Biomedical subjects
D S Sanders
Publications and source records attributed to D S Sanders.
Familial occurrence of microscopic colitis: an opportunity to study the relationship between microscopic colitis and coeliac disease?
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Prospective validation of the Rockall risk scoring system for upper GI hemorrhage in subgroups of patients with varices and peptic ulcers.
OBJECTIVES: The Rockall risk assessment score was devised to allow prediction of the risk of rebleeding and death in patients with upper GI hemorrhage. The score was derived by multivariate analysis in a cohort of patients with upper GI hemorrhage and subsequently validated in a second cohort. Only 4.4% of patients included in the initial study had esophageal varices, and analysis was not performed according to the etiology of the bleeding. Our aim was to assess the validity of the Rockall risk scoring system in predicting rebleeding and mortality in patients with esophageal varices or peptic ulcers. METHODS: Admissions (n = 358) over 32 months to a single specialist GI bleeding unit were scored prospectively. The distribution of episodes of rebleeding and mortality by Rockall score were statistically analyzed using Fisher's exact test with 99% CIs calculated using a Monte Carlo method. The Child-Pugh score was determined in patients with esophageal varices. RESULTS: The Rockall score was predictive of both rebleeding and mortality in patients with variceal hemorrhage (both ps < 0.0005), as was the Child-Pugh score (p = 0.001 and p < 0.0005, respectively). The initial Rockall score was predictive of mortality in patients with peptic ulcers (p = 0.01), although the complete score was not (p > 0.05). The complete score did, however, predict rebleeding in these patients (p = 0.001). CONCLUSION: This is the first study to validate the Rockall score in specific subgroups of patients with esophageal varices or peptic ulcers and suggests that it is particularly applicable to variceal hemorrhage.
Percutaneous endoscopic gastrostomy: a prospective audit of the impact of guidelines in two district general hospitals in the United Kingdom.
OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) is the accepted method for long-term enteral nutrition. Recent studies have suggested a higher mortality than was initially reported. The demands for gastrostomy insertion have risen, encompassing indications where the long-term outcomes are uncertain. We, therefore, constructed guidelines to try and improve the appropriateness of patient selection. Our aim was to prospectively assess the impact of guidelines for PEG insertion over a 1-yr period in a single center, Rotherham District General Hospital (hospital A) and compare against an adjacent center serving a similar population, Doncaster Royal Infirmary (hospital B) where guidelines had not been instituted. METHODS: Data were collected from June, 1998 to May, 1999. Indication for PEG was documented and survival analysis performed using the Kaplan-Meier survival method. RESULTS: The number of PEG insertions had been rising each year in both centers. After guidelines were introduced in hospital A, the number of procedures fell by 20, whereas in hospital B, the PEG insertion rate continued to rise (p = 0.02). There was a lower mortality observed in hospital A (at 1 month, 16%; at 3 months, 26%; at 6 months, 39%; and at 1 yr, 46%) than in hospital B (at 1 month, 26%; at 3 months, 44%; at 6 months, 58%; and at I yr, 68%), although this did not achieve statistical significance (log rank test, p = 0.1). CONCLUSIONS: This is the first study to prospectively assess the impact of guidelines and a proactive role in the decision for PEG insertion. Fewer procedures were performed, and there was a trend toward a reduction in mortality.
Changing face of adult coeliac disease: experience of a single university hospital in South Yorkshire.
OBJECTIVE: To determine the incidence and presenting features of adult coeliac disease in a single university hospital in South Yorkshire. DESIGN: A retrospective case finding study. Data were obtained from pathology and immunology databases, clinical notes, dietetic records, and patient questionnaires. SETTING: Royal Hallamshire Hospital in South Yorkshire, England. PARTICIPANTS: All recorded cases of coeliac disease. MAIN OUTCOME MEASURES: Crude annual incidence rates for coeliac disease was obtained. The numbers of coeliac antibody profiles requested per year from the Royal Hallamshire Hospital were ascertained. Age at diagnosis, sex, year of diagnosis, presenting symptoms, associated conditions, and delay in diagnosis was documented. In addition the specialty of the clinician who made the diagnosis was noted. RESULTS: There were 264 cases in total (male n=86, ratio 1:2). Mean age at diagnosis was 44.9 years (range 1-82, median 44.5). A trend was observed from 1990 to 2000 inclusive, of an annual increase in the incidence of coeliac disease. There has been a coincidental increase in the measurement of associated antibodies. Although 28.4% of patients presented with gastrointestinal symptoms, 20.1% had iron deficiency anaemia. The ratio of typical to atypical symptoms was 1:2.5. (single sample test of proportions p<0.001). The diagnosis was made by a gastroenterologist in only 52.7% of cases. The median duration of symptoms before the diagnosis of coeliac disease was 4.9 years (range 0.25-16 years). CONCLUSION: Coeliac disease is now presenting more commonly without gastrointestinal symptoms and often to specialties other than gastroenterology. Although more cases are diagnosed, this may be a reflection of increasing recognition rather than a true increase in incidence.
Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care.
BACKGROUND: Irritable bowel syndrome has a high prevalence. Consensus diagnostic criteria (ROME II) based on symptoms have been established to aid diagnosis. Although coeliac disease can be misdiagnosed as irritable bowel syndrome, no prospective study has been published in which patients with this disorder are investigated for coeliac disease. We aimed to assess the association of coeliac disease with irritable bowel syndrome in patients fulfilling ROME II criteria. METHODS: We undertook a case-control study at a university hospital. 300 consecutive new patients who fulfilled Rome II criteria for irritable bowel syndrome, and 300 healthy controls (age and sex matched) were investigated for coeliac disease by analysis of serum IgA antigliadin, IgG antigliadin, and endomysial antibodies (EMA). Patients and controls with positive antibody results were offered duodenal biopsy to confirm the possibility of coeliac disease. FINDINGS: 66 patients with irritable bowel syndrome had positive antibody results, of whom 14 had coeliac disease (11 EMA positive, three EMA negative). Nine patients with positive antibody results were lost to follow-up or refused biopsy (only one EMA-positive patient refused biopsy), and 43 had normal duodenal mucosa. Two controls, both of whom were EMA positive, had coeliac disease. Compared with matched controls, irritable bowel syndrome was significantly associated with coeliac disease (p=0.004, odds ratio=7.0 [95% CI 1.7-28.0]). INTERPRETATION: Patients with irritable bowel syndrome referred to secondary care should be investigated routinely for coeliac disease. With only EMA, three of 14 cases would have been missed.
The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC)--results of an international collaborative study.
Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is an autosomal dominant condition accounting for 2-5% of all colorectal carcinomas as well as a small subset of endometrial, upper urinary tract and other gastrointestinal cancers. An assay to detect the underlying defect in HNPCC, inactivation of a DNA mismatch repair enzyme, would be useful in identifying HNPCC probands. Monoclonal antibodies against hMLH1 and hMSH2, two DNA mismatch repair proteins which account for most HNPCC cancers, are commercially available. This study sought to investigate the potential utility of these antibodies in determining the expression status of these proteins in paraffin-embedded formalin-fixed tissue and to identify key technical protocol components associated with successful staining. A set of 20 colorectal carcinoma cases of known hMLH1 and hMSH2 mutation and expression status underwent immunoperoxidase staining at multiple institutions, each of which used their own technical protocol. Staining for hMSH2 was successful in most laboratories while staining for hMLH1 proved problematic in multiple labs. However, a significant minority of laboratories demonstrated excellent results including high discriminatory power with both monoclonal antibodies. These laboratories appropriately identified hMLH1 or hMSH2 inactivation with high sensitivity and specificity. The key protocol point associated with successful staining was an antigen retrieval step involving heat treatment and either EDTA or citrate buffer. This study demonstrates the potential utility of immunohistochemistry in detecting HNPCC probands and identifies key technical components for successful staining.
Percutaneous endoscopic gastrostomy: a prospective analysis of hospital support required and complications following discharge to the community.
INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) is the commonest method of long-term enteral nutrition. In the UK there is no nationally funded framework to provide community support for patients with gastrostomies. OBJECTIVES: To assess the hospital support required and the complications occurring in a cohort of patients discharged into the community with a gastrostomy in-situ. DESIGN AND SETTING: We prospectively collected data between June and November 1998 regarding patients (n=87) with PEG complications in the community following discharge from two adjacent hospitals in South Yorkshire (Rotherham District General Hospital and the Royal Hallamshire Hospital). RESULTS: The mortality within this cohort during the study period was 17.2%. Of these 15 patients 10.3% (n=9) were thought to have died as a result of the progression of their disease, whilst in the other 6.9% (n=6) pneumonia was documented as the cause of death. Problems with gastrostomies requiring telephone advice occurred in 24.1% of patients and 65.5% necessitated a home visit. However during this period of 6 months, 23% of patients were admitted as an emergency, accounting for 61 in-patient days. All were from nursing or residential homes and the emergency occurred after normal surgery hours. General practitioners dealt with aspiration pneumonia in 25.2% of the cohort but other tube problems were referred to the endoscopy unit. DISCUSSION: This is the first study to specifically highlight the specialist intervention and support required by patients discharged into the community with PEGs, a group for whom there is often no formal aftercare. A specialist nurse or dietician could establish a liaison service focusing on primary care and using hospital resources when appropriate. This study provides further evidence to support the recommendations for tube feeding made by the British Association for Parenteral and Enteral Nutrition.
