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Background: Patients with pancreatic cancer have a poor prognosis apart from the few suitable for surgery. Photodynamic therapy (PDT) produces localised tissue necrosis but previous studies using the photosensitiser meso-tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photosensitivity. This study assessed a shorter acting photosensitiser, verteporfin. Methods: Fifteen inoperable patients with locally advanced cancers were sensitised with 0.4 mg kg−1 verteporfin. After 60–90 min, laser light (690 nm) was delivered via single (13 patients) or multiple (2 patients) fibres positioned percutaneously under computed tomography (CT) guidance, the light dose escalating (initially 5 J, doubling after each three patients) until 12 mm of necrosis was achieved consistently. Results: In all, 12 mm lesions were seen consistently at 40 J, but with considerable variation in necrosis volume (mean volume 3.5 cm3 at 40 J). Minor, self-limiting extrapancreatic effects were seen in multifibre patients. No adverse interactions were seen in patients given chemotherapy or radiotherapy before or after PDT. After PDT, one patient underwent an R0 Whipple's pancreaticoduodenectomy. Conclusions: Verteporfin PDT-induced tumour necrosis in locally advanced pancreatic cancer is feasible and safe. It can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds.

Photodynamic therapy (PDT) is already being used in the treatment of many cancers. This review examines its components and the new developments in our understanding of its immunological effects as well as pre-clinical and clinical studies, which have investigated its potential use in the treatment of breast cancer.

Protoporphyrin IX (PpIX)-induced photodynamic therapy (PDT) is being utilised within dermatological practice as a topical method of localised ablation of nonmelanoma skin cancer/precancer. Standardised protocols have been implemented to good effect when the disease remains superficial but improvement is required to widen the application of this light activated drug therapy to treat thicker or acrally located conditions. As innate haem biosynthesis is exploited to accumulate the light sensitive PpIX from a topically applied inert prodrug (aminolaevulinic acid; ALA), this pathway can be further manipulated through the concurrent administration of an iron chelating agent to hyper-accumulate PpIX by temporarily reducing its iron dependent conversion to haem. A topical preparation of ALA was applied to normal rat skin with or without the hydroxypyridinone iron chelator, CP94. Image analysis quantification of tissue fluorescence following excision indicated that ALA plus CP94 produced 29.0% more fluorescence than ALA alone (p < 0.09), peaking at 5 hours. Furthermore, fluorescence spectroscopy of frozen skin samples from each treatment group were characteristic of PpIX (maxima 636 +/- 2 nm), indicating that topical CP94 administration elevated PpIX levels without significantly producing any other fluorescent species. When PDT efficacy was considered post irradiation, a substantial three-fold increase in effect was observed 4 days after treatment when the iron chelator CP94 was co-administered topically with the prodrug (p < 0.07). It has therefore been established that the hydroxypyridinone CP94, is topically active within normal rat skin, effectively chelating iron to elevate PpIX accumulation and thus improve PDT efficacy.

Endoscopic radiofrequency ablation (RFA) is an effective treatment for high-grade dysplasia in Barrett's esophagus in ablation-naïve patients, but no studies have evaluated its use in patients in whom ablative therapy has previously failed. We describe 14 patients with residual high-grade dysplasia following aminolevulinic acid or Photofrin (porfimer sodium) photodynamic therapy (PDT). An overall complete reversal of dysplasia was achieved in 86 % with a combination of RFA and rescue endoscopic mucosal resection. The median total follow-up is 19 months. The rate of strictures was 7 % (1/14) and there was a low rate of buried glands (0.5 % follow-up biopsies). These data suggest RFA is both safe and effective for eradication of high-grade dysplasia in patients in whom PDT has failed.

Background and aims: DNA ploidy abnormalities (aneuploidy/tetraploidy) measured by flow cytometry (FC) are strong predictors of future cancer development in untreated Barrett's oesophagus, independent of histology grade. Image cytometric DNA analysis (ICDA) is an optical technique allowing visualisation of abnormal nuclei that may be undertaken on archival tissue. Our aim was to determine the accuracy of ICDA vs FC, and evaluate DNA ploidy as a prognostic biomarker after histologically successful treatment with photodynamic therapy (PDT). Methods: Nuclei were extracted from 40 μm sections of paraffin-embedded biopsies and processed for ICDA at UCL and FC at UW using standardised protocols. Subsequently, DNA ploidy was evaluated by ICDA on a cohort of 30 patients clear of dysplasia 1 year after aminolaevulinic acid PDT for high-grade dysplasia (HGD). The results were correlated with long-term outcome. Results: In the comparative study, 93% (41 out of 44) of cases were classified identically. Errors occurred in the near-diploid region by ICDA and the tetraploid region by FC. In the cohort study, there were 13 cases of late relapse (7 cancer, 6 HGD) and 17 patients who remained free of dysplasia after a mean follow-up of 44 months. Aneuploidy post-PDT was highly predictive for recurrent HGD or cancer with a hazard ratio of 8.2 (1.8–37.8) (log-rank P=0.001). Conclusions: ICDA is accurate for the detection of DNA ploidy abnormalities when compared with FC. After histologically successful PDT, patients with residual aneuploidy are significantly more likely to develop HGD or cancer than those who become diploid. DNA ploidy by ICDA is a valuable prognostic biomarker after ablative therapy.

Background and Objectives: Prostate cancer is increasing in incidence, but current treatments including surgery and radiotherapy have significant side effects. This pilot study was designed to assess the potential of photodynamic therapy (PDT) using meso tetra hydroxy phenyl chlorin (mTHPC) for organ confined prostate cancer. Study Design/Patients and Methods: Six men with organ confined prostate cancer were photosensitised with mTHPC (0.15 mg/kg). Between 2 and 5 days later, red light (652 nm) was delivered to areas of biopsy proven cancer via fibres inserted through transperineal needles (50–100 J per site). Results: After 8 of 10 PDT sessions, the prostate specific antigen (PSA) fell by up to 67%. Early MRI scans showed oedema and patchy necrosis, which resolved over 2 months. Biopsies of treated areas revealed necrosis and fibrosis at 1–2 months. Conclusions: PDT for primary prostate cancer appears safe and can reduce PSA levels. As this was a phase I study, no attempt was made to treat the whole prostate; this or targeted tumour ablation could be attempted in a phase II study with an increased number of fibres. This technique merits further investigation in early prostate cancer. Lasers Surg. Med. 38:356–363, 2006. 2006 Wiley-Liss, Inc.

