- Email: [email protected]
Enteryx
Best Practice & Research Clinical Gastroenterology Vol. 18, No. 1, pp. 49–59, 2004 doi:10.1053/ybega.2004.414, available online at http://www.sciencedirect.com
4 Enteryx Hubert Louis*
MD, PhD
Associated Clinical Professor Department of Gastroenterology and Hepatopancreatology, Erasme Hospital, Universite´ Libre de Bruxelles, Brussels, Belgium
Jean Closset
MD
Clinical Professor Department of Abdominal Surgery, Erasme Hospital, Universite´ Libre de Bruxelles, Brussels, Belgium
Jacques Devie`re MD, PhD Professor and Chairman Department of Gastroenterology and Hepatopancreatology, Erasme Hospital, Universite´ Libre de Bruxelles, Brussels, Belgium
Enteryx (ethylene vinyl alcohol copolymer) was developed as a bulking agent to be injected endoscopically at the lower oesophageal sphincter (LOS) to increase the competency of the gastro-oesophageal barrier in patients suffering from gastro-oesophageal reflux disease (GORD). Preliminary clinical studies have shown that Enteryx implantation is a fast, minimally invasive and safe procedure. In prospective multicentre studies, significant improvement in reflux symptoms, reduction in the use of proton pump inhibitors (PPIs), and objective improvement in acid oesophageal exposure time were observed after 6 months of follow-up. Improvement of GORD symptoms seems to be correlated with the persistence of the implant. Preliminary data suggest a lengthening and an increase in the LOS relaxation pressure as mechanisms of action of this injection technique. Longer follow-up and controlled sham studies are needed to confirm the efficacy of this technique before it can be proposed as a routine alternative to medical or surgical therapies for GORD. Key words: gastro-oesophageal reflux disease; endoscopy.
Gastro-oesophageal reflux disease (GORD) is one of the most prevalent upper gastrointestinal disorders in western countries. Epidemiological studies have suggested that almost 50% of adults in the USA experience heartburn monthly, while nearly 10% of the population experience it daily.1 GORD is a chronic disease with relapsing symptoms, and lifelong treatment is used in 25– 50% of patients.2 The most common pathophysiological mechanism for gastroesophageal reflux is the transient or permanent loss of the barrier function of the lower oesophageal sphincter (LOS). In many patients with mild uncomplicated GORD, transient relaxations of * Corresponding author. Tel.: þ32-2-555-37-12; Fax: þ32-2-555-4697. E-mail address: [email protected] (H. Louis). 1521-6918/04/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
50 H. Louis, J. Closset and J. Devie`re
the LOS (TLOSRs)—occurring, for example, secondary to gastric distention after meals—are the major mechanism accounting for the reflux episodes.3 A permanent loss of the barrier function is observed in patients with hiatal hernia.4 Patients presenting for the first time with GORD symptoms are encouraged to initiate lifestyle modifications and are given therapy with antacids, H2 blockers, or proton pump 7inhibitors (PPIs). PPIs are, at present, the most potent medical therapy, leading to symptom improvement and endoscopic healing of oesophagitis in more than 90% of patients.5 Because of the large prevalence of GORD, drug therapy in GORD patients has an enormous economic impact. Antireflux surgery is indicated for the treatment of objectively documented, moderate to severe GORD unresponsive to medical therapy. Other candidates for surgery are patients who respond well to medical therapy but who choose surgery because of non-compliance, intolerance, cost of the medications or personal preference. Since the advent of laparoscopic surgery, Nissen fundoplication has become a less invasive procedure with a shorter hospitalization time which results in symptomatic improvement in 90 – 95% of patients.6,7 However, morbidity due to general anaesthesia, bleeding, organ injury, infection or secondary to the procedure itself (dysphagia for example), might be a problem in a significant proportion of patients. This potential morbidity and (even rare) mortality (0.3 –0.5%) make many physicians reluctant to propose surgery to young and otherwise healthy patients. Moreover, more than half the patients with a Nissen fundoplication are taking acid-reducing medications 10 years after surgery.8 For this purpose, alternative methods designed to be minimally invasive, easy to perform and less expensive, were designed for the treatment of GORD, using an endoscopic transoral approach. Alternative approaches were evaluated as early as 1984. O’Connor and colleagues investigated the use of both biodegradable and non-biodegradable material in dogs as a submucosal bulking agent to augment the LOS pressure.9 Following the results of these experiments, bovine dermal collagen, a biodegradable substance, was injected into the lower oesophagus in ten patients with clinically documented GORD.10 However, if the initial results were promising they were short-lived due to the absorption of the collagen. In the late 1980s, Donahue et al attempted to increase the competence of the LOS by sclerosing the gastric cardia. While the results were encouraging in dogs, they could not be reproduced in humans and the approach was abandoned.11 – 13 In 1996, Shafik
Practice points † GORD occurs secondarily to a transient or a permanent loss of barrier function of the gastro-oesophageal junction; the aim of endoscopic techniques is to increase the competency of the gastro-oesophageal junction † results of previous endoscopic implantation of bulking agents were disappointing because of sloughing or resorption of the materials † ideally, an implantable material should be chemically inert, non-carcinogenic, hypo-allergenic, capable of resisting mechanical strain, capable of being sterilized, capable of being delivered in a liquid form but solid in its stable form and persisting at the site of injection, this latter criterion not being met by the previously tested materials15
Enteryx 51
attempted to bulk the oesophagus at the level of the LOS using teflon material with marginal success and the caveat of previous knowledge of sloughing of this material.14
ENTERYX Enteryx (Boston Scientific Corp., Natick, MA, USA) is an injectable solution of 8% ethylene vinyl alcohol copolymer (EVOH) dissolved in dimethyl sulphoxide (DMSO). Upon contact with polar physiological fluids, the DMSO solvent diffuses away, resulting in solidification of the hydrophobic copolymer as a spongy mass (Figure 1). Micronized tantalum powder (30% weight/volume) is added to the polymer/solvent mixture to serve as the contrast for visualization under fluoroscopy. The viscosity of Enteryx before contact with tissue is extremely low, allowing injection through a 23 –25 gauge needle. It is not biodegradable and has no antigenic properties. Neither migration through vessels or lymphatics after polymerization, nor shrinkage after injection, have been reported. EVOH was originally developed as an embolic agent, and is currently under evaluation for the treatment of cerebral aneurysms and arteriovenous malformations, and for hypervascular tumours of the head and neck.16 – 19 The EVOH copolymer is also used as a haemodialysis and plasmapheresis membrane. Moreover, the homopolymers, polyethylene and polyvinyl alcohol (PVA), from which the copolymer EVOH is derived, have a long history as implant materials.20 – 22 Micronized tantalum powder, a contrast agent, is used to allow visualization under fluoroscopy during injection. It is insoluble, inert, possesses a high radiodensity, and has a history of successful use in permanent long-term implants.23 Dimethyl sulphoxide (DMSO), the carrier solvent, has been used in a variety of medical applications.24,25 Importantly, extended carcinogenicity experiments using transgenic mice implanted with Enteryx were negative.26
Figure 1. Polymerization of Enteryx solution as a spongy black material in a glass of saline.
