Mortality in Barrett's esophagus: three decades of experience at a single center.

BACKGROUND AND STUDY AIMS: There is a view that the majority of deaths in patients with Barrett's esophagus are from causes other than esophageal adenocarcinoma (EAC). The aim of this analysis was to establish the pattern of mortality for a number of causes in patients with Barrett's esophagus. PATIENTS AND METHODS: This was a single-center prospective cohort study of patients from Rotherham District General Hospital, which is a secondary referral center. The cohort consisted of 1239 patients who were diagnosed with Barrett's esophagus between April 1978 and March 2009.  Follow-up for mortality was undertaken by "flagging" the patients with the NHS Information Center. Causes of death were compared with UK Office of National Statistics age- and sex-specific mortality data for 1999, the median year of diagnosis. Analysis was by a "person - years at risk" calculation from date of diagnosis. RESULTS: The ratio of observed deaths from EAC compared with those expected in this cohort was 25.02 - a very large excess. There was no difference in mortality from colorectal cancer or circulatory disease and there were fewer deaths from cancers other than esophageal adenocarcinoma and colon cancer compared with national statistics. There was a small statistically significant difference in mortality from all causes but this disappeared completely when deaths from esophageal adenocarcinoma were excluded. CONCLUSIONS: Overall, mortality in Barrett's esophagus is increased significantly but only as a result of the large excess of deaths from EAC. This strengthens the case for endoscopic surveillance if successful interventions can be undertaken in patients with Barrett's esophagus to prevent development of esophageal adenocarcinoma.

Anti-neutrophil cytoplasmic antibody-associated systemic vasculitis: nature or nurture?

This review examines the environmental and genetic contributions to the anti-neutrophil cytoplasmic antibody-associated systemic vasculitides. The dominant environmental risk factors appear to be silica exposure for all three syndromes, and vitamin D deficiency is strongly suggested by the latitude and ultraviolet radiation gradient observed for Wegener's granulomatosis and Churg-Strauss syndrome. Genetic factors are generally not very strong, consistent with the rarity of these conditions in children. However, multiple genetic factors, each with a relatively small effect, may combine to create a state of susceptibility towards autoimmunity. With infection as a triggering agent, it is possible to synthesise a pathogenetic hypothesis that accounts for both environmental and genetic effects in regard to both necrotising vasculitis and granuloma formation.

Immunoglobulin secretion in the human autologous mixed leukocyte reaction. Definition of a suppressor-amplifier circuit using monoclonal antibodies.

The induction of immunoglobulin (Ig) synthesis in the autologous MLR has an absolute requirement for helper/inducer (Leu-3) T cells, whereas an excess of suppressor/cytotoxic (leu-2) cells suppresses the response. The current study was an effort to assess the immunoregulatory potential to T cells activated in the autologous mixed-leukocyte response (MLR). T cells were cultured with autologous non-T cells for 8-9 d, after which the activated T cells were fractionated into subsets with monoclonal antibodies to T cell markers and HLA-DR antigen. Each population was co-cultured in fresh autologous MLR, and on the 8th day of culture, Ig-secreting cells were measured in a reverse hemolytic plaque assay. The results show that activated Leu-2, DR+ T cells, but neither Leu-2, DR- nor Leu-3 T cells, were at least 50 times more potent as suppressors of IgM and IgG synthesis than fresh Leu-2 cells alone. The activation of this Leu-2, DR+ subpopulation required Leu-3 cells in the primary culture. Furthermore, in the absence of Leu-2 cells in the second culture, little or no suppression was observed, suggesting that the Leu-2, DR+ cells act to amplify or induce suppressor effects of fresh Leu-2 cells. This indicates that at least two distinct subpopulations of Leu-2 cells are required for maximal suppression of an immune response, and that immunoregulatory circuits analogous to those described in the mouse exist in man.

Antireflux surgery.

Gastro-oesophageal reflux disease is extremely common throughout Europe and the United States. This review on antireflux surgery examines the best evidence for surgical treatment of gastro-esophageal reflux disease. Comparison is made with medical antireflux therapy including histamine H2 receptor antagonist and proton pump inhibitor therapy. The randomized trials and systematic reviews available on gastro-esophageal reflux disease are reviewed and where data are scarce, the largest cohort studies available are discussed. Overall, laparoscopic antireflux surgery is safe and has a similar efficacy to open antireflux surgery and best medical therapy with proton pump inhibitors. There is a failure rate, which in some series is greater than 50% at 5 years. Due to the cost of a proportion of patients still taking antireflux medications, it cannot be recommended on cost-effectiveness grounds over best medical therapy. The choice of procedure lies between complete wrap with Nissen's fundoplication and partial fundoplication (most frequently Toupet). Division of the short gastric vessels is not usually necessary and is associated with increased wind-related complications. Total fundoplication tends to produce superior reflux control, but at the cost of increased risk of dysphagia. There is a trend for antireflux surgery to be superior to best medical therapy in cancer prevention in Barrett's oesophagus, but this has not reached statistical significance.

