Ablation Of High-grade Dysplasia Research Articles

A Single-Center Pilot Study Accessing Subject Tolerability and Quality of Life After Circumferential Anal Canal Radiofrequency Ablation of High-Grade Dysplasia

A Single-Center Pilot Study Accessing Subject Tolerability and Quality of Life After Circumferential Anal Canal Radiofrequency Ablation of High-Grade Dysplasia

Cryospray Ablation for Barrett’s High-Grade Dysplasia in a Community-Based Barrett’s Registry of 965 Patients: 7 Year Follow-up

Introduction: To report the 7 year experience of a community-based gastroenterology practice using primarily nitrogen based cryospray ablation (CSA) in the treatment of Barrett’s esophagus with highgrade dysplasia (HGD) in a registry of 965 patients. Methods: Over 14 years, a community-based 9 physician gastroenterology practice prospectively enrolled 965 patients with confirmed intestinal metaplasia (IM), with or without dysplasia on initial biopsy of BE, in a Barrett’s registry. Intervention for the ablation of HGD was primarily CSA with follow-up esophageal biopsies per Seattle protocol. Nodular lesions in BE were first treated with endoscopic mucosal resection (EMR). Endpoints were histology based; complete response was defined as all biopsies at most recent endoscopy (EGD) negative for intestinal metaplasia (CR-IM) or dysplasia (CR-D). Results: From within a BE registry of 965 patients begun in 1999, a total of 28 patients had HGD. The mean age of patients with HGD was 69 years (range 47-89), 82% men. Mean BE length was 5cm (range 1-13cm). Eleven patients had HGD on initial EGD, 16 developed HGD during surveillance. The mean time to develop HGD during surveillance was 56 months (range 2-139 mo). We used CSA for ablation in 27 of the 28 patients. Mean CSA to completion: 4. Twenty-one received CSA exclusively, while 7 had EMR as their initial treatment for some element of nodularity. One was cured by a single EMR; the remaining 6 had subsequent CSA. Two patients had EMR followed by radiofrequency ablation (RFA) at an outside tertiary institution and were then referred to our registry/center for CSA after being considered treatment failures. Mean EGD follow-up after HGD was confirmed eradicated was 25 months (range 4-51 months). Mean CSA to achieve eradication: 4 treatments. Conclusion: The development of HGD in a Barrett’s surveillance registry is a relatively uncommon event. Durable, long-term elimination of HGD can be reliably achieved with cryospray ablation with minimal adverse events. Cryospray ablation offers a promising alternative to other ablative modalities such as EMR and RFA.Table 1: Ablation Stats From Registry

Endoscopic resection with or without mucosal ablation of high grade dysplasia and early oesophageal adenocarcinoma – Long term follow up from a regional UK centre

Background: Endoscopic resection (ER) is emerging as a curative technique in patients with high-grade dysplasia (HGD), intramucosal cancer (IMC), and early submucosal cancer (T1sm1) within Barrett's oesophagus. Methods: This consecutive case series of 72 patients with HGD or IMC reports outcomes of ER, with or without mucosal ablation, in a single institution after a median of 38 months follow-up between 2004 and 2011. The primary outcome was disease progression to submucosal invasion. Secondary outcomes included disease regression, the effect of ER on staging compared to biopsy and procedure-related complications. Results: 72 patients (mean age 73.0 – range 52.0–93.0) were treated by ER ± ablative therapy with curative intent for HGD (88% patients) or IMC (12%). 38% had one or more severe systemic co-morbidities. A median of 4 (1–11) procedures were undertaken per patient. In addition to ER, 43% of patients were treated with argon plasma coagulation, 17% with radiofrequency ablation, and 11% with photodynamic therapy. 8 (13%) patients with HGD at baseline and 0 (0%) with IMC progressed to invasive carcinoma. The median time to progression was 26.3 and 12.6 months respectively. 51% patients experienced disease regression. Disease staging was upgraded by ER in 27% of patients. Discussion: This case series reports on a minimally invasive technique in an elderly population with multiple co-morbidities, demonstrating disease regression with long-term follow-up. Conclusion: ER ± ablation is an effective and potentially curative option for patients with HGD or IMC. The benefit of endoscopic resection for disease staging was clearly demonstrated.

