A randomized, prospective cross-over trial comparing methylene blue-directed biopsy and conventional random biopsy for detecting intestinal metaplasia and dysplasia in Barrett's esophagus.

BACKGROUND AND STUDY AIMS: The value of methylene blue-directed biopsies (MBDB) in detecting specialized intestinal metaplasia and dysplasia in Barrett's esophagus remains unclear. The aim of this study was to compare the accuracy of MBDB with random biopsy in detecting intestinal metaplasia and dysplasia in patients with Barrett's esophagus. PATIENTS AND METHODS: A prospective, randomized, cross-over trial was undertaken to compare MBDB with random biopsy in patients with Barrett's esophagus segments 3 cm or more in length without macroscopic evidence of dysplasia or cancer. Dysplasia was graded as: indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, or carcinoma, and was reported in a blinded fashion. RESULTS: Fifty-seven patients were recruited, 44 of whom were male. A total of 1,269 biopsies were taken (MBDB-651, random biopsie-618). Analysis of the results by per-biopsy protocol showed that the MBDB technique diagnosed significantly more specialized intestinal metaplasia (75 %) compared to the random biopsy technique (68 %; P = 0.032). The sensitivity and specificity rates of MBDB for diagnosing specialized intestinal metaplasia were 91 % (95 % CI, 88 - 93 %) and 43 % (95 % CI, 36 - 51 %), respectively. The sensitivity and specificity rates of MBDB for diagnosing dysplasia or carcinoma were 49 % (95 % CI, 38 - 61 %) and 85 % (95 % CI, 82 - 88 %), respectively. There were no significant differences in the diagnosis of dysplasia and carcinoma - MBDB 12 %, random biopsy 10 %. The methylene blue staining pattern appeared to have an influence on the detection of specialized intestinal metaplasia and dysplasia/carcinoma. Dark blue staining was associated with increased detection of specialized intestinal metaplasia (P < 0.0001), and heterogeneous staining (P = 0.137) or no staining (P = 0.005) were associated with dysplasia and/or carcinoma detection. The MBDB technique prolonged the endoscopy examination by an average of 6 min. CONCLUSION: The diagnostic accuracy of the MBDB technique was superior to that of the random biopsy technique for identifying specialized intestinal metaplasia, but not dysplasia or carcinoma. The intensity of methylene blue staining has an influence on the detection of specialized intestinal metaplasia and dysplasia or carcinoma, which may help in targeting the biopsies. Although MBDB prolongs the endoscopy procedure slightly, it is a safe and well-tolerated procedure. Further clinical studies on the MBDB technique exclusively in endoscopically normal dysplastic Barrett's esophagus are needed.

Photodynamic therapy (PDT) for oesophageal dysplasia and early carcinoma with mTHPC (m-tetrahydroxyphenyl chlorin): a preliminary study.

Barrett's oesophagus is a premalignant condition in which stratified squamous type mucosa of the normal oesophagus is replaced by specialised intestinal type columnar mucosa. Oesophageal resection was previously considered to be the treatment of choice for high-grade dysplasia or superficial carcinoma arising in this columnar-lined mucosa. We treated four patients with Barrett's oesophagus and high-grade dysplasia, and one patient with superficial oesophageal carcinoma with photodynamic therapy (PDT) using an argon-pumped dye laser light (652 nm). PDT was also delivered using a xenon arc lamp (Paterson lamp, light 652 nm +/- 15 nm) in two patients with Barrett's oesophagus and high-grade dysplasia. mTHPC (m-tetrahydroxyphenyl chlorin) 0.15 mg/kg was used as a photosensitiser in all the patients. We have been able to demonstrate the elimination of columnar-lined oesophageal mucosa, reduction in the length of the Barrett's segment or downgrading of the dysplasia in all of the patients. There is no evidence of recurrence in the patient who had oesophageal carcinoma, at 27 months follow-up. We conclude that mTHPC is useful as a photosensitiser for PDT in the management of Barrett's oesophagus with high-grade dysplasia or superficial carcinoma and the Paterson lamp is a potential alternative light source for PDT.

