Dear Editor,

我们读到布雷福特教授的critiqu与兴趣e of the new BSG guidelines for the diagnosis and management of Barrett’s oesophagus in the April edition of Gut (1). He rightly emphasises the dearth of evidence upon which to formulate policy but goes on to mention the prospect of obtaining such data in future from the AspECT trial and an upcoming HTA sponsored trial of the effectiveness of surveillance. We are writing to update your readership on these important trials.

AspECT (Aspirin and Esomprazole Chemoprevention Trial of Cancer in Barrett’s Oesophagus) is designed to investigate whether aspirin in combination with PPI can decrease both cancer conversion and vascular death. It is a 2x2 factorial trial of high dose esomeprazole (40 mg BD) versus standard dose 20 mg OD, and 300 mg aspirin versus no aspirin. The rationale for this form of chemoprevention is compelling (2,3) and is strongly supported by a recent in vivo biomarker study of esomeprazole 40 mg BD and aspirin in Barrett’s oesophagus patients(4). The trial is sponsored by MRC and CRUK. It started in the first centres in July 2005. It is recruiting well and is now one of the fastest recruiting NCRN trials. It will recruit 5000 UK patients in 2 years and follow up is over 8-10 years. As per the BSG guidelines OGD surveillance is carried out every 2 years and quadrantic biopsies are taken at 2 cm intervals. Infra structure is provided by NCRN (National Cancer Research Network) nurses. The numbers recruited in the AspECT study will allow detection of a 0.22 percentage point reduction in oesophageal adenocarcinoma per year assuming an annual incidence of 0.8% (5) at the 80% power and 95% significance level.

Professor Playford considers that “no PPI” or “true PRN” would be a better control group. However almost all patients require PPI for symptom control and we consider that a “no PPI” arm is unethical and unrealistic. Patients in the low dose arm (20 mg OD) have the option to increase the dosage if their symptoms are not adequately controlled All the indications are that these interventions will be effective but the trial will also be important in demonstrating if they are well tolerated. Although the trial is not directly about surveillance there will be important implications for surveillance if the treatments are effective in reducing cancer incidence since surveillance may then be demonstrated to be redundant.

The HTA sponsored trial of surveillance versus no surveillance has recently been awarded to the AspECT group. This trial which we have called BOSS (Barrett’s Oesophagus Surveillance Study) will be integrated with and make use of the AspECT infra structure. For the first time in any trial BOSS will randomise patients to surveillance or no surveillance, and it too will need to recruit a large number of patients. Patients who are excluded from AspECT because they are already taking aspirin can be entered in BOSS and stratified to ensure that equal numbers of patients taking aspirin are included in the two arms of the trial.

We believe that these trials can at last answer a number of questions that for too long have been the subject of speculation, anecdote and personal conviction. The BSG membership has the opportunity to make a tremendous contribution to our knowledge in this field by taking part in the trials. We very much welcome applications of interest from all our colleagues throughout the UK.

References

1.Playford RJ. New British Society of Gastroenterology (BSG) guidelines for the diagnosis and management of Barrett’s oesophagus. Gut 2006; 55: 442-3

2. Jankowski J, Moayyedi P. Aspirin as chemoprevention for Barrett’s esophagus: a large RCT underway in the UK . J Natl Cancer Inst 2004;96:885 -7.

3. Jankowski J, Hawk E. A methodological analysis of chemoprevention in the Gastrointestinal tract. (systematic review).

Nature Clin Pract Gastro 2006:3;101-111.

4.Kaur Triadafilopuolos G B Sood年代,Traxler B,Levine D, Weston A. The effects of esomproazole combined with aspirin or rofecoxib on prostaglandin E2 production in patients with Barrett’s oesophagus. Alimentary Pharmacology & Therapeutics 2006; 23: 997-1005.

5. Jankowski J, Provenzale D, Moayyedi P. Oesophageal adenocarcinoma arising from Barrett’s metaplasia has regional variations in the West. Gastroenterology 2002; 122: 588-90.

