How light dosimetry influences the efficacy of photodynamic therapy with 5-aminolaevulinic acid for ablation of high-grade dysplasia in Barrett’s esophagus

Photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) is a novel treatment for high-grade dysplasia (HGD) in Barrett’s esophagus (BE). Our aim was to evaluate the effectiveness of differing light doses. Patients with HGD in BE received oral ALA (60 mg/kg) activated by low (500 J/cm), medium (750 J/cm), high (1,000 J/cm), or highest (1,000 J/cm ×2) light dose at 635 nm. Follow-up was by regular endoscopy with quadrantic biopsies. Twenty-four patients were treated. Successful eradication of HGD was significantly correlated with light dose (log rank, p < 0.01). Six of eight patients (75%) treated with the highest light dose, one of two treated with high dose (50%), two of nine (22%) receiving medium light dose, and zero of five receiving low light dose had successful eradication of HGD (median follow-up 45 months, range 1–78 months). No skin photosensitivity or esophageal strictures occurred. The efficacy of ALA-PDT for eradication of HGD in BE is closely related to the light dose used. With a drug dose of 60 mg/kg and light at 635 nm, we recommend a minimum light dose of 1,000 J/cm of esophagus. This dose appears safe.     

Optimal conditions for successful ablation of high-grade dysplasia in Barrett’s oesophagus using aminolaevulinic acid photodynamic therapy

Photodynamic therapy (PDT) using 5-aminolaevulinic acid (ALA-PDT) is an attractive alternative to PDT with porfimer sodium for the treatment of high-grade dysplasia (HGD) in Barrett’s oesophagus (BO) because of the shorter duration of light photosensitivity and low risk of oesophageal stricture formation. Published results, however, show marked variation in its efficacy, and optimum treatment parameters have not been defined. This study investigated how the dose of ALA and the colour of the illuminating light influenced the biological effect. Twenty-seven patients were enrolled into a randomised controlled trial of red versus green (635 nm or 512 nm) laser light activation for the eradication of HGD with ALA-PDT in Barrett’s oesophagus. A further 21 patients were subsequently treated with the most effective regimen. Regular endoscopic follow-up with quadrantic biopsies every 2 cm was performed. The primary outcome measure was eradication of HGD. Patient’s receiving ALA at 30 mg/kg relapsed to HGD more than those receiving 60 mg/kg (P = 0.03). Additionally, for those treated with ALA 60 mg/kg, red laser light was more effective than green laser light (P = 0.008). Kaplan–Meier analysis of the 21 patients who were subsequently treated with this optimal regimen demonstrated an eradication rate of 89% for HGD and a cancer-free proportion of 96% at 36 months’ follow-up. Using an ALA dose of 60 mg/kg activated by 1,000J/cm red laser light, we found that ALA-PDT was a highly effective treatment for high-grade dysplasia in Barrett’s oesophagus.     

Importance of a multidisciplinary approach for the treatment of Barrett’s esophagus

Barrett's esophagus is a consequence of gastroesophageal reflux disease. Today, it is the most common cause of esophageal adenocarcinoma. Cancer is usually the end results of a cascade of events whereby metaplasia changes into low- and high-grade dysplasia and eventually cancer. Today, we have the unique opportunity to block this cascade and avoid the development of esophageal cancer. A multidisciplinary approach with a team composed of radiologists, gastroenterologists, pathologists, and surgeons allows individualization of care and the best results.     

Benefit of baseline cytometry for surveillance of patients with Barrett’s esophagus

Background  

The current gold standard for the surveillance of Barrett’s esophagus is the Seattle four-quadrant biopsies protocol (4-QB). Using endoscopic brush cytology, this study prospectively investigated whether digital image cytometry (DICM) is of additional benefit over regular histology as a predictor for progression to high-grade dysplasia or cancer during a surveillance of at least 3 years.     

Efficacy and safety of Hybrid-APC for the ablation of Barrett’s esophagus

Background and study aim

After thermal ablation of Barrett’s esophagus (BE), stricture formation is reported in 5 to over 10 % of patients. The question arises whether submucosal fluid injection prior to ablation may lower the risk of stricture formation. The aim of the present study was to evaluate the efficacy and safety of the new technique of Hybrid-APC which combines submucosal injection with APC.