52 H. Louis, J. Closset and J. Devie`re
Practice point † enteryx is a soluble mixture of ethylene vinyl alcohol copolymer with tantalum powder, dissolved in dimethyl sulphoxide, which precipitates as a spongy mass when in contact with physiological fluids
PRE-CLINICAL STUDIES Initial studies in animals confirmed that Enteryx injection in the lower oesophagus is safe in terms of local and systemic effects. In a long-term safety and feasibility study of Enteryx performed at the University of Southern California, Yucatan minipigs were used to evaluate the dosing and location of implants required to modify the distensibility of the LOS, to evaluate the acute and chronic safety associated with the submucosal or intramuscular LOS implants, and to assess LOS compliance changes as measured by resting pressure and yield pressure to provide an indication of clinical utility.27 A series of 12 animals were studied at post-implantation up to 12 months. All animals tolerated the implants well, had a normal eating pattern, continued to gain weight and none showed evidence of vomiting or regurgitation. There were no complications. The median injection volume was 4 ml (range 1 – 8). Intramuscular placement of the implant was durable, whereas sloughing occurred if the implants were placed submucosally. Sphincter length and resting pressure were unaffected by the injection. Functionally, endoscopic implantation of Enteryx led to a significant difference in the yield pressure (the intragastric pressure needed to equalize gastric and oesophageal pressures), suggesting that the healing process was associated with a reduced distensibility of the cardia. At autopsy, implants were found in 83% of the animals. Macroscopic and histological anatomic assessment demonstrated evolution of the tissue response to the Enteryx implants from acute inflammation through a subacute inflammatory process with accompanied fibrosis and, ultimately, to a welldeveloped foreign body reaction. By 6 months post-implantation the tissue surrounding the implant sites was quiescent. Mature, well-delineated capsules of varying thickness surrounded the sites, separating them from the oesophageal muscle or the interstitial connective tissue. Purposeful extraperitoneal, intrathoracic and even intravascular implants were well tolerated in animals.
ENTERYX PROCEDURE The first patients with GORD were treated in 1999 and the description of the procedure follows the experience acquired in Erasme Hospital in Brussels.28 Standard upper gastrointestinal endoscopy is performed as an outpatient procedure in an endoscopy suite equipped with fluoroscopy. A single intravenous injection of antibiotics is administered as an antibioprophylaxis. Sedation is administered using midazolam and meperidine, or propofol; glucagon (1 mg intravenous) is used as a smooth muscle relaxant. A 23-gauge, 4 mm-long catheter is flushed with DMSO and then entirely filled with Enteryx. The catheter is inserted through the accessory channel of the endoscope (forward or side-viewing scope) and the needle puncture is performed 1– 3 mm proximal to the squamocolumnar junction (z line), at an acute angle, advancing the needle into the LOS muscle. The injection is made with a 1 ml syringe loaded with
Enteryx 53
Enteryx under both fluoroscopic and endoscopic observation. This technique assures the prevention of both submucosal and transmural injections. If the polymer is injected into the submucosa, a grey or black bulge is seen endoscopically. Because superficial injections slough into the GI tract, such injections are discontinued immediately, and the needle is inserted a little deeper or a new injection site is chosen. In case of transmural injection, a deposit of the radiopaque material is not seen in the oesophageal wall but sharp thin vertical lines are observed on fluoroscopy. In that case, the injection is immediately stopped and the needle is retracted. When an intramuscular injection of Enteryx is observed fluoroscopically, without endoscopically visible submucosal injection, the injection is continued at a rate of approximately 1 ml/ minute. This slow injection rate allows for consistent placement of the implant within the muscle layer of the LOS and is required owing to the fact that polymerization is an exothermic reaction. Upon completion of the injection, the needle is left in place for 30 seconds and then withdrawn. Four quadrants of injections/implantations of 1 –2 ml each are made at the same level of the oesophagus. If, during an injection, diffusion of the material is seen around the inner circumference of the oesophagus, making an arcuate or ring appearance, the Enteryx implantation is continued up to 3 to 4 ml at the same puncture site. A plain X-ray film of the implant is made (see examples of Enteryx implants in Figure 2). The whole procedure lasts between 20 and 30 minutes; afterwards, patients remain in the recovery room for 2 hours. Patients are permitted to eat a soft diet on the day of the procedure and a normal diet the day after, and are treated with omeprazole 40 mg daily for 2 weeks after implantation.
Practice points † enteryx implantation is performed as an outpatient procedure, using standard upper gastrointestinal endoscopy † intramuscular injection at the gastro-oesophageal junction is performed with a sclerotherapy-type needle under both fluoroscopic and endoscopic guidance CLINICAL RESULTS A pilot study was conducted in Brussels and Rome between June 1999 and June 2000 in 15 adult patients.28 All patients had a history of GORD requiring continuous therapy with PPIs for at least 3 months. Inclusion criteria included (1) typical GORD symptoms (at least heartburn) responsive to PPI therapy, but returning upon discontinuation of the drug, (2) gastro-oesophageal reflux demonstrated by pH-metry, and (3) oesophagitis at endoscopy no greater than grade II (Savary Miller classification). Patients with oesophageal motility disorders, severe oesophagitis or Barrett’s epithelium, hiatal hernia longer than 3 cm, body mass index of 35 or greater, or unresponding to a standard dose of PPI, were excluded. The major endpoints of the study were to assess the safety of the procedure, the effect of Enteryx implantation on the LOS pressure and the persistence of the injected material. No major complication was noted in the study; eight patients complained of a mild, transient retrosternal pain, usually for 1– 3 days after the procedure, that was treated with orally administered analgesics. One patient developed mild dysphagia that spontaneously disappeared after 15 days. LOS pressure increased in all but three patients, and the increase was still
54 H. Louis, J. Closset and J. Devie`re
Figure 2. Examples of annular or semi-annular implants on successive radiographic images taken during Enteryx injection in three different patients (A– C). In patient C, a semi-annular implant is visible (white arrow) together with more dense and well-delineated spots which correspond to submucosal injections (asterisks).
