Marc C. Winslet

Routinely diagnosed low‐grade dysplasia in Barrett’s oesophagus: a population‐based study of natural history

Aims:u2002 To examine the natural history of columnar‐lined oesophagus with routinely diagnosed low‐grade dysplasia and ascertain the risk of oesophageal adenocarcinoma development.

Treatment modality and risk of development of dysplasia and adenocarcinoma in columnar-lined esophagus.

Columnar metaplasia is the precursor lesion for esophageal adenocarcinoma, resulting from prolonged gastroesophageal reflux. The influence of the efficacy of reflux control on the development of neoplastic change in columnar-lined esophagus is not established. This study compares the rate of development of dysplasia and adenocarcinoma in patients with columnar metaplasia of the esophagus between patients treated pharmacologically and those treated with antireflux surgery. This study is a retrospective review of a cohort of patients enrolled in a multicenter national registry involving 738 patients from seven UK centers. Forty-one were treated with antireflux surgery, 42 with H2 receptor antagonist, 532 with proton pump inhibitor, and 114 with a combination of these medications. Nine had none of these medications or surgery. Total follow-up was 3697 years. Mean age and follow-up for patients treated medically were 61.6 and 4.96 years and surgically were 50.5 and 6.19 years, respectively. No patient in the surgical group developed high-grade dysplasia (HGD) or adenocarcinoma. Twenty patients treated medically developed adenocarcinoma and 10 developed HGD. Hazards ratio comparing pharmacological to surgical therapy for development of all grades of dysplasia and adenocarcinoma 1.77 (P = 0.272). Log rank test comparing antireflux surgery to pharmacological therapy for development of HGD or adenocarcinoma P = 0.1287 and for adenocarcinoma P = 0.2125. Although there was a trend towards greater efficacy of antireflux surgery over pharmacological therapy in reducing the development of dysplasia and adenocarcinoma, this did not reach statistical significance.

Aspirin is not chemoprotective for Barrett's adenocarcinoma of the oesophagus in multicentre cohort.

Barretts columnar-lined oesophagus is the precursor lesion for oesophageal adenocarcinoma. The overall rate of progression to adenocarcinoma is 0.59% per annum. A large prospective multicentre trial is recruiting to assess the role of aspirin as a chemoprotective agent in prevention of development of cancer as well as cardiovascular protection in patients with Barretts oesophagus. This retrospective analysis of the large UK National Barretts Oesophagus Registry database seeks to analyse this question from within its large natural history study cohort. Multicentre UK retrospective cohort compared patients known to have been taking aspirin with those who did not take aspirin during the course of surveillance for columnar-lined oesophagus. End point was development of dysplasia or oesophageal adenocarcinoma. Analysis was undertaken using Coxs proportional hazard ratio. Total follow-up was 3683 patient-years. Eighty-six patients were taking aspirin, 650 were not taking aspirin (reference group). Numbers of patients developing all grades of dysplasia and adenocarcinoma were: 13 aspirin (15.1%) and 97 no aspirin (14.9%) (hazard ratio 0.723, 95% confidence interval 0.410–1.310, Pu2009=u20090.294), high-grade dysplasia and adenocarcinoma: five aspirin (5.8%) and 25 no aspirin (3.8%) (hazard ratio 0.898, 95% confidence interval 0.340–2.368, Pu2009=u20090.827) and adenocarcinoma: four aspirin (4.7%) and 16 no aspirin (2.5%) (hazard ratio 1.092, 95% confidence interval 0.358–3.335, Pu2009=u20090.877). No significant difference was observed in hazard of developing dysplasia or adenocarcinoma between patients taking aspirin and those not taking aspirin during the course of follow-up of surveillance for columnar-lined oesophagus. In conclusion, no difference in risk of development of dysplasia or adenocarcinoma was observed between patients taking aspirin and those not taking aspirin in this large cohort.

