1.21; and OR, 0.75, 0.46-1.22, respectively). Wine was inversely associated with reflux esophagitis (OR, 0.45, 0.27-0.75). Total alcohol consumption at age 21 years was significantly associated with reflux esophagitis (OR, 2.24, 1.35-3.74) but not with Barrett's esophagus or esophageal adenocarcinoma (OR, 1.06, 0.63-1.79 and OR, 1.27, 0.77-2.10, respectively). Conclusions: Alcohol consumption in early adulthood may lead to the development of reflux esophagitis. More recent alcohol consumption does not appear to confer any increased risk of reflux esophagitis, Barrett's esophagus, or esophageal adenocarcinoma. In fact, wine consumption may reduce the risk of these 3 esophageal disorders.

Toenail trace element status and risk of Barrett's oesophagus and oesophageal adenocarcinoma. Results from the FINBAR study

Trace elements have been cited as both inhibitory and causative agents of cancer but importantly exposure to them is potentially modifiable. Our study aimed to examine toenail trace element status and risk of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Toenail clippings from each hallux were obtained from 638 participants of the FINBAR (Factors Influencing the Barrett's Adenocarcinoma Relationship) study comprising 221 healthy controls, 98 reflux oesophagitis, 182 BO and 137 OAC cases. The concentrations of eight toenail trace elements were determined using instrumental neutron activation analysis. Using multivariable adjusted logistic regression analysis, odds ratios (OR) and 95% confidence intervals (CIs) were calculated within tertiles of trace element concentrations. A twofold increased risk of BO was observed, but not OAC, among individuals in the highest tertile of toenail zinc status OR 2.21 (95% CI, 1.11-4.40). A higher toenail selenium status was not associated with risk of OAC OR 0.94 (95% CI, 0.44-2.04) or BO OR 0.89 (95% CI, 0.37-2.12). A borderline significant increased risk of BO was detected with a higher toenail cobalt concentration, OR 1.97 (95% CI, 1.01-3.85). No association was found between toenail levels of chromium, cerium, mercury and OAC or BO risk. This is the first case-control study to investigate a variety of trace elements in relation to OAC and BO risk. Despite antioxidant and proapoptotic properties, no associations were found with selenium. Higher concentrations of toenail zinc and cobalt were associated with an increased BO risk, but not OAC. These findings need confirmation in prospective analysis.

Vitamin D, calcium and dairy intake, and risk of oesophageal adenocarcinoma and its precursor conditions

Evidence is accumulating that vitamin D may be protective against carcinogenesis, although exceptions have been observed for some digestive tract neoplasms. The aim of the present study was to explore the association between dietary vitamin D and related nutrients and the risk of oesophageal adenocarcinoma and its precursor conditions, Barrett's oesophagus and reflux oesophagitis. In an all-Ireland case-control study conducted between March 2002 and July 2005, 218 oesophageal adenocarcinoma patients, 212 Barrett's oesophagus patients, 208 reflux oesophagitis patients and 252 population-based controls completed a 101-item FFQ, and provided lifestyle and demographic information. Multiple logistic regression analysis was applied to examine the association between dietary intake and disease risk. Oesophageal adenocarcinoma risk was significantly greater for individuals with the highest compared with the lowest tertile of vitamin D intake (OR 1·99, 95 % CI 1·03, 3·86; P for trend = 0·02). The direct association could not be attributed to a particular vitamin D food source. Vitamin D intake was unrelated to Barrett's oesophagus and reflux oesophagitis risk. No significant associations were observed for Ca or dairy intake and oesophageal adenocarcinoma, Barrett's oesophagus or reflux oesophagitis development. High vitamin D intake may increase oesophageal adenocarcinoma risk but is not related to reflux oesophagitis and Barrett's oesophagus. Ca and dairy product intake did not influence the development of these oesophageal lesions. These findings suggest that there may be population subgroups at an increased risk of oesophageal adenocarcinoma if advice to improve vitamin D intake from foods is implemented. Limited work has been conducted in this area, and further research is required.

Impedance-pH reflux patterns can differentiate non-erosive reflux disease from functional heartburn patients

Symptom association is important to distinguish non-erosive reflux disease [NERD; abnormal oesophageal acid exposure time (AET) and/or positive symptom association] from functional heartburn (FH; normal AET and negative symptom association). Asymptomatic patients during reflux monitoring are challenging as symptom association cannot be assessed.

