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Pilot Animal Study of the Phthalocyanine Pc4 as a Topically-Applied Photosensitizer for PDT of Barrett's Esophagus
Abstracts
S1363 Oesophageal Capsule Endoscopy in Patients with Suspected Oesophageal Disease: Double Blinded Comparison with Oesogastro-Duodenoscopy and Assessment of Inter-Observer Variability Michel Delvaux, Ioannis S. Papanikolaou, Isaac Fassler, Heiko Pohl, Winfried Voderholzer, Thomas Rosch, Gerard Gay Capsule endoscopy (CE) has recently been introduced as an highly accurate test to diagnose oesophageal diseases. The aim of the present study was to evaluate the diagnostic yield of CE in patients with suspected oesophageal disease in comparison with oesogastroduodenoscopy (OGD) as gold standard. Secondary aims were to assess inter-observer variability in reading of CE recordings and safety of the procedure. Patients and Method. Ninety-eight patients (53 men, mean age 53 13 years) were included with an indication for OGD (GERD 32, Cirrhosis 30, Abdominal pain 13, Chronic diarrhoea 7, Barrett oesophagus 5, Pre-liver transplant 3 and others 5). The patient population was artifcially enriched to include 2/3 of patients with abnormal oesophageal findings at OGD. All patients underwent an OGD with videotape-recording of the oesophageal sequence followed by CE within the next 48 hours. CE recordings were blindly read by 3 endoscopists, one in the centre including the patient and two in the other. One of these latter two examiners received a specific training session for oesophageal CE. Study outcomes were the findings described on OGD and CE, agreement of OGD and CE for findings, quality of the CE recording, inter-observer agreement for CE quality and findings. Results. OGD was normal in 34 patients and showed various findings in the remaining 62 cases (oesophagitis 28, hiatus hernia 21, oesophageal varices 21, Barrett oesophagus 11, others 7). Average transit time of the capsule in the oesophagus was 361 393s (median Z 267s). CE was normal in 36 cases but detected oesophagitis in 23, hiatus hernia 0, oesophageal varices 23, Barrett oesophagus 18, others 4. Positive Predictive Value (PV) of CE was 80.0% and negative PV, 61.1%. Overall agreement per patient was moderate between the two methods (kappa Z 0.42). Agreement between OGD and CE was also moderate when findings were analyzed individually (kappa Z 0.40). Inter-observer agreement between CE readings was moderate for findings (kappa Z 0.39) but weaker for quality assessment (kappa Z 0.24). No adverse event was observed in this study for both OGD and CE. The training session did not improve the inter-observer agreement. Conclusion. In this study, despite an artificial prevalence enrichment, CE showed a moderate sensitivity and specificity in the detection of oesophageal diseases. Quality of the recordings needs to be improved, especially clearance of the saliva from the oesophagus.
S1365 Circumferential Ablation of Barrett Esophagus with Low Grade Dysplasia: One and Two Year Follow-Up of the AIM-LGD Trial Virender K. Sharma, H. Jae Kim, Danette Musil, Michael D. Crowell, Patrick J. Dean, David E. Fleischer Aims: To assess the long term safety, tolerability and effectiveness outcomes of a combination of primary circumferential ablation (CA) followed by secondary focal ablation (FA) using the HALO Ablation System for Barrett esophagus (BE) with lowgrade dysplasia (LGD). Methods: This is an extension of the AIM-LGD Trial, which commenced in 06/2004. Inclusion required 2-6 cm BE-LGD on 2 biopsy sessions in the prior 2 years and independently confirmed by 2 pathologists. The CA device ˆRRX Medical, Sunnyvale, CA) is a balloon-based electrode, which (HALO360, BA delivers a pre-set amount of energy (12 J/cm2) at high power (40 W/cm2) to BE tissue. The FA device (HALO90) is an endoscope-mounted electrode. CA was performed at baseline and again at 4 months if needed. After 12 month EGD with biopsy for the primary 1 year endpoint, FA was performed