ObjectivesPhotodynamic therapy (PDT, the combination of light with a photosensitising drug in the presence of oxygen) inhibits restenosis after angioplasty without stenting. This study assesses the potential of PDT for prevention of in-stent re-stenosis.Design and methodsNormal rabbits were given the photosensitising agent 5-aminolaevulinic acid (ALA) 60mg/kg, 3h prior to endovascular illumination of the iliac artery (635nm at 50J/cm2) either immediately before or after deployment of an oversized (3mm diameter) stent. PDT treated arteries were retrieved 3 or 28 days later and assessed for cell counts and vascular morphometry. Control arteries (stent but no PDT) were examined at 28 days.ResultsThere were no adverse events and all vessels were patent at the end of the study. At 3 days there was almost complete medial cell ablation when light was delivered before stent deployment (17±1cells/hpf), with little effect when illumination followed stent deployment (184±17cells/hpf, p

Photochemical internalisation (PCI) is a technique for releasing biologically active macromolecules from endocytic vesicles by light activation of a photosensitiser localised in the same vesicles of targeted cells. This study investigated the PCI of the toxin gelonin as a way of enhancing the effect of photodynamic therapy (PDT) on a human malignant fibrous histiocytoma transplanted into nude mice using the photosensitiser disulphonated aluminium phthalocyanine (AlPcS(2a)). Pharmacokinetic studies after intraperitoneal administration showed that the serum level of AlPcS(2a) fitted a biexponential model (half-lives of 1.8 and 26.7 h). The tumour concentration was roughly constant up to 48 h, although fluorescence microscopy showed that the drug location was initially mainly vascular, but became intracellular by 48 h. To compare PDT with PCI, 48 h after intraperitoneal injection of 10 mg kg(-1) AlPcS(2a), and 6 h after direct intratumour injection of 50 microg gelonin (PCI) or a similar volume of phosphate-buffered saline (PDT controls), tumour-bearing animals were exposed to red light (150 J cm(-2)). Complete response was observed for more than 100 days in 50% of the PCI tumours but only 10% of the PDT tumours (P0.01). In tumours examined histologically 4 days after light delivery, the depth of necrosis was 3-4 mm after PDT, but 7 mm after PCI. The deeper effect after PCI demonstrates that the light fluence needed to kill tumour is less than with PDT. We conclude that PCI with gelonin can markedly enhance the effect of PDT on this type of tumour and may have a role clinically as an adjunct to surgery to control localised disease.

Interstitial photodynamic therapy (IPDT) is a technique for applying photodynamic therapy (PDT) to internal tumours using light delivered via fibres inserted percutaneously. This phase I-II study assessed the safety and efficacy of IPDT for patients with persistent or recurrent head and neck cancer unsuitable for further treatment with surgery, radiotherapy or chemotherapy, recruited for 'last hope' salvage treatment. Patients were sensitised with 0.15 mg kg(-1) mTHPC (meso-tetrahydroxyphenyl chlorin) 4 days prior to light delivery from fibres inserted directly into the target tumour (20 J per site at 652 nm) under image guidance. In all, 45 patients were treated. Nine achieved a complete response. Five are alive and free of disease 10-60 months later. Symptomatic relief (mainly for bleeding, pain or tumour debulking) was achieved in a further 24. The median survival (Kaplan-Meier) was 16 months for the 33 responders, but only 2 months for the 12 nonresponders. The only serious complication was a carotid blow out 2 weeks after PDT. No loss of function was detected in nerves encased by treated tumours. Interstitial photodynamic therapy provides worthwhile palliation with few complications and occasional long-term survivors for otherwise untreatable advanced head and neck cancers. It is a treatment option worth adding to those available to integrated head and neck oncology teams.

Photodynamic therapy (PDT) requires a photosensitising drug, light and oxygen. While it is known that the haemoglobin oxygen saturation (HbSat) can be altered by PDT, little has been done to correlate this with microvascular changes and the final biological effect. This report describes such studies on the normal liver of rats sensitised with aluminium disulphonated phthalocyanine. In total, 50 J of light at 670 nm, continuous or fractionated at 25 or 100 mW, was applied with a single laser fibre touching the liver surface. HbSat was monitored continuously 1.5-5.0 mm from the laser fibre using visible light reflectance spectroscopy (VLRS). Vascular shutdown was assessed by fluorescein angiography 2-40 min after light delivery. Necrosis was measured at post mortem 3 days after PDT. In all treatment groups at a 1.5 mm separation, HbSat fell to zero with little recovery after light delivery. At 2.5 mm, HbSat also decreased during light delivery, except with fractionated light, but then recovered. The greatest recovery of fluorescein perfusion after PDT was seen using 25 mW, suggesting an ischaemia/reperfusion injury. Necrosis was more extensive after low power and fractionated light than with 100 mW, continuous illumination. We conclude that VLRS is a useful technique for monitoring HbSat, although the correlation between HbSat, fluorescein exclusion and necrosis varied markedly with the light delivery regimen used.

Watermelon stomach (gastric antral vascular ectasia) is a rare cause of gastric bleeding which can render patients transfusion-dependent. Laser therapy can be used to stop bleeding but the long-term success of this approach is not well described. We present a retrospective analysis of 24 consecutive transfusion-dependent patients who were treated in a national referral centre with Nd:YAG laser over an 18 year period. Laser therapy stopped all bleeding in 20 patients (83%) after a median of two sessions. Median follow up was 55 months (range 9-127). Patients remained transfusion free for a median of 16 months and a second course of treatment succeeded in all those who re-bled. One gastric perforation occurred early in the series and two patients developed pyloric stenosis which was successfully treated with balloon pyloric dilatation. Oestrogens were not used in these patients. Our experience shows that long-term remission from blood transfusion is seen in most patients treated with Nd:YAG laser. If bleeding recurs, further laser treatment is usually successful.