Pólipos hiperplásicos da junção gastro-esofágica em idade pediátrica

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Background: Esophageal adenocarcinoma (EA) is one of the fastest rising cancers in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Genetic risk factors for BE and EA are incompletely understood. This study aimed to identify novel genetic risk factors for BE and EA.Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available, involving 6,167 BE patients, 4,112 EA patients, and 17,159 representative controls, all of European ancestry, genotyped on Illumina high-density SNP-arrays, collected from four separate studies within North America, Europe, and Australia. Meta-analysis was conducted using the fixed-effects inverse variance-weighting approach. We used the standard genome-wide significant threshold of 5×10-8 for this study. We also conducted an association analysis following reweighting of loci using an approach that investigates annotation enrichment among the genome-wide significant loci. The entire GWAS-data set was also analyzed using bioinformatics approaches including functional annotation databases as well as gene-based and pathway-based methods in order to identify pathophysiologically relevant cellular pathways.Findings: We identified eight new associated risk loci for BE and EA, within or near the CFTR (rs17451754, P=4·8×10-10), MSRA (rs17749155, P=5·2×10-10), BLK (rs10108511, P=2·1×10-9), KHDRBS2 (rs62423175, P=3·0×10-9), TPPP/CEP72 (rs9918259, P=3·2×10-9), TMOD1 (rs7852462, P=1·5×10-8), SATB2 (rs139606545, P=2·0×10-8), and HTR3C/ABCC5 genes (rs9823696, P=1·6×10-8). A further novel risk locus at LPA (rs12207195, posteriori probability=0·925) was identified after re-weighting using significantly enriched annotations. This study thereby doubled the number of known risk loci. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. To our knowledge, this study identified for the first time an EA-specific association (rs9823696, P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45).Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Mutations in CFTR, one of the new risk loci identified in this study, cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology.

Quality of life and survival in patients treated with radical chemoradiation alone for oesophageal cancer

Aims: To report cancer-specific and health-related quality-of-life outcomes in patients undergoing radical chemoradiation (CRT) alone for oesophageal cancer. Materials and methods: Between 1998 and 2005, 56 patients with oesophageal cancer received definitive radical CRT, due to local disease extent, poor general health, or patient choice. Data from European Organization for Research and Treatment of Cancer quality-of-life questionnaires QLQ-30 and QLQ-OES24 were collected prospectively. Questionnaires were completed at diagnosis, and at 3, 6 and 12 months after CRT where applicable. Results: The median follow-up was 18 months. The median overall survival was 14 months, with a 51, 26 and 13% 1-, 3- and 5-year survival, respectively. At 12 months after treatment there was a significant improvement compared with before treatment with respect to dysphagia and pain. Global health scores were not significantly affected. Conclusions: Considering the relatively short long-term survival for this cohort of patients, maximising the quality of those final months should be very carefully borne in mind from the outset. The health-related quality-of-life data reported herein helps to establish benchmarks for larger evaluation within randomised clinical trials. © 2007 The Royal College of Radiologists.

18FDG uptake during induction chemoradiation for oesophageal cancer fails to predict histomorphological tumour response

To determine whether [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) could predict the pathological response in oesophageal cancer after only the first week of neoadjuvant chemoradiation. Thirty-two patients with localised oesophageal cancer had a pretreatment PET scan and a repeat after the first week of chemoradiation. The change in mean maximum standardised uptake value (SUV) and volume of metabolically active tissue (MTV) was compared with the tumour regression grade (TRG) in the final histology. Those who achieved a TRG of 1 and 2 were deemed responders and 3-5 nonresponders. In the responders (28%), the SUV fell from 12.6 (±6.3) to 8.1 (±2.9) after 1 week of chemoradiation (P = 0.070). In nonresponders (72%), the results were 9.7 (±5.4) and 7.1 (±3.8), respectively (P = 0.003). The MTV in responders fell from 36.6 (±22.7) to 22.3 (±10.4) cm3 (P = 0.180), while in nonresponders, this fell from 35.9 (±36.7) to 31.9 (±52.7) cm3 (P = 0.405). There were no significant differences between responders and nonresponders. The hypothesis that early repeat FDG-PET scanning may predict histomorphologic response was not proven. This may reflect an inflammatory effect of radiation that obscures tumour-specific metabolic changes at this time. This assessment may have limited application in predicting response to multimodal regimens for oesophageal cancer. © 2006 Cancer Research UK.

Gene amplified in oesophageal cancer 1 (GAEC1) amplification in colorectal cancers and its impact on patient's survival

GAEC1 (gene amplified in oesophageal cancer 1) is located at 7q22.1, first identified in oesophageal cancer.1 Initial work indicated that GAEC1 can act as an oncogene.2 Our pilot study found ∼80% of colorectal cancers showing amplification of GAEC1.3 In this research, we will study GAEC1 copy number in colon cancer cell lines and colorectal tissues, and its prognostic significance. Two human colon cancer cell lines (SW480 and SW48) and one normal colonic epithelial cell line (FHC) were obtained from American Type Culture Collection. Culturing conditions for these cell lines were as published previously.4 Tissues were collected from 283 patients (213 Australian; 70 Japanese) diagnosed with colorectal cancers. Ninety surgically removed non-cancer colorectal tissues (diverticular diseases, hyperplastic polyps and volvulus) were used as controls. H&E stained sections from each cancer were checked to select a block with sufficient cancer tissue and representative morphological features for each patient for DNA extraction...

