BBI Contributing Editor
BBI and Associate

CHICAGO More than 22,000 physicians, researchers and academicians attended the mid-May Digestive Disease Week (DDW) conference here, the largest international gathering in the fields of gastroenterology, hepatology, endoscopy, and gastrointestinal surgery. Four different societies with overlapping interests the American Association for the Study of Liver Diseases (AASLD; Alexandria, Virginia), the American Gastroenterological Association (AGA; Bethesda, Maryland), the American Society of Gastrointestinal Endoscopy (ASGE; Oak Brook, Illinois) and the Society for the Surgery of the Alimentary Tract (SSAT; Beverly, Massachusetts) all come together in a collaborative effort to further propel the understanding and treatment for digestive diseases. The meeting showcased about 5,000 abstracts and hundreds of presentations on advances in GI research and technology.

In a symposium titled "Advancing Endoluminal Therapies," new techniques were discussed for the treatment of gastroesophageal reflux disease (GERD). Some 15 million to 20 million Americans have daily episodes of GERD. Left unchecked, GERD may allow the development of Barrett's esophagus with its associated dysplasia, a major risk factor for esophageal cancer; in fact, 25% to 50% of patients with Barrett's disease will develop esophageal cancer over the next five years. Bergein Overholt, MD, of Thompson Cancer Survival Center of Knoxville (Knoxville, Tennessee), presented current and developing technologies for the ablation of Barrett's lesions. He said he believes that the current, FDA approved, standard of care for ablation of Barrett's lesions is porfimer photodynamic therapy, using Photofrin, manufactured by Axcan Pharma (Birmingham, Alabama).

Other therapies currently in FDA trials include ablation by KTP laser, YAg laser and thermal ablation; but Overholt's pick for displacing photodynamic therapy is BARRX Medical's (Sunnyvale, California) Halo360 system. An energy controller and BARRX Medical dilation and ablation catheter work together to ablate a large epithelial surface area, automatically delivering circumferential RF energy to 3 cm of esophageal tissue that is completed in less than one second and is performed on an outpatient basis, under conscious sedation. The Halo360 system for the treatment of Barrett's esophagus is in multi-center trials.

Virender Sharma, MD, director of the esophageal clinic and associate professor of medicine at the Mayo Clinic (Scottsdale, Arizona), also spoke highly of the potential of the Halo360 system. Thus far, "there is no effective treatment for Barrett's esophagus," he told The BBI Newsletter, but added that the studies presented indicate early stage hope for use of the Halo360 as a cure. Sharma termed the data from all three studies "encouraging" and that they lay key groundwork supporting the device's early term efficacy.

The Halo360 provides ablation of abnormal cell development in the lining of the esophagus termed dysplasia and characterized by Sharma as "chaotic" which is primarily the result of acid reflux. The device delivers rapid bursts of radio frequency (RF) energy that kill the abnormal cells.

Sharma terms the device's method of action as "a flash burn [that] doesn't translate to heat but serves to destroy the cells." Then, he says, "If you kill these cells and let them heal back, with strong acid control, the lining comes back as normal." And thus far, he and his research team have not seen the return of pre-cancerous cells indicating Barrett's or problems with underlying cell tissues.

The three trials presented are all different in procedure and endpoint:

The Ablation of Intestinal Metaplasia (AIM-I) trial, with treatment of 31 patients, focused on the safety and tolerability of the Halo360, delivered 10 joules of energy, its goal being to explore appropriate dosing for ablating short segments of Barrett's.

It found that at six months 75% of patients from the treatment group had no Barrett's tissue cells. Additionally, there were no complications or findings of abnormal "buried" glands that may produce disease recurrence.

Sharma noted that the other 25% of the group had "90%-plus of Barrett's esophagus removed."

Results of the AIM-II multi-center trial, evaluating treatment of 70 patients, was presented by David Fleischer, MD, also of the Scottsdale Mayo Clinic. This trial employed 12 joules of RF energy, with the majority of patients having no evidence of Barrett's tissue on follow-up. And those patients with persistent disease experienced significant reduction in their Barrett's and remained eligible for retreatment. Follow-up tests revealed no strictures or buried glands, Fleischer reported. The researchers concluded "that the safe removal of Barrett's esophagus in a single treatment is achievable" with the Haolo360.

The third study presented the evaluation of patients with low-grade dysplasia, a more advanced stage of Barrett's esophagus. Sharma reported an 80% patient response rate after just one treatment "at a slightly higher energy dose than that applied in the AIM trials." He reported that with a second treatment, the cure rate at six months increased to 100%. The data suggest that the Halo360 system can safely and effectively eliminate low-grade dysplasia in patients with Barrett's esophagus, he said.