for any visible mucosal abnormality (max 1 session). Patients received lansoprazole 30 mg bid throughout study. Symptoms of chest, throat and abdominal pain, odynophagia, dysphagia were quantified for 14 days after each ablation session using a diary (visual analog scale, 0-100 mm). Patients underwent EGD with 4Q/1 cm biopsies at 1, 3, 6, 12, 24 mo. Pathology review was blinded. Complete Response (CR) is defined as all biopsies negative for BE-LGD or BE (% pts with CR for each endpoint). Results: Ten patients (9 men, mean age 56 years, range 26-79) with BE-LGD (median 4 cm, range 3-6) were treated with CA. Sedation: midazolam (median 5 mg), meperidine (median 50 mg). Median procedure time 47 min. Diary results after CA; all median scores !20/100 on day 1 and all completely resolved by day 5. There was one mild self-limited bleed. At 1 year, CR-BE was 80% and CR-LGD was 100%. After 1 year, all patients had complete resolution of visible BE, except for irregular z-line in all. Nine of 10 patients underwent FA of irregular z-line (median procedure time 11 min). Sedation: midazolam (median 5 mg), meperidine (median 50 mg). Diary results after FA were similar to those after CA; all median scores !20/100 on day 1 and all completely resolved by day 6. There were no adverse events. Histological outcomes at 2 years are available for 5 patients; CR-BE 100%, CR-LGD 100%. There were no strictures or buried glands at 12 or 24 months. Conclusion: A combined regimen of primary circumferential ablation and secondary focal ablation using the HALO System appears to safely and effectively eradicate BE and LGD at 1 and 2 year follow-up. Such an intervention could have implications for management and surveillance strategies for LGD. A randomized, sham-controlled trial is underway to confirm the results of this pilot trial.
S1366 Cervical Inlet Patch of the Esophagus: A Cause for Concern? Shailaja Jamma, Krishnarao Tangella, Davendra P. Ramkumar
S1364 Pilot Animal Study of the Phthalocyanine Pc4 as a TopicallyApplied Photosensitizer for PDT of Barrett’s Esophagus Farees T. Farooq, Jeffrey Berlin, Elma Baron, Ashley L. Faulx, Jeffrey M. Marks, Amitabh Chak Background: Photodynamic therapy (PDT) is a treatment option for Barrett’s esophagus with high grade dysplasia. A major drawback of PDT using Photofrin is the lengthy period of cutaneous photosensitivity that follows treatment. A photosensitizer that can be applied topically in the esophagus may eliminate the side-effect of cutaneous photosensitivity that results from systemically-administered photosensitizers, making PDT a more attractive therapeutic option. The phthalocyanine Pc4, a photosensitizer that selectively accumulates in tumors and has a peak absorption at 675 nm, has been shown in animal studies to be more efficacious than Photofrin. Ongoing Phase I clinical trials have shown that Pc4 can be applied topically for the treatment of dermal tumors. Aims: To determine whether Pc4 can be applied topically to esophageal mucosa at endoscopy and to determine the depth of penetration of topically-applied Pc4. Methods: EGD was performed on three anesthetized pigs. Pc4 diluted in 5% ethanol-saline solution was applied uniformly to the distal porcine esophagus using an endoscopic spray catheter. After a 30 min. incubation period, esophagectomy was performed. Subsequently, tissue was sectioned, fixed, and examined by single-photon confocal microscopy. Results: Gross specimens demonstrated a fairly uniform application of Pc4 as evidenced by the resultant bluish discoloration of treated tissue. Confocal microscopy demonstrated penetration of the stratified squamous epithelium at depths in the range of 100-200 microns. Conclusions: Pc4 applied to the porcine esophagus using an endoscopic spray catheter demonstrates significant epithelial penetration. Additional studies are needed to determine the optimal delivery vehicle, incubation period to maximize tissue penetration and the depth of tissue injury with PDT in this model.