Superficial and early cancers of the esophagus.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the evolution of Barrett's dysplasia to early cancer; the early detection of esophageal cancer in China; new technologies of treatment for dysplasia; the prognostic value of molecular markers expression in esophageal squamous cell carcinoma; the follow-up schedule after ablation of high-grade dysplasia; intramucosal cancers; and tubular widespread endoscopic esophageal submucosal dissection with high-dose steroid stricture prevention.

Long-term Outcome of Ablation of Anal High-grade Squamous Intraepithelial Lesions

High-grade dysplasia is the anal carcinoma precursor. Clinicians ablate high-grade dysplasia with laser, electrocautery, and infrared coagulation to prevent cancer. The aim of this study was to determine the long-term effectiveness of high-grade dysplasia ablation and the incidence of cancer. This study is a retrospective chart review of patients who were treated for high-grade dysplasia from February 1998 until May 2012. This study was conducted in a surgical practice screening patients for anal cancer and high-grade dysplasia. The patients identified were HIV-positive and -negative men who have sex with men. The ablation of high-grade dysplasia was performed. The primary outcomes measured were the probability of high-grade dysplasia recurrence postablation and the incidence of cancer. Four hundred fifty-six HIV-positive men who have sex with men (mean age, 45 ± 9 years) and 271 HIV-negative men who have sex with men (mean age, 41 ± 11 years) followed for a median of 2.2 (range, 0.2-13) years underwent high-grade dysplasia ablation by laser, infrared coagulation, and/or electrocautery. Median time to recurrence was 6.8 and 6.9 months for HIV-positive and -negative patients. Kaplan-Meier curves predict a rate of recurrence 1 year after the first ablation for HIV-positive and -negative patients of 53% (95% CI, 49%-58%) and 49% (95% CI, 43%-55%). At 2 and 3 years, the rate of recurrence was 68% (95% CI, 63%-73%) and 77% (95% CI, 7%2-82%) for HIV-positive patients and 57% (95% CI, 51%-64%) and 66% (95% CI, 59%-73%) for HIV-negative patients. The median number of recurrent lesions was ≤2 for HIV-positive patients and ≤1 for HIV-negative patients. Recurrence increased with HIV infection (HR, 1.3; 95% CI, 1.1-1.6) and each additional lesion treated (HR 1.6, 95% CI, 1.1-1.2). Five HIV-positive men who have sex with men developed cancer. The Kaplan-Meier probability of cancer 3 years postablation was 1.97% (95% CI, 0.73%-5.2%). This is a retrospective study by 1 surgeon who has extensive experience treating anal dysplasia. There was no pathology review, and the type of recurrence cannot be definitively determined because the location could be inaccurate. Patients undergoing ablation of intra-anal high-grade dysplasia have high recurrence, but the probability of developing anal cancer is low. HIV infection and increased number of high-grade dysplasias increases the risk of recurrence.

Sa1388 Low Pressure Cryospray Ablation of High Grade Dysplasia in Barrett's Esophagus: 2 Year Follow-up

Sa1388 Low Pressure Cryospray Ablation of High Grade Dysplasia in Barrett's Esophagus: 2 Year Follow-up

13. Long-term effectiveness of intra-anal high-grade dysplasia ablation and near 100% prevention of progression to anal cancer

