May 2014

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The Independent Monthly Newspaper for Gastroenterologists

Volume 65, Number 5 • May 2014

Physicians Grapple With EHRs

BY BEN GUARINO With increasing frequency, doctors and patients are finding a third party crowding the examination room: the electronic health record (EHR). To some practitioners, EHRs are a boon, offering electronic prescribing, notes that are more legible and remote access to patient files. But to others, the systems are barriers to effective communication, demanding that attention be split between patients and computers. see EHRs, page 24

Telemedicine Altering Medical Care Delivery

BY BEN GUARINO It was nighttime in Berlin, Md., when a patient was admitted to Atlantic General Hospital in early February, with a suspected diagnosis of necrotizing fasciitis.

Given the rarity of the flesh-eating bacterial infection, the ICU nurse sought the opinion of a critical care physician to corroborate the diagnosis. One obstacle: No specialist was at hand.

H E PAT O L O G Y

IN

FOCUS

What’s Behind the Rise in Rates Of Hepatocellular Carcinoma?

BY CAROLINE HELWICK E SAN FRANCISCO—Although — rates of hepatoccellular carcinoma (HCC C) and HCC-related d mortality have been n declining in areas of high incidence, including China and Japan, the rates aree increasing in traditionally low w-incidence areas, including th he United States, Canada and d parts of Europe.

In the United Staates, for example, the incideence of HCC has nearly trripled over the past 30 yyears, with the most raapid increase observved since the 1990s an nd

the highest rates seen in Texas, Mississippi and Alabama (El-Seerag HB. N Engl J Med 2011;365:1 1118-1127).

“The sou uthern part of Texas has a [[liver-related mortallity] rate that is close to some parts of China,” noted Hashem El-S Serag, MD, MPH, the Dan L.. Duncan Professor of Med dicine and chief of gastroenterrology and hepatology, B Baylor College of Medicinee, Houston. Dr. El-Seragg discussed possible causses of the increased inciden nce of HCC at the 2014 American Society of C Clinical Oncology Gastrointestinal Cancerss Symposium. see HCC, page 20

see Telemedicine, page 23

I N S I D E

Experts Call for H. Pylori Eradication Program To Prevent Gastric Cancer

HEPATOLOGY

I N

FOCUS

Noninvasive Liver Fibrosis Scores Fall Short In Children With NAFLD .......................................page 14 Emergency Room Testing Chips Away at Hidden HCV Epidemic ......................................................page 15

BY CAROLINE HELWICK SAN FRANCISCO—Gastric cancer could be—and should be—essentially eliminated through a program aimed at eradicating Helicobacter pylori, according to one of the foremost

Liver Transplantation Leads to Surprising Improvements In Young Patient With Lathosterolosis ..................page 18 Trial of Sunitinib in Patients With HCC Halted For Futility .............................................................page 21

see Eradication, page 9

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

From the Literature

The Case of the Drunken Teetotaler

BY CHRISTINA FRANGOU Did you hear the one about the Texas man who became drunk without touching a drop of alcohol?

That’s no joke. It’s a case study published last year that should be required reading for every gastroenterologist, say authors and experts in gastroenterology.

In a paper published in the International

Journal of Clinical Medicine (2013;4:309312), authors Barbara Cordell, RN, PhD, dean of nursing at Panola College in Carthage, Texas, and Justin McCarthy, MD, a gastroenterologist in Lubbock, Texas, detail how a man spent five years becoming inexplicably drunk before doctors realized the cause was an overgrowth of Saccharomyces cerevisiae, also known as brewer’s yeast.

The 61-year-old man was treated with

‘In this case, alcohol is the byproduct of that interaction between carbohydrates and certain types of organisms in the GI tract.’

—William D. Chey, MD antifungals and a strict low-carbohydrate diet. Ten weeks after treatment started, the man’s stool cultures were negative for the yeast and his episodes of drunkenness ceased.

This relatively unknown phenomenon is called “gut fermentation syndrome” or “auto-brewery syndrome.” The underlying mechanism is thought to be an overgrowth of yeast in the gut: The yeast ferments sugars in the diet from carbohydrates into ethanol, resulting in high blood alcohol levels (BALs). Only a handful of cases has ever been reported.

“This is a rare syndrome but should be recognized because of the social implications such as loss of job, relationship difficulties, stigma and even possible arrest and incarceration,” the authors wrote.

“It would behoove health care providers to listen more carefully to the intoxicated patient.”

This latest case study adds to a growing body of evidence demonstrating the broad health effects of dysbiosis, which occurs when an imbalance in the bacteria and fungi that live within the gastrointestinal (GI) tract exists, said William D. Chey, MD, professor of internal medicine at the University of Michigan, Ann Arbor.