Patients and methods

Patients who had a residual BE segment of at least 1 cm after endoscopic resection of early Barrett’s neoplasia underwent thermal ablation of BE by Hybrid-APC. Prior to thermal ablation, submucosal injection of sodium chloride 0.9 % was carried out using a flexible water-jet probe (Erbejet 2; Erbe Elektromedizin, Tuebingen, Germany). Check-up upper GI endoscopy was carried out 3 months after macroscopically complete ablation including biopsies from the neo-Z-line and the former BE segment, and recording of stricture formation.

Results

From May 2011 to November 2012, a total of 60 patients (pt) were included in the study [55 pt male (92 %); mean age 62 ± 9 years, range 42–79]. Ten patients were excluded from the study. In the remaining 50 pt, Hybrid-APC ablation and check-up endoscopy at 3 months were carried out. Forty-eight out of 50 pt (96 %; ITT: 49/60, 82 %) achieved macroscopically complete remission after a median of 3.5 APC sessions [SD 2.4; range 1–10]. Freedom from BE was histopathologically observed in 39/50 patients (78 %). There was one treatment-related stricture (2 %). Minor adverse events of Hybrid-APC were observed in 11 patients (22 %).

Conclusions

According to this pilot series, Hybrid-APC was effective and safe for BE ablation in a tertiary referral center. The rate of stricture formation was only 2 %. Further studies are required to confirm the present results.

German Clinical Trials Register

DRKS00003369.

     

Length of Barrett’s segment predicts success of extensive endomucosal resection for eradication of Barrett’s esophagus with early neoplasia

Background  

Although the efficacy and safety of extensive endomucosal resection (EMR) in eradicating Barrett’s esophagus (BE) harbouring early neoplasia have been established, factors predicting efficacy remains unclear.     

Laparoscopic treatment of Barrett’s esophagus: long-term results

Background Gastroesophageal reflux disease (GERD) is considered the main etiologic process in the metaplastic development of Barrett’s esophagus (BE). The most serious complication of BE is the possible dysplastic evolution to esophageal carcinoma. Many treatments have been described to prevent the progression of BE. The outcomes of these interventions are controversial. The aim of this study was to assess whether laparoscopic fundoplication for GERD had an impact on the development of BE. Methods Prospective data were collected from patients who were treated with a laparoscopic fundoplication for BE. Data was collected and analyzed for a variety of clinical and pathologic outcomes. Results Laparoscopic fundoplications were completed between 1993 and 2001, with a total sample size of 92 (mean age 53 ± 11.8 years). Each patient was diagnosed with GERD associated with BE confirmed by both endoscopy and biopsy. A laparoscopic fundoplication was performed in all patients (360° fundoplication in 81 patients and partial fundoplication in 11 patients). There was no postoperative mortality or major complications from the procedure. The mean postoperative stay was 3 ± 1 days. Seventy patients (76% of the overall sample size) were followed up for a mean 4.2 ± 2.6 years. Of the patients available for follow-up, 33% (n = 23) had a complete regression of their BE; 21% (n = 15) had a decrease in the degree of metaplasia/dysplasia; 39% (n = 27) had no significant change; and 7% (n = 5) experienced a progression of the BE. Five patients required further procedures for three reasons: (1) GERD recurrence (n = 2), (2) progression of BE (n = 2), and (3) intrathoracic migration (n = 1). No patients developed high-grade dysplasia or esophageal carcinoma. Conclusions The results of this study suggest that laparoscopic fundoplication offers a safe and effective long-term treatment for BE. The procedure also demonstrated regression of BE in more than 50% of the sample size. Presented at the 5th Belgian Surgical Week in Ostend, Belgium, May 2004     

Esophageal adenocarcinoma after Nissen’s fundoplication for Barrett’s esophagus: report of a case

It remains unclear whether surgical treatment of gastro-esophageal reflux disease (GERD) and Barrett’s esophagus (BE) decreases the long-term risk of lower esophagus malignancy; yet, proposed reductions in Barrett’s epithelial transformation have been used as a rationale for antireflux surgery. We report the case of a 63-year-old woman with a 40-year history of GERD, whose symptoms returned after a Nissen fundoplication. A gastroscopy done 3 years later revealed BE. Despite close surveillance, adenocarcinoma of the lower esophagus was diagnosed 8 years after the original surgery. Thus far, there is insufficient evidence to convince practitioners that surgery should be the first line of treatment to prevent malignant change in BE. Further well-standardized, prospective trials are required. Our case demonstrates that antireflux surgery in a patient with GERD and BE cannot be relied upon to prevent adenocarcinoma.     