observed after a median follow-up of 6 months. Persistence of Enteryx was more often observed when a ring appearance was obtained (which was the case in 10 out of 15 patients). Most of the patients had improvement in their heartburn score after Enteryx injection. In two patients who had received multiple injections that appeared radiographically as spots without achievement of a circular injection ring, most of the implanted material was lost after 6 months of follow-up. Those two patients were
Enteryx 55
among the four who had to resume PPI therapy. In one of these patients, a laparoscopic Nissen fundoplication was later successfully performed. The oesophagus appeared normal, without evidence of adhesions or peri-oesophageal fibrosis. Recently, followup imaging has been performed in patients who had been treated for more than 3 years, showing the persistence of the implants at this later follow-up (Figure 3). Preliminary observations of these patients suggest that those with symptomatic improvement at 6 months are still improved after 3 years. To further evaluate the safety and the efficacy of endoscopic implantation of Enteryx for the treatment of GORD, multicentre studies were started. These studies included patients from the USA, Canada and Europe, who will be followed for 1 year after treatment. The inclusion and exclusion criteria were similar to those of the pilot study28 with a primary endpoint which was the reduction in use of PPI medication. Secondary endpoints included improvement in patient symptoms, 24-hour pH-metry and LOS pressure recordings. Concerning an international study in which patients were enrolled in the USA, Canada and Belgium, preliminary results are available with 6 months follow-up and indicate that 75% of the 85 treated subjects remain off all PPIs 6 months after the implantation.29 In addition, 9% of the patients reduced their usage of PPIs by more than 50% from baseline, which means that a large majority of the patients have discontinued their use of PPIs and other GORD medications. Enteryx treatment also resulted in a significant improvement in both physical and mental component scores when compared to patients’ scores measured at baseline off PPI therapy. Subject scores following treatment with Enteryx were similar to baseline scores recorded with patients on PPI therapy for GORD management. The GORD symptom scores at 6 months showed an approximate 70% improvement from baseline values off PPIs. Mean heartburn and regurgitation scores measured off PPIs at baseline and at 6 months dropped from 24 to 4 and from 11 to 1, respectively. This favourable outcome was confirmed more recently when analysing results from 170 patients treated in Europe and America.30 Seventy-three percent of the patients were able to stop PPIs or H2 antagonist medications and an additional 10% reduced by more than 50% their medication after 6 months. The X-ray analysis of implant volume remaining in place at 3 months seems to indicate that it is correlated to the success of this procedure, and that superficial
Figure 3. Spiral CT showing persistence of Enteryx implants in oesophageal wall 3 years after implantation on a coronal slice (white arrow) (A), and on an axial slice (B). Tantalum powder, mixed in Enteryx implant, was used as a contrast agent to be detected fluoroscopically as it possesses a high radiodensity.
56 H. Louis, J. Closset and J. Devie`re
submucosal injections slough within 3 months after Enteryx injection. After the material sloughs, the resulting ulceration heals in 7– 10 days. These findings support the conclusion that the main reason for clinical failure after Enteryx injection is an inadequate volume of material injected in the LOS during the original procedure or a loss of the implant due to sloughing after a superficial injection. For this reason, 10% of the patients were re-implanted after 3 months of follow-up when they could not reduce their use of PPIs by more than 50%29; repeated implantation led to improvement in GORD symptoms in 63% of these patients at 6 months. No clinically severe complication has been currently reported following Enteryx injection in the LOS region. The majority of patients (92%) exhibited mild to moderate retrosternal discomfort which generally disappeared within 1 week of the treatment, but occasionally lasted into the second or third week post-implant.29 The patient’s pain was easily managed with oral analgesics. The other adverse events noted were dysphagia (17%), requiring dilation in only one case when lasting more than 1 month, and low-grade fever (12%). Post-operative dysphagia is a common complication of antireflux surgery, but lasts for 3 months in up to 25% of the cases.31 The lack of permanent dysphagia after Enteryx implantation is probably due to both the fast resolution of inflammation after implantation and the spongy nature of the Enteryx polymer once it has precipitated. Low-grade fever resolved in the first few days postimplant. Other side-effects consisted in bloating/flatulence (6%) and the perception of a body odour or a bad taste for several days after the implantation, probably due to the diffusion of the DMSO solvent. Objective improvement of gastro-oesophageal acid reflux was demonstrated by intra-oesophageal pH monitoring, showing that the mean acid exposure time at baseline off PPIs fell from 9.5 to 6.7% 6 months after Enteryx implantation.29 Almost 40% of the patients achieved normal pH scores by 6 months. Statistically significant reductions were also observed for percentage upright and supine times and for total number of reflux episodes. These objective results were confirmed when combining data from America and Europe, showing a significant decrease of mean oesophageal acid exposure time from 15% at baseline off PPIs to 7.5% at 6 months.32 No significant change in LOS resting pressure has been evidenced in the multicentric studies29, although this may be due to variations in manometry technique across centres. In a smaller study performed on 13 patients in Europe, a significant increase in LOS relaxation pressure was found together with a trend to a decrease in the incidence of post-prandial TLOSRs.33 Interestingly, in the international study29, mean LOS length increased slightly at 6 months, compared to baseline (3.1 versus 2.6 cm). In the same line, the importance of a sufficient LOS length to ensure LOS barrier function was recently underlined.34 The shorter the overall length of the LOS, the higher the pressure must be to maintain sufficient resistance to remain competency. This observation of lengthening of the LOS may play an important role in restoration of competency of the LOS function.