An update in the palliative management of malignant dysphagia.

BACKGROUND: Oesophageal cancer is generally associated with late presentation and poor prognosis. Therefore palliative surgery has been largely superseded by less invasive non-surgical techniques. Once palliation is indicated, the aims of the management should be: the maintenance of oral intake, minimizing hospital stay, relief of pain, elimination of reflux and regurgitation and the prevention of aspiration. METHODS: This study was a review of all published English language data on the palliation of malignant dysphagia between 1994-1999. The Medline and Bids databases were searched and other references were derived from the material perused. RESULTS AND CONCLUSIONS: Palliative treatment for oesophageal cancer should be individualized and relate to tumour stage, size and location, the patient's medical condition and his/her personal wishes. The palliative treatment largely includes self-expanding metal stents (SEMS), laser (including photodynamic therapy (PDT)) or a combination of the two to relieve symptoms, this may be employed with or without other treatments such as radiotherapy/chemotherapy (RT/CT) with the aim of reducing tumour bulk and possibly prolonging survival. A multi-disciplinary approach is vital in patients with advanced oesophageal cancer.

Photodynamic therapy using 5-aminolaevulinic acid for oesophageal adenocarcinoma associated with Barrett's metaplasia.

Photodynamic therapy (PDT) is a novel technique for local endoscopic treatment of gastrointestinal neoplasia. Current photosensitisers for PDT may cause prolonged skin phototoxicity. 5-Aminolaevulinic acid (ALA), a precursor of the photosensitiser protoporphyrin IX (PpIX), is more acceptable because of its short half-life and preferential accumulation in mucosa and mucosal tumour. We have treated 12 patients, median age 73 years (range 55-88) with oesophageal adenocarcinoma arising from Barrett's metaplasia (two carcinomas-in-situ, grade 0; 10 carcinomas, grade 1-11A based on endoluminal ultrasound in two and CT scanning in 10 patients). ALA (60 and 75 mg/kg body weight) was given orally in two or five equally divided doses. The PpIX distribution in stomach, normal oesophagus, Barrett's mucosa and carcinoma was measured by quantitative fluorescence photometry. PDT was performed using laser light (630 nm) delivered via a cylindrical diffuser 4-6 h after the first dose of ALA. The patients received one to four sessions of PDT. PpIX accumulation in the mucosa was two to three times that in the lamina propria. The differential distribution between carcinomatous and normal oesophageal mucosa was less marked (carcinoma:normal mucosa ratio = 1.4). Higher doses of ALA increased PpIX accumulation in all tissues but did not increase the differential PpIX distribution between tumour and normal oesophageal mucosa. After PDT using ALA (ALA/PDT), all mucosa showed superficial white necrotic changes and the histology confirmed fibrinoid necrosis. One patient with carcinoma-in-situ had the tumour eradicated after one treatment with no recurrence at 28 months. Another patient with a small T1 tumour required four ALA/PDT treatments, and died of other disease after 36 months. There was no evidence of recurrence. The tumour bulk in the other carcinomas was not significantly reduced. ALA/PDT has a potential for the eradication of small tumours but careful patient selection with endoluminal ultrasound is needed when using ALA/PDT to treat oesophageal cancer.

Laser therapy in maintenance of the patency of expandable metal stents.

Re-establishment of the oesophageal lumen is the main focus of care in patients with dysphagia due to re-blockage of in situ expandable metal stent (EMS). A total of 51 patients aged 44-89 years were intubated with EMS for dysphagia due to inoperable oesophagogastric carcinoma. Of these patients, 25 required follow-up endoscopy at variable intervals after stent insertion; 17 patients were found to have significant tumour in-growth (9), overgrowth (4) or both (4). All these patients were treated with Nd-YAG (70 W/s) or diode laser (30-50 W, continuous) for maintenance of satisfactory swallowing. The intensity of tumour ablation was similar with both types of lasers but four patients being treated with Nd-YAG laser developed deformity of EMS. This complication was not encountered with diode laser. The timing of the stent insertion should be carefully chosen since the longer the stent is in situ, the greater is the likelihood of tumour ingrowth or overgrowth. The combination of endoscopic laser therapy (ELT) and EMS may offer the best palliation, particularly when patient survival of several months is anticipated. ELT can effectively deal with tumour in-growth and overgrowth but care must be exercised in the use of Nd-YAG which can damage the structure of the EMS.