Diode laser treatment of Barrett’s esophagus: long-term results

Different ablation techniques have been utilized in the treatment of Barrett’s esophagus (BE) to reduce the risk of degeneration. Treatment complications, risk of recurrence, and buried intestinal metaplasia (IM) are all major concerns. The effect of diode laser treatment on BE, studied in a group of patients over a long-term period, is presented here. All patients with histology of IM or low-grade dysplasia (LGD) treated with diode laser therapy for BE and followed for at least 24 months were included in the study. Treatment sessions were carried out every 3 months and bioptic follow-up examinations were done yearly. Patients without antireflux surgery received proton pump inhibitors. A total of 20 patients with IM, four of them with LGD, were treated with 161 laser sessions (in mean eight per patient) without complications. Complete, sustained endoscopic and histologic remission was obtained in 13 patients (11/12 with BE ≤ 3 cm and 2/8 with BE >3 cm, p < 0.01) and a mean of 83 ± 27% of the metaplasic tissue was removed in all the patients. All four cases of LGD healed to squamous tissue. No buried metaplasia, recurrences, or disease progressions were reported after a mean follow-up of 6 years and 2 months. Diode laser ablation is a safe and effective method in most cases of short BE, while it is less effective in the long form, requiring a large number of sessions. Long-term results show that the risk of recurrence and of buried intestinal metaplasia underneath neosquamous epithelium is negligible.     

High-resolution endoscopy and endoscopic ultrasound for evaluation of early neoplasia in Barrett’s esophagus

Background  

Endoscopic ultrasound (EUS) is useful for detecting depth of invasion and nodal involvement in patients with early Barrett’s neoplasia (EBN), precluding endoscopic management. This study aimed to determine whether the lesion morphology of the EBN shown on high-resolution endoscopy predicts EUS and histologic tumor stage.     

Significance of Nissen fundoplication after endoscopic radiofrequency ablation of Barrett’s esophagus

Objective

HALO radiofrequency ablation (RFA) has been proven as safe and efficient in eradication of both non- and dysplastic Barrett’s esophagus (BE). Definitive post-RFA treatment is yet to be determined.

Methods

RFA was performed in 56 patients with BE, 38 with intestinal metaplasia (IM) and 18 with low-grade dysplasia (LGD), and repeated in case of residual BE. Length of the BE was classified according to C&M criteria. Follow-up included regular upper GI endoscopies with biopsies 6 months, 1 and 2 years after the complete resolution of BE. Patients were divided into two groups regarding post-RFA treatment: those maintaining proton pump inhibitors (PPI) daily and those submitted to laparoscopic Nissen fundoplication (LNF) at least 3 months after BE eradication or synchronous with RFA.

Results

There were no perforations or strictures related to RFA. Complete endoscopic resolution of BE was observed in 83.92 % patients (86.84 % IM and 77.77 % LGD), in 25 that maintained PPI and 22 in whom LNF was done. In PPI group, 2-year follow-up revealed BE recurrence in biopsy samples in 20 % of patients, while in LNF group 9.1 % of patients had recurrent IM. In overall sample of patients, no difference was noted regarding the influence of post-RFA treatment (p < 0.423). LNF proved superiority over PPI treatment in patients with long-segment BE (cutoff C > 4 cm, p < 0.021).

Conclusion

HALO RFA is a safe procedure, with high rate of success in complete eradication of BE in symptomatic GERD patients. LNF provides good protection for neosquamous epithelium and in selected group of patients could be offered as a first line of treatment after HALO RFA.

     

Expert pathology review and endoscopic mucosal resection alters the diagnosis of patients referred to undergo therapy for Barrett’s esophagus

Background

Endoscopic therapy has emerged as an alternative to surgical esophagectomy for the management of Barrett’s esophagus (BE)-associated neoplasia. Accurate pretreatment staging is essential to ensure an appropriate choice of therapy and optimal long-term outcomes. This study aimed to assess the frequency with which expert histopathologic review of biopsies combined with endoscopic mucosal resection (EMR) would alter the pretreatment diagnosis of BE-associated neoplasia.

Methods

Patients referred to the Vanderbilt Barrett’s Esophagus Endoscopic Treatment Program (V-BEET) were retrospectively identified. Demographic, histopathologic, and endoscopic data were extracted from the medical record.

