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Background and Aims: Endoscopic surveillance of Barrett's oesophagus currently relies on multiple random biopsies. This approach is time consuming, has a poor diagnostic yield, and significant interobserver variability. Elastic scattering spectroscopy is a real time in vivo optical technique which detects changes in the physical properties of cells. The aim of this study was to assess the potential for elastic scattering to detect high grade dysplasia or cancer within Barrett's oesophagus., Methods: Elastic scattering spectroscopy measurements collected in vivo were matched with histological specimens taken from identical sites within Barrett's oesophagus. All biopsies were reviewed by three gastrointestinal pathologists and defined as either "low risk" (non-dysplastic or low grade dysplasia) or "high risk" (high grade dysplasia or cancer). Two different statistical approaches (leave one out and block validation) were used to validate the model., Results: A total of 181 matched biopsy sites from 81 patients, where histopathological consensus was reached, were analysed. There was good pathologist agreement in differentiating high grade dysplasia and cancer from other pathology (kappa = 0.72). Elastic scattering spectroscopy detected high risk sites with 92% sensitivity and 60% specificity and differentiated high risk sites from inflammation with a sensitivity and specificity of 79%. If used to target biopsies during endoscopy, the number of low risk biopsies taken would decrease by 60% with minimal loss of accuracy. A negative spectroscopy result would exclude high grade dysplasia or cancer with an accuracy of >99.5%., Conclusions: These preliminary results show that elastic scattering spectroscopy has the potential to target conventional biopsies in Barrett's surveillance saving significant endoscopist and pathologist time with consequent financial savings. This technique now requires validation in prospective studies.

Background: Few pancreatic cancers are suitable for surgery and few respond to chemoradiation. Photodynamic therapy produces local necrosis of tissue with light after prior administration of a photosensitising agent, and in experimental studies can be tolerated by the pancreas and surrounding normal tissue., Aims: To undertake a phase I study of photodynamic therapy for cancer of the pancreas., Patients: Sixteen patients with inoperable adenocarcinomas (2.5-6 cm in diameter) localised to the region of the head of the pancreas were studied. All presented with obstructive jaundice which was relieved by biliary stenting prior to further treatment., Methods: Patients were photosensitised with 0.15 mg/kg meso-tetrahydroxyphenyl chlorin intravenously. Three days later, light was delivered to the cancer percutaneously using fibres positioned under computerised tomographic guidance. Three had subsequent chemotherapy., Results: All patients had substantial tumour necrosis on scans after treatment. Fourteen of 16 left hospital within 10 days. Eleven had a Karnofsky performance status of 100 prior to treatment. In 10 it returned to 100 at one month. Two patients with tumour involving the gastroduodenal artery had significant gastrointestinal bleeds (controlled without surgery). Three patients developed duodenal obstruction during follow up that may have been related to treatment. There was no treatment related mortality. The median survival time after photodynamic therapy was 9.5 months (range 4-30). Seven of 16 patients (44%) were alive one year after photodynamic therapy., Conclusions: Photodynamic therapy can produce necrosis in pancreatic cancers with an acceptable morbidity although care is required for tumours invading the duodenal wall or involving the gastroduodenal artery. Further studies are indicated to assess its influence on the course of the disease, alone or in combination with chemoradiation.

Background: Many patients with advanced malignant dysphagia are not suitable for definitive treatment. The best option for palliation of dysphagia varies between patients. This paper looks at a simple technique for enhancing laser recanalisation., Aim: To assess the value of adjunctive brachytherapy in prolonging palliation of malignant dysphagia by endoscopic laser therapy., Patients: Twenty two patients with advanced malignant dysphagia due to adenocarcinoma of the oesophagus or gastric cardia, unsuitable for surgery or radical chemoradiotherapy., Methods: Patients able to eat a soft diet after laser recanalisation were randomised to no further therapy or a single treatment with brachytherapy (10 Gy). Results were judged on the quality and duration of dysphagia palliation, need for subsequent intervention, complications, and survival., Results: The median dysphagia score for all patients two weeks after initial treatment was 1 (some solids). The median dysphagia palliated interval from the end of initial treatment to recurrent dysphagia or death increased from five weeks (control group) to 19 weeks (brachytherapy group). Three patients had some odynophagia for up to six weeks after brachytherapy. There was no other treatment related morbidity or mortality. Further intervention was required in 10 of 11 control patients (median five further procedures) compared with 7/11 brachytherapy patients (median two further procedures). There was no difference in survival (median 20 weeks (control), 26 weeks (brachytherapy))., Conclusions: Laser therapy followed by brachytherapy is a safe, straightforward, and effective option for palliating advanced malignant dysphagia, which is complementary to stent insertion.