Background High-grade dysplasia (HSIL) is the anal squamous cell carcinoma (ASCC) precursor. Ablation with surgery, electro cautery (ECA) and infrared coagulation (IRC) might prevent ASCC. We endeavoured to determine long-term effectiveness of HSIL ablation and progression to ASCC. Methods: A retrospective chart review of patients undergoing HSIL ablation by any modality between February 1998 until May 2012. Results: In 456 HIV+ MSM (mean age 45 ± 9 years) and 271 HIV– MSM (mean age 41 ± 11years) followed for a mean of 3 (range 0.2–13) years, 1673 HSILs were treated by laser, IRC and/or ECA. ASCC developed in 5 (0.7%) MSM but only one (0.1%) was undergoing active treatment. For HIV+ MSM, recurrence after 1st, 2nd, 3rd and 4th treatment was 66%, 64%, 62% and 54%, respectively. For HIV– MSM, HSIL recurrence after the 1st, 2nd, 3rd and 4th treatment was 59%, 44%, 46% and 50%, respectively. Median number of recurrent lesions was never greater than 2 for HIV+ MSM and 1 for HIV– MSM. The cure rate of lesions treated once in HIV+ and HIV– MSM was 73% and 84%, respectively. KM curves demonstrate that most recurrence occurs within the first 12 months after treatment. Recurrence increased with HIV infection (HR 1.3; 95% CI: 1.1–1.6) and each additional lesion treated (HR 1.6; 95% CI: 1.1–1.2). Age and treatment modality did not affect recurrence. Conclusions: Patients undergoing active ablation for cure of intra-anal HSIL appear to have limited progression to ASCC. Recurrence remains high but falls over time and repeated treatment.

OC-020 Recurrence after radiofrequency ablation for barrett's related high grade dysplasia is due to persistence of epithelial mutations

IntroductionRadiofrequency ablation (RFA) is a relatively new endoscopic method for ablation of high grade dysplasia (HGD) and intramucosal adenocarcinoma (IMC) in Barrett's oesophagus. Clinical trials have shown enduring eradication of...

Tu1116 Recurrence After Radiofrequency Ablation for Barretts Related High Grade Dysplasia is Due to Persistence of Epithelial Mutations

Introduction Radiofrequency ablation (RFA) is a relatively new endoscopic method for ablation of high grade dysplasia (HGD) and intramucosal adenocarcinoma (IMC) in Barrett9s oesophagus. Clinical trials have shown enduring eradication of these pathologies. 1 However, some patients develop recurrent dysplasia or cancer. 1 The reason for this is unknown. The aim of the study was to investigate whether this is related to the persistence of known cancer driving mutations after radiofrequency ablation. Methods Patient records were searched for patients with recurrent HGD or IMC after RFA. Biopsies and endoscopic mucosal resection (EMR) specimens were available before and after RFA for each case. Whole biopsies underwent nested polymerase chain reaction (PCR) sequencing for mutations commonly implicated in progression to adenocarcinoma ( TP53, CDKN2A, K-ras ). Results Tissue was obtained for six patients before and after RFA. All patients were male (mean age 67 SD±2). Samples from five patients contained detectable mutations. In 3/5 patients, the same mutation was found in material taken before RFA as after (all TP53 mutations). The indication for RFA in all three patients was HGD; two of the patients developed IMC after RFA. In these two cases laser microdissection was performed on the post-RFA EMR samples. PCR revealed the pre RFA mutation to also be present throughout the IMC specimen. Dysplastic tissue adjacent to the IMC contained a mixture of crypts that were either wild type for the mutation in the IMC or contained the mutation indicating that the IMC was a monoclonal outgrowth and that the persistent mutation was driving the development of the recurrence. Furthermore, in all three cases, PCR of a further specimens (performed at a later time point to the first post-RFA EMR), revealed the same mutation as the initial biopsy before RFA, and the first post-RFA EMR. Conclusion The recurrence of dysplasia and cancer after RFA is likely to be due to failure to remove persistent, cancer driving mutations. Further work will need to be done to assess whether this is because of technical errors, or related to specific problems such as “buried Barrett9s”. Competing interests None declared. Reference 1. Shaheen N , Overholt B, Sampliner RE. Durability of radiofrequency ablation in barrett9s esophagus with dysplasia. Gastroenterology 2011; 141 :460–8.