Peter Watson, Janusz Jankowski, Paul Moayyedi, Stephen Attwood and Hugh Barr ApECT and BOSS management group Oncology Trials Unit Oxford OCTO AspECT websitehttp://www.octo-oxford.org.uk/Trials/Aspect/Aspect.aspx

Dear Editor,

巴尔我的纸,在肠道hepatiti报道等人s C virus (HCV) clearance in 4,720 residents of an Egyptian village having an HCV antibody (anti-HCV) prevalence of 19.3%.1 They reported 61.5% of those having anti-HCV also had HCV-RNA. Compared to males, females were more likely to have cleared the virus: 55.4% of anti-HCV positive females had HCV-RNA compared with 66.3% of males (P = 0.001). However, they noted no age-related differences in clearance and results of analysis of coinfections with schistosomiasis were not reported.

我们的数据收集和处理是非常相似的to theirs and the virology was performed in the same laboratory.2-5 Variables investigated were gender; age stratified by decades; and history of, and infection with, schistosomiasis. The statistical significance of observed differences in HCV persistence rates was assessed using the Pearson Chi Square test. To estimate associations with persistence, while controlling for other variables, we used Mantel-Haenszel estimate of relative risks. S. mansoni and S. haematobium ova were microscopically detected in stool using a modified Kato technique and in urine using nucleopore filters.

In two communities,2,3 14.9% of 10,030 subjects had anti-HCV and 61.0% of these also had HCV-RNA . Anti-HCV positive males were more likely than females to have HCV-RNA: age adjusted relative risk (RR) was 1.2 (P=0.10; Table). Anti-HCV positive inhabitants under age 20 were less likely (p=0.04) to be HCV-RNA positive than older persons (55.3% vs 62.2%). A history of schistosomiaisis was not a risk for RT-PCR positivity. However, 70.9% of the 117 anti-HCV positive subjects with active schistosomal infections had HCV-RNA in comparison (p=0.03) with 59.4% of the 1,031 who did not have Schistosoma ova detected in their urine or stools. This increased risk was only present in the Nile delta village where S. mansoni is transmitted;2 72.8% of 103 with S. mansoni ova in their stools were RT-PCR positive compared (RR=1.7; P=0.02) with 58.8% of 640 not having schistosomiasis (Table). When adjusted for gender and age S. mansoni infection remained a risk for HCV-RNA persistence.

Analysis of data from pregnant women from three other villages showed 15.5% of 1,798 had anti-HCV and 158 (56.6%) of these 279 also had HCV- RNA.4 The RT-PCR positive rate in women less than 20 (47.8%) was less (P=0.37) than in those 20 or older (57.4%) and those with active S. mansoni infections (72.2%) were more likely (P=0.13) to have HCV-RNA than those not having schistosomiasis (52.3%). Age-adjusted RR for the association between S. mansoni infection and RT-PCR positivity was 2.3 (95% CI; 0.8-7.1; P=0.13), but none of these differences were statistically significant.

Even if clearance is one percent per year, it would reduce prevalence of HCV-RNA in older adults and might hide evidence that the young are more likely to clear infections.6,7 Another potential bias could occur when older subjects with persistent infections are dropped from the sampled population because of death or are not available due to complications of HCV infection. Cross-sectional prevalence studies, unlike incidence studies, cannot pinpoint risk of persistence, but several potential biases would be towards reducing ability to show HCV infections in women and children are more likely to clear than those in men and adults, and it would dilute the effect co-infections with S. mansoni would have on HCV persistence. We elected not to combine data from our cross-sectional survey and pregnant women studies because of differences in selection criteria. Although HCV clearance differences among our subgroups were often large, statistical significance at the 5% level, despite the relatively large numbers of subjects, was not always reached.

Infection with S. mansoni, but not S. haematobium, was associated with persistence of HCV infections. Previous studies by Kamal and her colleagues of acute HCV infections in patients with, and without, concomitant schistosomiasis mansoni reported those with schistosomiaisis were less likely to clear HCV-RNA.8 Biological plausibility supports this relationship between schistosomiasis mansoni and persistence of HCV. S. mansoni, but not S. haematobium, causes many granulomas in the liver which could locally inhibit generation of HCV-specific CD4+/Th1 T-cell responses,8 leading to greater persistence and severity of HCV infections in patients with coinfections. Our community-based data showing persistence following HCV infection may be less frequent than reported from hospital-based patients, also supports reports that children and women are more likely to clear their infections than adults and men.1, 9- 11

References

1.Bakr I, Rakacewicz C, El-Hosseiny M, Ismail S, El-Daly M, El-Kafrawy S, et al. Higher clearance of HCV infection in females compared to males. Gut 2006; Jan 24 [Epub ahead of print].