Reperfusion injury can occur when blood flow is restored after a transient period of ischaemia. The resulting cascade of reactive oxygen species damages tissue. This mechanism may contribute to the tissue damage produced by 5-aminolaevulinic acid-induced photodynamic therapy, if this treatment temporarily depletes oxygen in an area that is subsequently reoxygenated. This was investigated in the normal colon of female Wistar rats. All animals received 200 mg kg−1 5-aminolaevulinic acid intravenously 2 h prior to 25 J (100 mW) of 628 nm light, which was delivered continuously or fractionated (5 J/150 second dark interval/20 J). Animals were recovered following surgery, killed 3 days later and the photodynamic therapy lesion measured macroscopically. The effects of reperfusion injury were removed from the experiments either through the administration of free radical scavengers (superoxide dismutase (10 mg kg−1) and catalase (7.5 mg kg−1) in combination) or allopurinol (an inhibitor of xanthine oxidase (50 mg kg−1)). Prior administration of the free radical scavengers and allopurinol abolished the macroscopic damage produced by 5-aminolaevulinic acid photodynamic therapy in this model, regardless of the light regime employed. As the specific inhibitor of xanthine oxidase (allopurinol) protected against photodynamic therapy damage, it is concluded that reperfusion injury is involved in the mechanism of photodynamic therapy in the rat colon. British Journal of Cancer (2002) 86, 989–992. DOI: 10.1038/sj/bjc/6600178 www.bjcancer.com © 2002 Cancer Research UK

The major limitation of the long term success of percutaneous coronary interventions is the development of restenosis, which occurs in 30–50% of patients within six months.1 2 Restenosis is the result of a complex pathophysiological process in the arterial wall in response to balloon dilatation or stent insertion. For many years the hallmark of this response to injury was considered to be the development of intimal hyperplasia resulting from the proliferation and migration of smooth muscle cells from the arterial media.3More recently, it has become clear that this is not the only factor involved. Other key aspects in the development of the restenotic lesion are the extracellular matrix, elastic vessel recoil, and arterial remodelling.4 While our understanding of the processes induced by balloon injury has improved, treatment strategies to limit this have been disappointing in clinical practice.5Stenting, which is now used in up to 80% of all coronary interventional procedures, has almost eliminated problems from elastic recoil and has reduced restenosis rates, but neointimal hyperplasia around stent struts can still lead to in-stent restenosis.6 Intracoronary brachytherapy is one technique that has proved promising in the prevention of restenosis using either catheter based systems for radiation delivery or radioactive stents.7 Concerns have been expressed about late thrombotic occlusion after brachytherapy.8 However, the prolonged use of antiplatelet drugs may control this problem. Brachytherapy is probably the best option for treating restenosis currently available. Nevertheless, it would be attractive to find a method of preventing restenosis after percutaneous intervention that does not involve ionising radiation or prolonged drug treatment. Photodynamic therapy (PDT), which in contrast to brachytherapy uses non-ionising radiation, is emerging as another possible strategy. PDT involves the interaction of a photosensitising drug, light, and tissue oxygen9 (fig 1). Photosensitising agents, many …

Background Photodynamic therapy (PDT) reduces neointimal hyperplasia and negative remodelling following balloon injury in small and large animal models. This clinical study investigated the role of adjuvant PDT following femoral percutaneous transluminal angioplasty (PTA). Methods Eight PTAs in seven patients (two women) with a median age of 70 (range 59–86) years were performed with adjuvant PDT. All patients had previously undergone conventional angioplasty at the same site which resulted in symptomatic restenosis or occlusion between 2 and 6 months. Each was sensitized with oral 5-aminolaevulinic acid 60 mg/kg, 5–7 h before the procedure. Following a second femoral angioplasty, up to 50 J/cm2 red light (635 nm) was delivered to the angioplasty site via a laser fibre within the angioplasty balloon. Patients were kept in subdued light overnight and discharged the following day. Outcome was assessed by duplex imaging at 24 h, 1, 3 and 6 months and by intravenous digital subtraction angiography at 6 months. A peak systolic velocity ratio (PSVR) of more than 2·0 at the angioplasty site was taken to represent restenosis. Results All patients tolerated the procedure well without adverse complications or death. All were rendered asymptomatic which was sustained throughout the study interval. All vessels remained patent and no lesion attained the duplex definition of restenosis. Median (interquartile range) PSVR across stenotic segments was 4·7 (3·7–5·7) before angioplasty, 1·1 (0·9–1·3) at 24 h and 1·4 (1·0–1·8) at 6 months after intervention (P = 0·04 compared with preoperative value). Conclusion This pilot study suggests that endovascular PDT is safe and may reduce restenosis following angioplasty. The data justify a randomized controlled trial.

Fibroadenomas are benign lesions of the breast that are common in young women. Most can safely be treated conservatively, but if they are not excised, the majority persist for several years and some increase in size. Interstitial Laser Photocoagulation is a new approach to treating these lesions. Under local anaesthesia and sedation, using ultrasound guidance, fine needles are inserted into the fibroadenoma and a laser fibre passed through each needle to coagulate the lesion in situ. Twenty-nine lesions (diameter 14–35 mm) have been treated in 24 patients. Twenty eight (97%) shrank in size on follow up ultrasound assessment. Fourteen were followed for a year, at which time none was palpable and only one could still be detected on ultrasound. In early cases there were three minor complications (a small scar at a site of needle insertion), later prevented by improved technique. This is a simple and safe outpatient procedure for ablating fibroadenomas that does not require open surgery.

Objectives: to test the hypothesis that intravascular light could be delivered via a balloon catheter for arterial photodynamic therapy (PDT). Design: pig non-injury model. Materials: clinical catheter equipment. Methods: large White pigs (15–20 μg) were photosensitised with 5-aminolaevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) at a concentration of 120mg/kg. Arterial biopsies were taken at intervals between 30 mins and 24h and frozen sections analysed using a CCD camera to give a temporal profile of fluorescence in each arterial layer. PDT was given to normal arterial segments via a 4mm transparent PTA balloon inflated so as to occlude flow, but not distend the artery. Animals were culled at 3 and 14 days and the above segments harvested. Results: fluorescence peaked in the adventitia, intima and medial layers at 1.5, 4 and 6h respectively. PDT at all time points produced VSMC depletion compared with controls. The degree of depletion mirrored the fluorescence profile of PpIX. Conclusions: PDT can be delivered via a standard PTA balloon with a transparent channel. This depletes the VSMC population within the arterial wall without complications. Intra-arterial PDT is therefore a potential therapy to reduce the incidence of restenosis post-angioplasty.