C. Daniel Smith, MD, of Emory University School of Medicine (Atlanta), presented still another study evaluating the optimal parameters for the ablation of Barrett's esophagus with high-grade dysplasia. This study found that the complete ablation of esophageal high-grade dysplasia is possible without causing injury to the healthy underlying tissue.

"This is not a treatment for GERD," Sharma emphasized, but rather for the more serious consequences of GERD. Other systems for treating the precancerous condition of Barrett's have been "point-and-shoot devices," he said, and he described them as inadequate and "cumbersome" and having a variety of complications. By contrast, he pointed to the safety and efficacy of the Halo360, while underlining its procedural benefits.

The system's generator, he said, is "a neat thing that controls the whole treatment [and] takes the human factor out of [the procedure]. You step on a button [to treat] three centimeters length of Barrett's in less than a second." The procedure, which in clinical studies had an average procedure time of 26 minutes, is performed without incisions, using conscious sedation in an outpatient setting.

The next step in the research, Sharma said, will be to collect longer-term data concerning use of the Halo360, including a pilot multi-center trial evaluating the treatment of low-grade dysplasia with the device as compared to the standard therapy using acid-suppressing medications. He expects this trial will include 70 to 100 patients, with evaluation over a two-year period.

BARRX, founded to develop solutions for Barrett's esophagus, estimates 1 million to 2 million adults in the U.S. under surveillance of their acid reflux essentially a strategy of watching and waiting.

Glen Lehman, MD, of the Indiana University School of Medicine (Indianapolis), spoke during the same symposium on endoluminal remodeling and anti-reflux therapies, which hopefully are performed before the patient develops Barrett's esophagus. He considers GERD to be a failure of the lower esophageal sphincter (LES) and its supporting structures, a mechanical problem mostly being treated with gastric acid reducing medicines today such as proton pump inhibitors (PPI). Anti-reflux surgery (Nissan's procedure) works well but has a 9% complication rate, a 5% re-operation rate, and most of the patients end up on a PPI anyway, albeit often in a lower dose. He said he feels that the answer to this condition is an improved mechanical barrier, which can be achieved by a large suturing bite (Plicator) or small suturing bite (Endocinch) of esophageal mucosa to endoscopically plicate LES tissue, a polymer injection (Enteryx), or radiofrequency (RF) stimulation to the surrounding tissue (Stretta). To this end, he compared these four FDA approved devices, noting that they all have a good safety profile, leaving his comparison to efficacy, symptom improvement, and technical difficulty (see Table 5). Although the newest product on the market the Plicator by NDO Surgical (Mansfield, Massachusetts) did not have 24-month data to fit his charts, good data on the Plicator was presented by Greg Haber, MD, of Lenox Hill Hospital (New York). The Plicator procedure is a non-surgical, endoscopic procedure that allows the physician to create a full-thickness plication at the gastroesophageal junction under direct endoscopic visualization, enhancing the competency of the gastric cardia and restoring the normal anti-reflux barrier. Patients are treated on an outpatient basis and usually are able to return to normal activities the following day.

Curon Medical (Fremont, California) offers both the Stretta procedure for the treatment of GERD and the Secca procedure for the treatment of bowel incontinence, both using RF energy delivered to the surrounding sphincteric tissue that remodels collagen, bulks and strengthens the sphincter. Stretta's durability was reported in a poster, "Sustained Improvement of Anti-secretory Drug Use and GERD Symptom at 4 Years Follow-up," by Mark Noar, MD, of Heartburn and Reflux Center/Endoscopic Microsurgery Associates (Towson, Maryland), who has performed more than 350 Stretta treatments to date and found that improvement of GERD symptoms in Stretta treated patients lasted over 48 months.

Curon's other product, the Secca device, addresses the 16 million to 20 million American adults who suffer from fecal or bowel incontinence. Until Secca, their choices have been palliative such as diapers, biofeedback training or dietary management or surgery, which carries a $20,000 price tag and a 30% infection and rejection rate. Secca bridges this gap by offering a 20-minute outpatient treatment with conscious sedation while RF energy is delivered to the anal sphincter. Studies have shown 60% to 80% response rates with durable results out to two years. This procedure is ideal for those patients who have failed conservative or surgical therapies and/or desire a less-invasive treatment than surgery.