Practice points † 6 months follow-up of published uncontrolled trials suggests efficacy of Enteryx implantation in GORD, seeing improvement of GORD symptoms in the majority of the patients and objective improvement of oesophageal acid exposure at pH-metry
Enteryx 57
† superficial submucosal implants slough into the oesophagus while deep intramuscular implants persist at the site of injection † relief of GORD symptoms after 3 months seems to be correlated with the persistence of implants † enteryx implantation is safe, no serious complication being currently reported
Research agenda † only results from uncontrolled clinical trials are currently available † randomized sham controlled trials are awaited to establish the real efficacy of Enteryx implantation in GORD patients † longer-term follow-up is needed to assess long-term efficacy and safety before this procedure can be recommended routinely in the management of GORD patients † further studies are awaited to determine the mechanism of action of Enteryx implant (effect on LOS length, LOS pressure and occurrence of TLOSRs) † currently, clinical trials have enrolled patients with typical GORD symptoms responding to PPIs; future trials will assess endoscopic Enteryx implantation in other categories of patients suffering from GORD, i.e. atypical symptoms, incomplete response to PPIs, failure of Nissen fundoplication or bile reflux after gastrectomy † future comparative trials will balance this new technique with medical and surgical treatments of GORD † technical points concern the optimization of implant technique, regarding the location and volume of implants and the number of sessions needed
SUMMARY: IS ENTERYX READY FOR PRIME TIME IN 2003? The implantation of Enteryx polymer in the LOS is a fast and minimally invasive procedure with anticipated low procedure risks and limited costs. Preliminary clinical results after 6 months of follow-up show good results in more than 80% of the patients. The effectiveness of Enteryx in the management of GORD is currently evidenced by the ability of GORD patients with a history of use of PPIs and other GORD medications to eliminate or significantly reduce the use of these medications, and by a significant reduction in oesophageal acid exposure time. A more solid evidence of the efficacy of Enteryx oesophageal implants will be provided by a sham-controlled study. Mechanisms of action of Enteryx implantation suggest a change in the distensibility of the LOS, allowing a greater competency of the cardia. LOS relaxation pressure and LOS length might be increased after polymer implantation, and further studies are needed to study the effect of Enteryx on TLOSRs, which is the prevalent mechanism of reflux in patients with mild GORD. Challenges with this procedure will refine technique in order to deliver adequate volume in each case and determine whether the ring-shaped implant is needed. Beside typical GORD symptoms, other indications for this treatment could be atypical symptoms, failure of Nissen fundoplication or bile reflux after gastrectomy. Finally, as for any other procedure for GORD treatment, further studies and registries are needed to definitively establish the safety of the procedure. This is a major point
58 H. Louis, J. Closset and J. Devie`re
because gastroenterologists are not dealing with ill patients but with individuals having, in the majority, a good quality of life when taking PPIs. Beside a safe profile, the endoscopic technique should also not compromise future anti-reflux surgery in unsatisfied patients.
REFERENCES 1. Locke GR, Talley NJ, Fett SL et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997; 112: 1448–1456. 2. Pope CE. Acid-reflux disorders. New England Journal of Medicine 1994; 331: 656–660. * 3. Schoeman MN, Tippett MD, Akkermans LM et al. Mechanisms of gastroesophageal reflux in ambulant healthy human subjects. Gastroenterology 1995; 108: 83–91. * 4. Mittal RK & Balaban DH. The esophagogastric junction. New England Journal of Medicine 1997; 336: 924 –932. 5. Dent J. Gastro-oesophageal reflux disease. Digestion 1998; 59: 433–445. 6. Watson DI & Jamieson GG. Antireflux surgery in the laparoscopic era. British Journal of Surgery 1998; 85: 1173–1184. 7. Hinder RA, Filipi CJ, Wetscher G et al. Laparoscopic Nissen fundoplication is an effective treatment for gastroesophageal reflux disease. Annals of Surgery 1994; 220: 472 –481. 8. Spechler SJ, Lee E, Ahnen D et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial. Journal of the American Medical Association 2001; 285: 2331–2338. 9. O’Connor KW, Madison SA, Smith DJ et al. An experimental endoscopic technique for reversing gastroesophageal reflux in dogs by injecting inert material in the distal oesophageal. Gastrointestinal Endoscopy 1984; 30: 275–280. * 10. O’Connor KW & Lehman GA. Endoscopic placement of collagen at the lower esophageal sphincter to inhibit gastroesophageal reflux: a pilot study of 10 medically intractable patients. Gastrointestinal Endoscopy 1988; 34: 106 –112. 11. Donahue PE, Carvalho P, Yoshida J et al. Endoscopic sclerosis of the cardia affects gastroesophageal reflux. Surgical Endoscopy 1989; 3: 11 –12. 12. Donahue PE, Carvalho PJ, Davis PE et al. Endoscopic sclerosis of the gastric cardia for prevention of experimental gastroesophageal reflux. Gastrointestinal Endoscopy 1990; 36: 253–256. 13. Donahue PE, Sugitani A & Carvalho P. Endoscopic control of gastro-esophageal reflux: status report. World Journal of Surgery 1992; 16: 343–346. * 14. Shafik A. Polytef injection for the treatment of reflux esophagitis. Surgical Endoscopy 1996; 10: 329–331. * 15. Lehman GA. Endoscopic and endoluminal techniques for the control of gastroesophageal reflux: are they ready for widespread clinical application? Gastrointestinal Endoscopy 2000; 52: 808–811. 16. Elahi MM, Parnes LS, Fox AJ et al. Therapeutic embolization in the treatment of intractable epistaxis. Archives of Otolaryngology—Head and Neck Surgery 1995; 121: 65 –69. 17. Gobin YP, Murayama Y, Milanese K et al. Head and neck hypervascular lesions: embolization with ethylene vinyl alcohol copolymer—laboratory evaluation in swine and clinical evaluation in humans. Radiology 2001; 221: 309 –317. 18. Martin ML, Dolmatch BL, Fry PD et al. Treatment of type II endoleaks with Onyx. Journal of Vascular and Interventional Radiolology 2001; 12: 629 –632. 19. Jahan R, Murayama Y, Gobin YP et al. Embolization of arteriovenous malformations with Onyx: clinicopathological experience in 23 patients. Neurosurgery 2001; 48: 984 –995. 20. Emmett JR. Plasti-pore implants in middle ear surgery. Otolaryngology Clinics of North America 1995; 28: 265–272. 21. Griffith SL, Shelokov AP, Buttner-Janz K et al. A multicenter retrospective study of the clinical results of the LINK SB Charite intervertebral prosthesis. The initial European experience. Spine 1994; 19: 1842–1849. 22. Wroblewski BM, Siney PD, Dowson D et al. Prospective clinical and joint simulator studies of a new total hip arthroplasty using alumina ceramic heads and cross-linked polyethylene cups. Journal of Bone and Joint Surgery 1996; 78: 280 –285. 23. Black J. Biological performance of tantalum. Clinical Materials 1994; 16: 167 –173. 24. Parkin J, Shea C & Sant GR. Intravesical dimethyl sulfoxide (DMSO) for interstitial cystitis-a practical approach. Urology 1997; 49: 105– 107.