Retrospective cohort study of an enhanced recovery programme in oesophageal and gastric cancer surgery.

Introduction Enhanced recovery programmes have been established in some areas of elective surgery. This study applied enhanced recovery principles to elective oesophageal and gastric cancer surgery. Methods An enhanced recovery programme for patients undergoing open oesophagogastrectomy, total and subtotal gastrectomy for oesophageal and gastric malignancy was designed. A retrospective cohort study compared length of stay on the critical care unit (CCU), total length of inpatient stay, rates of complications and in-hospital mortality prior to (35 patients) and following (27 patients) implementation. Results In the cohort study, the median total length of stay was reduced by 3 days following oesophagogastrectomy and total gastrectomy. The median length of stay on the CCU remained the same for all patients. The rates of complications and mortality were the same. Conclusions The standardised protocol reduced the median overall length of stay but did not reduce CCU stay. Enhanced recovery principles can be applied to patients undergoing major oesophagogastrectomy and total gastrectomy as long as they have minimal or reversible co-morbidity.

Assessment of HIV status using the polymerase chain reaction in antibody-positive patients and high-risk antibody-negative haemophiliacs.

The polymerase chain reaction (PCR) was used to identify the presence of DNA sequences homologous to HIV-1 in the buffy-coat leukocytes of antibody-positive and antibody-negative individuals in a haemophiliac population. The presence of HIV sequences was demonstrated in all of the antibody-positive haemophiliacs with the exception of one patient who was repeatedly negative. None of the seronegative haemophiliacs gave an overall positive result, although there were clear differences between this population and the negative controls who were examined. We conclude that, in our hands, PCR represents a reliable test which represents a useful diagnostic advance in HIV medicine.

Helper and suppressor activities of lymphocyte subsets on antithyroglobulin production in vitro.

We studied the regulatory activities of T cells on specific antithyroglobulin (anti-Tg) and nonspecific immunoglobulin secretion in cultures of peripheral blood lymphocytes (PBL) of five patients with autoimmune thyroid diseases and high levels of serum anti-Tg. PBL were separated into a non-T population, including B-cells and monocytes, and a T-cell population by rosetting with sheep red cells. T-Cells were further separated into T helper (Th) and T suppressor (Ts) subsets by a panning technique using the monoclonal antibodies anti-Leu 3a and anti-Leu 2a, respectively. The three sets of cells, i.e. B, Th, and Ts, from patients and from normal individuals were cocultured in various combinations and stimulated with the polyclonal stimulant pokeweed mitogen. A sensitive plaque assay was used to enumerate cells producing anti-Tg and protein A-binding immunoglobulins. The PBL of both patients and normal individuals had Tg-specific suppressor cells. Ts-cells from patients in syngeneic or allogeneic combinations with B- and Th-cells at a ratio of 1:1:1 suppressed the pokeweed mitogen-induced anti-Tg response to 41 +/- 8% (+/-SE) and 50 +/- 20% of the control value, respectively, while Ts from normal individuals suppressed the response to 7 +/- 3% of the control value. The suppressive effect of the Ts-cells from patients and normal individuals on nonspecific immunoglobulin secretion was similar (reduced to 10-15% of control). Thus, there appeared to be a deficiency in Tg-specific suppressor activity in PBL of patients. On the other hand, Th-cells from patients (syngeneic or allogeneic) cocultured with patient B-cells produced a greater anti-Tg response than Th-cells from normal individuals. The helper activities of Th-cells of patients and normal individuals on nonspecific immunoglobulin secretion were similar. Thus, there appeared to be an increase in Tg-specific helper activity in PBL of patients.

Class II antigen expression and T lymphocyte subsets in chronic inflammatory demyelinating polyneuropathy.