2. Abdel-Aziz F, Habib M, Mohamed MK, et al. Hepatitis C virus (HCV) infection in a community in the Nile Delta: Population description and HCV prevalence. Hepatology 2000;32:111-5.

3. Nafeh MA, Medhat A, Shehata M, et al. Hepatitis C in a community in Upper Egypt: 1. Cross-sectional survey. Am J Trop Med Hyg 2000;63:236-41.

4.Stoszek SK, Narooz S, Saleh D, Mikhail N, Kassem E, Hawash Y, et al. Prevalence of and risk factors for hepatitis C in rural Egyptian women. Trans R Soc Trop Med Hyg 2006;100:102-7.

5. Abdel-Hamid M, Edelman DC, Highsmith WE, Constantine NT. Optimization, assessment, and proposed use of a direct nested reverse transcription-polymerase chain reaction protocol for the detection of hepatitis C virus. J Hum Virol 1997;1:58-65.

6. Alter HJ, Seeff LB. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome. Semin Liver Dis 2000;20:17-35.

7. Thomas DL, Astemborski J, Rai RM, Anania FA, Schaeffer M, Galai N, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA 2000;284:450-6.

8. Kamal SM, Rasenack JW, Bianchi L, Al-Tawil A, El-Sayed Khalifa K, Peter T, et al. Acute hepatitis C without and with schistosomiasis: correlation with hepatitis C-specific CD4(+) T-cell and cytokine response. Gastroenterology 2001;121:646-56.

9. Yamakawa Y, Sata M, Suzuki H, Noguchi S, Tanikawa K. Higher elimination rate of hepatitis C virus among women. J Viral Hepat 1996;3:317-21.

10. Kenny-Walsh E for the Irish Hepatology Research Group. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. N Engl J Med 1999;340:1228-33.

11. Vogt M, Lang T, Frosner G, Klinger C, Sendl AF, Zeller A, et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999;341:866-70.

Dear Editor,

We have read with great interest the recent manuscript published in GUT by Professor Tack and colleagues entitled “A randomised controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation (IBS-C)”.[Tack et al. 2005] To date, this is the largest clinical trial assessing the efficacy and safety of repeated tegaserod therapy in women with IBS-C. Furthermore, it is currently the only published trial to address the recent guidelines from the CHMP (formerly known as the CPMP, and the following article is published under this name) regarding the design and performance of IBS therapies for short-term, repeated treatment.[CPMP 2003]

Data from this large, placebo-controlled trial demonstrate that tegaserod provides relief of overall symptoms of IBS, and relief of individual IBS symptoms including abdominal pain, bloating and constipation. The effects of tegaserod were rapid, being significantly greater than placebo during the first week of treatment, and were sustained throughout the duration of treatment. Patients who experienced symptom recurrence following cessation of initial treatment received a further cycle of tegaserod or placebo. It is noteworthy that tegaserod appeared even more effective at alleviating patients’ IBS symptoms during retreatment, the effect being approximately 16% greater than observed with placebo for both overall IBS-C symptoms and abdominal pain relief. This finding is of considerable importance given that IBS is a chronic, intermittent disorder, and therefore, likely to require long-term, intermittent therapy.

Most physicians in Europe agree that IBS is not adequately treated, if indeed it is treated at all. The therapies IBS-C patients in Europe generally receive include antispasmodics, unspecified stool softeners, or laxatives, coupled with dietary recommendations. While some patients’ symptoms are managed effectively by such means, others feel their symptoms are not properly addressed. Furthermore, the safety and efficacy of many of these agents have not been established in clinical trials, and some are associated with side effects that exacerbate other symptoms of IBS, such as increased bloating and abdominal pain.[Brandt et al. 2002] Given the multiple symptoms that IBS patients experience, based on the complex aetiology of this disorder, it is quite clear that the needs of some patients with IBS cannot be met satisfactorily by simple measures such as bulking agents and reassurance.