Enteryx 59 25. Yu ZW & Quinn PJ. Dimethyl sulphoxide: a review of its applications in cell biology. Bioscience Reports 1994; 14: 259– 281. 26. Devie`re J, Wustenberg W, Mishra N et al. A transgenic mouse model for carcinogenicity testing of Enteryx—an implantable biopolymer for treatment of GERD. Gut 2001; 49: 1587. (abstact). * 27. Mason M, Hughes GA, Lehman GA et al. Endoscopic augmentation of the cardia with a biocompatible injectable polymer (Enteryx) in a porcine model. Surgical Endoscopy 2002; 16: 386–391. * 28. Devie`re J, Pastorelli A, Louis H et al. Endoscopic implantation of a biopolymer in the lower esophageal sphincter for gastroesophageal reflux: a pilot study. Gastrointestinal Endoscopy 2002; 55: 335–341. * 29. Lehman GA, Johnson D, Aisenberg J et al. Endoscopic deep mural implantation of Enteryx for the treatment of GERD: a 6 month follow-up of a multicenter trial. American Journal of Gastroenterology 2003; 98: 250 –258. 30. Johnson D, Aisenberg J, Cohen L et al. Enteryx, an injectable treatment for GERD: multicenter results. American Journal of Gastroenterology 2002; 97(supplement): S12. (abstract). 31. Kamolz T, Bammer T & Pointner R. Predictability of dysphagia after laparoscopic Nissen fundoplication. American Journal of Gastroenterology 2000; 95: 408 –414. 32. Lehman GA, Aisenberg J, Cohen L et al. Improvement in esophageal pH probe studies after Enteryx therapy for GERD. Gastroenterology 2002; 122: S1235. (abstract). 33. Louis H, Voderholzer W, Le Moine O et al. Lower esophageal sphincter function after endoscopic polymere injection for GERD treatment: 1,6 and 12 months results. Gut 2002; 51(supplement III): A25. (abstract). * 34. DeMeester TR, Peters JH, Bremner CG et al. Biology of gastroesophageal reflux disease; pathophysiology relating to medical and surgical treatment. Annual Review of Medicine 1998; 50: 469–506.
4 Enteryx Hubert Louis*
MD, PhD
Associated Clinical Professor Department of Gastroenterology and Hepatopancreatology, Erasme Hospital, Universite´ Libre de Bruxelles, Brussels, Belgium
Jean Closset
MD
Clinical Professor Department of Abdominal Surgery, Erasme Hospital, Universite´ Libre de Bruxelles, Brussels, Belgium
Jacques Devie`re MD, PhD Professor and Chairman Department of Gastroenterology and Hepatopancreatology, Erasme Hospital, Universite´ Libre de Bruxelles, Brussels, Belgium
Enteryx (ethylene vinyl alcohol copolymer) was developed as a bulking agent to be injected endoscopically at the lower oesophageal sphincter (LOS) to increase the competency of the gastro-oesophageal barrier in patients suffering from gastro-oesophageal reflux disease (GORD). Preliminary clinical studies have shown that Enteryx implantation is a fast, minimally invasive and safe procedure. In prospective multicentre studies, significant improvement in reflux symptoms, reduction in the use of proton pump inhibitors (PPIs), and objective improvement in acid oesophageal exposure time were observed after 6 months of follow-up. Improvement of GORD symptoms seems to be correlated with the persistence of the implant. Preliminary data suggest a lengthening and an increase in the LOS relaxation pressure as mechanisms of action of this injection technique. Longer follow-up and controlled sham studies are needed to confirm the efficacy of this technique before it can be proposed as a routine alternative to medical or surgical therapies for GORD. Key words: gastro-oesophageal reflux disease; endoscopy.
Gastro-oesophageal reflux disease (GORD) is one of the most prevalent upper gastrointestinal disorders in western countries. Epidemiological studies have suggested that almost 50% of adults in the USA experience heartburn monthly, while nearly 10% of the population experience it daily.1 GORD is a chronic disease with relapsing symptoms, and lifelong treatment is used in 25– 50% of patients.2 The most common pathophysiological mechanism for gastroesophageal reflux is the transient or permanent loss of the barrier function of the lower oesophageal sphincter (LOS). In many patients with mild uncomplicated GORD, transient relaxations of * Corresponding author. Tel.: þ32-2-555-37-12; Fax: þ32-2-555-4697. E-mail address: [email protected] (H. Louis). 1521-6918/04/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
50 H. Louis, J. Closset and J. Devie`re
the LOS (TLOSRs)—occurring, for example, secondary to gastric distention after meals—are the major mechanism accounting for the reflux episodes.3 A permanent loss of the barrier function is observed in patients with hiatal hernia.4 Patients presenting for the first time with GORD symptoms are encouraged to initiate lifestyle modifications and are given therapy with antacids, H2 blockers, or proton pump 7inhibitors (PPIs). PPIs are, at present, the most potent medical therapy, leading to symptom improvement and endoscopic healing of oesophagitis in more than 90% of patients.5 Because of the large prevalence of GORD, drug therapy in GORD patients has an enormous economic impact. Antireflux surgery is indicated for the treatment of objectively documented, moderate to severe GORD unresponsive to medical therapy. Other candidates for surgery are patients who respond well to medical therapy but who choose surgery because of non-compliance, intolerance, cost of the medications or personal preference. Since the advent of laparoscopic surgery, Nissen fundoplication has become a less invasive procedure with a shorter hospitalization time which results in symptomatic improvement in 90 – 95% of patients.6,7 However, morbidity due to general anaesthesia, bleeding, organ injury, infection or secondary to the procedure itself (dysphagia for example), might be a problem in a significant proportion of patients. This potential morbidity and (even rare) mortality (0.3 –0.5%) make many physicians reluctant to propose surgery to young and otherwise healthy patients. Moreover, more than half the patients with a Nissen fundoplication are taking acid-reducing medications 10 years after surgery.8 For this purpose, alternative methods designed to be minimally invasive, easy to perform and less expensive, were designed for the treatment of GORD, using an endoscopic transoral approach. Alternative approaches were evaluated as early as 1984. O’Connor and colleagues investigated the use of both biodegradable and non-biodegradable material in dogs as a submucosal bulking agent to augment the LOS pressure.9 Following the results of these experiments, bovine dermal collagen, a biodegradable substance, was injected into the lower oesophagus in ten patients with clinically documented GORD.10 However, if the initial results were promising they were short-lived due to the absorption of the collagen. In the late 1980s, Donahue et al attempted to increase the competence of the LOS by sclerosing the gastric cardia. While the results were encouraging in dogs, they could not be reproduced in humans and the approach was abandoned.11 – 13 In 1996, Shafik
Practice points † GORD occurs secondarily to a transient or a permanent loss of barrier function of the gastro-oesophageal junction; the aim of endoscopic techniques is to increase the competency of the gastro-oesophageal junction † results of previous endoscopic implantation of bulking agents were disappointing because of sloughing or resorption of the materials † ideally, an implantable material should be chemically inert, non-carcinogenic, hypo-allergenic, capable of resisting mechanical strain, capable of being sterilized, capable of being delivered in a liquid form but solid in its stable form and persisting at the site of injection, this latter criterion not being met by the previously tested materials15