The inflammatory infiltrate within human sural nerve, biopsied from six patients with active chronic inflammatory demyelinating neuropathy (CIDP) was studied for T lymphocyte subsets and Class II antigen (Ia)-expressing cells. Immunohistochemical staining with mouse monoclonal antibodies, acid phosphatase staining, and electron microscopy were used to provide an alternative assessment of macrophage and other mononuclear cell numbers. In normal control nerves Class II antigen was present upon endothelial cells, very occasional mononuclear cells and sparsely within the perineurium. In CIDP nerve dense Class II antigen staining was prominent within nerve fascicles, in capillary endothelial cells and within the perineurium. T lymphocytes of suppressor and helper type were present in small numbers only. Moderate numbers of macrophage-monocytes were found in the patients within nerve fascicles but these cells accounted for only part of the dense Ia staining. Since two nerves with hypertrophic changes, Schwann cells forming 'onion bulbs', were clearly Ia positive, the dense and widespread staining in all nerves studied is best explained by Ia antigen expression upon mononuclear and some Schwann cells.

The role of complement in the aetiopathogenesis of systemic lupus erythematosus.

The role of classical pathway complement components in systemic lupus erythematosus (SLE) is reviewed. Their importance in maintaining immune complexes (IC) in soluble form and in enhancing clearance of IC through binding to red cell CR1 is such that deficiency, complete or partial, of these components or some of their controlling enzymes can lead to IC mediated disease like SLE. C2 and C4 are encoded within the class III region of the major histocompatibility complex (MHC). There are certain well described associations between class II MHC genes and the occurrence of SLE and the relative importance of the two sets of gene products and their potential interactions are discussed. Complement C4 plays a role in drug induced lupus as many of the lupus associated drugs bind to C4 and interfere with its protective functions. Classical genetic studies provide clear evidence that non MHC genes are important in the aetiopathogenesis of SLE. Non MHC encoded complement deficiencies and functional deficits may well represent some of these other genetic factors and is clearly a fertile area for future research.

Detection and typing of paraproteins: comparison of different methods in a routine diagnostic laboratory.

In this paper we review four methods: Protein electrophoresis (PE), immunoelectrophoresis (IEP), immunofixation electrophoresis (IFE) and a nephelometric kappa:lambda ratio method for the ability, first, to detect, and second, to isotype paraproteins in urine and serum. IFE was the most sensitive assay both in the detection of paraproteins and the most accurate in their typing. The nephelometric kappa:lambda ratio was associated with false-positive and false-negative results and cannot be considered suitable for routine diagnostic use. Although IFE was the most sensitive assay it was not without problems. Dilution of the serum to produce a concentration suitable for IFE is critical, and the assay is demanding in operator skill and time. The extra paraproteins identified by IFE are generally of low concentration and with the exception of certain well-defined clinical situations are probably not of great importance in patient management. In the case of diseases where the demonstration of a small amount of paraprotein is important, such as amyloidosis, then IFE should be performed in case other techniques fail to demonstrate a paraprotein. Otherwise, IFE is best reserved for paraproteins detected by PE which cannot be typed by IEP. A schema for the management of paraprotein identification for use in a routine diagnostic laboratory is presented.

Anti-neutrophil cytoplasmic antibodies (ANCA): their detection and significance: report from workshops.

Anti-neutrophil cytoplasmic antibodies (ANCA) are antibodies directed against enzymes that are found mainly within the azurophil or primary granules of neutrophils. There are 3 types of ANCA that can be distinguished by the patterns they produce by indirect immunofluorescence when tested on normal ethanol-fixed neutrophils. Diffuse fine granular cytoplasmic fluorescence (cANCA) is typically found in Wegener's granulomatosis, in some cases of microscopic polyarteritis and Churg Strauss syndrome, and in some cases of crescentic and segmental necrotising glomerulonephritis, but it is rare in other conditions. The target antigen is usually proteinase 3. Perinuclear fluorescence (pANCA) is found in many cases of microscopic polyarteritis and in other cases of crescentic and segmental necrotising glomerulonephritis. These antibodies are often directed against myeloperoxidase but other targets include elastase, cathepsin G, lactoferrin, lysozyme and beta-glucuronidase. The third group designated "atypical" ANCA includes neutrophil nuclear fluorescence and some unusual cytoplasmic patterns, and while a few of the target antigens are shared with pANCA, the others have not been identified. Sera that produce a pANCA or atypical ANCA pattern on alcohol-fixed neutrophils result in cytoplasmic fluorescence when formalin acetone fixation is used. pANCA or atypical ANCA occur in about 2/3 of all individuals with ulcerative colitis or primary sclerosing cholangitis, and they are found in a third of patients with Crohn's disease. The reported incidence of ANCA in rheumatoid arthritis and SLE varies considerably but the patterns are predominantly pANCA and atypical ANCA.(ABSTRACT TRUNCATED AT 250 WORDS)

The limited (needle biopsy) autopsy and the acquired immunodeficiency syndrome.