Background/aims: A major drawback of laser endoscopy in the palliation of malignant dysphagia is the need for repeated treatments. This study was designed to test whether external beam radiotherapy would reduce the necessity for repeated laser therapy., Patients/methods: Sixty seven patients with inoperable oesophageal or gastric cardia cancers and satisfactory swallowing after initial laser recanalisation were randomised to palliative external beam radiotherapy (30 Gy in 10 fractions) or no radiotherapy. All patients underwent a 'check' endoscopy five weeks after initial recanalisation and were subsequently reendoscoped only for recurrent dysphagia, which occurred in 59 patients., Results: Dysphagia was relieved equally well in both groups and the improvement was maintained with further endoscopic treatment. The initial dysphagia controlled interval and the duration between procedures required to maintain lifelong palliation (treatment interval) increased from five to nine weeks (median) in the radiotherapy group (p < 0.01 both parameters). Radiotherapy was well tolerated in all but three patients. One perforation occurred and two fistulae opened after dilatation in patients who received radiotherapy., Conclusion: Additional radiotherapy reduces the necessity for therapeutic endoscopy for a patient's remaining life. It has an important role in relatively well patients who are likely to survive long enough to benefit.

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.

The first study of photodynamic therapy in the human gastrointestinal tract using 5 aminolaevulinic acid (ALA) induced protoporphyrin IX as the photosensitising agent is described. Eighteen patients with colorectal, duodenal, and oesophageal tumours were studied. After 30-60 mg/kg of ALA given orally, biopsy specimens of tumour and adjacent normal mucosa were taken 1-72 hours later. These specimens were examined by quantitative fluorescence microscopy for assessment of sensitisation with protoporphyrin IX. Ten patients were given a second dose of ALA a few weeks later and their tumours were treated with red laser light (628 nm). With 30 mg/kg ALA, the highest fluorescence values were detected in the duodenum and oesophagus, and the lowest in the large bowel. Doubling the ALA dose in patients with colorectal tumours gave protoporphyrin IX fluorescence intensities similar to those in patients with upper gastrointestinal lesions and improved the tumour:normal mucosa protoporphyrin IX sensitisation ratio. The treated patients showed superficial mucosal necrosis in the areas exposed to laser light. Six patients had transient rises in serum aspartate aminotransferases, two mild skin photosensitivity reactions, and five mild nausea and vomiting. In conclusion, photodynamic therapy with systemically administered ALA may be a promising technique for the treatment of small tumours and areas of dysplasia such as in Barrett's oesophagus.

Laser therapy offers rapid relief of dysphagia for patients with cancers of the oesophagus and gastric cardia but repeat treatments are required approximately every five weeks to maintain good swallowing. To try to prolong the treatment interval, 22 elderly patients were given additional external beam radiotherapy. Nine had squamous cell carcinoma and 13 adenocarcinoma: five had documented metastases. Six received 40 Gy and 16,30 Gy in 10-20 fractions. A 'check' endoscopy was performed three weeks after external beam radiotherapy. Dysphagia was graded from 0-4 (0 = normal; 4 = dysphagia for liquids). The median dysphagia grade improved from 3 to 1 after laser treatment. This improvement was maintained in the 30 Gy group but there was a noticeable deterioration in three of those who had received the higher radiation dose. A lifelong dysphagia grade of 2 or better was enjoyed by 14 of 16 patients in the 30 Gy group but only two of six in the 40 Gy group. The dysphagia controlled interval was 9 weeks (median) after check endoscopy and subsequent endoscopic procedures were required every 13 weeks to maintain good swallowing. There were no endoscopy related complications. Combined treatment is a promising approach for reducing the frequency of endoscopic treatments. The 30 Gy dose seems more appropriate and may prolong survival. A randomised study to test these conclusions is in progress.