Pancreatic cancer is difficult to treat, even for tumours localized to the pancreas. Photodynamic therapy (PDT) is a non-thermal technique for producing localized tissue necrosis with light after prior administration of a photosensitizing drug and it could have a role in the local treatment of these cancers. We studied PDT in a transplanted cancer in the hamster pancreas using the photosensitizer mTHPC (meta-tetrahydroxyphenylchlorin). Fluorescence microscopy showed maximum levels of mTHPC in normal pancreas 2-4 days after sensitization and in tumour at 4-5 days. For PDT, animals were given 0.1 or 0.3 mg kg(-1) mTHPC and the tumour was treated at laparotomy 2 or 4 days later with red light (50 J at 650 nm, continuous or fractionated) delivered via a single fibre touching the tumour surface. The maximum zone of tumour necrosis (seen 3 days after PDT) was 8.7 mm in diameter with continuous irradiation, increasing to 12.4 mm with light fractionation (four equal fractions with 3 min between fractions). The main complication was sealed duodenal perforation, seen in 3 of 16 animals, probably due to inadequate shielding of the duodenum from the light. The duodenal problems seen in hamsters are unlikely to cause trouble in the much thicker human duodenum. PDT tumour necrosis in this animal model has now been shown with a range of photosensitizers, but mTHPC is attractive as it is likely to produce the largest volumes of necrosis around each treatment point with short light exposure times. This technique could have a role in the treatment of localized cancers of the pancreas in patients unsuitable for surgery and can now be considered for preliminary clinical trials. Images Figure 2 Figure 3

SummaryAim - To correlate the magnetic resonance imaging signal changes observed during interstitial laser photocoagulation (ILP) therapy with histopatho-logical analysis of tissue necrosis. A 1.5T MR system was used. Lesions were produced with a diode laser (805 nm) in the liver of normal Wistar rats at laparotomy under general anaesthesia and imaged during treatment. Seventeen lesions were monitored with a T1-weighted spin echo (T1WSE) sequence, and 15 with a FLASH sequence. Treated tissue was removed and stained for NADPH-diaphorase to determine the extent of devitalization. Per-procedural T1WSE showed an expanding area of low signal which developed a high signal rim as ILP progressed. FLASH imaging showed an expanding area of low intensity which was replaced by a complex region of signal change as treatment progressed. Good imaging-histopathological correlation was shown: for T1WSE, r2=0.88 (P < 0.001) and for FLASH, r2=0.95 (P < 0.001). MR imaging during hepatic ILP accurately shows the extent of tis...

Background and Objective Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) for sensitization is a promising treatment for carcinoma in situ and diffuse premalignant changes of the bladder. We studied the biodistribution of PpIX in a range of tissues with oral and intravesical routes of administration of ALA and compared the photodynamic effects on bladder and skin. Study Design/Materials and Methods: Normal Wistar rats were given oral or intravesical ALA and PpIX levels in the liver, kidney, skin, and bladder measured by fluorescence microscopy on tissue sections. At the time of maximum PpIX levels, the bladder and skin on the back were illuminated with light at 630 nm and the PDT effects compared. Results PpIX fluorescence in the urothelium after 200 mg/kg given intravesically was comparable to that found after 100 mg/kg orally. The ratio of PpIX levels between the urothelium and the underlying muscle was the same for both routes of administration, although there appeared to be more selectivity of urothelial PDT necrosis after intravesical administration. Skin photosensitization was greater after oral ALA, the epidermal PpIX level being three times higher than after intravesical administration for comparable urothelial levels and the PDT effect being more marked. Conclusions Intravesical instillation is preferable to oral administration of ALA for PDT ablation of the urothelium of the rat bladder without damage to the underlying tissue layers and for minimizing skin photosensitivity. The technique is now ready for clinical trials. Lasers Surg. Medicine 20:254–264, 1997. © 1997 Wiley-Liss, Inc.

SummaryInterstitial laser photocoagulation (ILP) is currently limited by deficient per-procedural monitoring. The purpose of this study was to evaluate MR control of ILP of hepatic metastases. Twenty-two laser activations were used to treat eight metastases in seven patients under local anaesthesia and sedation. Laser energy was delivered via optical fibres positioned in the tumour under ultrasound guidance. T1-weighted FLASH and spin-echo sequences were used to monitor the procedure. Enhanced CT was performed at 24 h to assess thermal necrosis. FLASH imaging showed an enlarging area of signal change during ILP. The final extent of this correlated closely with the extent of tissue necrosis on CT. Spin-echo imaging was disappointing because of poor contrast between the treated tissue and normal liver/untreated tumour. Per-procedural MR imaging accurately and reliably depicts ILP-induced necrosis. MR control may permit more widespread application of ILP to the treatment of hepatic tumours.

We undertook a phase I dose-escalation study of verteporfin photodynamic therapy (PDT) in 15 patients with locally advanced pancreatic cancer. Needle placement and laser delivery were technically successful in all patients. Thirteen patients were treated with a single laser fibre. Three treatments were carried out each at 5, 10 and 20 J/cm2; and 5 treatments (4 patients) at 40 J/cm2. A further 2 patients were treated with 2 or 3 laser fibres at 40 J/cm2. Tumour necrosis was measured on CT (computed tomography) by two radiologists 5 days after treatment. There was a clear dosedependent increase in necrosis with a median area of 20 x 16 mm (range 18 x 16 to 35 x 30 mm) at 40 J/cm2. In the 2 patients treated with multiple fibres, necrosis was 40 x 36 mm and 30 x 28 mm, respectively. There were no early complications in patients treated with a single fibre. Both patients treated with multiple fibres had evidence on CT of inflammatory change occurring anterior to the pancreas but without clinical deterioration. These results suggest that single fibre verteporfin PDT is safe in a clinical setting up to 40J/cm2 and produces a dose-dependent area of pancreatic necrosis.