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Introduction: Inlet patch is a distinct region of heterotopic gastric mucosa occurring in the proximal one-third of the esophagus with a prevalence of 0.1% to 10% in patients undergoing esophagogastroduodenoscopy (EGD). This wide range in prevalence is due to the special interest of some endoscopists who specifically look for it. It has largely been documented as asymptomatic, although there are associated symptoms like heartburn and dysphagia along with complications such as esophagitis, ulceration, perforation, stricture and adenocarcinoma of the cervical esophagus. However, cough and hoarseness secondary to inlet patch have rarely been reported. In our study, we retrospectively determined the prevalence and histologic types of inlet patch as well as its association with aero-digestive symptoms including cough and its response to high-dose acid suppression. Method: We reviewed 349 consecutive EGD reports done by a single endoscopist from December 2004 to December 2005, and cases with described inlet patch were corroborated by pathology reports. Biopsies were reevaluated by a pathologist looking for the presence of gastric metaplasia, other types of mucosa, and the presence of inflammation. An immunohistochemical method was used to detect Helicobacter pylori. We also evaluated the association of inlet patch with aerodigestive symptoms and subsequent response to therapy. Demographic data with age, sex, symptoms, pathological findings, treatment and response to treatment were tabulated. Results: Inlet patch was found in seven patients out of 349, with a prevalence of 2.01%. In six patients, it appeared as a single patch and in one patient as a twin patch. None of them had evidence of Barrett’s esophagus. In the inlet patch, oxyntic mucosa was seen in six and cardiac mucosa in one. Six of the seven specimens showed mild chronic inflammation. None of them showed intestinal metaplasia. All of them were negative for H. pylori. One patient had cough and sore throat. One patient had hoarseness. Five patients had retrosternal discomfort. Two patients had dysphagia. Six patients showed alleviation of symptoms with high dose acid suppression. Conclusion: Though largely considered asymptomatic, inlet patch can cause supraesophageal symptoms like cough, sore throat and hoarseness apart from dysphagia and retrosternal discomfort. Hence, it should be carefully looked for during EGD in patients with refractory aero-digestive symptoms. In patients with identified inlet patch, treatment should be attempted with high dose acid suppression.
Volume 65, No. 5 : 2007 GASTROINTESTINAL ENDOSCOPY AB155
S1363 Oesophageal Capsule Endoscopy in Patients with Suspected Oesophageal Disease: Double Blinded Comparison with Oesogastro-Duodenoscopy and Assessment of Inter-Observer Variability Michel Delvaux, Ioannis S. Papanikolaou, Isaac Fassler, Heiko Pohl, Winfried Voderholzer, Thomas Rosch, Gerard Gay Capsule endoscopy (CE) has recently been introduced as an highly accurate test to diagnose oesophageal diseases. The aim of the present study was to evaluate the diagnostic yield of CE in patients with suspected oesophageal disease in comparison with oesogastroduodenoscopy (OGD) as gold standard. Secondary aims were to assess inter-observer variability in reading of CE recordings and safety of the procedure. Patients and Method. Ninety-eight patients (53 men, mean age 53 13 years) were included with an indication for OGD (GERD 32, Cirrhosis 30, Abdominal pain 13, Chronic diarrhoea 7, Barrett oesophagus 5, Pre-liver transplant 3 and others 5). The patient population was artifcially enriched to include 2/3 of patients with abnormal oesophageal findings at OGD. All patients underwent an OGD with videotape-recording of the oesophageal sequence followed by CE within the next 48 hours. CE recordings were blindly read by 3 endoscopists, one in the centre including the patient and two in the other. One of these latter two examiners received a specific training session for oesophageal CE. Study outcomes were the findings described on OGD and CE, agreement of OGD and CE for findings, quality of the CE recording, inter-observer agreement for CE quality and findings. Results. OGD was normal in 34 patients and showed various findings in the remaining 62 cases (oesophagitis 28, hiatus hernia 21, oesophageal varices 21, Barrett oesophagus 11, others 7). Average transit time of the capsule in the oesophagus was 361 393s (median Z 267s). CE was normal in 36 cases but detected oesophagitis in 23, hiatus hernia 0, oesophageal varices 23, Barrett oesophagus 18, others 4. Positive Predictive Value (PV) of CE was 80.0% and negative PV, 61.1%. Overall agreement per patient was moderate between the two methods (kappa Z 0.42). Agreement between OGD and CE was also moderate when findings were analyzed individually (kappa Z 0.40). Inter-observer agreement between CE readings was moderate for findings (kappa Z 0.39) but weaker for quality assessment (kappa Z 0.24). No adverse event was observed in this study for both OGD and CE. The training session did not improve the inter-observer agreement. Conclusion. In this study, despite an artificial prevalence enrichment, CE showed a moderate sensitivity and specificity in the detection of oesophageal diseases. Quality of the recordings needs to be improved, especially clearance of the saliva from the oesophagus.