Forty two patients with haemorrhage from peptic ulcers with visible vessels were enrolled in a randomised study comparing endoscopic haemostasis with adrenaline (1:10,000) injections (adrenaline group) and adrenaline injection + neodymium yttrium-aluminium-garnet (Nd:YAG) laser photocoagulation (adrenaline + laser group). The two groups (21 patients each) were well matched for factors affecting outcome. Surgery was performed for continued haemorrhage uncontrolled by endoscopic treatment or rebleeding after two endoscopic treatments. Haemostasis after one treatment was similar in the two groups: adrenaline 16/21 (76%), adrenaline + laser 18/21 (86%). Haemostasis after two treatments was numerically (0.05 less than p less than 0.10) greater in the adrenaline + laser group: 21/21 (100%) v 18/21 (86%). Three patients (14%) in the adrenaline group underwent uneventful emergency surgery. There were no deaths or procedure related complications in either group. Most bleeds from peptic ulcers with visible vessels can be controlled endoscopically without the need for surgery. Both treatments in this study proved highly efficacious in securing haemostasis. Adrenaline injection treatment seems to be the treatment of choice in view of its simplicity, low cost, and availability. Additional Nd:YAG laser treatment may provide a marginal improvement in efficacy, although a much larger trial would be required to prove this.

Photodynamic therapy is a photochemical technique for the local destruction of tumours, entailing the interaction of light with an administered photosensitiser to produce a cytotoxic effect. We investigated the tissue distribution of the photosensitiser aluminium sulphonated phthalocyanine (AlSPc) in dimethylhydrazine induced colonic tumours and adjacent normal colon in rats. Forty eight hours after intravenous injection, most tumours contained twice as much AlSPc as normal colon. Tumour size and position in the colon did not affect AlSPc concentration. Microscopic fluorescence localisation of AlSPc showed significant photosensitiser accumulation in tumour stroma, whereas tumour and normal mucosa contained similar amounts. Thus, some normal tissue damage, where malignant cells invade normal areas, would inevitably accompany eradication of tumours. Tumour destruction and healing of colon after tumour eradication were examined histologically. There was sharp demarcation between necrotic areas (tumour or normal) and adjacent tissue and, whether the treated area was tumour or normal, healing occurred by regeneration of normal tissue. Some incompletely eradicated large tumours showed evidence of delayed bleeding. The possibility of selective uptake or preferential retention of the photosensitiser in tumours formed the initial basis for investigation of photodynamic therapy, but it is now clear that this is seldom the most important factor for tumour eradication. Of far greater importance is the nature of the biological effect of photodynamic therapy as necrosis of small tumours involving the full thickness of the bowel wall can be achieved with safe healing by regeneration of normal colon. The maximum depth of necrosis produced was only a few millimetres, so this technique is unlikely to be of value as the primary treatment for large colonic tumours but may prove of value for eradicating small lesions or as adjunctive therapy for eradication of small nests of tumour remaining or recurring in the tumour bed after conventional surgery.

Considerable discussion still centres around the relative merits of the Argon and Neodymium Yttrium Aluminum Garnet (NdYAG) lasers for the endoscopic treatment of gastrointestinal haemorrhage, although both are undoubtedly effect. We have carried out experiments to elucidate which factors determine the safety and efficacy of NdYAG laser photocoagulation. Histological studies on normal gastric mucosa showed that the depth of tissue damage depended mainly on the total incident laser energy, whereas the effectiveness of photocoagulation of induced gastric ulcers in heparinised animals depended on the laser power and the exposure time used. Optimum haemostasis with minimum tissue damage was obtained using pulses of 300 to 500 ms duration with energies of 25 to 40 J. We consider these parameters safe and effective for use in pilot clinical studies.

The effects of low power (1-2 Watts), long exposure (30-400 seconds), interstitial Nd YAG laser therapy on dimethylhydrazine induced rat colonic neoplasms and normal rat colon have been studied. After a single exposure with appropriate laser parameters, dimethylhydrazine induced rat colonic neoplasms underwent coagulative necrosis, sloughed off over a four day period, and left an ulcer which healed within 28 days. Inadequate laser energy resulted in incomplete tumour necrosis whilst excessive laser power or energy increased the likelihood of perforation. Treatment of normal colon with 1 Watt for 30 seconds or longer resulted in coagulative damage which healed by granulation. Mean colonic bursting pressures were significantly decreased one hour after treatment with 1 Watt for 75 or 100 seconds compared with untreated colon (p less than 0.05 and p less than 0.001 respectively) but not in colon treated with 1 Watt for 30 or 50 seconds. In animals treated with 1 Watt for 100 seconds mean bursting pressures were significantly lower than untreated animals when the animals were killed two, four, and seven days after lasering (p less than 0.001 in each case) but not in animals killed at 11, 17, or 21 days. The technique may be of value in the treatment of some inoperable colorectal cancers and sessile polyps in man.