BACKGROUND: Palliation of malignant dysphagia is possible by a variety of methods although all have significant drawbacks. Laser therapy is an effective and safe treatment but has to be repeated at four to five weekly intervals to maintain palliation. A means of augmenting the benefits while reducing the need for repeat treatments would be highly beneficial to these patients. AIMS: To prospectively explore the safety and efficacy of intraluminal radiotherapy (brachytherapy) when used to augment laser recanalisation for malignant dysphagia. PATIENTS: Nineteen patients with dysphagia due to advanced adenocarcinoma of the oesophagus or cardia were recruited. METHODS: All patients received laser recanalisation until able to swallow a soft diet or better, before the application of a single dose of brachytherapy (10 Gy at 1 cm from the source). Patients were followed up and treated promptly by further endoscopic means in the event of their dysphagia worsening. RESULTS: Six patients (32%) required no further treatment until death at a median of 10 weeks (range 1-20 weeks). Further therapy was required at a median of 11 weeks (range 4-37 weeks) after brachytherapy for those 13 patients with recurrent dysphagia. Subsequent symptom control required endoscopic intervention at an average of once every nine weeks. There was no mortality associated with laser or brachytherapy. Median survival from initial treatment and including the one survivor was 36 weeks (range 5-132 weeks). CONCLUSIONS: Laser plus brachytherapy offers a safe and effective means of palliating malignant dysphagia due to adenocarcinoma, with a longer dysphagia free interval than historical controls treated with laser alone.

Experimental studies have been carried out using 5-aminolaevulinic acid (ALA) to induce transient porphyrin photosensitisation for photodynamic therapy (PDT) in a pancreatic cancer model in Syrian golden hamsters. ALA was given either intravenously or orally (in bolus or fractionated doses) with the laser light delivered by means of a bare fibre touching the tissue surface or external irradiation using a light-integrating cylindrical applicator. Animals were killed 1-24 h after ALA administration for pharmacokinetic studies and 3-7 days after light exposure to study PDT-induced necrosis. A separate survival study was also performed after a fractionated oral dose of ALA and external irradiation. Protoporphyrin IX sensitisation in the tumour tissue as measured by quantitative fluorescence microscopy was highest after intravenous administration of 200 mg kg-1 ALA and then in decreasing order after oral fractionated and oral bolus doses (both 400 mg kg-1). Laser light application at 630 nm to give 12-50 J from the bare fibre or 50 J cm-2 using surface illumination with the cylindrical applicator resulted in tumour necrosis up to 8 mm in depth. In larger tumours a rim of viable tumour was observed on the side opposite to illumination. In a randomised study, survival of treated animals was significantly longer than in the untreated control group (log-rank test, P < 0.02), although all animals died of recurrent tumour. This technique shows promise in the treatment of small volumes of tumour in the pancreas. Images Figure 2 Figure 3 Figure 4

The diagnosis and treatment of pancreaticobiliary malignancy is of major interest to our group. Building on prior work, we undertook a phase I study of verteporfin photodynamic therapy in patients with locally advanced, unresectable, pancreatic cancer. We also initiated an optical diagnostic study using elastic scattering spectroscopy (ESS) of the normal-appearing periampullary duodenal mucosa in vivo to investigate the hypothesis of a field effect in pancreaticobiliary malignancy. In a phase I dose escalation study, patients were treated with interstitial verteporfin PDT via a single fibre, to determine its general safety profile and the optimum treatment parameters needed to achieve effective and safe necrosis of tumour, With increasing light doses, there was a linear increase in the extent of tumour necrosis around the fibre, without serious adverse events. Follow-on studies using multiple fibres are planned. In 30 patients with benign or malignant pancreaticobiliary disease undergoing clinically-indicated endoscopy, ESS spectra were collected from the normal-appearing duodenum and antrum and a diagnostic algorithm generated by principle component and linear discriminant analysis. Pooled data from duodenal sites distal to the ampulla gave a sensitivity of 86% and a specificity of 72% (82% AUC) for the detection of malignancy, whereas those from the periampullary region had a sensitivity of 77% and a specificity of 61% (72% AUC); antral measurements were not able to discriminate with such accuracy. These early results suggest that ESS of the duodenal mucosa could represent a novel minimally invasive diagnostic test for pancreaticobiliary malignancy.

The management of patients with ’field cancerization‘ of the oral mucosa, with multicentric foci of invasion, presents a considerable problem for the head and neck surgeon. Surgical resection of synchronous or metachronous primary squamous cell carcinomas, along with adjacent premalignant lesions, is likely to be associated with considerable mutilation. Photodynamic therapy (PDT) has been shown to be of value in the treatment of superficial tumours in the upper aerodigestive tract, with excellent healing of treated areas. This study reports the use of PDT to treat 11 patients with ’field cancerization‘ occurring in the oral cavity. Six patients had multiple primary cancers and five had single primary tumours. All had associated areas of leukoplakia. Each received Photofrin 2 mg/kg 48 hours prior to photoirradiation with 50–100 J/cm² red laser light by surface illumination. Six to eight weeks later treated areas in 10 of the 11 patients showed a complete response to PDT; one patient had areas of residual leukoplakia. Two patients developed further areas of leukoplakia or erythroplakia within 12 months but no patient has had evidence of recurrent invasive carcinoma in the treated areas. Longer term follow-up will be necessary to exclude further recurrence. It is concluded that PDT offers an effective repeatable treatment option, whether on its own or as an adjunct to local excision, for patients with ’field cancerization‘ of the oral cavity.

Fifty-five liver metastases in 21 patients were treated with interstitial laser photocoagulation (ILP). Tumors were irradiated with a neodymium yttrium aluminum garnet laser via optical fibers passed through 19-gauge needles inserted under ultrasound (US) guidance. Heating of the tumor was evident at real-time US as an expanding and coalescing echogenic zone around the needle tips. After ILP, dynamic computed tomography (CT) showed laser-induced necrosis as a new area of nonenhancement. Necrosis of tumor volume was more than 50% in 82% (45 of 55) of the tumors, and 100% necrosis was achieved in 38% (21 of 55). Metastases smaller than 4 cm in diameter were treated more effectively and required fewer treatment sessions than did those larger than 4 cm. Complications were minor and included severe pain in four cases, persistent pain for up to 10 days in 11 cases, and asymptomatic subcapsular hematoma (four cases) and pleural effusion (six cases) seen with CT. ILP is safe and effective for liver tumor destruction, and US and CT are useful in different aspects of treatment monitoring.

