Wilda Rosmolen

Stepwise Radical Endoscopic Resection Is Effective for Complete Removal of Barrett's Esophagus with Early Neoplasia: A Prospective Study

OBJECTIVES:Endoscopic therapy for early neoplasia in Barretts esophagus (BE) is evolving rapidly. Aim of this study was to prospectively evaluate safety and efficacy of stepwise radical endoscopic resection (ER) of BE containing early neoplasia.METHODS:Patients with early neoplasia (i.e., high-grade intraepithelial neoplasia or early cancer) in BE ≤5 cm, without signs of submucosal infiltration or lymph node/distant metastases, were included. Patients underwent resection sessions (cap technique after submucosal lifting) with intervals of 6 wk.RESULTS:Between January 2003 and December 2004, 39 consecutive patients were included. Therapy was discontinued in two patients due to unrelated comorbidity. Complete eradication of early neoplasia was achieved in all 37 treated patients in a median number of three sessions. Complete removal of all Barretts mucosa was achieved in 33 (89%) patients: 4 patients (all had undergone APC [argon plasma coagulation]) were found to have small isles of Barretts mucosa underneath neosquamous mucosa. Complications occurred in two out of 88 (2%) ER procedures: one asymptomatic perforation, one delayed bleeding. Symptomatic stenosis occurred in 10 of 39 (26%) patients and was effectively treated by endoscopic bougienage. During a median follow-up of 11 months, no patients died and none had recurrence of neoplasia or Barretts mucosa.CONCLUSIONS:Stepwise radical ER is effective for selected patients with early neoplasia in BE; provides optimal histopathological diagnosis; and may reduce recurrence rate, since all mucosa at risk is effectively removed. Use of APC should be limited to prevent buried Barretts mucosa. Methods for prevention of stenosis should be developed.

Endoscopic treatment of high-grade dysplasia and early stage cancer in Barrett's esophagus

BACKGROUND The aim of this study was to prospectively evaluate endoscopic resection (ER) combined with photodynamic therapy (PDT) for the treatment of selected patients with early neoplasia in Barretts esophagus. METHODS Patients with Barretts esophagus and neoplastic lesions <2 cm in diameter and no sign of submucosal infiltration, positive lymph nodes, or distant metastasis underwent diagnostic ER (cap technique). Patients with a T1sm tumor in the resection specimen were referred for surgery; those with a T1m or a less invasive tumor underwent additional endoscopic therapy (ER, PDT, and/or argon plasma coagulation [APC]), or they were followed. PDT was performed with 5-aminolevulinic acid and a light dose of 100 J/cm 2 at lambda = 632 nm. RESULTS Thirty-three patients underwent diagnostic ER. Endoscopic treatment was not performed in 5 patients, who underwent surgery (4 T1sm; 1, patient preference). Five patients were immediately entered into a follow-up protocol, and 23 received additional endoscopic treatment (13 additional ER, 19 PDT, 3 APC). Endoscopic treatment was successful in 26/28 patients; no severe complication was observed. During follow-up (median 19 months, range 13-24 months), 5/26 patients had a recurrence of high-grade dysplasia: all were successfully re-treated with ER. At the end of follow-up, 26/33 originally enrolled patients (79%) and 26/28 endoscopically treated patients (93%) were in local remission. CONCLUSIONS Endoscopic therapy is safe and effective for selected patients with early stage neoplasia in Barretts esophagus.

A randomized crossover study comparing light-induced fluorescence endoscopy with standard videoendoscopy for the detection of early neoplasia in Barrett's esophagus

BACKGROUND Light-induced fluorescence endoscopy (LIFE) may improve the detection of high-grade dysplasia (HGD) and early stage cancer (EC) in Barretts esophagus (BE). The aim of this study was to compare LIFE with standard endoscopy (SE) in a randomized crossover study. METHODS Fifty patients with BE underwent SE and LIFE in a randomized sequence (4 to 6-week interval between procedures). The two procedures were performed by two different endoscopists who were blinded to the findings of the other examination. Targeted biopsy specimens were taken from detected lesions, followed by random biopsy specimens with a 2-cm interval, 4-quadrant protocol. Biopsy specimens were routinely evaluated and subsequently reviewed by a single, blinded expert GI pathologist. RESULTS Targeted biopsy specimens had a sensitivity for the diagnosis of HGD/EC of 62% (8/13) for both techniques. The overall sensitivity (all biopsy specimens) was 85% for SE and 69% for LIFE (p = 0.69). All targeted biopsy specimens had a positive predictive value (PPV) for HGD/EC of 41% for SE and 28% for LIFE (p = 0.40); autofluorescence-targeted biopsy specimens had a PPV of 13%. False-positive lesions had a significantly higher rate of acute inflammation than random biopsy specimens. CONCLUSIONS In this study, LIFE did not improve the detection of HGD or EC in patients with BE compared with SE.