Enteryx 51
attempted to bulk the oesophagus at the level of the LOS using teflon material with marginal success and the caveat of previous knowledge of sloughing of this material.14
ENTERYX Enteryx (Boston Scientific Corp., Natick, MA, USA) is an injectable solution of 8% ethylene vinyl alcohol copolymer (EVOH) dissolved in dimethyl sulphoxide (DMSO). Upon contact with polar physiological fluids, the DMSO solvent diffuses away, resulting in solidification of the hydrophobic copolymer as a spongy mass (Figure 1). Micronized tantalum powder (30% weight/volume) is added to the polymer/solvent mixture to serve as the contrast for visualization under fluoroscopy. The viscosity of Enteryx before contact with tissue is extremely low, allowing injection through a 23 –25 gauge needle. It is not biodegradable and has no antigenic properties. Neither migration through vessels or lymphatics after polymerization, nor shrinkage after injection, have been reported. EVOH was originally developed as an embolic agent, and is currently under evaluation for the treatment of cerebral aneurysms and arteriovenous malformations, and for hypervascular tumours of the head and neck.16 – 19 The EVOH copolymer is also used as a haemodialysis and plasmapheresis membrane. Moreover, the homopolymers, polyethylene and polyvinyl alcohol (PVA), from which the copolymer EVOH is derived, have a long history as implant materials.20 – 22 Micronized tantalum powder, a contrast agent, is used to allow visualization under fluoroscopy during injection. It is insoluble, inert, possesses a high radiodensity, and has a history of successful use in permanent long-term implants.23 Dimethyl sulphoxide (DMSO), the carrier solvent, has been used in a variety of medical applications.24,25 Importantly, extended carcinogenicity experiments using transgenic mice implanted with Enteryx were negative.26
Figure 1. Polymerization of Enteryx solution as a spongy black material in a glass of saline.
52 H. Louis, J. Closset and J. Devie`re
Practice point † enteryx is a soluble mixture of ethylene vinyl alcohol copolymer with tantalum powder, dissolved in dimethyl sulphoxide, which precipitates as a spongy mass when in contact with physiological fluids
PRE-CLINICAL STUDIES Initial studies in animals confirmed that Enteryx injection in the lower oesophagus is safe in terms of local and systemic effects. In a long-term safety and feasibility study of Enteryx performed at the University of Southern California, Yucatan minipigs were used to evaluate the dosing and location of implants required to modify the distensibility of the LOS, to evaluate the acute and chronic safety associated with the submucosal or intramuscular LOS implants, and to assess LOS compliance changes as measured by resting pressure and yield pressure to provide an indication of clinical utility.27 A series of 12 animals were studied at post-implantation up to 12 months. All animals tolerated the implants well, had a normal eating pattern, continued to gain weight and none showed evidence of vomiting or regurgitation. There were no complications. The median injection volume was 4 ml (range 1 – 8). Intramuscular placement of the implant was durable, whereas sloughing occurred if the implants were placed submucosally. Sphincter length and resting pressure were unaffected by the injection. Functionally, endoscopic implantation of Enteryx led to a significant difference in the yield pressure (the intragastric pressure needed to equalize gastric and oesophageal pressures), suggesting that the healing process was associated with a reduced distensibility of the cardia. At autopsy, implants were found in 83% of the animals. Macroscopic and histological anatomic assessment demonstrated evolution of the tissue response to the Enteryx implants from acute inflammation through a subacute inflammatory process with accompanied fibrosis and, ultimately, to a welldeveloped foreign body reaction. By 6 months post-implantation the tissue surrounding the implant sites was quiescent. Mature, well-delineated capsules of varying thickness surrounded the sites, separating them from the oesophageal muscle or the interstitial connective tissue. Purposeful extraperitoneal, intrathoracic and even intravascular implants were well tolerated in animals.
ENTERYX PROCEDURE The first patients with GORD were treated in 1999 and the description of the procedure follows the experience acquired in Erasme Hospital in Brussels.28 Standard upper gastrointestinal endoscopy is performed as an outpatient procedure in an endoscopy suite equipped with fluoroscopy. A single intravenous injection of antibiotics is administered as an antibioprophylaxis. Sedation is administered using midazolam and meperidine, or propofol; glucagon (1 mg intravenous) is used as a smooth muscle relaxant. A 23-gauge, 4 mm-long catheter is flushed with DMSO and then entirely filled with Enteryx. The catheter is inserted through the accessory channel of the endoscope (forward or side-viewing scope) and the needle puncture is performed 1– 3 mm proximal to the squamocolumnar junction (z line), at an acute angle, advancing the needle into the LOS muscle. The injection is made with a 1 ml syringe loaded with
Enteryx 53
Enteryx under both fluoroscopic and endoscopic observation. This technique assures the prevention of both submucosal and transmural injections. If the polymer is injected into the submucosa, a grey or black bulge is seen endoscopically. Because superficial injections slough into the GI tract, such injections are discontinued immediately, and the needle is inserted a little deeper or a new injection site is chosen. In case of transmural injection, a deposit of the radiopaque material is not seen in the oesophageal wall but sharp thin vertical lines are observed on fluoroscopy. In that case, the injection is immediately stopped and the needle is retracted. When an intramuscular injection of Enteryx is observed fluoroscopically, without endoscopically visible submucosal injection, the injection is continued at a rate of approximately 1 ml/ minute. This slow injection rate allows for consistent placement of the implant within the muscle layer of the LOS and is required owing to the fact that polymerization is an exothermic reaction. Upon completion of the injection, the needle is left in place for 30 seconds and then withdrawn. Four quadrants of injections/implantations of 1 –2 ml each are made at the same level of the oesophagus. If, during an injection, diffusion of the material is seen around the inner circumference of the oesophagus, making an arcuate or ring appearance, the Enteryx implantation is continued up to 3 to 4 ml at the same puncture site. A plain X-ray film of the implant is made (see examples of Enteryx implants in Figure 2). The whole procedure lasts between 20 and 30 minutes; afterwards, patients remain in the recovery room for 2 hours. Patients are permitted to eat a soft diet on the day of the procedure and a normal diet the day after, and are treated with omeprazole 40 mg daily for 2 weeks after implantation.
