Clinical trial: randomized study of clarithromycin versus placebo in active Crohn's disease.

BACKGROUND: Crohn's disease is characterized by defective innate immune responses to intestinal bacteria. Clarithromycin is a broad-spectrum antibiotic that has good penetration into macrophages. AIM: To assess the efficacy of clarithromycin in active Crohn's disease. METHODS: Patients with Crohn's disease activity index > 200 and serum C-reactive protein > or = 10 mg/L were randomized to receive clarithromycin 1 g o.d. or placebo for 3 months. Patients taking more than 10 mg/day prednisolone or 3 mg/day budesonide were excluded. Primary outcome was remission (CDAI < or = 150) or response (fall in CDAI > or = 70 from pre-treatment level) at 3 months. RESULTS: The trial was stopped after 41 patients had been recruited because of poor overall efficacy. There was no difference in combined remission or response rates at 3 months between clarithromycin: 26% (five of 19) and placebo: 27% (six of 22) (P = 1.00). The mean (s.d.) fall in Crohn's disease activity index was 35 (80) clarithromycin and -2 (114) placebo (P = 0.24). However, post hoc analysis showed a significant difference in response/remission determined by Crohn's disease activity index after 1 month: 53% (10 of 19) clarithromycin vs. 14% (three of 22) placebo (P = 0.01). CONCLUSION: Clarithromycin 1 g for 3 months is ineffective in active Crohn's disease but possible benefit was observed at 1 month, suggesting that an initial effect may be attenuated by subsequent bacterial resistance.

Treatment of radiation proctitis.

Late complications of pelvic radiotherapy occur in 5-20% of patients, particularly chronic radiation proctitis (CRP). Rectal bleeding is the most common symptom. Other symptoms include difficulty in defaecation or tenesmus because of loss of distensibility of the rectum or rectal structuring. Treatment options of CRP include oral therapy (5-aminosalicylates, metronidazole), rectal instillation therapy (hydrocortisone, sucralfate, 5-aminosalicylates, formalin), thermal therapy (argon plasma coagulation, heater probe or laser) and hyperbaric oxygen. It is difficult to recommend evidence-based therapy. There are no adequately powered studies of the treatment of CRP and most data are uncontrolled, non-blinded observation studies from single sites. There are no standard evaluation tools (including endoscopic grading, symptom scores and quality-of-life scores), adequate description of preceding radiotherapy dose or adequate follow-up in most studies. Many studies have poor documentation of complications and few are carried out prospectively. A pragmatic approach is to use sucralfate enemas and oral metronidazole. Thermal methods seem to be effective and safe. Simple heater probe treatment or argon plasma coagulation are the preferred methods due to their better safety profile. Intra-rectal formalin seems to be effective, but possibly has a higher rate of complications. For resistant disease, hyperbaric oxygen may be an option.

Treatment of oesophago-gastric tumours.

The incidence of oesophageal adenocarcinoma continues to rise rapidly in the West whereas cancer of the stomach is becoming less common. Most patients present with advanced disease that is not amenable to curative treatment. This review focuses on recent evidence on the endoscopic therapy of oesophago-gastric cancer. Although there are many treatment modalities available, there is a paucity of good quality randomised trial evidence on which to base palliative treatment decisions. Furthermore, although palliation of dysphagia may be improved by expandable metal stents or ablative therapy, there is no evidence that this improves survival and each of these therapies has a high frequency of complications particularly in longterm survivors. Exciting developments have however been reported in the therapy of early stage oesophago-gastric cancer. Endoscopic mucosal resection is particularly promising with high rates of complete removal of early cancer or high grade dysplasia. Long-term follow up of these patients is required because of high rates of metachronous tumour formation and at present there are no randomised trial data comparing endoscopic mucosal resection with conventional surgery.

A prospective, randomized, controlled trial of covered expandable metal stents in the palliation of malignant esophageal obstruction at the gastroesophageal junction.