Surveillance of Barrett's columnar-lined oesophagus in the UK: endoscopic intervals and frequency of detection of dysplasia

Objectives Endoscopic surveillance of patients with columnar-lined oesophagus (CLO) may identify those with early adenocarcinoma (AC). The benefits of surveillance are unproven and there is little evidence to support recommendations for precise endoscopic intervals. We sought to examine surveillance practice for CLO in the UK and the impact of endoscopic intervals on detection of dysplastic disease. Methods Eight hundred and seventeen patients with CLO, registered with the UK National Barretts Oesophagus registry and undergoing surveillance were studied. Endoscopic intervals were calculated and frequency of detection of dysplastic disease analysed using χ2 test of association. Factors affecting surveillance intervals were analysed using multiple linear regression. Results 94.7% of patients with low-grade dysplasia (LGD), 95.0% with high-grade dysplasia (HGD) and 71.4% with AC were diagnosed on surveillance endoscopies. Mean endoscopic surveillance intervals varied between the centres from 1.07 to 1.63 years for nondysplastic CLO; 0.69–1.19 years for LGD, and 0.35–1.17 years for HGD; with overall mean surveillance intervals of 1.29, 1.01 and 0.44 years, respectively. When LGD was surveyed, significantly higher proportions of HGD/AC were detected at intervals of 3 months or less (P=0.013). Shorter endoscopic intervals were significantly associated with the presence of oesophageal strictures (P=0.002), ulcers (P=0.046), increasing patient age (P<0.001) and higher grade of dysplasia surveyed (P<0.001). Conclusion A variation in surveillance practice for CLO was observed throughout the UK. A large proportion of dysplastic disease is detected on specific surveillance endoscopies. Shorter endoscopic intervals for surveillance of LGD are associated with an increased detection of HGD/AC.

Barrett's, blood groups and progression to oesophageal cancer: is nitric oxide the link?

Introduction Incidence of oesophageal adenocarcinoma (OAC) is increasing rapidly. OAC arises in columnar-lined oesophagus (CLO), a metaplastic change affecting some patients with gastro-oesophageal reflux disease (GORD). As yet there is no reliable method of identifying those at highest risk. Our earlier observation of an association between OAC and blood group O Rhesus negative, if confirmed, may help identify those at greatest risk. Aim and methods To assess the distribution of blood group and Rhesus D (RhD) factor in patients with GORD compared with the blood donating general population. GORD was categorized as nonerosive reflux (NER), erosive oesophagitis, CLO and OAC. The Rotherham Hospital database holds details of all GORD, CLO and OAC patients seen in the Gastroenterology Unit. Blood group information for patients with GORD was obtained from patients records and the hospitals blood transfusion service. The blood group distribution in the general population was obtained from the National Blood Transfusion Service. The number of expected to observed patients in each blood group for each subtype was compared. Results Two thousand six hundred and ten NER, 2813 erosive oesophagitis, 568 CLO and 73 OAC patients had a recorded blood group. For RhD positive patients observed proportions in each blood group were similar to expected. The most striking difference was the marked excess of OAC in blood group O, Rhesus negative (P=0.002). Conclusion CLO patients with blood group O, RhD negative carry a disproportionately higher risk of developing OAC. The mechanism is unknown but the finding has practical application in guiding risk stratification and intensity of surveillance.

Are newly diagnosed columnar-lined oesophagus patients getting younger?

Objectives The prevalence of columnar-lined oesophagus seems to have increased steadily in the past three decades in Europe and North America. Although the vast majority of columnar-lined oesophagus will not progress to malignancy, it is nevertheless important to identify the risk factors associated with this condition. This study investigates whether there has been a change, at diagnosis, in age of columnar-lined oesophagus patients between 1990 and 2005, or an increase in the number of patients aged less than 50 years. Methods Data on age of diagnosis were abstracted from medical records of 7220 patients from 19 centres registered with UK National Barretts Oesophagus Registry, between the years 1990 and 2005. Linear regression analysis was carried out to assess any trends in the mean age of diagnosis. Results Overall there was a mean decrease in age at diagnosis for each 1-year increase in time. This equated to a mean decrease of 3 years over the study period, 1990–2005 with the greatest difference being seen in female patients. About 18% of patients in the study were aged less than 50 years at the time of diagnosis. With this group also, the trend was similar, with an increase in the number of patients aged less than 50 years, at the time of diagnosis, with increasing years. Conclusion The mean age of diagnosis of columnar-lined oesophagus has decreased between the years 1990 and 2005 in both men and women, more so in women. This is also reflected in an increase in newly diagnosed columnar-lined oesophagus patients below the age of 50 years.