Practice points † enteryx implantation is performed as an outpatient procedure, using standard upper gastrointestinal endoscopy † intramuscular injection at the gastro-oesophageal junction is performed with a sclerotherapy-type needle under both fluoroscopic and endoscopic guidance CLINICAL RESULTS A pilot study was conducted in Brussels and Rome between June 1999 and June 2000 in 15 adult patients.28 All patients had a history of GORD requiring continuous therapy with PPIs for at least 3 months. Inclusion criteria included (1) typical GORD symptoms (at least heartburn) responsive to PPI therapy, but returning upon discontinuation of the drug, (2) gastro-oesophageal reflux demonstrated by pH-metry, and (3) oesophagitis at endoscopy no greater than grade II (Savary Miller classification). Patients with oesophageal motility disorders, severe oesophagitis or Barrett’s epithelium, hiatal hernia longer than 3 cm, body mass index of 35 or greater, or unresponding to a standard dose of PPI, were excluded. The major endpoints of the study were to assess the safety of the procedure, the effect of Enteryx implantation on the LOS pressure and the persistence of the injected material. No major complication was noted in the study; eight patients complained of a mild, transient retrosternal pain, usually for 1– 3 days after the procedure, that was treated with orally administered analgesics. One patient developed mild dysphagia that spontaneously disappeared after 15 days. LOS pressure increased in all but three patients, and the increase was still
54 H. Louis, J. Closset and J. Devie`re
Figure 2. Examples of annular or semi-annular implants on successive radiographic images taken during Enteryx injection in three different patients (A– C). In patient C, a semi-annular implant is visible (white arrow) together with more dense and well-delineated spots which correspond to submucosal injections (asterisks).
observed after a median follow-up of 6 months. Persistence of Enteryx was more often observed when a ring appearance was obtained (which was the case in 10 out of 15 patients). Most of the patients had improvement in their heartburn score after Enteryx injection. In two patients who had received multiple injections that appeared radiographically as spots without achievement of a circular injection ring, most of the implanted material was lost after 6 months of follow-up. Those two patients were
Enteryx 55
among the four who had to resume PPI therapy. In one of these patients, a laparoscopic Nissen fundoplication was later successfully performed. The oesophagus appeared normal, without evidence of adhesions or peri-oesophageal fibrosis. Recently, followup imaging has been performed in patients who had been treated for more than 3 years, showing the persistence of the implants at this later follow-up (Figure 3). Preliminary observations of these patients suggest that those with symptomatic improvement at 6 months are still improved after 3 years. To further evaluate the safety and the efficacy of endoscopic implantation of Enteryx for the treatment of GORD, multicentre studies were started. These studies included patients from the USA, Canada and Europe, who will be followed for 1 year after treatment. The inclusion and exclusion criteria were similar to those of the pilot study28 with a primary endpoint which was the reduction in use of PPI medication. Secondary endpoints included improvement in patient symptoms, 24-hour pH-metry and LOS pressure recordings. Concerning an international study in which patients were enrolled in the USA, Canada and Belgium, preliminary results are available with 6 months follow-up and indicate that 75% of the 85 treated subjects remain off all PPIs 6 months after the implantation.29 In addition, 9% of the patients reduced their usage of PPIs by more than 50% from baseline, which means that a large majority of the patients have discontinued their use of PPIs and other GORD medications. Enteryx treatment also resulted in a significant improvement in both physical and mental component scores when compared to patients’ scores measured at baseline off PPI therapy. Subject scores following treatment with Enteryx were similar to baseline scores recorded with patients on PPI therapy for GORD management. The GORD symptom scores at 6 months showed an approximate 70% improvement from baseline values off PPIs. Mean heartburn and regurgitation scores measured off PPIs at baseline and at 6 months dropped from 24 to 4 and from 11 to 1, respectively. This favourable outcome was confirmed more recently when analysing results from 170 patients treated in Europe and America.30 Seventy-three percent of the patients were able to stop PPIs or H2 antagonist medications and an additional 10% reduced by more than 50% their medication after 6 months. The X-ray analysis of implant volume remaining in place at 3 months seems to indicate that it is correlated to the success of this procedure, and that superficial
Figure 3. Spiral CT showing persistence of Enteryx implants in oesophageal wall 3 years after implantation on a coronal slice (white arrow) (A), and on an axial slice (B). Tantalum powder, mixed in Enteryx implant, was used as a contrast agent to be detected fluoroscopically as it possesses a high radiodensity.