OBJECTIVE: Palliation of malignant esophageal obstruction is an important clinical problem. Expandable metal stents are a major advance in therapy, but many stents become obstructed because of tumor ingrowth. The aim of this study was to compare a new, membrane-covered expandable metal stent to conventional prostheses in a randomized controlled trial. METHODS: Sixty-two patients with malignant inoperable esophageal obstruction at the gastroesophageal junction participated in the study. Patients were randomly assigned to covered or uncovered stents. The principal outcome measure was the need for reintervention because of recurrent dysphagia or migration. Secondary endpoints were relief of dysphagia measured by a dysphagia score (grade 0 = no dysphagia, grade 1 = able to eat solid food, grade 2 = semisolids only, grade 3 = liquids only, grade 4 = complete dysphagia) and the rate of complications and functional status. All patients were observed at monthly intervals until death or for 6 months. RESULTS: One week after stenting the dysphagia score improved significantly in both the uncovered (n = 32, 3 +/- 0.1 to 1 +/- 0.1 [means +/- SEMs], p < 0.001) and covered (n = 30, 3 +/- 0.1 to 1 +/- 0.2 [means +/- SEMs], p < 0.001) stents. Obstructing tumor ingrowth was significantly more likely in the uncovered stent group (9/30) than in the covered group (1/32) (p = 0.005). Significant stent migration occurred in 2/30 patients with uncovered stents, as compared with 4/32 patients in the covered group (p = 0.44). Reinterventions for tumor ingrowth were significantly greater in the uncovered stent group (27%), as compared with 0% in the covered group (p = 0.002). Life table analysis showed similar survival in both groups. CONCLUSION: Membrane-covered stents have significantly better palliation than conventional bare metal stents because of decreased rates of tumor ingrowth that necessitate endoscopic reintervention for dysphagia.

Open label trial of oral clarithromycin in active Crohn's disease.

BACKGROUND: Crohn's disease seems likely to be due in some way to bacteria. Clarithromycin is a broad spectrum macrolide antibiotic with good penetration into macrophages and may be effective in eradicating the organisms that are presumed to be at the centre of the granulomatous reaction in Crohn's disease. METHODS: Twenty-five patients with active Crohn's disease were treated with oral clarithromycin 250 mg b.d. in an open label study. Treatment was for an initial 4-week period, continued to 12 weeks in patients who had shown a partial or complete response. The patients had a median age of 30 years (range 17-72), and disease duration of 5 years (range 2 months-28 years); 14 had ileocolonic, four small bowel, seven colonic disease and 10 had previous resections. Twenty patients were receiving a 5-ASA preparation, 15 corticosteroids (prednisolone median dose 10 mg range 2-30 mg) and nine azathioprine. All patients receiving corticosteroids or azathioprine had been on unchanged treatment for at least 12 weeks. RESULTS: Median pre-treatment Harvey Bradshaw index (HBI) was 9 (range 5-16) and median serum C-reactive protein was 21.5 mg/L (range < 5-117). By 4 weeks the median HBI had decreased to 5 (range 0-18) (P < 0.001) and median CRP to 17 mg/L (range < 5-157) (P=0.16). Sixteen patients (64%) had at least a 3 point fall in HBI and remission (defined as a HBI less than or equal to 4) was achieved in 12 patients (48%). By 12 weeks median HBI was 5 (range 0-18) (P < 0.001) and median CRP was 14.5 mg/L (range < 5-157) (P=0.05). Eleven of the 25 patients studied continued on oral clarithromycin after 12 weeks for a median of 28 weeks (range 20-60). Eight (73%) remained in remission on treatment. When treatment with clarithromycin was stopped three remained in remission and five relapsed after a median of 5 months (range 4-9). Two patients withdrew due to non-serious side-effects. Treatment was well tolerated in the remaining patients. CONCLUSION: This open label study has shown an impressive response to clarithromycin in a group of patients with active Crohn's disease, many of whom had been resistant to other therapy. A formal randomized controlled trial of clarithromycin in active Crohn's disease is needed.