Forty one patients with bleeding vascular ectasias of the upper gastrointestinal tract who required blood transfusion were treated with endoscopic Nd:YAG laser photocoagulation and followed for 34 months (median). Four distinct groups of patients were identified. There was a sustained reduction in transfusion requirements after laser treatment in all those with single (nine patients) and multiple (seven patients) angiodysplasia, in 12 of 16 (75%) patients with watermelon stomachs, and in six of nine (66%) patients with hereditary haemorrhagic telangiectasia. Overall, 25 patients (61%) required minimal or no transfusion after treatment and nine (22%) whose bleeding was controlled initially, later developed recurrent bleeding which was controlled with further laser (total 34 of 41, 83%). Surgery succeeded in a further three patients (7%) in whom laser had failed (in one case possibly because of laser induced haemorrhage). Five more cases of possible laser induced haemorrhage resolved with conservative treatment. One patient sustained a treatment related perforation and died: one patient with cirrhosis died of encephalopathy within one month of starting laser treatment. In two patients transfusion requirements were unchanged despite laser. Nd:YAG laser is a safe and effective treatment for most patients with upper gastrointestinal angiodysplasia.

Background Intraoperative diagnosis of sentinel node metastases enables an immediate decision to proceed to axillary lymph node dissection, avoiding a second operation in node-positive women with breast cancer. Methods An optical scanner was developed that interrogated the cut surface of bivalved, but otherwise unprocessed, sentinel lymph nodes with pulses of white light by elastic scattering spectroscopy (ESS). The scattered light underwent spectral analysis, and individual spectra were initially correlated with conventional histology to develop a diagnostic algorithm. This algorithm was used to create false colour-coded maps of scans from an independent set of nodes, and the optimal criteria for discriminating between normal and cancer spectra were defined statistically. Results The discriminant algorithm was developed from a training set of 2989 spectra obtained from 30 metastatic and 331 normal nodes. Subsequent scans from 129 independent nodes were analysed. The scanner detected macrometastases (larger than 2 mm) with a sensitivity of 76 per cent (69 per cent including micrometastases) and specificity of 96 per cent. Conclusion In this proof-of-principle study, the ESS results were comparable with current intraoperative diagnostic techniques of lymph node assessment.

Pancreatic adenocarcinoma ranks as the fourth most common cause of cancer death in the USA. Patients usually present late with advanced disease, limiting attempted curative surgery to 10% of cases. Overall prognosis is poor with one-year survival rates of less than 10% with palliative chemotherapy and/or radiotherapy. Given these dismal results, a minimally invasive treatment capable of local destruction of tumor tissue with low morbidity may have a place in the treatment of this disease. In this paper we review the preclinical photodynamic therapy (PDT) studies which have shown that it is possible to achieve a zone of necrosis in normal pancreas and implanted tumour tissue. Side effects of treatment and evidence of a potential survival advantage are discussed. We describe the only published clinical study of pancreatic interstitial PDT, which was carried out by our group (Bown et al Gut 2002), in 16 patients with unresectable locally advanced pancreatic adenocarcinoma. All patients had evidence of tumor necrosis on follow-up imaging, with a median survival from diagnosis of 12.5 months. Finally, we outline a phase I dose-escalation study of verteporfin single fibre PDT followed by standard gemcitabine chemotherapy which our group is currently undertaking in patients with locally advanced pancreatic cancer. Randomized controlled studies are also planned.

The palliative management of hepatic metastases remains unsatisfactory. There is a need for a simple non invasive technique which can stop or retard the rate of tumour growth. In principle, Interstitial Laser hyperthermia may fulfil such a role. In experimental studies, this technique produced precise in situ necrosis within solid organs which healed safely. In a pilot feasibility study, we treated ten patients with a total of 18 hepatic metastases on 31 occasions using a percutaneous approach to achieve an overall objective response rate of 44%. The treatment proved simple to perform, was well tolerated and produced radiological evidence of necrosis in small metastases (diameter less than or equal to 3 cm). However, further research is required before the technique can be regarded as established. Its future role in most cases will be to control the growth of discrete hepatic metastases unsuitable for resection. In instances where the extent of necrosis can be matched accurately to tumour volume, the potential for cure exists. Images Figure 1 Figure 2 Figure 3

Photodynamic therapy (PDT) is often thought to be able to effect selective tumour necrosis. This therapeutic selectivity, based on transient diferences in tumour: normal tissue photosensitizer concentration ratios, is rarely useful clinically in extracranial tumours, although PDT itself may be of value by virtue of the nature of the damage produced and healing of normal tissue by regeneration. This report describes the effects of PDT on normal pancreas and chemically induced pancreatic cancers in the hamster, where a diferent mechanism of selective necrosis may be seen. Photosensitizer distribution in normal and neoplastic pancreas was studied by chemical extraction and fluorescence microscopy. Correlation of distribution studies with necrosis produced by PDT shows that the photodynamic dose (product of tissue concentration of sensitizer and light dose) threshold for damage is seven times as high for normal pancreas as for pancreatic cancer. Tumour necrosis extended to the point where tumour was invading normal areas without damaging the normal tissue. In rat colonic cancer, photodynamic dose thresholds in tumour and normal tissue are similar and so such marked selectivity of necrosis is not possible. The reason for this selectivity in the pancreas is not clear, but recent evidence has suggested a diference in response to PDT between normal and neoplastic pancreatic cell lines and the presence of a singlet oxygen scavenger in normal pancreas is postulated. Furthermore, the present fluorescence microscopy studies suggest that tumour stroma contains the highest level of photosensitizer and thus receives the highest photodynamic dose during PDT. These results suggest a possible role for PDT in treating small pancreatic tumours or as an adjuvant to other techniques, such as surgery, that reduce the main bulk of tumours localized to the pancreas.