Results

For this study, 29 subjects referred for endoscopic staging of BE fulfilled the entry criteria. The referral diagnosis was low-grade dysplasia (LGD) in 3 % (1/29), high-grade dysplasia (HGD) in 62 % (18/29), intramucosal adenocarcinoma (T1a) adenocarcinoma in 17 % (5/29), and invasive adenocarcinoma in 17 % (5/29) of the subjects. Expert histopathologic review of available referral biopsy specimens altered the diagnosis in 33 % (5/15) of the cases. Further diagnostic staging with EMR showed BE without dysplasia in 10 % (3/29), LGD in 14 % (4/29), HGD in 34 % (10/29), T1a adenocarcinoma in 28 % (8/29), and invasive adenocarcinoma in 14 % (4/29) of the patients. The combination of expert histopathologic review and EMR altered the initial diagnosis for 55 % (16/29) of the subjects, with 56 % (9/16) upstaged to more advanced disease and 44 % (7/16) downstaged to less advanced disease.

Conclusions

The practice of combined expert histopathologic review and EMR alters the pretreatment diagnosis for the majority of patients with BE-associated neoplasia. Caution is advised for those embarking on endoscopic or surgical treatment for BE-associated neoplasia in the absence of these staging methods.     

Effects of 5-aminolevulinic acid–mediated photodynamic therapy on antibiotic-resistant staphylococcal biofilm: an in vitro study

Background

Treatments of infections are not always successful because of multi-antibiotic-resistant organisms. It is therefore particularly urgent to provide more effective anti-infective strategy against these organisms. 5-Aminolevulinic acid (ALA), with the chemical structure C₅H₉NO₃, is the only photodynamic therapy agent that is a biochemical precursor of a photosensitizer (protoporphyrin IX [PpIX]), which is naturally produced by the body. 5-Aminolevulinic acid–mediated photodynamic therapy (ALA-PDT) has been shown to have a strong effect on the treatment of localized cancerous and precancerous lesions, and further study demonstrated its efficacy for gram-positive and gram-negative bacteria. However, its effect on biofilm formed by antibiotic-resistant strains has not been reported.

Methods

In this study, we evaluated the effectiveness of ALA-PDT on biofilms formed by methicillin-resistant Staphylococcus aureus (ATCC 43300) and methicillin-resistant S epidermidis (MRSE 287). The strains were cultured with 40 mM of ALA in 24-well microtiter plates containing coverslips at 37°C for 24 h in the dark. PpIX fluorescence in biofilms formed by the two strains was observed by confocal laser scanning microscopy (CLSM). ALA-treated biofilms were irradiated at different doses (0, 100, 200, and 300 J/cm²) using a semiconductor laser. Biofilm exposed only to Tryptone Soy Broth or irradiation (300 J/cm²) was investigated. Viability determination, CLSM, and scanning electron microscopy were used to investigate the photodynamic inactivation of ALA-PDT.

Results

ALA was absorbed and converted to PpIX by both methicillin-resistant S aureus and methicillin-resistant S epidermidis. No cell inactivation was detectable in biofilms of either strain incubated with ALA without exposure to light, incubated with Tryptone Soy Broth only, or irradiated with red light only. However, a significant number of cells within biofilms were inactivated during irradiation with different doses of red light in the presence of 40 mM of ALA in a dose-dependent manner. The drastic reduction in cell survival within biofilms and the disruption of biofilms were confirmed by CLSM and scanning electron microscopy.

Conclusions

ALA-PDT has the potential to eliminate the biofilm of Staphylococcus, especially antibiotic-resistant strains, effectively. It will be suitable for the treatment of superficial local infections such as surface wounds, burns, oral and dental infections, dermatologic infections such as acne and rosacea, and soft tissue and bone infections with bone exposure.     