The relationship between smoking and severe dysplastic disease in patients with Barrett's columnar-lined oesophagus.

The aim of this study was to examine the relationship between smoking and oesophageal high-grade dysplasia (HGD) or adenocarcinoma (AC) in a large cohort of patients with Barrett’s columnar-lined oesophagus (CLO). A total of 1280 patients diagnosed with CLO and registered with the UK National Barrett’s Oesophagus Registry were included. Data, including smoking habits, were collected from the patient’s notes and development of HGD or AC noted. Analysis was performed with SPSS using logistic regression for calculation of odds ratios (ORs) for development of HGD/AC. Data on smoking habits were available in 956 (74.6%) patients. There was no significant difference between smokers and nonsmokers in mean age (P=0.877) or length of follow-up (P=0.359). There was a significant risk of HGD/AC in patients with any history of smoking compared with those who had never smoked (P<0.001, OR 2.81). Ex-smokers of 10 years or more remained at a significantly higher risk of HGD/AC compared with those who had never smoked (P=0.001, OR 3.37). Current smokers were not at a significantly higher risk of HGD/AC compared with ex-smokers (P=0.857) nor were those who smoked at least 20 a day compared with those who smoked fewer than 20 a day (P=0.632). In patients with CLO, smoking appears to be a significant risk factor for the development of severe dysplastic disease; however, we did not observe a dose-dependent effect of smoking on progression of disease.

Projections for oesophageal cancer incidence in England to 2033

The United Kingdom has the highest age-standardized incidence of oesophageal cancer in Europe. This study projects the number of cases of oesophageal cancer arising in England over a 25-year period. Data from National Statistics were used to determine the number and incidence of oesophageal cancers diagnosed during 2001–2007 (separated by age and sex). These data were used with population projections to model the number of cancers that would develop in the future. Variant estimates were undertaken with high/low rates of migration and life expectancy and by varying the rate of change in the incidence of oesophageal cancer. The principal projection showed that, compared with the 2007 baseline, the number of oesophageal cancers in men is predicted to rise by 20% by 2014 and by 40% by 2020. In women, after an initial predicted decline, the number of cancers is predicted to rise above the 2007 baseline by 2012 and to be 5% higher by 2023. The variant projections showed that only a small effect was likely to be caused by changes in net migration (<1% change by 2030) and life expectancy (1% change by 2020). The effect of a 1% increase or decrease in the rate of change of incidence had a more marked effect (10% change by 2017 or 2018). None of the modelled scenarios resulted in an overall decrease in the number of projected cases because of the change in population demographics. The number of cases of oesophageal cancer in England is likely to continue to increase.

Morbidity and Mortality Associated With Desmoplasia in Midgut (Carcinoid) Neuroendocrine Tumours