Enhancement of photodynamic therapy in gastric cancer cells by removal of iron.

BACKGROUND: Aminolaevulinic acid (ALA) is an endogenous substrate in the haem biosynthetic pathway. Protoporphyrin IX (PPIX), the immediate haem precursor in the pathway, has photoexcitable properties. Exogenous ALA has been used previously as a precursor agent in photodynamic therapy (PDT). Its main advantage is a short half-life and hence reduced incidence of skin photosensitivity. ALA can be toxic, however, causing, for example, transient increases in liver enzyme concentrations when given systemically and this may be dose related. AIM: To assess whether accumulation of PPLX and ultimately the efficacy of PDT could be improved by modulating both ends of the haem biosynthetic pathway. METHODS: Gastric cancer cells (MKN 28) were incubated with ALA (0-1000 mumolar) and desferrioxamine (0-800 mumolar) for 24 hours before exposure to argon-pumped dye laser (630 nm) at different energy levels (0-40 J/cm2). Cell viability was assessed by use of the methyl-tetrazolium (MTT) assay four hours after exposure to light. RESULTS: Total PPIX accumulation increased linearly with increasing extracellular concentrations of ALA up to 1 mmolar (r = 0.973, p < 0.005). Adding 200 molar of desferrioxamine trebled PPIX accumulation over the same period of incubation. Cell viability after exposure to light decreased with low doses (0-30 mumolar) of desferrioxamine (r = 0.976, p = 0.024). However, higher doses of desferrioxamine (more than 40 molar) seemed to confer a protective effect against PDT. CONCLUSION: PDT using ALA can be improved by removal of available iron with desferrioxamine. The reason for the protective effect of desferrioxamine seen at higher doses is not clear.

Helicobacter pylori eradication--comparison of three drug regimens and symptomatic assessment in duodenitis and antral gastritis.

Helicobacter pylori (Hp) eradication in peptic ulcer disease is associated with a greatly reduced recurrence rate. The optimal drug regimen for HP eradication remains uncertain. It is also unclear if eradication of Hp in duodenitis and antral gastritis improves symptoms. The aims of this study were to compare the efficacy of three drug regimens in the eradication of Hp and to assess if Hp eradication improved symptoms in patients with duodenitis and antral gastritis. Patients (n = 79) found to have duodenal ulcer, duodenitis and/or antral gastritis with a positive urease test (CLO) at endoscopy were allocated to one of the three regimens: A. omeprazole 20 mg b.d. and clarithromycin 500 mg t.d.s. for two weeks (n = 27), B. De-Nol 240 mg b.d. for four weeks, metronidazole 400 mg t.d.s. and amoxicillin 500 mg t.d.s. for one week (n = 26), and C. omeprazole 20 mg b.d. and amoxicillin 500 mg t.d.s. for two weeks (n = 26). In conclusion, traditional 'triple' therapy with bismuth and two antibiotics achieved the highest Hp eradication rate and was best tolerated. Recolonisation with Hp was uncommon after eradication. Dyspeptic symptoms improved with Hp eradication in duodenitis and antral gastritis.

Eradication of high-grade dysplasia in columnar-lined (Barrett's) oesophagus by photodynamic therapy with endogenously generated protoporphyrin IX.