Consequently, it is fortunate that this study,[Tack et al. 2005] together with clinical experiences in countries where tegaserod is available, show that previously unmet needs of IBS-C patients can be significantly improved by intermittent cycles of tegaserod therapy during symptom relapse. Firstly, the most intriguing clinical symptoms of IBS-C, namely abdominal pain and discomfort, can be significantly improved by a relatively short period of treatment. Secondly, patients experience sustained improvements in bowel movement frequency and associated constipation problems. Thirdly, additional positive clinical effects can be observed, including relief of long-term symptoms such as bloating, and improvements in patients’ satisfaction with treatment, work productivity and quality of life (QoL) following treatment with tegaserod. These observations are of considerable importance, given the substantial burden IBS places on sufferers’ QoL and their daily activities.

From the patient´s point of view, these data suggest a clear-cut advance in the complicated and frequently undertreated clinical setting of IBS, at least for a large subgroup of women with IBS-C-like symptoms. The publication of these data is welcomed as it gives valuable information on the efficacy of this new treatment in a setting relevant to clinical practice.

疗效和安全性的数据从这个大审判, together with other international clinical trials and the post-marketing experience, (tegaserod was first licensed in the US in 2002 and is currently approved for IBS-C in over 50 countries), demonstrate that tegaserod offers considerable benefits to patients. It has a scientifically established efficacy with a favourable safety profile. Even by using a very critical appraisal, a growing number of clinical researchers and IBS experts agree that this pharmacologic treatment should also be made available in the European Union, where it will resolve at least some of the unmet needs that the majority of patients with IBS-C experience. The efficacy and safety of tegaserod, together with the improvements observed in patients’ treatment satisfaction, work productivity, and QoL following treatment, strongly call for licensing of the drug by the CHMP. Licensing of this drug may also help to reduce the use of multiple, suboptimal agents, which do not have established safety profiles, in this patient population.

References

Brandt LJ, Bjorkman D, Fennerty B, Locke R, Olden K, Peterson W, Quigley E, Schoenfield P, Schuster M Talley N. Systematic review on the management of irritable bowel syndrome in North America. Am J Gastroenterol 2002;97 (11 Suppl):S7–S26.

CPMP. Points to consider on the evaluation of medicinal products for the treatment of irritable bowel syndrome. 2003;(CPMP/EWP/785/97).

Tack J, Muller-Lissner S, Bytzer P, Corinaldesi R, Chang L, Viegas A, Schnekenbuehl S, Dunger-Baldauf C Rueegg P. A randomised controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation (IBS-C). Gut 2005;54:1707- 1713.

Dear Editor,

In his recent Gut commentary, Pinzani discusses approaches to non- invasive evaluation of liver fibrosis and addresses some of the methods currently under investigation.(1) We agree that liver histology is a surrogate end-point and Pinzani emphasises the need for longitudinal studies based on hard clinical endpoints. However, he states "At present, CT and MR can indicate the presence of cirrhosis with high specificity but with very low sensitivity". In reply, we wish to counter this statement and would like to emphasise data from emerging technologies, including magnetic resonance spectroscopy (MRS), ultrashort echo time (UTE) MR imaging (MRI) and microbubble ultrasound.

For example, we have used in vivo 31P MRS to characterise hepatic fibrosis in chronic hepatitis C (CHC) infection (2). The phosphomonoester to phosphodiester (PME/PDE) ratio provided an index of cell membrane turnover and was found to correlate closely with disease severity assessed by liver histology (Ishak system). A PME/PDE ratio ≥0.3 provided a sensitivity and specificity of 82% and 81% respectively for the diagnosis of cirrhosis, comparable to many indirect serological markers.(1) There was a monotonic increase in PME/PDE ratio with increasing disease activity and statistically significant differences between mild hepatitis, moderate/severe hepatitis and cirrhosis.(2) We also demonstrated the potential utility of UTE MRI (3) and showed the relaxation time, T2*, was significantly different between controls and patients with cirrhosis. Functionally-decompensated liver disease (Child's grade C) differed significantly from functionally-compensated liver disease (Child's A/B). Significant differences in diffusion-weighting MRI indices between patients with cirrhosis and normal volunteers have also been reported.(4)