Risk factors for oesophageal, lung, oral and laryngeal cancers in black South Africans

The authors used data collected from 1995 to 1999, from an on-going cancer case–control study in greater Johannesburg, to estimate the importance of tobacco and alcohol consumption and other suspected risk factors with respect to cancer of the oesophagus (267 men and 138 women), lung (105 men and 41 women), oral cavity (87 men and 37 women), and larynx (51 men). Cancers not associated with tobacco or alcohol consumption were used as controls (804 men and 1370 women). Tobacco smoking was found to be the major risk factor for all of these cancers with odds ratios ranging from 2.6 (95% CI 1.5–4.5) for oesophageal cancer in female ex-smokers to 50.9 (95% CI 12.6–204.6) for lung cancer in women, and 23.9 (95% CI 9.5–60.3) for lung cancer and 23.6 (95% CI 4.6–121.2) for laryngeal cancer in men who smoked 15 or more grams of tobacco a day. This is the first time an association between smoking and oral and laryngeal cancers has been shown in sub-Saharan Africa. Long-term residence in the Transkei region in the southeast of the country continues to be a risk factor for oesophageal cancer, especially in women (odds ratio=14.7, 95% CI 4.7–46.0), possibly due to nutritional factors. There was a slight increase in lung cancer (odds ratio=2.9, 95% CI 1.1–7.5) in men working in ‘potentially noxious’ industries. ‘Frequent’ alcohol consumption, on its own, caused a marginally elevated risk for oesophageal cancer (odds ratio=1.7, 95% CI 1.0–2.9, for women and odds ratio=1.8, 95% CI 1.2–2.8, for men). The risks for oesophageal cancer in relation to alcohol consumption increased significantly in male and female smokers (odds ratio=4.7, 95% CI=2.8–7.9 in males and odds ratio=4.8, 95% CI 3.2–6.1 in females). The above results are broadly in line with international findings.

Cough and reflux esophagitis in children: their co-existence and airway cellularity

Background There are no prospective studies that have examined for chronic cough in children without lung disease but with gastroesophageal reflux (GER). In otherwise healthy children undergoing flexible upper gastrointestinal endoscopy (esophago-gastroscopy), the aims of the study were to (1) define the frequency of cough in relation to symptoms of GER, (2) examine if children with cough and reflux esophagitis (RE) have different airway cellularity and microbiology in bronchoalveolar lavage (BAL) when compared to those without. Methods Data specific for chronic cough (>4-weeks), symptoms of GER and cough severity were collected. Children aged <16-years (n = 150) were defined as 'coughers' (C+) if a history of cough in association with their GER symptoms was elicited before BAL were obtained during elective esophago-gastroscopy. Presence of esophagitis on esophageal biopsies was considered reflux esophagitis positive (E+). Results C+ (n = 69) were just as likely as C- (n = 81) to have esophagitis, odds ratio 0.87 (95%CI 0.46, 1.7). Median neutrophil percentage in BAL was significantly different between groups; highest in C+E- (7, IQR 28) and lowest in C-E+ (5, IQR 6). BAL positive bacterial culture occurred in 20.7% and were more likely present in current coughers (OR 3.37, 95%CI 1.39, 8.08). Airway neutrophilia (median 20%, IQR 34) was significantly higher in those with BAL positive bacterial cultures than those without (5%, 4; p = 0.0001). Conclusion In children without lung disease, the common co-existence of cough with symptoms of GER is independent of the occurrence of esophagitis. Airway neutrophilia when present in these children is more likely to be related to airway bacterial infection and not to esophagitis.

'Free' surfactant in gastric aspirates and bronchoalveolar lavage in children with and without reflux oesophagitis

Aim: Dipalmitoylphosphatidycholine (DPPC) is the characteristic and main constituent of surfactant. Adsorption of surfactant to epithelial surfaces may be important in the masking of receptors. The aims of the study were to (i) compare the quantity of free DPPC in the airways and gastric aspirates of children with gastroesophageal reflux disease (GORD) to those without and (ii) describe the association between free DPPC levels with airway cellular profile and capsaicin cough sensitivity. Methods: Children aged <14 years were defined as 'coughers' if a history of cough in association with their GORD symptoms was elicited before gastric aspirates and nonbronchoscopic bronchoalveolar lavage (BAL) were obtained during elective flexible upper gastrointestinal endoscopy. GORD was defined as histological presence of reflux oesophagitis. Spirometry and capsaicin cough-sensitivity test was carried out in children aged >6 years before the endoscopy. Results: Median age of the 68 children was 9 years (interquartile range (IQR) 7.2). Median DPPC level in BAL of children with cough (72.7 μg/mL) was similar to noncoughers (88.5). There was also no significant difference in DPPC levels in both BAL and gastric aspirates of children classified according to presence of GORD. There was no correlation between DPPC levels and cellular counts or capsaicin cough-sensitivity outcome measures. Conclusion: We conclude that free DPPC levels in the airways and gastric aspirate is not influenced by presence of cough or GORD defined by histological presence of reflux oesophagitis. Whether quantification of adsorbed surfactant differs in these groups remain unknown. Free DPPC is unlikely to have a role in masking of airway receptors. © 2006 Royal Australasian College of Physicians.