Hendrik Manner

Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett's oesophagus.

Objective: Endoscopic therapy is increasingly being used in the treatment of high-grade intraepithelial neoplasia (HGIN) and mucosal adenocarcinoma (BC) in patients with Barrett’s oesophagus. This report provides 5 year follow-up data from a large prospective study investigating the efficacy and safety of endoscopic treatment in these patients and analysing risk factors for recurrence. Design: Prospective case series. Setting: Academic tertiary care centre. Patients: Between October 1996 and September 2002, 61 patients with HGIN and 288 with BC were included (173 with short-segment and 176 with long-segment Barrett’s oesophagus) from a total of 486 patients presenting with Barrett’s neoplasia. Patients with submucosal or more advanced cancer were excluded. Interventions: Endoscopic therapy. Main outcome measures: Rate of complete remission and recurrence rate, tumour-associated death. Results: Endoscopic resection was performed in 279 patients, photodynamic therapy in 55, and both procedures in 13; two patients received argon plasma coagulation. The mean follow-up period was 63.6 (SD 23.1) months. Complete response (CR) was achieved in 337 patients (96.6%); surgery was necessary in 13 (3.7%) after endoscopic therapy failed. Metachronous lesions developed during the follow-up in 74 patients (21.5%); 56 died of concomitant disease, but none died of BC. The calculated 5 year survival rate was 84%. The risk factors most frequently associated with recurrence were piecemeal resection, long-segment Barrett’s oesophagus, no ablative therapy of Barrett’s oesophagus after CR, time until CR achieved >10 months and multifocal neoplasia. Conclusions: This study showed that endoscopic therapy was highly effective and safe, with an excellent long-term survival rate. The risk factors identified may help stratify patients who are at risk for recurrence and those requiring more intensified follow-up.

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Long-term Efficacy and Safety of Endoscopic Resection for Patients With Mucosal Adenocarcinoma of the Esophagus

BACKGROUND & AIMS Barretts esophagus-associated high-grade dysplasia is commonly treated by endoscopy. However, most guidelines offer no recommendations for endoscopic treatment of mucosal adenocarcinoma of the esophagus (mAC). We investigated the efficacy and safety of endoscopic resection in a large series of patients with mAC. METHODS We collected data from 1000 consecutive patients (mean age, 69.1 ± 10.7 years; 861 men) with mAC (481 with short-segment and 519 with long-segment Barretts esophagus) who presented at a tertiary care center from October 1996 to September 2010. Patients with low-grade and high-grade dysplasia and submucosal or more advanced cancer were excluded. All patients underwent endoscopic resection of mACs. Patients found to have submucosal cancer at their first endoscopy examination were excluded from the analysis. RESULTS After a mean follow-up period of 56.6 ± 33.4 months, 963 patients (96.3%) had achieved a complete response; surgery was necessary in 12 patients (3.7%) after endoscopic therapy failed. Metachronous lesions or recurrence of cancer developed during the follow-up period in 140 patients (14.5%) but endoscopic re-treatment was successful in 115, resulting in a long-term complete remission rate of 93.8%; 111 died of concomitant disease and 2 of Barretts esophagus-associated cancer. The calculated 10-year survival rate of patients who underwent endoscopic resection of mACs was 75%. Major complications developed in 15 patients (1.5%) but could be managed conservatively. CONCLUSIONS Endoscopic therapy is highly effective and safe for patients with mAC, with excellent long-term results. In an almost 5-year follow-up of 1000 patients treated with endoscopic resection, there was no mortality and less than 2% had major complications. Endoscopic therapy should become the standard of care for patients with mAC.

Comparison between endoscopic and surgical resection of mucosal esophageal adenocarcinoma in Barrett's esophagus at two high-volume centers.