56 H. Louis, J. Closset and J. Devie`re
submucosal injections slough within 3 months after Enteryx injection. After the material sloughs, the resulting ulceration heals in 7– 10 days. These findings support the conclusion that the main reason for clinical failure after Enteryx injection is an inadequate volume of material injected in the LOS during the original procedure or a loss of the implant due to sloughing after a superficial injection. For this reason, 10% of the patients were re-implanted after 3 months of follow-up when they could not reduce their use of PPIs by more than 50%29; repeated implantation led to improvement in GORD symptoms in 63% of these patients at 6 months. No clinically severe complication has been currently reported following Enteryx injection in the LOS region. The majority of patients (92%) exhibited mild to moderate retrosternal discomfort which generally disappeared within 1 week of the treatment, but occasionally lasted into the second or third week post-implant.29 The patient’s pain was easily managed with oral analgesics. The other adverse events noted were dysphagia (17%), requiring dilation in only one case when lasting more than 1 month, and low-grade fever (12%). Post-operative dysphagia is a common complication of antireflux surgery, but lasts for 3 months in up to 25% of the cases.31 The lack of permanent dysphagia after Enteryx implantation is probably due to both the fast resolution of inflammation after implantation and the spongy nature of the Enteryx polymer once it has precipitated. Low-grade fever resolved in the first few days postimplant. Other side-effects consisted in bloating/flatulence (6%) and the perception of a body odour or a bad taste for several days after the implantation, probably due to the diffusion of the DMSO solvent. Objective improvement of gastro-oesophageal acid reflux was demonstrated by intra-oesophageal pH monitoring, showing that the mean acid exposure time at baseline off PPIs fell from 9.5 to 6.7% 6 months after Enteryx implantation.29 Almost 40% of the patients achieved normal pH scores by 6 months. Statistically significant reductions were also observed for percentage upright and supine times and for total number of reflux episodes. These objective results were confirmed when combining data from America and Europe, showing a significant decrease of mean oesophageal acid exposure time from 15% at baseline off PPIs to 7.5% at 6 months.32 No significant change in LOS resting pressure has been evidenced in the multicentric studies29, although this may be due to variations in manometry technique across centres. In a smaller study performed on 13 patients in Europe, a significant increase in LOS relaxation pressure was found together with a trend to a decrease in the incidence of post-prandial TLOSRs.33 Interestingly, in the international study29, mean LOS length increased slightly at 6 months, compared to baseline (3.1 versus 2.6 cm). In the same line, the importance of a sufficient LOS length to ensure LOS barrier function was recently underlined.34 The shorter the overall length of the LOS, the higher the pressure must be to maintain sufficient resistance to remain competency. This observation of lengthening of the LOS may play an important role in restoration of competency of the LOS function.
Practice points † 6 months follow-up of published uncontrolled trials suggests efficacy of Enteryx implantation in GORD, seeing improvement of GORD symptoms in the majority of the patients and objective improvement of oesophageal acid exposure at pH-metry
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† superficial submucosal implants slough into the oesophagus while deep intramuscular implants persist at the site of injection † relief of GORD symptoms after 3 months seems to be correlated with the persistence of implants † enteryx implantation is safe, no serious complication being currently reported
Research agenda † only results from uncontrolled clinical trials are currently available † randomized sham controlled trials are awaited to establish the real efficacy of Enteryx implantation in GORD patients † longer-term follow-up is needed to assess long-term efficacy and safety before this procedure can be recommended routinely in the management of GORD patients † further studies are awaited to determine the mechanism of action of Enteryx implant (effect on LOS length, LOS pressure and occurrence of TLOSRs) † currently, clinical trials have enrolled patients with typical GORD symptoms responding to PPIs; future trials will assess endoscopic Enteryx implantation in other categories of patients suffering from GORD, i.e. atypical symptoms, incomplete response to PPIs, failure of Nissen fundoplication or bile reflux after gastrectomy † future comparative trials will balance this new technique with medical and surgical treatments of GORD † technical points concern the optimization of implant technique, regarding the location and volume of implants and the number of sessions needed
SUMMARY: IS ENTERYX READY FOR PRIME TIME IN 2003? The implantation of Enteryx polymer in the LOS is a fast and minimally invasive procedure with anticipated low procedure risks and limited costs. Preliminary clinical results after 6 months of follow-up show good results in more than 80% of the patients. The effectiveness of Enteryx in the management of GORD is currently evidenced by the ability of GORD patients with a history of use of PPIs and other GORD medications to eliminate or significantly reduce the use of these medications, and by a significant reduction in oesophageal acid exposure time. A more solid evidence of the efficacy of Enteryx oesophageal implants will be provided by a sham-controlled study. Mechanisms of action of Enteryx implantation suggest a change in the distensibility of the LOS, allowing a greater competency of the cardia. LOS relaxation pressure and LOS length might be increased after polymer implantation, and further studies are needed to study the effect of Enteryx on TLOSRs, which is the prevalent mechanism of reflux in patients with mild GORD. Challenges with this procedure will refine technique in order to deliver adequate volume in each case and determine whether the ring-shaped implant is needed. Beside typical GORD symptoms, other indications for this treatment could be atypical symptoms, failure of Nissen fundoplication or bile reflux after gastrectomy. Finally, as for any other procedure for GORD treatment, further studies and registries are needed to definitively establish the safety of the procedure. This is a major point
58 H. Louis, J. Closset and J. Devie`re
because gastroenterologists are not dealing with ill patients but with individuals having, in the majority, a good quality of life when taking PPIs. Beside a safe profile, the endoscopic technique should also not compromise future anti-reflux surgery in unsatisfied patients.
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Enteryx 59 25. Yu ZW & Quinn PJ. Dimethyl sulphoxide: a review of its applications in cell biology. Bioscience Reports 1994; 14: 259– 281. 26. Devie`re J, Wustenberg W, Mishra N et al. A transgenic mouse model for carcinogenicity testing of Enteryx—an implantable biopolymer for treatment of GERD. Gut 2001; 49: 1587. (abstact). * 27. Mason M, Hughes GA, Lehman GA et al. Endoscopic augmentation of the cardia with a biocompatible injectable polymer (Enteryx) in a porcine model. Surgical Endoscopy 2002; 16: 386–391. * 28. Devie`re J, Pastorelli A, Louis H et al. Endoscopic implantation of a biopolymer in the lower esophageal sphincter for gastroesophageal reflux: a pilot study. Gastrointestinal Endoscopy 2002; 55: 335–341. * 29. Lehman GA, Johnson D, Aisenberg J et al. Endoscopic deep mural implantation of Enteryx for the treatment of GERD: a 6 month follow-up of a multicenter trial. American Journal of Gastroenterology 2003; 98: 250 –258. 30. Johnson D, Aisenberg J, Cohen L et al. Enteryx, an injectable treatment for GERD: multicenter results. American Journal of Gastroenterology 2002; 97(supplement): S12. (abstract). 31. Kamolz T, Bammer T & Pointner R. Predictability of dysphagia after laparoscopic Nissen fundoplication. American Journal of Gastroenterology 2000; 95: 408 –414. 32. Lehman GA, Aisenberg J, Cohen L et al. Improvement in esophageal pH probe studies after Enteryx therapy for GERD. Gastroenterology 2002; 122: S1235. (abstract). 33. Louis H, Voderholzer W, Le Moine O et al. Lower esophageal sphincter function after endoscopic polymere injection for GERD treatment: 1,6 and 12 months results. Gut 2002; 51(supplement III): A25. (abstract). * 34. DeMeester TR, Peters JH, Bremner CG et al. Biology of gastroesophageal reflux disease; pathophysiology relating to medical and surgical treatment. Annual Review of Medicine 1998; 50: 469–506.