BACKGROUND: High-grade dysplasia in columnar-lined (Barrett's) oesophagus presents a difficult therapeutic dilemma. Choices for management are endoscopic surveillance to detect a cancer or oesophagectomy. One carries the risk of missing invasive cancer, the other carries worrying morbidity and mortality. We have used endoscopic photodynamic therapy to eradicate high-grade dysplasia. METHODS: After the oral administration of 5-aminolaevulinic acid, the accumulation of the endogenously generated photosensitiser protoporphyrin IX was measured with quantitative fluorescence microscopy. Five patients with histologically confirmed high-grade dysplasia were treated with endoscopic photodynamic therapy with 630 nm laser light to activate the photosensitiser. FINDINGS: Protoporphyrin IX accumulated in the dysplastic epithelium rather than the adjacent stroma. Selective necrosis of the dysplastic epithelium in columnar-lined oesophagus occurred after light activation. High-grade dysplasia was eradicated in all patients and squamous regeneration occurred after acid suppression with a protonpump inhibitor. There were no complications or recurrence of dysplasia after 26-44 months' endoscopic and histological follow-up. In two cases we saw non-dysplastic Barrett's epithelium underneath regenerative squamous mucosa. INTERPRETATION: High-grade dysplasia in columnar-lined oesophagus can be eradicated by endoscopic photodynamic therapy with endogenously generated PpIX. Remaining non-dysplastic Barrett's epithelium will require surveillance, but overall the technique has interrupted or delayed the worsening of the dysplasia through to carcinoma. This technique may prevent the need for surgical excision in these patients.

Mucosal ablation using photodynamic therapy for the treatment of dysplasia: an experimental study in the normal rat stomach.

Surgery is the only effective treatment for dysplasia in the gastrointestinal tract with considerable associated morbidity and mortality and is difficult to justify without confirmed malignancy. Photodynamic therapy (PDT) produces localised necrosis, which can be limited to the mucosa. This study examined the mechanical properties of the normal rat stomach after PDT. The aim of this study was to measure the bursting pressure of PDT lesions in the stomach and to assess gastric emptying after producing circumferential mucosal necrosis at the pylorus by PDT. Two photosensitising agents were used--5-aminolaevulinic acid (ALA), and aluminium disulphonated phthalocyanine (A1S2Pc). Normal rats were sensitised and PDT lesions created in the stomach with red light. The bursting pressure was measured and compared with that in thermal control lesions. In further experiments, circumferential mucosal necrosis was produced at the pylorus, and animals observed for subsequent eating and weight gain. It was found that gastric bursting pressure was reduced after thermal injury, but not at any time after PDT (with A1S2Pc, but not ALA, adhesive omental reinforcement was required to maintain the gastric wall strength at one week). For the pyloric lesions, gastric emptying was permanently impaired using A1S2Pc, but with low dose ALA (20 mg/kg) had returned to normal by three days. With ALA, but not A1S2Pc, necrosis could be limited to the mucosa. In conclusion, using ALA, selective ablation of the gastric mucosa is possible, which does not reduce the strength of the stomach and only temporarily delays gastric emptying. PDT is a promising technique for the circumferential ablation of dysplastic mucosa.

Photodynamic therapy for villous adenomas of the colon and rectum.

Endoscopic thermal laser therapy of colorectal villous adenomas is associated with a high recurrence rate due to incomplete tumor ablation, as treatment over carries a risk of perforation. Photodynamic therapy has been shown to be a promising in the treatment of small malignant tumors, and may be useful for benign adenomas. Eight patients with nine colosigmoid villous adenomas measuring 1-5 cm in length were treated with photodynamic therapy using either haematoporphyrin derivative or Photofrin as photosensitizer and multiple (4-16) applications of interstitial photoirradiation with red light (630 nm, 100 mW x 500 s per application). All but one adenoma had previously been incompletely treated with Nd-YAG laser therapy. Some skin sensitivity to light was seen in one patient. Seven adenomas were eradicated (follow-up 9-56 months, median = 12) as judged by follow-up endoscopy and biopsy. No local complications were seen. Substantial necrosis was produced in the other two adenomas, but they were not completely destroyed, probably due to inadequate light. PDT holds promise in the non-surgical management of villous adenomas, particularly after initial tumour debulking with the Nd-YAG laser.

The effect of antioxidant supplementation on a serum marker of free radical activity and abnormal serum biochemistry in alcoholic patients admitted for detoxification.