Multiband mucosectomy for endoscopic resection of Barrett's esophagus : feasibility study with matched historical controls

Background and aims Piece-meal endoscopic resection of early neoplastic lesions larger than 15–20 mm is a laborious procedure with the cap technique. Multiband mucosectomy is a new technique using a modified variceal band ligator. Submucosal lifting and prelooping of the snare in the cap is not necessary and multiple resections can be performed with a single snare. We prospectively evaluated the feasibility of multiband mucosectomy for widespread endoscopic resection in patients with a Barretts esophagus with early neoplasia and compared results retrospectively with prospectively registered endoscopic cap resection procedures. Results Eighty multiband mucosectomy procedures were performed in 40 patients and 86 endoscopic cap resection procedures in 53 patients. Median duration of the multiband mucosectomy procedures was 37 vs. 50 min for endoscopic cap resection procedures (P=0.06); median duration per resection was 6 vs. 12 min, respectively (P<0.001). Mean diameter of the specimens was 17 vs. 21 mm (P<0.001). One perforation in the endoscopic cap resection group was successfully treated conservatively. Mild bleeding occurred in 6% of multiband mucosectomy and 20% of endoscopic cap resection procedures (P=0.012). Technical difficulties during multiband mucosectomy procedures included a decreased visibility owing to the black bands and the releasing wires. Conclusions Multiband mucosectomy allows safe and easy widespread piece-meal resections in Barretts esophagus. Time and costs appear to be saved compared with the cap technique, and multiband mucosectomy appears to cause less bleeding during the endoscopic resection procedure. Multiband mucosectomy, however, results in smaller specimens and is, therefore, most suited for en-bloc resection of lesions smaller than 10 mm or for widespread resection of flat mucosa.

Surveillance history of endoscopically treated patients with early Barrett's neoplasia: nonadherence to the Seattle biopsy protocol leads to sampling error

SUMMARY The studys aim was to retrospectively evaluate the surveillance history of Barretts esophagus (BE) patients with endoscopically treated early neoplasia. All BE patients endoscopically treated for early cancer (EC) or high-grade intraepithelial neoplasia (HGIN) in a lesion or mass between 1998 and 2005 were included. Endoscopy and histology records were reviewed. Ninety-four patients (78 males, mean age 67 years, 24 HGIN, 70 EC) were included. In 36 (38%) patients, HGIN/EC was diagnosed at (or within 6 months after) initial endoscopy. The remaining 58 (62%) patients had a surveillance history (median duration 7 years, mean 6.7 endoscopies). Seventy-nine percent of these had low-grade intraepithelial neoplasia (LGIN) diagnosed at least once during their surveillance period with a median of seven endoscopies and a median number of biopsies that was 50% of what should have been taken according to the Seattle protocol. Patients without any dysplasia during earlier surveillance (n = 12, 21%) had undergone significantly less endoscopies (median four endoscopies, P = 0.02) and had a median biopsy percentage that was 23% of the Seattle protocol (P < 0.001 versus 50% in LGIN). In this selected cohort of patients with early Barretts neoplasia, 38% of patients were diagnosed at initial endoscopy. Of the patients with a surveillance history, 79% had shown LGIN prior to HGIN/EC diagnosis. Only 21% of patients had a surveillance history without any dysplasia, which in general encompassed endoscopies with an insufficient number of biopsies, suggesting sampling error. This underlines the importance of obtaining an adequate number of biopsies during surveillance endoscopies.

Efficient automated assessment of genetic abnormalities detected by fluorescence in situ hybridization on brush cytology in a Barrett esophagus surveillance population

Automated assessment of genetic abnormalities detected by fluorescence in situ hybridization (FISH) in brush cytology specimens from patients with Barrett esophagus (BE) may enhance the clinical applicability of this methodology. The objectives of this study were to validate a novel, automated, proprietary system (CytoVison SPOT AX) for the assessment of FISH abnormalities in BE brush cytology and, subsequently, to use this automated method for screening of a BE surveillance cohort.

Quality of life and fear of cancer recurrence after endoscopic and surgical treatment for early neoplasia in Barrett's esophagus

BACKGROUND AND STUDY AIMS Endoscopic treatment of early neoplasia in Barretts esophagus preserves the esophagus and is minimally invasive compared with surgical treatment. However, the influence of endoscopic therapy on quality of life (QOL) and fear of cancer recurrence is unknown. We explored QOL and fear of cancer recurrence 12 - 60 months after endoscopic and surgical treatment for early Barretts neoplasia, using a cross-sectional design. PATIENTS AND METHODS A total of 81 patients with early Barretts neoplasia underwent endoscopic treatment and 33 patients underwent surgery. The choice of treatment was based on tumor size, depth of penetration or patient preference. QOL was measured using the SF-36, EORTC-QLQ-C30, and the EORTC-QLQ-OES18 questionnaires. Anxiety and fear of recurrence were measured using the Hospital Anxiety and Depression Scale (HADS) and the Worry Of Cancer Scale (WOCS). RESULTS In total, 66 endoscopy patients and 29 surgery patients were eligible for the study. Questionnaires were completed by 64/66 (97 %) endoscopy patients and 27 / 29 (93 %) surgery patients. Multivariate analyses were conducted, with sex, age, comorbidity, and histology of the resected specimen used as covariates. Patients in the surgery group reported significantly more eating problems (OR = 18.3; P < 0.001) and reflux symptoms (OR = 3.4; P = 0.05) on the EORTC-OES18 questionnaire, whereas endoscopy patients reported more fear of recurrence on the WOCS than surgery patients ( P = 0.003). No significant differences were found between the two groups on the other outcomes. CONCLUSION Preservation of the esophagus after endoscopy treatment, which is preferred from a clinical perspective, may induce fear of cancer recurrence. Proper patient education with specific attention to fear of cancer recurrence may therefore be required.