Enteroscopy.

It is now more than 25 years since small bowel enteroscopy (SBE) was first described. For several reasons, this technique developed more slowly than other more usual forms of endoscopy. First, small bowel disease is relatively rare in comparison with other gastrointestinal diseases. Also, there was lack of initial design agreement, and three different types of enteroscopes were developed within a short time of each other, two of which (push-type and sonde) are now available commercially. Finally, commercial interests of the manufacturers of endoscopes were mainly focused on the more conventional, large volume markets. In the last few years, specifically designed modern small bowel enteroscopes have become available and, in centers that have access to them, they have superseded attempts at SBE using adult or pediatric colonoscopes. There are now clear indications for SBE, such as: the investigation of obscure causes of bleeding and anemia; malabsorption; clarification of x-ray abnormalities; and, increasingly, the application of therapeutic endoscopy to lesions within the small bowel. Problem areas remain, but with advancing technology and more professional interest in this area, these will be addressed during the next few years.

New classification of oesophageal and gastric carcinomas derived from changing patterns in epidemiology.

The current ICD-O classification of carcinomas of the oesophagus and stomach causes epidemiological and clinical confusion. This study compares the epidemiological and clinical features of each subtype and subsite of adenocarcinomas of the oesophagus and stomach, to assess requirements for a new classification of these carcinomas. Data were extracted with appropriate validity checks on all cases of oesophageal and gastric carcinomas identified throughout the period 1974-1993 by the Merseyside and Cheshire Cancer Registry, which covers a population of 2.5 million. The incidence of adenocarcinomas of the lower oesophagus and cardia trebled in males, and doubled in females, whereas adenocarcinoma of the subcardia region of the stomach declined in both sexes. Adenocarcinomas of the lower oesophagus and of the cardia were similar for median age at diagnosis, male to female ratio, percentage of patients who smoked and survival; both were significantly different from carcinomas of the subcardia in these respects. These data imply that adenocarcinomas of the lower oesophagus and cardia are the same disease. A new subsite classification of oesophageal and gastric carcinomas is proposed that includes the gastro-oesophageal junction as a distinct subsite, to facilitate surveillance, management and research.

Review article: controversy in the therapy of gastro-oesophageal reflux disease--long-term proton pump inhibition or laparoscopic anti-reflux surgery?

The treatment of gastro-oesophageal reflux disease is controversial. Whilst medical treatment is successful in patients with mild to moderate disease, the threshold of severity above which an operation should be contemplated remains a matter for debate. Laparoscopic anti-reflux surgery may be lowering this threshold, as this form of therapy provides several advantages over its open counterpart, but it is not without risk, and few long-term results are available. This article reviews treatment options for reflux disease and examines the relative position of current medical and surgical therapies.

Quinone-induced DNA single strand breaks in a human colon carcinoma cell line.

It has been demonstrated that synthetic quinones, such as menadione, cause DNA damage in different cell systems, possibly being mediated by free radicals generated during redox cycling. It has been suggested that the damage caused could be related to tumor induction in different sites. To our knowledge it has not yet been demonstrated that the natural quinones, vitamin K1 and K2, exert the same activity. Using a colon carcinoma cell line, HT-29, we examined the extent of DNA damage induced by menadione, vitamin K1 and K2. Menadione caused significant DNA damage at low concentrations (25-200 microM) with a linear correlation of r = 0.95. In the presence of dicoumarol, a DT-diaphorase inhibitor, the damage was detected at concentrations five times lower indicating that free radicals generated during the redox cycling play a key role. Neither vitamin K1, incorporated in micelles, nor K2 caused detectable single strand breaks with respect to the controls either in the presence or in absence of dicoumarol. Our results demonstrate that, despite their redox cycling properties, the natural forms of vitamin K do not cause DNA damage in HT-29 cells as menadione does in the experimental conditions used.