Lehman said that the future holds more new technologies including another injectable product similar to Enteryx and a "sewing machine" that are in clinical trials. Of the FDA-approved products he presented, none have long term (five-to 10-year) data yet. He also noted that once physicians are fully comfortable with these newer modalities, he envisioned combination therapies (using more than one of these procedures on the same patient) becoming attractive since each address different areas.

Extraluminal approaches lauded

In a very futuristic approach, Tony Kalloo, MD, of Johns Hopkins University Medical Center (Baltimore), presented extraluminal therapies endoluminal approaches to organs outside of the GI tract. He described this new technique as a "philosophical change in thinking," asking laparoscopic surgeons to abandon their familiar triangulation methods for a working flexible scope. Using prototypes and techniques that he and the Apollo Group have developed, they inserted a flexible, per-oral transgastric endoscope through the oral cavity into the stomach, made a small incision through the stomach wall, and performed intra-abdominal procedures. They have successfully performed liver biopsies, gastrojejunostomies, fallopian tubal ligations, herniorrhaphies, cholecystectomies and splenectomies on animals. He claimed that the view was better than that of a laparoscope, the ability to maneuver was easier, and since there is no abdominal incision, the recovery time was quicker and with less pain (see Table 6).

Since trans-gastric surgery's main criticism is the potential for contamination of the peritoneal cavity by introduction of contaminants from the stomach and esophagus, they have developed a method that eliminates the potential for internal infection by operating in a sterile environment much like that of an OR, administering IV antibiotics, and irrigating the stomach with antibodies so far, they have seen no infections, which was one of their major concerns when they started this research.

Kalloo said the market demand is there for these less-invasive surgical procedures; now all that is required are "smart" endoscopic instruments.

Speaking to that very cause were three new companies, all addressing the flexible scope market, starting with the colonoscope, the largest market segment. Of the approximated 11 million potential colonoscopy patients in the U.S. each year, it is estimated that only about two-thirds of them actually have the procedure done. New technologies have been developed that not only address "looping" the biggest problem for colonoscopies but will, in the future, enable physicians to open the entire GI tract for both diagnostic as well as therapeutic procedures using a transluminal delivery system.

Venture-backed USGI Medical (San Clemente, California) exhibited its ShapeLock endoscopic guide that enters the GI tract in a flexible state and then is simply locked in the appropriate shape when required. They are pioneering endoluminal therapy to enable current laparoscopic and open surgical treatments for morbid obesity, GERD and GI cancers to be performed endoluminally. The company's ShapeLock endoscopic guide can be used as an adjunct for any type of scope to provide stabilization and eliminate looping. USGI has received a 510(k) clearance on its ShapeLock product and will be in test markets this fall, with their therapeutic devices still in development.

Invendo Medical (Kissing, Germany) also exhibited a new flexible, self-directing system that is in clinical studies, accentuating the demand for new technologies that can negotiate their way through the intestinal labyrinth.

Computer-assisted colonoscopy

An evaluation of a potentially significant new colonoscopy system that has the potential to all but eliminate a very common problem associated with the procedure was presented during the meeting. Developed by NeoGuide Systems (Los Gatos, California), the Navigator endoscopy system is designed to enhance physician control of colonoscopes and to eliminate looping, considered one of the primary limitations of colonoscopy. Colorectal cancer (CRC) is the second-leading cause of cancer deaths in the U.S. and colonoscopy is the "gold standard" for CRC screening, allowing early detection and prevention of the disease.

When performing a conventional colonoscopy, the endoscopist advances the scope and controls a bendable tip. The remainder of the scope's insertion tube is not controlled. The colon has multiple curves and floats within the abdomen; therefore, as the endoscopist advances the tip through the colon, the scope pushes against the colon wall and stretches the colon and its surrounding tissue.

Looping occurs when the endoscopist attempts to insert the scope further past the obstruction and the tip does not advance. Instead, the scope pushes the colon, forming a large loop. This phenomenon is responsible for the majority of patient pain in colonoscopy. Pain from looping leads to the need for sedation, with its associated expense and risks.

"Looping is the principle reason that many colonoscopy procedures are painful, time consuming, and difficult," said Amir Belson, MD, president and co-founder of NeoGuide Systems. "We believe that by addressing looping, the Navigator Endoscopy System has the potential to significantly increase the number of colonoscopies that endoscopists are able to perform, which will be particularly important as the demand for the procedure continues to grow."

Belson told BBI that the idea for the company could be traced back to his residency at the Tel Aviv Medical Center (Tel Aviv, Israel). As part of a gastroenterology elective, Belson performed his first colonoscopy. Using a traditional colonoscope, an optical device mounted on the end of a plastic tube, Belson experienced obstruction within the first 20 centimeters of the patient's five-foot-long colon.