Pinzani highlighted the controversy surrounding usage of Doppler- ultrasonography (US) parameters. The study he cited of Doppler-US indexes, in conjunction with clinical signs and biochemical measures, should be interpreted with caution, since the diagnostic accuracy of Doppler-US variables on an intention to diagnose basis was 87%, based on a protocol in which three variables were assessed in a step-wise manner.(5) However, in contrast, our analysis of Doppler-US in assessment of CHC fibrosis demonstrated no significant difference between Doppler indexes with increasing severity of liver disease.(6)

It should be noted that US microbubble contrast agents have also been employed to evaluate liver fibrosis, through hepatic vein transit time (HVTT) measurements.(7;8) HVTT decreases with increasing severity of liver disease, due to associated circulatory changes, which include arterialisation of the hepatic sinusoidal bed, the presence of intrahepatic and intrapulmonary shunting and the hyperdynamic circulation present in patients with cirrhosis.(7) An HVTT of less than 24s was 100% sensitive and 96% specific for the diagnosis of cirrhosis.(7;9) In a cohort of 85 CHC patients, HVTT demonstrated 100% sensitivity and 80% specificity for cirrhosis, and 95% sensitivity and 86% specificity for differentiation of mild hepatitis from more severe liver disease.(8) There was also a significant difference between moderate/severe hepatitis and these groups. Such a clear difference between Ishak grades of disease severity may, perhaps, inform treatment decisions.

对于一个非侵入性biomarker of liver disease to be employed in a clinical setting, its place in clinical practice must be appraised. In the context of CHC, a role in the decision to start antiviral therapy and in monitoring of treatment response would be important. Biomarkers may also have a role in the stratification of patients with cirrhosis according to risk of clinical outcomes, such as variceal bleeding and the development of hepatocellular carcinoma, as has been suggested for transient elastography by Foucher and colleagues.(10) While it is ideal to find a single biomarker, a profile of tests embracing different modalities, including imaging and serological markers is more realistic and will probably add value to clinical management algorithms.

Reference List

(1) Pinzani M. Non-invasive evaluation of hepatic fibrosis: don't count your chickens before they're hatched. Gut 2006;55(3):310-2.

(2) Lim AK, Patel N, Hamilton G et al. The relationship of in vivo 31P MR spectroscopy to histology in chronic hepatitis C. Hepatology 2003;37(4):788-94.

(3) Chappell KE, Patel N, Gatehouse PD et al. Magnetic resonance imaging of the liver with ultrashort TE (UTE) pulse sequences. J Magn Reson Imaging 2003;18(6):709-13.

(4) Aube C, Racineux PX, Lebigot J et al. [Diagnosis and quantification of hepatic fibrosis with diffusion weighted MR imaging: preliminary results]. J Radiol 2004;85(3):301-6.

(5) Aube C, Winkfield B, Oberti F et al. New Doppler ultrasound signs improve the non-invasive diagnosis of cirrhosis or severe liver fibrosis. Eur J Gastroenterol Hepatol 2004;16(8):743-51.

(6) Lim AK, Patel N, Eckersley RJ et al. Can Doppler sonography grade the severity of hepatitis C-related liver disease? AJR Am J Roentgenol 2005;184(6):1848-53.

(7) Albrecht T, Blomley MJ, Cosgrove DO et al. Non-invasive diagnosis of hepatic cirrhosis by transit-time analysis of an ultrasound contrast agent. Lancet 1999;353(9164):1579-83.

(8) Lim AK, Taylor-Robinson SD, Patel N et al。消息灵通的atic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C. Gut 2005;54(1):128-33.

(9) Albrecht T, Blomley MJ, Cosgrove DO et al. Transit-time studies with levovist in patients with and without hepatic cirrhosis: a promising new diagnostic tool. Eur Radiol 1999;9 Suppl 3:S377-S381.

(10) Foucher J, Chanteloup E, Vergniol J et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006;55(3):403-8.