Rapid endoscopic identification and destruction of degenerating Barrett’s mucosal neoplasia

There are distinct challenges implicit to the development of minimally invasive endoscopic surgery for the eradication of early neoplasia in Barrett’s oesophagus. Endoscopic resection and ablation of high-grade dysplasia and mucosal cancer offer alternative therapeutic options to those unsuitable or unwilling to contemplate radical surgical excision. It may also become the treatment of choice in the future. Technological developments enable the instantaneous and non-invasive diagnosis of microscopic tissue abnormalities in vivo. This is made possible by improving the level of information that can be obtained from the tissue. As well as the two-dimensional surface morphology image, which the traditional endoscope can view, we have used new techniques to enable structure at depth, using Optical Coherence Tomography, to be imaged in high resolution. Other advances, using Raman spectroscopy, enable the early endoscopic detection of biochemical and molecular changes in tissue that precede any changes in morphology, thus enabling earlier diagnosis of tissue abnormalities. This King James IV lecture details our recent work, to develop advanced imaging for the diagnosis of malignancy and pre-malignancy. After detection endoscopic photodynamic therapy and endoscopic mucosal resection can provide eradication of mucosal neoplasia. Following photodynamic therapy there was complete eradication of all high-grade dysplasia and intramucosal carcinoma in 40 of 42 patients with a maximum endoscopic follow-up period of 72 months. Following endoscopic resection of 95 patients, the mean survival for intramucosal adenocarcinoma and high-grade dysplasia was 40.6 and 60.8 months respectively.

Radiofrequency Ablation of High Grade Dysplasia in Barrett's Oesophagus Is Safe and Effective After Failed Photodynamic Therapy - First Results of the UK HALO RFA Registry

Radiofrequency Ablation of High Grade Dysplasia in Barrett's Oesophagus Is Safe and Effective After Failed Photodynamic Therapy - First Results of the UK HALO RFA Registry

Patient predictors of histopathologic response after photodynamic therapy of Barrett's esophagus with high-grade dysplasia or intramucosal carcinoma

Photodynamic therapy (PDT) has been used extensively for endoscopic ablation of Barrett's esophagus with high-grade dysplasia (HGD) or intramucosal carcinoma. To identify patient variables that influence the likelihood of response to PDT. A retrospective cohort study. Tertiary-referral center. A total of 116 patients with Barrett's esophagus and with HGD, intramucosal carcinoma, or T1 cancer. PDT with porfimer sodium. (1) Ablation of HGD and/or intramucosal carcinoma and (2) eradication of all Barrett's epithelium. Of the patients, 51% underwent treatment for HGD and 49% of patients had intramucosal carcinoma or T1 cancer. At 12-month follow-up, ablation of HGD and/or cancer was observed in 70% of patients, and ablation of all Barrett's epithelium was observed in 39%. In multivariate analysis, the pretreatment length of Barrett's esophagus was inversely correlated with successful ablation of all Barrett's epithelium. Patients with Barrett's esophagus length more than 3 cm were less likely to experience complete ablation compared with patients with Barrett's esophagus length 3 cm or less (odds ratio [OR] 0.15 [95% CI, 0.04-0.50]). Patients with intramucosal carcinoma were not significantly less likely to experience elimination of HGD and/or cancer (OR 0.77 [95% CI, 0.30-2.00]) or ablation of all Barrett's epithelium (OR 0.82 [95% CI, 0.32-2.07]) compared with patients with HGD alone. Retrospective study, limited sample size without a control group for comparison. PDT of Barrett's esophagus with HGD, intramucosal carcinoma, or T1 cancer can result in ablation of dysplasia and/or eradication of all Barrett's epithelium. Factors associated with the likelihood of response include length of Barrett's esophagus. The presence of intramucosal carcinoma or T1 cancer was not associated with higher likelihood of treatment failure.

Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett's high-grade dysplasia

Barrett's esophagus (BE) with high-grade dysplasia (HGD) is a risk factor for development of esophageal carcinoma. Photodynamic therapy (PDT) with Photofrin (PHO) has been used to eliminate HGD in BE. Our purpose was to compare PHOPDT plus omeprazole with omeprazole only (OM). Five-year follow-up of a randomized, multicenter, multinational, pathology-blinded HGD trial. 30 sites in 4 countries. 208. Patients with BE and HGD were randomized (2:1) to PHOPDT (n=138) or OM (n=70) into a 2-year trial followed up for 3 more years. PHOPDT patients received 2 mg/kg PHO intravenously followed by endoscopic laser light exposure of Barrett's mucosa at a wavelength of 630 nm within 40 to 50 hours to a maximum of 3 courses at least 90 days apart. Both groups received 20 mg of OM twice daily. Pathologists at one center assessed biopsy specimens in a blinded fashion. HGD ablation status over 5 years of follow-up. At 5 years PHOPDT was significantly more effective than OM in eliminating HGD (77% [106/138] vs 39% [27/70], P<.0001). A secondary outcome measure preventing progression to cancer showed a significant difference (P=.027) with about half the likelihood of cancer occurring in PHOPDT (21/138 [15%]) compared with OM (20/70 [29%]), with a significantly (P=.004) longer time to progression to cancer favoring PHOPDT. Not all patients were available for follow-up. This 5-year randomized trial of BE patients with HGD demonstrates that PHOPDT is a clinically and statistically effective therapy in producing long-term ablation of HGD and reducing the potential impact of cancer compared with OM.

Circumfrential Ablation of Barrett Esophagus with Persistent High-Grade Dysplasia Following Photodynamic Therapy with Halo 360

Purpose: Photodynamic therapy (PDT) is an FDA approved treatment for Barrett esophagus (BE) with high-grade dysplasia (HGD). It is unknown whether patients with persistent HGD following treatment with PDT could benefit from another ablative technique.We report initial safety and efficacy of the HALO360 bipolar balloon electrode in treatment of patients with BE and persistent HGD after treatment with PDT. Methods: Patients previously treated with PDT with persistent HGD confirmed by two pathologists and refusing repeat PDT or surgery were treated with the HALO360 bipolar balloon electrode. Patients underwent repeat treatment at 3 month intervals until all Barrett's epithelium was ablated. Lugol's chromoendoscopy with targeted biopsies from endoscopically visible Barrett and random biopsies from the ablated segment of original Barrett were obtained at regular follow-up interval to assess for dysplasia and residual Barrett epithelium. Endoscopic mucosal resection (EMR) was utilized for nodular HGD or early stage adenocarcinoma (ACA). Adverse events with the procedure were recorded. Results: Five patients with residual HGD after treatment with PDT have been treated with HALO360 bipolar balloon electrode. Two patients had complete ablation of HGD, 3 were found to have residual areas of focal nodular HGD/early stage ACA on follow-up and were treated with EMR. Two out of three had complete resection of ACA with EMR. One patient had involvement of the deep margin of the EMR with ACA and opted to undergo repeat PDT. All 3 patients were cancer/dysplasia free at the last follow-up. No adverse events were recorded. Conclusions: Ablation of BE with persistent HGD or early stage esophageal ACA following treatment with PDT is effective using HALO360 balloon electrode and EMR for nodular disease. Patient tolerance and safety with the procedure has been excellent. Long term follow-up is needed to establish the efficacy of this treatment.