Multiple four-fibre low-power interstitial laser hyperthermia was performed in the canine liver to establish the parameters with which large areas of thermal necrosis could be made. Using 1.5 W for 670s (4020 J in total) and a fibre spacing of 1.5 cm, lesions with dimensions of 3.6 × 3.1 × 2.8 cm were achieved in 75 per cent of those attempted. There was no mortality and a low morbidity rate. These lesions could be visualized in both their development and resolution using ultrasonography. Healing occurred by 1 year. Temperatures in the centre of the heated region were 60°C, which is more than enough to cause thermal cell death. There was good correlation between the temperatures recorded, the sonographic changes seen, and the pathological evidence of necrosis. Multiple-fibre low-power interstitial laser hyperthermia performed with ultrasonic guidance may be of use in the treatment of liver tumours.

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. Images Figure 3 Figure 4 Figure 5 Figure 9

Photodynamic therapy (PDT) is an anti-cancer treatment which involves the systemic administration of a photosensitising drug which is preferentially absorbed by tumour tissue. Relatively little drug should be absorbed by the surrounding normal tissues. Tumour destruction is achieved when the tumour is illuminated with light of a wavelength which activates the photosensitising drug thereby inducing a cytotoxic reaction. However studies in many tissues have shown that the hoped for tumour selectivity is rarely achieved. Using the rabbit mandible and gingiva as our models we have studied the effects of various doses of PDT on the tissues of the oral cavity, namely mucosa, bone, muscle and salivary gland. The photosensitiser used was di-sulphonated aluminium phthalocyanine. Results show that whereas bone is extremely resistant to PDT the other tissues are vulnerable to it. In the case of muscle and salivary gland this susceptibility is very much dose related. In salivary tissue necrotising sialometaplasia was observed in areas of the gland adjacent to those that had undergone necrosis. All tissues were noted to heal or regenerate well following PDT injury. Images Figure 2 Figure 3 Figure 5 Figure 6

Forty nine patients with rectosigmoid carcinoma considered unsuitable for surgery underwent endoscopic Nd:YAG laser treatment for palliation of symptoms and tumour eradication, if feasible. Altogether 25 (51%) of the lesions had distal margins less than 7 cm from the anus and 36 (73%) extended above the peritoneal reflection. In seven patients with tumours less than 3 cm in diameter, symptomatic improvement was achieved in all (mean follow up 16 months) and complete tumour eradication in three. In the remaining 42 patients with larger tumours (34 greater than 2/3 circumferential, mean length 5.5 cm), symptomatic improvement was achieved with repeated treatments (average 3.4) in 31 (74%) over a mean follow up of 19 weeks. Of the parameters assessed, only circumferential tumour extent proved significant in predicting functional outcome after treatment. All treatment failures (eight initial, three late) occurred in patients with extensive tumours, and only seven of these patients were considered fit for colostomy. Bowel perforation occurred in two patients (5%) but there was no treatment-related mortality. Mean stay in hospital for all laser treatments was nine days (30% were outpatient attendances). These results suggest that laser therapy may be the palliative treatment of choice in patients with rectal carcinoma unsuitable for surgery.

Ten patients with colorectal cancers unsuitable for operation were treated with endoscopic photodynamic therapy (PDT). The patients were assessed before treatment, and at 1 week and 1 month after treatment by colonoscopy with biopsy and endoluminal ultrasound examination. The depth of tumour was measured and the effect of PDT was quantified by measuring the reduction in tumour depth. All patients were sensitized with 2·5mg kg−1 of haematoporphyrin derivative, 48h before phototherapy. A standard treatment protocol of light exposure was used. Up to four parts of the tumour were treated with 50 J of red light (630 nm) from a tuneable dye laser, through a flexible optical fibre passed through the colonoscope and inserted into the tumour. Two patients with small lesions are tumour-free 20 and 28 months after PDT. One treatment of an advanced tumour was complicated by a haemodynamically significant secondary haemorrhage. PDT may be most suitable for the treatment of small tumours or for small areas of persistent tumour where the bulk has been removed by alternative techniques.

Recent reports suggest that the effect of photodynamic therapy (PDT) can be enhanced by fractionating the light dose or reducing the light fluence rate. We assessed these options on two tissues in rats (normal colon and a transplanted fibrosarcoma) using the photosensitiser meta-tetrahydroxyphenylchlorin (mTHPC). Animals were sensitised with 0.3 mg/kg mTHPC, 3 days prior to illumination with red light (652 nm) using a single fibre touching the target tissue and killed 1–3 days later for quantitative measurement of the extent of PDT necrosis. Results were similar for both tissues, although the differences between illumination regimens were less marked in tumour tissue. Using continuous illumination and a fixed low energy in colon, the extent of necrosis was up to almost three times larger with 5 mW than with 100 mW, although the maximum attainable necrosis was independent of power. The long treatment time using 5 mW could be halved without loss of effect by increasing the power during treatment. Dividing the light into two equal fractions at 100 mW increased the lesion size by up to 20% in colon (independent of the timing of the dark interval), but by only 10% in tumour and had no effect at 20 mW. Previous studies using 5-aminolaevulinic acid (ALA) showed a much larger effect of fractionation that was critically dependent on the timing of the dark interval. We postulate that enhancement of PDT by fractionation is due to improved oxygen supply to the treated area which may be due to reversal of temporary vascular occlusion (more likely with ALA) or less rapid photochemical consumption of oxygen (more likely with mTHPC). At lower fluence rates, the oxygen consumption rate is not fast enough to be improved by fractionation. We conclude that fractionated or low power light delivery can enhance PDT with mTHPC. Although the effects are not large, this may be of value for interstitial treatment of solid tumours when multiple sites are treated simultaneously.