Ranitidine bismuth citrate with clarithromycin alone or with metronidazole for the eradication of Helicobacter pylori.
BACKGROUND: Both triple therapy with ranitidine bismuth citrate (RBC) plus two antibiotics for 7 days and dual therapy of RBC with clarithromycin for 14 days have been extensively studied; both regimens effectively eradicate Helicobacter pylori. However, few studies have assessed the efficacy of dual therapy given for 7 days. AIM: To compare the efficacy and safety of RBC 400 mg with clarithromycin 500 mg, alone or with metronidazole 400 mg, given twice daily for 7 days for the eradication of H. pylori. METHODS: This single centre, randomized, double-blind study involved 118 patients with dyspepsia or a history of peptic ulcer disease. H. pylori infection was detected initially by CLO test, and confirmed in 109 patients by urea breath test and/or microbiology culture. H. pylori eradication was assessed 4 and 12 weeks after the end of treatment by urea breath test. H. pylori antibiotic susceptibility was assessed pre-study in all patients, and post-treatment in patients with a positive post-treatment urea breath test. Adverse events were recorded throughout the study. RESULTS: H. pylori was eradicated in 93% of patients who received RBC with clarithromycin and metronidazole and in 84% of patients who received RBC with clarithromycin (intention-to-treat rates). Per protocol eradication rates were 98% and 90% for triple therapy and dual therapy, respectively. The eradication of metronidazole-resistant H. pylori was achieved in 100% and 88% of patients following dual therapy and triple therapy, respectively, and acquired resistance to clarithromycin occurred in only one patient following treatment failure. Both treatments were well-tolerated; only one patient (2%) was withdrawn from each treatment group due to adverse events. CONCLUSIONS: RBC with clarithromycin and metronidazole is a highly effective and well-tolerated triple therapy regimen for the eradication of H. pylori. RBC with clarithromycin dual therapy has a similar efficacy, and offers an alternative to triple therapy when there are concerns about treatment with metronidazole or the use of multiple antibiotics. Both regimens are effective against antibiotic-resistant strains of H. pylori.
Helicobacter pylori antimicrobial resistance in the United Kingdom: the effect of age, sex and socio-economic status.
BACKGROUND: Helicobacter pylori antimicrobial resistance is the most common reason for eradication failure. Small studies have shown metronidazole resistance to be more prevalent in certain population groups. AIM: To determine the resistance rates in a large cohort of patients from a single centre in the UK, and to evaluate resistance patterns over time, according to age, sex and socio-economic status. METHODS: Consecutive patients with H. pylori-positive antral gastric biopsy samples were studied from 1994 to 1999. Susceptibility testing was performed to metronidazole, tetracycline, macrolide and amoxicillin by the modified disk diffusion METHOD: The Jarman under-privileged area score was used as a measure of socio-economic status. RESULTS: A total of 1064 patients were studied. Overall metronidazole resistance was 40.3%, decreasing with age (P < 0.0001, odds ratio for patients over 60 years 0.63, 95% CI: 0.48-0.80). Women were more likely to have metronidazole resistant strains (P=0.003, odds ratio 1.5, 95% CI: 1.15-1.91), but there was no association with Jarman score. Macrolide resistance was associated with metronidazole resistance (P=0.03, odds ratio 2.14, 95% CI: 1.07-4.28). CONCLUSIONS: Metronidazole resistance in H. pylori is highly prevalent and more common in women and the young, but does not appear to be related to socio-economic status.
Tonsillar metastasis: A rare presentation of gastric carcinoma.
Metastatic carcinoma of the tonsil is uncommon. Tonsillar metastases rarely become apparent before the diagnosis of the primary neoplasm. We describe only the second reported case of tonsillar metastasis as a presenting feature of gastric carcinoma. A review of the literature is also discussed.
Research outcomes in British gastroenterology: an audit of the subsequent full publication of abstracts presented at the British Society of Gastroenterology.
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Students sitting finals: ready to be house officers?
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Aberrant P-cadherin expression is a feature of clonal expansion in the gastrointestinal tract associated with repair and neoplasia.
The recognition of key roles for cadherins in the determination of epithelial cell phenotype, migration, differentiation, and tumour dissemination have stimulated much interest in this family of adhesion molecules. In the gastrointestinal tract, alteration of the expression of classical cadherins with aberrant P-cadherin up-regulation, associated with co-expression or loss of E-cadherin expression, is seen in neoplastic transformation of oral and oesophageal squamous mucosa and in lesions representing early neoplastic transformation of glandular mucosa, such as aberrant crypt foci and metaplastic and adenomatous polyps. This same phenotype is seen in enterocytes adjacent to foci of ulceration in the intestine in colitis, including inflammatory bowel disease, and in colitis-associated dysplasia. In coeliac disease, reversible E-cadherin down-regulation correlates with the degree of villous atrophy, but in contrast with colitis, aberrant P-cadherin expression is not a feature. Aberrant epithelial P-cadherin expression is thus associated with a proliferative phenotype related to ulceration and neoplastic transformation in the gastrointestinal tract, which may confer a survival advantage on these cells, but the relative functional roles of P-cadherin and E-cadherin and the molecular mechanisms underlyingP-cadherin/catenin interactions have yet to be elucidated.