Association of ablation of Barrett’s esophagus with high grade dysplasia and adenocarcinoma of the gastric cardia

There has been increasing application of endoscopic ablation therapy for patients with high-grade dysplasia (HGD) and Barrett's esophagus (BE). Three cases are reported in which the patient developed adenocarcinoma of the gastric cardia after thermal ablation of HGD. A definition of BE including endoscopic abnormality and intestinal metaplasia by biopsy was used. Strict and standardized criteria were utilized for the endoscopic landmarks. Three cases are reported with long-segment BE and a nodule or mass in the endoscopic cardia post-thermal ablation. Biopsies documented adenocarcinoma of the gastric cardia. The development of adenocarcinoma of the cardia is unexpected. Speculation is offered as to the potential of increased proliferation and mutations at the new squamocolumnar interface after endoscopic ablation therapy to explain this association.

A 5-Year Randomized Phase III Trial of Efficacy and Safety of Photodynamic Therapy Using Porfimer Sodium in High-Grade Dysplasia in Barrett's Esophagus

A 5-Year Randomized Phase III Trial of Efficacy and Safety of Photodynamic Therapy Using Porfimer Sodium in High-Grade Dysplasia in Barrett’s Esophagus Bergein Overholt, Kenneth Wang, Steven Burdick, Charles Lightdale, Michael Kimmey, Hector Nava, Michael Sivak, Norman Nishioka, Hugh Barr, Chad Davis, Norman Marcon, Marcos Pedrosa, Mary Bronner, Michelle Depot Purpose: Barrett’s esophagus (BE) with high-grade dysplasia (HGD) patients were enrolled in a two-year trial comparing photodynamic therapy (PDT) with porfimer sodium (POR) plus 20 mg BID omeprazole (O) [PORPDT] with standard therapy of acid suppression with O [O alone] and followed for an additional 3 years. At 2 years, HGD ablation occurred in 77% of PORPDT patients versus 39% in O alone patients (p ! 0.0001). As HGD and possible cancer development in BE are inextricably linked, the trial was continued over 5 years to assess longer-term HGD ablation and cancer occurrence. Methods: Patients with BE and HGD were randomized (2:1) to PORPDT (n Z 138) or O alone (n Z 70). Patients on PDT received 2 mg/kg i.v. of POR followed by endoscopic laser light exposure of Barrett’s mucosa at a wavelength of 630 nm within 40-50 hours up to a maximum of 3 courses administered at least 90 days apart. Every 3 months, patients underwent 4-quadrant jumbo esophageal biopsies at 2-cm intervals. Pathologists based at one center assessed biopsies and were blinded to treatment assignment and patient identity. Results: At 5 years, PORPDT was significantly more effective than O alone in eliminating HGD (p ! 0.0001) and in preventing progression to cancer (p Z 0.027) with about twice the likelihood of cancer occurring in O alone (29%) compared to PORPDT (15%). HGD ablation at 5 years confirmed the significant difference found at 2 years (77% PORPDT, 39% O alone). Conclusions: This 5-year large randomized trial showed clearly that PORPDT is a statistically and clinically effective endoscopic therapy in eliminating HGD and in reducing the incidence of cancer in BE patients with HGD compared to O alone.

Photodynamic Therapy With Porfimer Sodium for Ablation of High-Grade Dysplasia in Barrett's Esophagus: International, Partially Blinded, Randomized Phase III Trial

Photodynamic Therapy With Porfimer Sodium for Ablation of High-Grade Dysplasia in Barrett's Esophagus: International, Partially Blinded, Randomized Phase III Trial

Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international, partially blinded, randomized phase III trial