Introduction Midgut neuroendocrine tumours (NETs) form part of a heterogenous group characterised by their ability to secrete hormones and other mediators which may cause carcinoid syndrome. They may also present with complex problems related to fibrosis/desmoplasia. Products including 5-HT secreted by NETs may induce fibrosis. It has been previously reported that 30% of patients are found to have desmoplasia on CT at presentation while the incidence increases as disease progresses. Desmoplasia may cause symptoms secondary to mesenteric vein occlusion, ischaemia as well as bowel obstruction. Aim To assess morbidity and mortality associated with desmoplasia in midgut NETs. Methods A retrospective review of our NET Unit database for patients with a diagnosis of midgut NET and desmoplasia. Information available included: age, sex, diagnosis, previous treatment, current management and outcomes from MDT meetings. 107 midgut NET patients with desmoplasia were identified. Patients with non-midgut NETs were excluded. Overall survival (OS) was calculated from time of diagnosis. Results Full data was available for 99 patients. 51 male and 48 female patients. Desmoplasia was identified at surgery or at CT imaging. 61 (62%) patients were symptomatic from either obstructive or ischaemic cause at some point. 68 (69%) patients had undergone surgical procedures, including primary resection, re-resection, stoma formation and bypass. Of the 48 patients who had undergone surgical resection of the primary tumour, 31 (65%) had presented with obstructive symptoms. 38 (38%) were asymptomatic and desmoplasia was diagnosed incidentally on CT. 6 (6%) patients were symptomatic from SMV occlusion needing anticoagulation. 5 (5%) patients were treated with long-term TPN. 2 had short bowel syndrome. 36 patients had died. Total overall median survival was 96 months. Overall median survival in the symptomatic group was 81 months and not reached in the asymptomatic group (log-rank p=0.059). Conclusion Over half of patients with midgut NETs with desmoplasia are symptomatic needing surgical intervention. Patients may present acutely with bowel obstruction due to the tumour itself or the effects of desmoplasia. Desmoplasia can occur and may progress even after medical treatments. Patients with bowel ischaemia maybe managed with anticoagulation. It is difficult to differentiate desmoplasia from adhesions in obstructive patients. The median survival in the symptomatic group was 15 months less than the total median OS, this may reflect the complex nature of patients disease status. These patients have complex symptomatology which can only be dealt with by experienced multidisciplinary approach. Further research is required into the pathogenesis of desmoplasia to enable better treatment.

7048 Relief of dysphagia with self expanding metal stents is far from perfect.

Background: Most people with oesophageal cancer present with advanced disease and palliation of dysphagia is the main aim of therapy. Self expanding metal stents (SEMS) have become the standard treatment but patient outcome is not well documented, particularly in routine practice. This is a retrospective analysis of patients treated in 2 district general hospitals and 2 teaching hospitals. Patients and Methods: Hospital notes were reviewed on 75 consecutive patients in whom a SEMS was inserted between January 1996 and May 1997. Site of tumour was: 38 adenocarcinoma of distal oesophagus or cardia; 21 squamous cell carcinoma of the mid or upper body; 5 bronchogenic carcinoma with oesophageal involvement; in 11 the site was not noted. 5 had broncho-oesophageal fistulae and 1 an iatrogenic perforation following tumour dilatation. Results: 88 stents (44 covered) were placed in 75 patients (mean age 70, range 37-92). Stenting was primary therapy for most patients. 4/5 (80%) fistulae were adequately closed. Mean survival for all patients after stent insertion was 67 days (range 5-259). Most were only able to tolerate fluids before stent insertion. In the 42 patients for whom adequate records were kept, only slight improvement of dysphagia was achieved after stent insertion, and most tolerated only pureed food. In 9 of these patients, no improvement was seen in severity of dysphagia, and in 1 other, stenting made dysphagia worse. Severe pain occurred after stent insertion in at least 24 patients (32%) and was intractable in 7 (9%). 4 patients (5%) died within 10 days of stent insertion (2 aspiration pneumonia, 1 stridor, 1 haemorrhage). 16 patients (21%) developed late stent related morbidity. Tumour overgrowth or ingrowth was treated with an overlapping stent in 8 patients (1 required a total of 4 stents); tumour ingrowth was treated with laser in 1 patient; 1 patient died from massive haematemesis at 5 months. This patient had previously undergone radiotherapy. 2 covered metal stents migrated into the stomach whereas this was not seen with uncovered stents.A total of 45 extra endoscopies were performed after stent insertion. Conclusions:In routine practice, SEMS improve dysphagia less well than in trials from specialist centres. Pain is common and can be intractable. Early stent related morbidity is very common and late morbidity occurs in 21%. Furthermore, early mortality after stent insertion is significant and relief of dysphagia appears to be no better than that achieved with silicone rubber tubes.