Background and Objective:Esophagectomy has previously been the gold standard for patients with mucosal adenocarcinoma in Barretts esophagus (Barretts carcinoma, BC). Because of the minimal invasiveness and excellent results obtained with endoscopic resection (ER), the latter has become an accepted alternative. However, few data have so far been published comparing the 2 treatment methods. Methods:A total of 114 patients with mucosal BC who were treated surgically or endoscopically in 2 high-volume centers were included in this study. Between 1996 and 2009, 38 patients with mucosal BC received transthoracic esophageal resection with 2-field lymphadenectomy (median 29 lymph nodes removed; all pN0) in the Department of Surgery at the University of Cologne. Seventy-six patients with BC treated with ER followed by argon-plasma-coagulation of the remaining non-dysplastic Barretts esophagus in the Department of Gastroenterology in Wiesbaden were matched according to the following criteria: age, gender, infiltration depth (pT1m1–3), differentiation grade (G1/2 vs. 3) and follow-up period. Results:There were no significant differences between the 2 groups with regard to epidemiologic and tumor criteria. Complete remission (CR) was achieved in all patients in the surgery group and all but 1 patient in the ER group (98.7%; the patient died of other causes before CR was achieved). Major complications after surgery occurred in 32% of the patients, significantly more often than in the ER group (0% major complications, P < 0.001). The 90-day mortality rates were 0% in the ER group and 2.6% in the surgical group (1 of 38; P = 0.333). The median follow-up periods were 4.1 years in the ER group and 3.7 years in the surgical group. During this period, 1 patient in the ER group had a local recurrence and 4 had metachronous neoplasia (overall recurrence rate 6.6%). However, repeat endoscopic treatment was possible in all of the patients, and the long-term CR rates in the surgical and ER groups were 100% and 98.7%, respectively. No tumor-related mortality was observed in either group. Conclusions:For patients with mucosal BC, both surgery and ER are effective treatment modalities. Surgery is associated with a higher morbidity rate and shows a risk for procedure-related mortality. However, the recurrence rate is higher in patients treated with ER, so that thorough follow-up procedures are mandatory.

Early Barrett's Carcinoma With “Low-Risk” Submucosal Invasion: Long-Term Results of Endoscopic Resection With a Curative Intent

BACKGROUND: Endoscopic therapy (ET) has become a less risky alternative to open surgery in mucosal Barretts cancer (BC) because of the very low risk of lymph node (LN) metastasis. Recently published surgical series demonstrated that even in case of minimal submucosal invasion of BC, the risk for LN metastasis is very low. In consequence, also these patients might be eligible for curative ET. The aim of this study was to prospectively evaluate the efficacy and safety of endoscopic resection (ER) in these patients.METHODS: From September 1996 to September 2003, the suspicion or definite diagnosis of submucosal BC was made in 80 patients referred to our department. Of those, 21 patients (20 male [95.2%], mean age 62 ± 9 yr, range 47–78) fulfilled the definition of “low-risk” submucosal cancer: invasion of the upper submucosal third (sm1), absence of infiltration into lymph vessels/veins, histological grade G1/2, and macroscopic type I/II. ET was carried out using ER with the suck-and-cut technique with or without an additive ablation of non-neoplastic remnants of Barretts esophagus.RESULTS:One of the 21 patients was referred to surgery directly after the detection of sm1 invasion at the beginning of the study. One patient died (not tumor-related) before completion of ET. Using definitive ET, complete remission (CR) was achieved in 18 of 19 patients (95%) after a mean of 5.3 months (range 1–18) and a mean of 2.9 resections (range 1–9). Only one minor complication (bleeding without drop in hemoglobin level >2 g/dL) occurred (5% of patients). During a mean follow-up (FU) of 62 months (range 45–89), recurrent or metachronous carcinomas were found in 5 patients (28%). Repeat ET was carried out successfully using ER (4 patients) and argon plasma coagulation (1 patient). In one of the 19 patients (5%), tumor freedom had not been achieved after a total of 2 ER. This patient died of a heart attack before surgery could be performed. The calculated 5-yr survival rate of all 21 patients was 66%. No tumor-related death occurred.CONCLUSIONS: As in mucosal BC, ER is associated with favorable outcomes even in case of “low-risk” submucosal BC. Further and larger clinical trials are required before a general recommendation for ER as the treatment of choice in “low-risk” submucosal BC can be given.