Survival analysis in percutaneous endoscopic gastrostomy feeding: a worse outcome in patients with dementia.
OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) feeding has been validated in specific clinical situations such as acute stroke with dysphagia and oropharyngeal malignancy. The perception that gastrostomy insertion is safe and technically simple has led to an increase in the demands for PEG insertion, encompassing clinical applications such as in patients with dementia, in whom its role has not been justified. The purpose of this study was to compare the mortality of patients with dementia who were fed by PEG to that of other subgroups of patients requiring gastrostomy feeding. METHODS: The study focused on a cohort of 361 consecutive patients requiring PEG feeding between August 1992 and July 1997 from two District General Hospitals (Rotherham District General Hospital and Doncaster Royal Infirmary) in South Yorkshire. A retrospective cohort survival analysis was performed using the Kaplan-Meier survival method and Cox proportional hazards analysis. RESULTS: In all patients requiring gastrostomy feeding there is a high initial mortality of 28% at 30 days. However, patients with dementia have a worse prognosis compared to other subgroups, with 54% having died at 1 month and 90% at 1 yr (log rank test p < 0.0001). This difference remained significant (log rank p < 0.0001) after adjusting for age at the time of PEG insertion. CONCLUSIONS: This is the first demonstration in the United Kingdom that the mortality of patients with dementia who are fed by gastrostomy is considerable. Consequently, we may wish to advise against gastrostomy feeding in selected patients within this clinical setting.
Small cell malignant melanoma: a variant of naevoid melanoma. Clinicopathological features and histological differential diagnosis.
AIMS: To describe the clinical and histopathological features of a rare variant of naevoid melanoma, small cell melanoma, and discuss the histological differential diagnoses. METHODS: The clinical and histological features of cases of malignant melanoma with the histological features of small (non-Merkel like) melanoma were reviewed and documented. In addition, five cases had available material for immunohistochemistry and this was performed using antibodies to the S100 protein and melan-A, and the HMB-45 antibody. RESULTS: There were 15 cases of small cell melanoma from 14 (10 female, four male) patients, aged between 30 and 77 (mean, 48.6) years. The trunk was the most common location. In more than half the cases, the provisional diagnosis was melanoma/borderline lesion. All shared similar histological appearances of an intraepidermal component of in situ melanoma and a dermal component of nests of cells with hyperchromatic nuclei and scanty cytoplasm, usually in tightly packed nests. All components (junctional and intradermal) of the lesions investigated by immunohistochemistry were positive both for S100 protein and melan-A. All junctional components were positive with HMB-45, but with variable staining of the dermal components with this antibody. CONCLUSIONS: Small cell malignant melanoma is postulated to be a distinct histopathological entity and a rare variant of naevoid melanoma. Such lesions can be difficult to interpret and easily missed at scanning magnification because the cells of the dermal component mimic benign naevus cells.
Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer.
Inherited mutations in the E-cadherin gene ( CDH1 ) were described recently in three Maori kindreds with familial gastric cancer. Familial gastric cancer is genetically heterogeneous and it is not clear what proportion of gastric cancer susceptibility in non-Maori populations is due to germline CDH1 mutations. Therefore, we screened eight familial gastric cancer kindreds of British and Irish origin for germline CDH1 mutations, by SSCP analysis of all 16 exons and flanking sequences. Each family contained: (i) two cases of gastric cancer in first degree relatives with one affected before age 50 years; or (ii) three or more cases of gastric cancer. Novel germline CDH1 mutations (a nonsense and a splice site) were detected in two families (25%). Both mutations were predicted to truncate the E-cadherin protein in the signal peptide domain. In one family there was evidence of non-penetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to six cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years. We have confirmed that germline mutations in the CDH1 gene cause familial gastric cancer in non-Maori populations. However, only a minority of familial gastric cancers can be accounted for by CDH1 mutations. Loss of E-cadherin function has been implicated in the pathogenesis of sporadic colorectal and other cancers, and our findings provide evidence that germline CDH1 mutations predispose to early onset colorectal cancer. Thus, CDH1 should be investigated as a cause of inherited susceptibility to both gastric and colorectal cancers.
Ileal pouch-anal anastomosis for Crohn's disease.
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