It is often uncertain whether deaths that occur during active treatment for complications of AIDS result from diagnostic or therapeutic failure. Accurate diagnosis of infections is particularly important, and has relevance not only for the patient but also to partners, relatives, hospital staff and other patients. In the absence of adequate physical facilities and in view of the lack of success in obtaining formal autopsies in patients dying with AIDS, a limited autopsy protocol was devised for routine application at our hospital, beginning in 1989. The major aim of this protocol was to enable the safe collection of diagnostic material from patients who died despite active therapy, to ascertain unrecognized conditions and confirm existing diagnoses. We present findings from the first 16 limited autopsies which resulted in 12 additional diagnoses and a revision of the principal cause of death in 7 cases.

Alpha-interferon (Wellferon) as an adjunct to standard surgical therapy in the management of recurrent respiratory papillomatosis.

Ten patients received lymphoblastoid alpha-interferon (Wellferon) in a crossover study so that Wellferon and standard microsurgical laryngeal laser therapy could be compared to laser therapy alone. Wellferon was administered initially at an intravenous high dose of 15 megaunits/m2 for 5 days followed by a daily dose of 2 megaunits/m2 subcutaneously for 6 months. Dosage was adjusted according to predefined toxicity. One patient was withdrawn from the study. Of the others, all but one received over 75% of the planned total dose. At follow-up of the nine assessable patients, complete remission was achieved in two of them, partial remission in four, and no response in the remainder. The two complete remissions were sustained for 2 years, but the four partial remissions were not sustained. Thus, a role for alpha-interferon in the kind of regimen used here remains to be established.

Antiphospholipid syndrome. A clearer understanding of an old problem.

The concept of the antiphospholipid syndrome has only become possible since the development of easy to perform solid phase anticardiolipin assays, leading to a clarification of the true relationship of a number of otherwise disparate clinical features. This review of a multi-factorial problem pays special attention to the immunological markers and their significance.

Creation of an academic medical centre: management and service delivery at the Canberra Clinical School.

The Canberra Clinical School is attached to Woden Valley Hospital, the principal hospital in the Australian Capital Territory. The clinical school arose out of a memorandum of understanding signed between the University of Sydney and the ACT Department of Health (as it then was) in March 1993. One of the aspirations of those who negotiated the memorandum of understanding was that the creation of the clinical school would lead to a cultural shift in attitudes towards change within the health care system. This paper looks at the management structure of Woden Valley Hospital and at what the development of a clinical school in Canberra can achieve, particularly in relation to hospital and health service management.

The influence of symptom type and duration on the fate of the metaplastic columnar-lined Barrett's oesophagus.

BACKGROUND: Prolonged gastro-oesophageal reflux resulting in columnar metaplasia of the oesophagus is the main risk factor for oesophageal adenocarcinoma. AIM: To examine the duration of symptoms and associations of different symptoms with the development of columnar-lined oesophagus, dysplasia and adenocarcinoma. METHODS: UK multicentre cohort study of patients with columnar-lined oesophagus whose date of symptom onset (1082 patients) and/or types of symptoms reported (1681 patients) were documented. Follow-up was examined by analysis of histological reports from the registering centers. RESULTS: Symptoms of dysphagia/odynophagia and nausea/vomiting were associated with development of dysplasia. High-grade dysplasia and adenocarcinoma were associated with dysphagia/odynophagia and weight loss. Median duration from symptom onset to detection of columnar-lined oesophagus without intestinal metaplasia: 2.6 years, columnar-lined oesophagus with intestinal metaplasia: 5.0 years, indefinite changes for dysplasia: 19.3 years and low-grade dysplasia: 30.0 years. One tenth of patients had developed high-grade dysplasia at 9.6 years and one tenth had developed adenocarcinoma at 13.8 years from symptom onset. CONCLUSIONS: In patients with columnar-lined oesophagus, symptoms of dysphagia/odynophagia and nausea/vomiting were associated with a higher risk of development of dysplasia and adenocarcinoma. There is a trend for longer duration of symptoms to the detection of dysplasia.