S1365 Circumferential Ablation of Barrett Esophagus with Low Grade Dysplasia: One and Two Year Follow-Up of the AIM-LGD Trial Virender K. Sharma, H. Jae Kim, Danette Musil, Michael D. Crowell, Patrick J. Dean, David E. Fleischer Aims: To assess the long term safety, tolerability and effectiveness outcomes of a combination of primary circumferential ablation (CA) followed by secondary focal ablation (FA) using the HALO Ablation System for Barrett esophagus (BE) with lowgrade dysplasia (LGD). Methods: This is an extension of the AIM-LGD Trial, which commenced in 06/2004. Inclusion required 2-6 cm BE-LGD on 2 biopsy sessions in the prior 2 years and independently confirmed by 2 pathologists. The CA device ˆRRX Medical, Sunnyvale, CA) is a balloon-based electrode, which (HALO360, BA delivers a pre-set amount of energy (12 J/cm2) at high power (40 W/cm2) to BE tissue. The FA device (HALO90) is an endoscope-mounted electrode. CA was performed at baseline and again at 4 months if needed. After 12 month EGD with biopsy for the primary 1 year endpoint, FA was performed for any visible mucosal abnormality (max 1 session). Patients received lansoprazole 30 mg bid throughout study. Symptoms of chest, throat and abdominal pain, odynophagia, dysphagia were quantified for 14 days after each ablation session using a diary (visual analog scale, 0-100 mm). Patients underwent EGD with 4Q/1 cm biopsies at 1, 3, 6, 12, 24 mo. Pathology review was blinded. Complete Response (CR) is defined as all biopsies negative for BE-LGD or BE (% pts with CR for each endpoint). Results: Ten patients (9 men, mean age 56 years, range 26-79) with BE-LGD (median 4 cm, range 3-6) were treated with CA. Sedation: midazolam (median 5 mg), meperidine (median 50 mg). Median procedure time 47 min. Diary results after CA; all median scores !20/100 on day 1 and all completely resolved by day 5. There was one mild self-limited bleed. At 1 year, CR-BE was 80% and CR-LGD was 100%. After 1 year, all patients had complete resolution of visible BE, except for irregular z-line in all. Nine of 10 patients underwent FA of irregular z-line (median procedure time 11 min). Sedation: midazolam (median 5 mg), meperidine (median 50 mg). Diary results after FA were similar to those after CA; all median scores !20/100 on day 1 and all completely resolved by day 6. There were no adverse events. Histological outcomes at 2 years are available for 5 patients; CR-BE 100%, CR-LGD 100%. There were no strictures or buried glands at 12 or 24 months. Conclusion: A combined regimen of primary circumferential ablation and secondary focal ablation using the HALO System appears to safely and effectively eradicate BE and LGD at 1 and 2 year follow-up. Such an intervention could have implications for management and surveillance strategies for LGD. A randomized, sham-controlled trial is underway to confirm the results of this pilot trial.