Photodynamic therapy (PDT) is a promising technique for the treatment of small tumours in organs where it is essential to minimise damage to immediately adjacent normal tissue as PDT damage to many tissues heals by regeneration rather than scarring. As preservation of function is one of the main aims of treating laryngeal tumours, this project studied the effects of PDT on the normal rabbit larynx with two photosensitisers, endogenous protoporphyrin IX (PPIX) induced by the administration of 5-aminolaevulinic acid (ALA) and disulphonated aluminium phthalocyanine (AIS2Pc). The main aims of the study were to examine the distribution of protoporphyrin IX and AIS2Pc by fluorescence microscopy in the different regions of the larnyx and to assess the nature and subsequent healing of PDT damage. Peak levels of PPIX were found 0.5-4 h after administration of ALA (depending on dose) with highest levels in the epithelium of the mucosa. With 100 mg kg-1, PDT necrosis was limited to the mucosa, whereas with 200 mg kg-1 necrosis extended to the muscle. With 1 mg kg-1 AIS2Pc, 1 h after administration, the drug was mainly in the submucosa and muscle, whereas after 24 h, it was predominantly in the mucosa. PDT at 1 h caused deep necrosis whereas at 24 h it was limited to the mucosa. All mucosal necrosis healed by regeneration whereas deeper effects left some fibrosis. No damage to cartilage was seen in any of the animals studied. The results of this study have shown that both photosensitisers are suitable for treating mucosal lesions of the larynx, but that for both it is important to optimise the drug dose and time interval between drug and light to avoid unacceptable changes in normal areas. Images Figure 2 Figure 3 Figure 5 Figure 6 Figure 7 Figure 8

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 (PDT) produces localised necrosis with light after prior administration of a photosensitising drug. As PDT lesions in the gastrointestinal tract heal so well, the technique is suitable for repeated endoscopic use. In this study, PDT was used to treat large polyps (four duodenal and two colorectal) unsuitable for surgery in 6 patients with familial adenomatous polyposis (FAP). Patients were sensitised with 60 mg/kg 5-aminolaevulinic acid (ALA) orally or intravenous (i.v.) 2.0 mg/kg Photofrin. Laser treatment was performed 6 h after ALA or 48 h after Photofrin using a gold vapour laser. Necrosis was only superficial (up to 1.8 mm) using ALA but much deeper using Photofrin. The one malignant polyp (8 mm diameter in the colon) showed a complete response using Photofrin. All healed safely with no complications. Photofrin worked better, but caused cutaneous photosensitivity lasting up to 3 months. ALA cleared within 2 days, but its use is limited by the superficial effect. Better results with ALA may be obtained using higher drug doses or modified light dosimetry. Fluorescence microscopy showed no evidence of selectivity of photosensitisation between neoplastic and normal tissue. PDT is a promising treatment for inoperable polyps in patients with FAP, but further work is required to optimise the treatment conditions.

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.

Photodynamic therapy of cancer exposes adjacent arteries to the risk of injury and the possibility of haemorrhage and thrombosis. The nature of photodynamic injury to normal arteries has not been satisfactorily defined, and the ability of arteries to recover with time is unclear. To clarify these issues, we have investigated the effects of PDT on rat femoral arteries, using a second-generation photosensitiser, disulphonated aluminium phthalocyanine, and a new method of photosensitisation, using endogenous synthesis of protoporphyrin IX following systemic administration of 5-aminolaevulinic acid (ALA). Pharmacokinetic studies of sensitiser fluorescence were carried out to determine peak levels of sensitiser. Subsequently photodynamic therapy at times corresponding to maximal fluorescence was performed using two light doses, 100 and 250 J cm-2. The nature of injury sustained and recovery over a 6 month period was investigated. Three days following PDT, all vessels treated showed complete loss of endothelium, with death of all medial smooth muscle cells, leaving an acellular flaccid artery wall. No vascular occlusion, haemorrhage or thrombosis was found. A striking feature was the lack of inflammatory response in the vessel wall at any time studied. Re-endothelialisation occurred in all vessels by 2 weeks. The phthalocyanine group showed repopulation of the media with smooth muscle cells to be almost complete by 3 months. However, the ALA group failed to redevelop a muscular wall and remained dilated at 6 months. Luminal cross-sectional area of the ALA-treated group was significantly greater than both control and phthalocyanine groups at 6 months. All vessels remained patent. This study indicates that arteries exposed to PDT are not at risk of catastrophic haemorrhage or occlusion, a finding that is of significance for both the local treatment of tumours and the use of PDT as an intraoperative adjunct to surgery for the ablation of microscopic residual malignant disease. Images Figure 1 Figure 3

Background—Intestinal metaplastic mucosa in Barrett's oesophagus can be replaced by squamous epithelium after mucosal thermal ablation associated with acid suppression therapy. Aims—To assess whether restoration of squamous epithelium can be obtained after ablation of Barrett's oesophagus using argon plasma coagulation (APC) associated with proton pump inhibitor (PPI) therapy. Methods—Thirty one patients with Barrett's oesophagus received APC. Omeprazole (40 mg/day) was given from the first APC application to one month after completion of the treatment, then given symptomatically. Twenty four hour pH-metry was performed during endotherapy. Results—Complete re-epithelialisation was visualised at endoscopy in 25/31 patients (81%) after a mean number of 2.4 APC sessions (range 1-4). Only partial squamous re-epithelialisation was observed in three patients and three others had no eradication. At histological assessment, eradication of Barrett's oesophagus was only confirmed in 19/31 patients (61%) due to the presence of a few residual Barrett's glands under the new squamous epithelium. Complete eradication was related to a Barrett's oesophagus segment length of less than 4 cm and the absence of circumferential extension but not to the normalisation of oesophageal acid exposure under PPI therapy. Seventeen patients with apparently complete endoscopic and histological eradication of Barrett's oesophagus were re-evaluated at one year; eight (47%) disclosed relapsing islands of Barrett metaplasia despite continuous omeprazole therapy (10-40 mg/day). Conclusions—APC combined with 40 mg omeprazole daily can eradicate Barrett's mucosa with apparent squamous re-epithelialisation in the majority of patients even in the absence of normalisation of oesophageal acid exposure. However, one year after endotherapy for Barrett's oesophagus, relapse is frequent but limited in extent.

Photodynamic therapy with intravenous photosensitising drugs has been shown to be effective in the ablation of superficial cancers, but long-lasting photosensitivity is a serious disadvantage. Similar photosensitivity is a feature of certain types of porphyria. We present the first report of tumour necrosis brought about by photodynamic activation of a temporary endogenous porphyrin accumulation, after an oral dose of the haem precursor, 5-aminolaevulinic acid. In 4 patients, quantitative fluorescence microscopy showed that accumulation of the photoactive intermediate protoporphyrin IX peaked after 4-6 h in 4 oral cavity squamous cell carcinomas, returning to background in 24 h. Irradiation with non-thermal red laser light caused tumour necrosis in 3 patients.