Treatment of ulcerative colitis with an engineered human anti-TNFalpha antibody CDP571.

BACKGROUND: Tumour Necrosis Factor-alpha (TNFalpha) is a pro-inflammatory cytokine whose expression is increased in the colonic mucosa of patients with active ulcerative colitis. TNFalpha antibodies have been shown to be beneficial in animal models of bowel inflammation and in Crohn's disease but have not previously been studied in ulcerative colitis. METHODS: Patients with mild/moderate ulcerative colitis were treated openly with a single intravenous infusion of 5 mg/kg of an engineered human IgGgamma4 antibody CDP571 and monitored for 8 weeks. RESULTS: Fifteen patients entered the study, eight males and seven females, with a mean age of 44 years. Eleven had left-sided disease, four extensive disease and six patients were steroid-unresponsive. The treatment was well tolerated and plasma half-life of CDP571 was approximately 7 days. There was a significant reduction from 6.7 to 4.6 (P = 0.023) in the mean Powell-Tuck score by 1 week post-infusion and a reduction to 5.5 was seen at 2 weeks (P = 0.218). Significant but modest reductions also occurred in erythrocyte sedimentation rate and serum C reactive protein in the first 2 weeks. Mean Interleukin-6 plasma concentrations fell from 6.9 to 5.4 pg/mL by week 1, and to 6.1 pg/mL by week 2 (NS). Reductions in sigmoidoscopic score and number of liquid stools were noted but failed to reach statistical significance. CONCLUSION: A consistent improvement in disease activity was seen in the initial 2 weeks after infusion and the treatment was well tolerated. These promising results support the testing of CDP571 in a larger controlled trial.

Treatment of corticosteroid-resistant ulcerative colitis with heparin--a report of 16 cases.

BACKGROUND: Heparin, a group of sulphated glycosaminoglycans, in addition to its anticoagulant activity, has a wide range of potentially anti-inflammatory effects. These include inhibition of neutrophil elastase and inactivation of chemokines. Previous reports of fortuitous improvement in ulcerative colitis patients treated with heparin for prophylaxis of venous thrombosis, prompted us to perform a pilot study in patients with corticosteroid-resistant ulcerative colitis. METHODS: Sixteen hospitalized patients in relapse from ulcerative colitis and unresponsive to high-dose corticosteroid therapy were treated with intravenous standard heparin (subcutaneous in two patients), the dose was adjusted to provide standard anticoagulant activity. Five patients continued with subcutaneous injections on discharge, with a gradual reduction in the frequency of doses. RESULTS: Within 1 week of starting heparin, 12/16 patients had shown a considerable reduction in stool frequency. After 2 weeks of heparin therapy median stool frequency had improved from 8.0/day (range 6.3-10.0) pre-treatment to 3.5/day (2.5-5.25) (P = 0.008), and by 4 weeks 12/16 achieved clinical remission, Four patients required elective colectomy. Three patients were treated with heparin on a second occasion during a relapse, two failed to respond and required subsequent colectomy. Nine remain well. No serious complications were seen due to the anticoagulant activity, apart from bruising at subcutaneous injection sites. CONCLUSION: The response to heparin in patients with ulcerative colitis resistant to standard therapy is encouraging and supports the previous uncontrolled evidence for a therapeutic effect. A controlled trial of heparin in ulcerative colitis is clearly indicated.

Recent developments in the management of Peutz-Jeghers syndrome in childhood.

A combined surgical and endoscopic approach for managing extensive polyposis in a child with Peutz-Jeghers syndrome (PJS) is presented. Application of this technique offers the following advantages over conventional surgical practice -- 1) an accurate assessment can be made of the extent of intestinal polyposis; 2) small polyps can be easily removed endoscopically; 3) endoscopy can direct the operating surgeon to selected enterotomy sites for open excision of larger polyps and 4) multiple laparotomy, extensive intestinal resection(s) and the potential threat of short-gut syndrome in PJS patients may be avoided.