Prospective Multicenter Trial Comparing Push-and-Pull Enteroscopy With the Single- and Double-Balloon Techniques in Patients With Small-Bowel Disorders

OBJECTIVES:Double-balloon enteroscopy (DBE) is now an established method for diagnostic and therapeutic small-bowel endoscopy. Single-balloon enteroscopy (SBE) has been introduced to simplify the technique. A prospective randomized study was carried out to compare the two methods.METHODS:The study included 100 patients (50 in each group; 63 men, 37 women; mean age 55 years), with no previous small-bowel or colon surgery. The indications for enteroscopy were (suspected) mid-gastrointestinal bleeding, Crohns disease, small-bowel masses, chronic diarrhea or abdominal pain or both, and other conditions. Fujinon instruments were used, with either two balloons or one. The end point of the study was complete enteroscopy as the most objective parameter.RESULTS:No severe complications such as perforation, bleeding, or pancreatitis occurred. Instrument preparation time was significantly faster with SBE than with DBE (P<0.0001). Complete enteroscopy was achieved with the DBE technique in 66% of cases (33 patients), either with the oral route alone or with combined oral and anal approaches. With the SBE technique, the complete enteroscopy rate was significantly lower at 22% (P<0.0001; 11 patients, only with oral and anal routes combined). The rate of therapeutic consequences for the patients based on diagnostic yield and negative complete enteroscopy was significantly higher (P=0.025) in the DBE group at 72%, compared with 48% in the SBE group.CONCLUSIONS:The complete enteroscopy rate was three times higher with DBE than with SBE, accompanied by a higher diagnostic yield. DBE must therefore continue to be regarded as the nonsurgical gold standard procedure for deep small-bowel endoscopy.

Efficacy, Safety, and Long-term Results of Endoscopic Treatment for Early Stage Adenocarcinoma of the Esophagus With Low-risk sm1 Invasion

BACKGROUND & AIMS Patients with early-stage mucosal (T1a) esophageal adenocarcinoma (EAC) are increasingly treated by endoscopic resection. EACs limited to the upper third of the submucosa (pT1b sm1) could also be treated by endoscopy. We assessed the efficacy, safety, and long-term effects of endoscopic therapy for these patients. METHODS We analyzed data from 66 patients with sm1 low-risk lesions (macroscopically polypoid or flat, with a histologic pattern of sm1 invasion, good-to-moderate differentiation [G1/2], and no invasion into lymph vessels or veins) treated by endoscopic therapy at the HSK Hospital Wiesbaden from 1996 through 2010. The efficacy of endoscopic therapy was assessed on the basis of rates of complete endoluminal remission (CER), metachronous neoplasia, lymph node events, and long-term remission (LTR). Safety was assessed on the basis of rate of complications. RESULTS Remissions were assessed in 61 of the 66 patients; 53 of the 61 achieved CER (87%). Of patients with small focal neoplasias ≤2 cm, 97% achieved CER (for those with tumors ≥2 cm, 77%; P = .026). Metachronous neoplasias were observed in 10 of 53 patients (19%; 9 of the 10 underwent repeat endoscopic resection). One patient developed a lymph node metastasis (1.9%). Fifty-one patients achieved LTR (84%); 90% of those with focal lesions ≤2 cm achieved LTR after a mean follow-up period of 47 ± 29.1 months (range, 8-120 months). No tumor-associated deaths were observed, and the estimated 5-year survival rate was 84%. The rate of major complications from endoscopic resection was 1.5%, and no patients died. CONCLUSIONS Endoscopic therapy appears to be a good alternative to esophagectomy for patients with pT1b sm1 EAC, on the basis of macroscopic and histologic analyses. The risk of developing lymph node metastases after endoscopic resection for sm1 EAC is lower than the risk of surgery.