"I tried twice, and I failed twice," said Belson. While he noted that this was very frustrating, he discovered that he was not alone. "Most of the attending GIs had the same issue," he said. Indeed, Belson noted that looping occurs in more than 90% of all colonoscopy procedures. He added that this pain from looping leads to the need for sedation, with its associated expense and risks. He also pointed out that in many cases, looping leads to incomplete procedures and missed polyps.

NeoGuide was formed in late 2000 when Belson joined forces with two lecturers from Stanford University's (Palo Alto, California) mechanical engineering school, Matt Ohline, the current chief technology officer and electrical engineer group manager, and Craig Milroy.

Belson likened the traditional colonoscope to a semi-pressurized garden hose in which the only thing that can be controlled is the pitch. "You can control it up, down, right and left," but the colon is very flexible so the colonoscope follows the curve of the colon and causes the painful loops.

The Navigator is designed to traverse the natural shape of the colon, based on a computerized map, generated with the aid of the company's Foresight computer-assisted technology, so less force is applied to the colon wall, which could potentially eliminate or significantly reduce the incidence of looping.

In addition, the system offers advanced capabilities and procedural features unavailable with conventional colonoscopes, including the ability to display a real-time 3-D map of the colon and the ability for physicians to mark the location of polyps on this map, as a sort of GPS system.

Additionally, the company redesigned the colonoscope so that it is segmented, as opposed to the traditional flexible tube. "Those segments are controlled by computer. [The scope] just follows the direction that the physician decided that the device should take" based on what the mapping software revealed.

Jacques Van Dam, MD, professor of medicine at Stanford University School of Medicine, presented the results of simulated-use bench testing and in vivo animal studies at the DDW meeting. Compared to a conventional colonoscope in the bench studies, he said the Navigator applied significantly less force to the colon wall at the sigmoid flexure, which is the primary location of looping in colonoscopy. The in vivo animal studies demonstrated the safety of the Navigator, with no tissue damage or perforations associated with the device.

"Colonoscopy is one of the most frequently performed outpatient examinations," said Van Dam, lead investigator for the studies. "However, it is still technically challenging, largely due to unpredictable looping, which has been demonstrated to occur in the majority of cases. We believe this device has the potential to have profound implications for colorectal cancer screening, and may thereby represent an important advance for public health."

While the company believes that the colonoscopy market is a great opportunity all by itself, with about 14 million colonoscopies performed in the U.S. annually and a potential worldwide market for colonoscopy equipment running up to several hundred million dollars, it also believes that its Foresight computer-assisted technology has the potential to address several other large market opportunities in various clinical areas. "It is clear that this is a real platform technology that you can take to any part of the body where we actually need to control scopes," Belson said.

The system is still subject to FDA 510(k) review and the company is in the process of putting together clinical trial protocols. NeoGuide said it expects commercial availability of the product in 2006.

The company said it has established a world-class scientific advisory board and has made significant investment in research and development. To date, NeoGuide has raised a total of $17.5 million dollars from venture investors, including Utah Ventures, Versant Ventures, 3i, Kaiser Permanente Ventures, DC Capital, The Angels Forum, Tenex and Arboretum Ventures, with the most recent $14 million round coming in December 2003. Belson said he thinks the company may need to raise another round sometime before the end of the year to get through clinical trials.

Other reports at DDW

E-Z-EM (Lake Success, New York) reported the results of a study indicating that computed tomography enterography (CTE) is superior to capsule endoscopy in detecting Crohn's disease (CD) in the small bowel (SB) as measured by specificity and overall accuracy, and provided comparable sensitivity. CTE is a study that uses an oral contrast, like VoLumen low Hounsfield value oral contrast, to distend the bowel and improve bowel wall visualization.

The 42-patient study "Small Bowel Imaging in Crohn's Disease: A Prospective, Blinded, 4-Way Comparison Trial" by researchers at the Mayo Clinic (Rochester, Minnesota) evaluated the sensitivity, specificity and accuracy of CT Enterography (CTE), ileocolonoscopy (IC), capsule endoscopy (CE) and small bowel follow-through (SBFT) in the diagnosis of Crohn's disease in the small bowel.