Systemic vs local administration of δ-aminolevulinic acid for laparoscopic fluorescence diagnosis of malignant intra-abdominal tumors

apd: 12 December 2000     

Barrett’s esophagus: Histopathologic definitions and diagnostic criteria

Adenocarcinoma of the distal esophagus is rising more rapidly in incidence than any other visceral malignancy in the Western world. It is well established that most, if not all, of these tumors develop in Barretts esophagus via the metaplasia-dysplasia-carcinoma sequence and could theoretically be detected at an early stage, but despite this, the majority of these tumors are still detected late in their course. This highlights the fact that the goal of effective surveillance for patients at risk for developing an adenocarcinoma of the distal esophagus is still far off. In addition, adenocarcinomas of the esophagogastric junction and gastric cardia are also rising in incidence, but their carcinogenesis and their relation to Barretts esophagus are still being defined, as are the meaning and significance of the relatively new entities short-segment Barretts and ultra-short-segment Barretts. This review attempts to clarify the main histopathologic issues concerned with the definition of Barretts esophagus, its distinction from intestinal metaplasia of the gastric cardia, as well as the criteria for the histologic diagnosis of dysplasia and carcinoma in Barretts esophagus.This article is part of the World Progress in Surgery symposium on Barretts esophagus and esophageal cancer, which was published in Volume 27, Number 9 of World Journal of Surgery.     

Endoscopic endoluminal radiofrequency ablation of Barrett’s esophagus in patients with fundoplications

Background Endoscopic endoluminal radiofrequency ablation using the Barrx device is a new technique to treat Barrett’s esophagus. This procedure has been used in patients who have not had antireflux surgery. This report is presents an early experience of the effects of endoluminal ablation on the reflux symptoms and completeness of ablation in post-fundoplication patients. Methods Seven patients who have had either a laparoscopic or open Nissen fundoplication and Barrett’s esophagus underwent endoscopic endoluminal ablation of the Barrett’s metaplasia using the Barrx device (Barrx Medical, Sunnyvale, CA). Preprocedure, none of the patients had significant symptoms related to gastroesophageal reflux disease. One to two weeks after the ablation, patients were questioned as to the presence of symptoms. Preprocedure and postprocedure, they completed the GERD-HRQL symptom severity questionnaire (best possible score, 0; worst possible score, 50). Patients had follow-up endoscopy to assess completeness of ablation 3 months after the original treatment. Results All patients completed the ablation without complications. No patients reported recurrence of their GERD symptoms. The median preprocedure total GERD-HRQL score was 2, compared to a median postprocedure score of 1. One patient had residual Barrett’s metaplasia at 3 months follow-up, requiring re-ablation. Conclusions This preliminary report of a small number of patients demonstrates that endoscopic endoluminal ablation of Barrett’s metaplasia using the Barrx device is safe and effective in patients who have already undergone antireflux surgery. There appears to be no disruption in the fundoplication or recurrence of GERD-related symptoms. Nevertheless, longer-term follow-up with more patients is needed. Presented in part at the 2006 Annual Scientific Session of the Society of American Gastrointestinal and Endoscopic Surgeons     

The impact of laparoscopic anti-reflux surgery in patients with Barrett’s esophagus

Background

Barrett’s esophagus (BE) is a major risk factor for esophageal adenocarcinoma. It is believed that BE is caused by chronic gastro-esophageal reflux disease (GERD). Laparoscopic anti-reflux surgery (LARS) restores the competency of the cardia and may thereby change the natural course of BE. We studied the impact of LARS on the histological profile of BE and on the control of GERD.

Methods

We identified all patients with BE who underwent LARS from 1994 to 2007 and contacted them to assess post-operative GERD symptoms via questionnaire. Endoscopy findings, histology, 24 hour pH monitoring, and manometry were also collected using our prospectively maintained database. Histological regression was defined as either loss of dysplasia or disappearance of BE.

Results

Two hundred and fifteen patients met the initial inclusion criteria; in 82 of them histology from post-operative endoscopy was available for review. Endoscopy was performed a median of 8 years (range, 1–16 years) after surgery. Regression of BE occurred in 18 (22 %) patients while in 6 (7 %) BE progressed to dysplasia or cancer. Thirty-six (43 %) patients underwent pre- and post-operative manometry. The median lower esophageal sphincter pressure increased from 9 to 17 mmHg in these patients. Thirty-four (41 %) patients underwent pre- and post-operative pH studies. The median DeMeester score decreased from 54 to 9. Sixty-seven (82 %) of 82 patients completed the post-operative questionnaire; 86 % of these patients reported improvement in heartburn and regurgitation.

Conclusions

LARS was associated with both physiologic and symptomatic control of GERD in patients with BE. LARS resulted in regression of BE in 22 % of patients and progression in 7 %. Thus, continued surveillance of Barrett’s is needed after LARS.