Ablation of Nonneoplastic Barrett's Mucosa Using Argon Plasma Coagulation with Concomitant Esomeprazole Therapy (APBANEX): A Prospective Multicenter Evaluation

BACKGROUND:Complete reversal of Barretts epithelium (BE) achieved by treatment with argon plasma coagulation (APC) is variable. The aim of this prospective study was to evaluate the effectiveness of high-power APC in a multicenter trial.METHODS:In seven study centers, 60 patients (mean age 57, range 27–77) with nonneoplastic BE (length 1–8 cm) were recruited for treatment with high-power APC (90 W) in combination with esomeprazole 80 mg/day. Video endoscopy, chromoendoscopy, and four-quadrant biopsies (4QB) were carried out during baseline endoscopy and regular intervals. The effect of ablation was classified as complete remission (CR), partial remission, or minor response.RESULTS:Fifty-one of the 60 patients completed ablation therapy. Three patients were lost to follow-up (FU). After a mean of 2.6 APC sessions (range 1–5) and a mean FU of 14 months (range 12–32), CR was achieved in 37 of 48 patients (77%). Major complications occurred in five of 51 patients (9.8%).CONCLUSIONS:Complete ablation of BE can be achieved in a high percentage of patients even in a multicenter design using high-power APC. However, APC has a relevant morbidity. Therefore, ablation of nonneoplastic BE cannot be recommended generally because incidence of cancer in BE is low.

Prospective, cross-over, single-center trial comparing oral double-balloon enteroscopy and oral spiral enteroscopy in patients with suspected small-bowel vascular malformations

BACKGROUND AND STUDY AIMS Spiral enteroscopy is a new, promising rapid enteroscopy technique. A prospective cross-over study was carried out to compare this new method with the established technique of double-balloon enteroscopy (DBE). PATIENTS AND METHODS From an initial group of 18 patients with suspected mid-gastrointestinal bleeding due to vascular malformations but no previous history of small-bowel or colonic surgery, 10 patients (mean age 69 years) completed the study. Patients underwent both enteroscopy techniques with an oral approach, in a randomized sequence. The deepest point reached during advancement in the first enteroscopy was marked with India ink. The primary end point of the study was the total examination time. RESULTS For spiral enteroscopy, the mean examination time was significantly shorter than with DBE (43 minutes vs. 65 minutes; P = 0.007), as was the mean time required for advancement of the enteroscope to the deepest point (24 minutes vs. 43 minutes; P = 0.03). However, the median maximum insertion depth was greater in the DBE group than in the spiral enteroscopy group (310 cm vs. 250 cm; P = 0.004). In all cases in which DBE followed spiral enteroscopy, DBE passed the India ink mark by a mean of over 100 cm. When DBE was performed first, spiral enteroscopy was either unable to reach the mark or else unable to advance deeper into the small bowel. No severe complications occurred. CONCLUSIONS The results confirm that the new spiral enteroscopy technique reduces the examination time, although the insertion depth with DBE is at present superior.

Long-term outcome after argon plasma coagulation of small-bowel lesions using double-balloon enteroscopy in patients with mid-gastrointestinal bleeding.

BACKGROUND AND STUDY AIMS Vascular malformations are the most common sources of bleeding in the small bowel. They can be treated with argon plasma coagulation (APC) during double-balloon enteroscopy (DBE). This study aimed to evaluate the long-term follow-up of the effectiveness of APC for small-bowel bleeding by means of a single-center retrospective study. PATIENTS AND METHODS Between June 2003 and December 2005, APC treatment for small-bowel lesions was carried out during DBE in 63 patients with known or suspected mid-gastrointestinal bleeding. Fifty patients were included in the analysis. Main outcome measurements were comparison of hemoglobin values and blood transfusion requirements before and after APC, and rebleeding rates. RESULTS Twenty-nine patients (58%) had only oral DBE, whereas 21 patients (42%) underwent combined oral and anal approaches. The most frequent bleeding sources treated with APC were angiodysplasias in 44 patients (88%). Hemoglobin levels increased distinctly and stabilized after APC during a mean long-term follow-up of 55 ± 7 months, with mean levels of 7.6 g/dL before APC and 11.0 g/dL afterwards. Blood transfusion requirements substantially declined, from 30 patients (60%) before APC to 8 (16%) afterwards. However, small-bowel bleeding recurred in 21 patients (42%), particularly in patients with Osler disease (6 of 8 patients, 75%). CONCLUSIONS Bleeding sources in the small bowel can be effectively treated with APC using DBE, and long-term follow-up data show a clear increase in hemoglobin levels and reduced blood transfusion requirements after APC. Further efforts are needed to reduce the rebleeding rate, possibly through more intensive initial treatment.