Alcoholics admitted for detoxification were entered into a double blind placebo controlled trial of oral supplementation with an antioxidant cocktail (vitamin E, beta carotene, vitamin C and selenium) in order to determine the effect of this supplementation on the rate of resolution of a serum marker of free radical activity and abnormal serum biochemistry. The molar proportion of linoleic acid that was diene conjugated (a marker of free radical activity), was increased in the alcoholics 2.9% +/- 1.2 (mean +/- S.D.) compared to normal controls 1.3% +/- 0.6 (P < 0.0001) but fell at a similar rate during the first week of hospitalisation in supplemented and placebo-treated patients with a mean fall of 53.7% (+/- 16.4 S.D.) in the placebo group and 56.0% (+/- 23.7) (P = 0.32, NS) in the antioxidant supplemented group. Similarly, there was no difference in the rate of fall between serum aspartate transaminase (AST) concentration in the two groups: the placebo group falling by a mean of 68.9% (+/- 35.2) and the antioxidant supplemented group falling by 70.1% (+/- 10.0) (P = 0.41, NS) over the first 7 days of hospitalization. Alcoholics had low serum concentrations of vitamin E compared with controls (15.6 mg/l +/- 6.2 S.D.) which rose more in the supplemented group over the period of a week (7.7 mg/l +/- 4.4 to 21.6 mg/l +/- 5.1) (a mean rise of 180.5%) compared with the placebo group (8.6 mg/l +/- 6.8 to 9.6 mg/l +/- 5.7)--a mean rise of 11.6% (P = 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)

Oral versus intravenous administration of 5-aminolaevulinic acid for photodynamic therapy.

Endogenously synthesised protoporphyrin IX (PpIX) following the administration of 5-amino-laevulinic acid (ALA) is an effective photosensitiser for photodynamic therapy (PDT). Following intravenous administration, PpIX accumulates predominantly in mucosa of hollow viscera and on light exposure, mucosal ablation results with relative sparing of the submucosa and muscularis layers. Oral administration is effective with ALA in contrast to conventional exogenous photosensitisers such as haematoporphyrin derivative and phthalocyanines. Oral administration of ALA is also simpler, safer, cheaper and more acceptable to patients. We studied the porphyrin sensitisation kinetics profile in the stomach, colon and bladder in normal rats following enterally and parenterally administered ALA using microscopic fluorescence photometric studies of frozen tissue sections. Mucosal cells in all three organs exhibit higher fluorescence levels as compared with underlying smooth muscle following both intravenous and oral administration. Peak concentration were seen 4 h after sensitisation at the highest doses used (200 mg kg-1 i.v., 400 mg kg-1 oral), and slightly earlier with lower doses. The temporal kinetics of both routes of administration were similar although a higher oral dose was required to achieve the same tissue concentration of PpIX. The highest level of fluorescence was achieved in the gastric mucosa and in decreasing levels, colonic and bladder mucosa. A similar degree of mucosal selectivity was achieved in each organ with each route of administration but an oral dose in excess of 40 mg kg-1 was required to achieve measurable PpIX sensitisation. In a pilot clinical study, two patients with inoperable rectal adenocarcinomas were given 30 mg kg-1 and one patient with sigmoid colon carcinoma was given 60 mg kg-1 ALA orally. Serial biopsies of normal and tumour areas were taken over the subsequent 24 h. Fluorescence microscopy of these specimens showed maximum accumulation of PpIX 4 to 6 h after administration of 30 mg kg-1 ALA. There was greater PpIX accumulation in tumour than adjacent normal mucosa in two patients. Preferential PpIX accumulation in tumour was greater in the patient receiving 60 mg kg-1 ALA.

Is the endoscopic view too narrow?

Palliative laser therapy for gastrointestinal tumors is now well established. Its use however may be associated with complications not directly attributable to the laser therapy. These complications potentially decrease the quality of life which opposes the aim of treatment.

Photodynamic therapy of the normal rat stomach: a comparative study between di-sulphonated aluminium phthalocyanine and 5-aminolaevulinic acid.