S1366 Cervical Inlet Patch of the Esophagus: A Cause for Concern? Shailaja Jamma, Krishnarao Tangella, Davendra P. Ramkumar
S1364 Pilot Animal Study of the Phthalocyanine Pc4 as a TopicallyApplied Photosensitizer for PDT of Barrett’s Esophagus Farees T. Farooq, Jeffrey Berlin, Elma Baron, Ashley L. Faulx, Jeffrey M. Marks, Amitabh Chak Background: Photodynamic therapy (PDT) is a treatment option for Barrett’s esophagus with high grade dysplasia. A major drawback of PDT using Photofrin is the lengthy period of cutaneous photosensitivity that follows treatment. A photosensitizer that can be applied topically in the esophagus may eliminate the side-effect of cutaneous photosensitivity that results from systemically-administered photosensitizers, making PDT a more attractive therapeutic option. The phthalocyanine Pc4, a photosensitizer that selectively accumulates in tumors and has a peak absorption at 675 nm, has been shown in animal studies to be more efficacious than Photofrin. Ongoing Phase I clinical trials have shown that Pc4 can be applied topically for the treatment of dermal tumors. Aims: To determine whether Pc4 can be applied topically to esophageal mucosa at endoscopy and to determine the depth of penetration of topically-applied Pc4. Methods: EGD was performed on three anesthetized pigs. Pc4 diluted in 5% ethanol-saline solution was applied uniformly to the distal porcine esophagus using an endoscopic spray catheter. After a 30 min. incubation period, esophagectomy was performed. Subsequently, tissue was sectioned, fixed, and examined by single-photon confocal microscopy. Results: Gross specimens demonstrated a fairly uniform application of Pc4 as evidenced by the resultant bluish discoloration of treated tissue. Confocal microscopy demonstrated penetration of the stratified squamous epithelium at depths in the range of 100-200 microns. Conclusions: Pc4 applied to the porcine esophagus using an endoscopic spray catheter demonstrates significant epithelial penetration. Additional studies are needed to determine the optimal delivery vehicle, incubation period to maximize tissue penetration and the depth of tissue injury with PDT in this model.
www.giejournal.org
Introduction: Inlet patch is a distinct region of heterotopic gastric mucosa occurring in the proximal one-third of the esophagus with a prevalence of 0.1% to 10% in patients undergoing esophagogastroduodenoscopy (EGD). This wide range in prevalence is due to the special interest of some endoscopists who specifically look for it. It has largely been documented as asymptomatic, although there are associated symptoms like heartburn and dysphagia along with complications such as esophagitis, ulceration, perforation, stricture and adenocarcinoma of the cervical esophagus. However, cough and hoarseness secondary to inlet patch have rarely been reported. In our study, we retrospectively determined the prevalence and histologic types of inlet patch as well as its association with aero-digestive symptoms including cough and its response to high-dose acid suppression. Method: We reviewed 349 consecutive EGD reports done by a single endoscopist from December 2004 to December 2005, and cases with described inlet patch were corroborated by pathology reports. Biopsies were reevaluated by a pathologist looking for the presence of gastric metaplasia, other types of mucosa, and the presence of inflammation. An immunohistochemical method was used to detect Helicobacter pylori. We also evaluated the association of inlet patch with aerodigestive symptoms and subsequent response to therapy. Demographic data with age, sex, symptoms, pathological findings, treatment and response to treatment were tabulated. Results: Inlet patch was found in seven patients out of 349, with a prevalence of 2.01%. In six patients, it appeared as a single patch and in one patient as a twin patch. None of them had evidence of Barrett’s esophagus. In the inlet patch, oxyntic mucosa was seen in six and cardiac mucosa in one. Six of the seven specimens showed mild chronic inflammation. None of them showed intestinal metaplasia. All of them were negative for H. pylori. One patient had cough and sore throat. One patient had hoarseness. Five patients had retrosternal discomfort. Two patients had dysphagia. Six patients showed alleviation of symptoms with high dose acid suppression. Conclusion: Though largely considered asymptomatic, inlet patch can cause supraesophageal symptoms like cough, sore throat and hoarseness apart from dysphagia and retrosternal discomfort. Hence, it should be carefully looked for during EGD in patients with refractory aero-digestive symptoms. In patients with identified inlet patch, treatment should be attempted with high dose acid suppression.
Volume 65, No. 5 : 2007 GASTROINTESTINAL ENDOSCOPY AB155