The study showed that CTE with VoLumen and CE "have similarly high sensitivity 82% and 83% respectively for detecting active Crohn's disease, and appear to be superior to IC and SBFT 74% and 65% respectively," according to a statement from E-Z-EM. "The specificity for CTE with VoLumen was 89%, as compared to 100% for IC, 94% for SBFT, and only 53% for CE. As measured by general accuracy, CTE with VoLumen was comparable to IC 85% and 86% respectively and superior to both CE (67%) and SBFT (79%)."

Anthony Lombardo, president and CEO of E-Z-EM, said, "Small bowel imaging is often done prior to capsule endoscopy due to the risk of capsule retention in an undetected blockage. These results strongly suggest that for suspected Crohn's disease, small bowel imaging with CTE can obviate the need for follow-up study with capsule endoscopy."

He said that, together with previous research, the study supports the "expanding role for CTE and VoLumen in the diagnosis of Crohn's disease. In fact, researchers involved in this study have since standardized the use of VoLumen in their CTE procedures."

E-Z-EM makes contrast agents for gastrointestinal radiology. It recently introduced VoLumen, calling it "the next-generation, low-density barium sulfate suspension for use as an oral contrast in multidetector CT (MDCT) and PET/CT studies." The company also offers Empower a family of CT injectors on the market with patented EDA and offering a complete product set for virtual colonoscopy.

Boston Scientific (Natick, Massachusetts) reported results from two canine studies assessing effectiveness, safety and ulcer healing rates of the company's Resolution Clip Device in controlling gastrointestinal bleeding as compared with other endoscopic hemoclips, thermal coagulation and epinephrine injection treatments.

The Resolution Clip a pre-loaded, ready-to-use clip device, intended for hemostasis of bleeding gastric ulcers, among other indications features an 11 mm-wide jaw span, designed to grasp enough tissue to improve wound closure.

Data presented showed that clip retention rates (percent of ulcers with less than 1 CLIP) at one and two weeks post-procedure were higher for the Resolution Clip compared with the Olympus and Wilson-Cook brand clips.

Dennis Jensen, MD, professor of medicine in the Gastrointestinal Division at the University of California-Los Angeles (UCLA) School of Medicine, a principal study investigator, said that the studies "provide physicians with new endoscopic comparative laboratory data concerning the strengths and weaknesses of various techniques for hemostasis of bleeding acute gastric ulcers." He added that the data "suggest that the use and retention of hemostatic clips may accelerate the healing of gastric ulcers in comparison to thermal coagulation. Boston Scientific's Resolution Clip had significantly higher retention rates compared to the other approved hemostatic clips that were studied."

He said further comparative human trial will help to define the best clinical applications and indications of the hemoclips as compared to "older hemostasis methods such as thermocoagulation."

In addition, canine gastric ulcer healing rates were compared for hemoclips versus multipolar electrocoagulation (MPEC). The study yielded similar results, indicating significantly higher retention rates for the Resolution Clip at one and two weeks post-procedure. Retained clips appeared to accelerate rather than delay gastric ulcer healing relative to control or MPEC. The Resolution Clip is FDA-cleared and available for distribution worldwide, Boston Sci said.

Ralf Kiesslich, MD, of Mainz University Hospital (Mainz, Germany), reported 99.2% accuracy in diagnosing colon cancer amongst ulcerative colitis sufferers in a clinical trial using the Optiscan-Pentax endo-microscope.

The trial at Mainz University Hospital assessed 153 patients with an elevated cancer risk due to ulcerative colitis in a randomized prospective blinded protocol. This is the largest clinical study reported so far using Optiscan Imaging's (Melbourne, Australia) flexible endo-microscope technology.

The protocol had three formal objectives: to evaluate the use of the endo-microscope to predict the outcome of pathology after biopsy; to compare the diagnostic yield of the current "standard of care" procedure (which relies on larger numbers of random biopsies) to the new procedure (use of the endo-microscope to target fewer biopsies); and to measure the ability to detect early cancer with fewer biopsies, using the endo-microscope.

It also was observed in the study that four early cancers were detected in 73 patients by the standard procedure compared to detection of 19 early cancers in 80 patients using the endo-microscope procedure (greater than four-fold increase in yield);

"This technology allows prediction of the outcome of biopsies with a high specificity, sensitivity and overall accuracy," said Kiesslich. "We therefore believe that a smaller number of smart biopsies, targeted biopsies' could be taken with a significantly improved diagnostic yield in managing ulcerative colitis."

Optiscan, a developer of microscopic imaging technologies for medical markets, and Japanese imaging giant Pentax have collaborated over the past three years on the development of the new device, which combines Pentax's miniaturized camera endoscope technology and Optiscan's miniaturized microscope technology.

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