Barrett's esophagus (BE) may lead to high-grade dysplasia (HGD) and adenocarcinoma. The objective was to examine the impact of treating patients with BE and with HGD by using porfimer sodium (POR) and photodynamic therapy (PDT) for ablating HGD and reducing the incidence of esophageal adenocarcinoma. The design was a multicenter, partially blinded (pathology), randomized clinical trial conducted in patients with BE who have HGD. There were 30 contributing centers. A total of 485 patients were screened, with 208 in the intent-to-treat population and 202 in the safety population. Patients were randomized on a 2:1 basis to compare PDT with POR plus omeprazole (PORPDT) with omeprazole only (OM). The main outcome measurement was complete HGD ablation occurring at any time during the study period. There was a significant difference (p < 0.0001) in favor of PORPDT (106/138 [77%]) compared with OM (27/70 [39%]) in complete ablation of HGD at any time during the study period. The occurrence of adenocarcinoma in the PORPDT group (13%) (n=18) was significantly lower (p < 0.006) compared with the OM group (28%) [corrected] (n=20). The safety profile showed 94% of patients in the PORPDT group and 13% of patients in the OM group had treatment-related adverse effects. The limitations of the study were that PDT therapy may have had to be applied more than once and that patients spent more time in treatment. The patients and the physicians were not blinded to the treatment. PORPDT in conjunction with omeprazole is an effective therapy for ablating HGD in patients with BE and in reducing the incidence of esophageal adenocarcinoma.

Is Photodynamic Therapy Effective for HGD Ablation in BE Patients

Endoscopic ablative therapies for treating Barrett esophagus (BE)-related dysplasia include photodynamic therapy (PDT) and thermal therapy with laser, argon plasma coagulation, or multipolar electrocautery. Although promising, none of these techniques have been evaluated in a prospective randomized trial. In this 30-center, international, multicenter trial, researchers randomized 208 BE patients with biopsy-proven high-grade dysplasia (HGD) to receive omeprazole (20 mg twice per day) alone or with PDT. After porfimer sodium injection, PDT was delivered using …

Optimization of Aminolevulinic Acid-based Photodynamic Therapy of Barrett's Esophagus with High Grade Dysplasia

Background: Photodynamic therapy (PDT) has become an accepted method for eradicating Barrett's esophagus (BE). Aminolevulinic acid (ALA) is an attractive photosensitizer for PDT because it can be given orally just prior to illumination and has minimal side effects. Trials to date with ALA-PDT have demonstrated high rates of dysplasia ablation but it has not gained widespread acceptance because of its poor ablation efficiency of BE relative to other agents such as porfirmer sodium. This study is modifying ALA-PDT treatment parameters with the goal of improving PDT efficiency. There are two specific aims: (1) enhance ALA-PDT using differentiation therapy (retinoids) which may augment protoporphyrin IX (in vivo photosensitizer) production, and (2) enhance ALA-PDT by modifying light delivery (light fractionation, to improve oxygen diffusion during PDT). Methods: This is a prospective, randomized trial involving patients with BE and high-grade dysplasia (HGD) or T1N0M0 esophageal cancer (IMCA). Patients are randomized to one of four groups: pretreatment with 13-cis retinoic acid or placebo for 14 days followed by ALA-PDT with or without a 60-second light fractionation sequence. ALA is administered po (30 mg/kg) and patients undergo PDT four hours later. Light dose is constant at 150 J/cm2. EGD is performed at 3-month intervals to document change in BE length and ablation of HGD or IMCA. Results: Six patients (all men) have been treated. Average age is 67.7 (range 54-81). Mean length of BE is 3.7 cm (range 1-8 cm). Five of six patients have undergone follow-up (mean follow up is 5.5 months). The rate of HGD/IMCA ablation has only been 20% (1/5 patients). 2/5 patients experienced new onset atrial fibrillation following administration of ALA (one after and one before PDT). Both spontaneously converted. Another patient died 24 hours following ALA-PDT with acute cardiopulmonary failure. Post-mortem examination revealed aspiration pneumonitis. Two of three patients with adverse events were randomized to pre-treatment with 13-cis retinoic acid. Conclusions: Preliminary results with ALA-PDT have been disappointing with the ablation efficiency much lower than expected and with a high frequency of unexpected adverse events. These adverse events have not been well-documented in prior experiences with this agent. The limited ablation effect in combination with the frequency of adverse effects calls into question the overall viability of ALA-PDT as a treatment of complicated Barrett's esophagus.