Laser photocoagulation is one of a number of methods currently under investigation for the endoscopic treatment of gastrointestinal haemorrhage. The Argon ion and Neodymium Yttrium Aluminium Garnet (Nd YAG) lasers are theoretically suitable as the beam from each may be transmitted via a flexible fibre. Argon laser photocoagulation has been shown to be effective and we have elucidated which factors determine its safety and efficacy. Studies on normal canine gastric mucosa showed that the depth of tissue damage depended chiefly on the total incident laser energy on any one spot, and that below 50 J the risk of perforation was extremely low. The energy density was much less important. The haemostatic effect depended more on the laser power. In artificial bleeding gastric ulcers in heparinised dogs the most effective level was 7--9 W, at which 22 out of 23 ulcers (96%) stopped bleeding completely, compared with one out of 12 controls. Photocoagulation was achieved in these cases with energies well within the safe limits. The procedure was effective endoscopically, and these results justify early clinical studies in man.

The tissue changes in canine gastric mucosa caused by exposure to an argon laser beam vary from mild mucosal oedema to complete cell destruction. Intermediate degrees of damage cause an inflammatory cell response with the formation of granulation tissue, particularly in the submucosa. The rate of healing is similar to that after other forms of injury to the gastric mucosa. Cell destruction at the surface of the mucosa starts with energies greater than 8 Joules on any one spot, and occurs at greater depths as the energy is increased but, unless cells are actually destroyed, the extent of histological damage is limited to a zone 1 mm lateral to, or below, the area exposed to the laser beam. Haemostasis is achieved by thermal contraction of bleeding vessels and of the surrounding tissue, thrombosis only occurring as a secondary effect.

Palliative treatment of malignant dysphagia aims to optimise swallowing for the maximum time possible with the minimum of general distress to these seriously ill patients. Thirty four patients considered unsuitable for surgery because of advanced malignancy, other major pathology or in whom previous surgery had been unsuccessful were treated endoscopically with the Nd YAG laser. Significant improvement was achieved in 29 (85%). On a scale of 0-4 (0 = normal swallowing; 4 = dysphagia for all fluids), mean improvement was 1.7, with 25 patients (74%) able to swallow most, or all solids after treatment. With increasing experience, the average number of treatment sessions required for each patient became less; initial time in hospital became comparable to that needed for intubation. Failures were caused by inappropriate patient selection (3), or laser related perforation (2). The mean survival in the whole group was 19 weeks (range 2-44). Eighteen patients needed further treatment for recurrent dysphagia, a mean of six weeks (range 2-15) after initial therapy. Ten of these responded, but eight eventually required insertion of a prosthetic tube. The duration of good palliation was very variable after initial laser therapy.

Tissue changes produced in the dog stomach by exposure to a Nd YAG laser varied from mild mucosal oedema to cell vaporisation. Intermediate degrees of damage caused a marked inflammatory response leading to extensive fibrosis in the submucosa and muscularis propria. The true extent of tissue damage was not apparent immediately, and treated mucosa that initially appeared intact sometimes sloughed several days later to leave an ulcer. The extent of damage and the rate of healing depended on the amount of laser energy used. With pulses at optimum laser power (75 w) and exposure time (0.4 sec), however, haemostasis was achieved in induced ulcers with total energy concentrations that did not produce full thickness tissue damage nor alter the healing rate from that observed in untreated ulcers. Thermal contraction was the primary haemostatic mechanism, thrombosis only occurring as a secondary effect.

Vascular anomalies of the gastrointestinal tract are an important source of both acute and chronic blood loss. They present difficult management problems as they are often multiple, involving more than one part of the gastrointestinal tract, and may give rise to bleeds of increasing frequency and severity over a period of many years. We present the results of endoscopic argon and Nd YAG laser treatment of 18 patients with documented recurrent, severe haemorrhage from vascular lesions of the upper gastrointestinal tract with follow up of up to five years. Four patients with hereditary haemorrhagic telangiectasia, five with single angiodysplasias and three with multiple angiodysplasias have had their transfusion requirements reduced to minimal levels after one or more courses of laser treatment. Two of these have required no blood for over two years despite previous total requirements of 52 and 129 units of blood. Four patients were submitted to surgery (two in whom the laser failed to control haemorrhage and two who did not have immediate access to laser therapy at the time of severe bleed). Two of these, however, bled again soon afterwards. Two patients are still undergoing courses of laser therapy although have already shown reductions in transfusion requirements. Both lasers were effective. The Nd YAG laser appears to produce better long term results as its greater penetration makes it possible to ablate the main areas of vascular ectasia in the submucosa, although it does have a slightly higher risk of causing haemorrhage in the first few days after treatment.