Dysplasia in the upper gastrointestinal tract carries a risk of invasive malignant change. Surgical excision of the affected organ is the only treatment available. Photodynamic therapy has been shown to be promising in the treatment of early and superficial tumours and may be useful for the ablation of dysplastic mucosa. Because of the diffuse nature of the disease, such treatment would necessarily involve destruction of large areas of mucosa and it is desirable to confine its effect to the mucosa in order that safe healing can take place. By means of photometric fluorescence microscopy, we have studied the pattern of photosensitisation in the normal rat stomach using di-sulphonated aluminium phthalocyanine (AlS2Pc) and 5-aminolaevulinic acid (ALA) as photosensitisizers. AlS2Pc resulted in a panmural photosensitisation of the gastric wall with the highest level encountered in the submucosa. The mucosa and muscularis propria were sensitised to equal extent. Following light exposure, a full thickness damage resulted. ALA is a natural porphyrin precursor and exogenous administration gave rise to accumulation of protoporphyrin IX (PPIX) in the cells. The resultant pattern of photosensitisation was predominantly mucosal and its photodynamic effect was essentially confined to the mucosa. ALA produced a selective photosensitisation of the gastric mucosa for its photodynamic ablation with sparing the underlying tissue layers.

Prospective quality-of-life analysis after palliative photoablation for the treatment of malignant dysphagia.

Forty patients were treated for the relief of malignant dysphagia by using laser photoablation. Their quality of life was assessed before the start of treatment and at monthly intervals until death. Two methods were used, a physician's assessment (QL index) and a patient's self-assessment, the linear analogue self-assessment (LASA). There was significant correlation between assessments done at different times by different physicians (QL index rs, 0.786; P less than 0.001; LASA rs, 0.865; P less than 0.001). The correlation coefficient of the QL index and the LASA score with the patient's dysphagia grade was 0.459 and 0.336, respectively. The patient's swallowing ability, QL index, and LASA all were improved significantly at some time after laser therapy. The mean survival was 16 weeks with 58% of patients dying at home, 28% in the hospital, and 18% in a hospice. It was concluded that laser photoablation improves the overall quality of life in patients with malignant dysphagia.

Enteral feeding as sole treatment for Crohn's disease: controlled trial of whole protein v amino acid based feed and a case study of dietary challenge.

A controlled trial was performed to compare enteral feeding with either an amino acid based feed or a whole protein feed as sole treatment for active Crohn's disease. Twenty four patients were studied (nine with ileal, 11 with ileocolonic, and four with colonic disease). Both feeds proved effective; nine of 13 patients randomised to receive the amino acid based feed were in clinical remission within three weeks as defined by a simple activity index compared with eight of 11 treated with the whole protein feed. Patients in clinical remission were then crossed over onto the other feed. None of the six patients who were changed to the whole protein feed relapsed over the subsequent three week period compared with three of seven patients who were changed to the amino acid based feed. In responders the median serum C reactive protein concentration fell from 21 mg/l (range 9-82) on entry to 6 mg/l (range 3-19) at six weeks. Seven patients relapsed within eight months of starting solid food (mean 3.7 months), while nine were still in remission (follow up period 3-9 months, median six months). Detailed studies of staged reintroduction of food and permitted food additives were carried out over a four year period in a patient with extensive stricturing small bowel Crohn's disease who had been brought into remission by open treatment with enteral feeding. Carrageenan, other permitted emulsifiers, bread, meat, potatoes, oranges, refined sugar, dairy produce, flour, and rice were all reintroduced without any objective ill effect, but green vegetables provoked a clinical and biochemical relapse within one week of introduction. Remission was rapidly achieved by switching back to the enteral feed but reintroduction of the low residue diet that had been previously tolerated produced a brisk relapse. Clinical and biochemical remission was again achieved by a return to the enteral feed but relapse again occurred with reintroduction of the low residue diet. These studies confirm the therapeutic effect of enteral feeding in Crohn's disease. This effect does not seem to be due to avoidance of whole protein, but the very low residue of chemically defined enteral feeds may be important, particularly in patients with intestinal strictures.