Stepwise Radical Endoscopic Resection of the Complete Barrett's Esophagus With Early Neoplasia Successfully Eradicates Pre-Existing Genetic Abnormalities

OBJECTIVES: Malignant transformation of Barretts mucosa is associated with the accumulation of genetic alterations. Stepwise radical endoscopic resection of the Barretts segment with early neoplasia is a promising new treatment resulting in complete re-epithelialization of the esophagus with neosquamous epithelium. It is unknown whether radical resection also eradicates genetic abnormalities. The aim of this study was to prospectively evaluate whether genetic abnormalities as found in the Barretts segment before radical resection are effectively eradicated and absent in the neosquamous epithelium.METHODS: Nine patients with early neoplasia who successfully underwent radical resection were included. Immunohistochemistry (IHC) was performed to assess p53 protein overexpression. DNA fluorescent in-situ hybridization was (DNA-FISH) performed for evaluation of numerical abnormalities of chromosomes 1 and 9, and losses of p16 and p53. Immunohistochemistry and DNA-FISH were performed on endoscopic resection specimens of the neoplasia and on follow-up biopsies of the neosquamous epithelium.RESULTS: DNA-FISH and IHC showed alterations in the pretreatment samples of all patients. All showed aneusomy of chromosome 1 and 9. Loss of p16 and p53 were seen in 6 and 8 patients. IHC showed intense p53 nuclear staining in seven patients. Post-treatment biopsies showed neosquamous epithelium with a normal diploid signal count for all DNA-FISH probes and normal IHC stainings in all patients.CONCLUSIONS: Radical resection of Barretts esophagus with early neoplasia successfully eradicates pre-existing genetic abnormalities and results in neosquamous epithelium without these genetic abnormalities.

The effect of oral administration of ursodeoxycholic acid and high-dose proton pump inhibitors on the histology of Barrett’s esophagus

Bile acids may play a role in the pathogenesis of Barretts esophagus (BE). Bile composition can be influenced by oral administration of ursodeoxycholic acid (UDCA). We prospectively investigated the effect of proton pump inhibitors (PPI) supplemented with UDCA in vivo in patients with BE. Patients with no or low-grade dysplasia who were clinically asymptomatic on PPI were eligible for the study. In order to exclude the effects of acid reflux, all patients were initially treated with 40 mg esomeprazole (ESO) twice daily for 6 months and continued on this dose till the end of the study (t = 12 months). During a period of 6 months (t = 6 month - t = 12 month) patients were treated with oral UDCA (600 mg twice daily). Patients underwent endoscopy at t = 0 months, t = 6 months and t = 12 months with multiple biopsies of the distal and proximal BE segment, normal squamous and gastric cardia. In addition, pH was measured at t = 0 months and t = 6 months using a BRAVO wireless pH capsule. Bile was sampled at the beginning of the UDCA treatment and 6 months later (t = 6 month and t = 12 month). All biopsies were reviewed for the extent of metaplasia, dysplasia, and acute and chronic inflammation. In addition, proliferation (Ki67), differentiation (villin, cytokeratins 7 and 20) and inflammation (COX-2) were investigated by immunohistochemistry (IHC). Nine patients (mean age 60 years, median BE length 7 cm) were included, of whom six had no dysplasia and three had low-grade dysplasia. pH measurements revealed a normal acid exposure in most patients at t = 0 and t = 6 months. In addition, bile composition analysis demonstrated the efficacy of UDCA. Combining the results of both phases of the study, no significant changes were seen in any of the histological or IHC parameters. Differentiation and proliferation parameters showed no significant changes. In this study, in BE patients who were clinically asymptomatic on PPI, increasing the PPI dose to the maximum for 6 months followed by the addition of UDCA for 6 months did not result in significant histological or IHC changes in their BE.

Derivation of genetic biomarkers for cancer risk stratification in Barrett’s oesophagus: a prospective cohort study

Objective The risk of developing adenocarcinoma in non-dysplastic Barretts oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. Methods In a prospective cohort of patients with non-dysplastic Barretts oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. Results A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barretts length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an ‘Abnormal Marker Count’ that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barretts length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). Conclusions A prediction model based on age, Barretts length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barretts oesophagus.