“In this case, alcohol is the byproduct of that interaction between carbohydrates and certain types of organisms in the GI [gastrointestinal] tract,” Dr. Chey explained.

Gastroenterologists should be aware of the syndrome, although it is very rare, he said.

“Certainly, it’s biologically possible.

Gastroenterologists and physicians in general need to be open-minded to the possibility that patients who present with symptoms of intoxication without history of ethanol ingestion might indeed see Gut Fermentation, page 4

4

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

From the Literature

Gut Fermentation continued from page 3

have a physiologically plausible explanation,” said Dr. Chey.

Symptoms and Treatment In this case, the man’s bouts of baffling intoxication began in 2004, not long after he underwent surgery for a broken foot and treatment with antibiotics. He began to seem excessively intoxicated after two drinks and on occasion appeared drunk despite not drinking. His wife, a nurse, began to document the phenomenon with a Department of Transportation– approved alcohol breathalyzer. The man’s BALs frequently reached 0.40%. The alcohol level at which an individual is considered legally impaired in the United States is 0.08%.

In the following years, the man’s episodes of intoxication began to increase in severity and frequency. In November 2009, he arrived at the emergency department with a blood alcohol concentration of 371, or 0.37%. The physicians believed him to be a “closet drinker.”

Several months later, the patient presented to Dr. McCarthy’s gastroenterology practice where he underwent a

complete GI workup. He denied taking any type of yeast as nutritional supplementation and reported no history of GI disorders or treatments.

The patient’s stool cultures were positive for rare budding yeast and S. cerevisiae. The man was admitted to the hospital for a 24-hour observation period during which no visitors were permitted.

He underwent a glucose challenge with a high-carbohydrate diet and snacks throughout the day. BALs were measured at regular intervals. At one point during the afternoon, the man’s BAL rose to 0.12%.

For treatment, the patient was given an oral course of fluconazole 100 mg daily for three weeks, followed by a three-week course of Nystatin 500,000 IU, four times daily. He also took daily acidophilus tablets and followed a strict no-sugar, no-carbohydrate diet.

The patient also received a course of tetracycline for the treatment of Helicobacter pylori, which had been isolated from his stomach during initial testing. The authors believe that H. pylori may have been a confounding variable, although the man’s symptoms resolved with treatment for S. cerevisiae.

Dr. Cordell said that eight other

patients with possible gut fermentation syndrome have contacted her since the article was published. In each case, the individuals have complained of autointoxication but have been sent home by hospitals or physicians.

She called on gastroenterologists and physicians to be open-minded and listen carefully to patients who deny drinking.

“Be an investigator who digs to try to find answers for patients,” she said. “The people I am talking to are desperate and frightened to death because they don’t know what’s going on with their bodies.”

Dr. Chey said that the increased attention given to gut fermentation syndrome could lead to a better understanding of many postprandial effects. Autointoxication may represent an extreme form of the subtle postprandial syndromes that patients often talk about—things like headaches and sleepiness, which have long been thought to result from blood diversion to the stomach after digestion, may be related to products of fermentation, he said.

“It’s a previously unrecognized possibility that holds all sorts of interesting and potentially important implications in regards to diet and manipulations of the microbiome,” Dr. Chey said.

■

Vol. 65, No. 5 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

5

ACOs, Thumb Wrestling and ‘Oklahoma!’

Jon C. White, MD Professor of Surgery George Washington University Chief of Surgical Services VAMC Washington, DC This article comes with a disclaimer. You must read to the end to discover how I am going to connect a child’s game and a Broadway musical to accountable health care.

Accountable Care Organizations Let me start with the accountable care organization (ACO), which is the brainchild of Elliot Fisher, MD, MPH, of Dartmouth Institute for Health Care Policy. Dr. Fisher’s group at Dartmouth made the initial observation that we have a poor distribution of physicians

The second important observation by the Dartmouth group and others is that 80% of all health care spending in this country is for chronic illnesses such as diabetes, cardiovascular disease, chronic obstructive pulmonary disease (COPD) and osteoarthritis. These diseases are on the upswing in our aging and increasingly obese population, and are better managed by primary care physicians. Dr. Fisher’s idea was that most health care should be based on primary care, and providers should have accountability for maintaining the health of patients rather than treating episodes of acute illness. This idea was recognized by Mark McClellan, MD, head of the Centers for Medicare & Medicaid Services (CMS) under former president George W. Bush, as the best way to meet the health care needs of Medicare patients while saving some money for that agency.

Although I have spent my entire

and keep them separated but seamlessly integrated. Does this sound like bureaucratic-speak? What I am getting at is that primary care is something that is better done in the community, and even in the home, whereas secondary and tertiary care are better done in a hospital.

Acute care and primary care providers offer different services that require different environments. Acute care tends to focus on individual problems, whereas primary care deals more with populations. Surgeons operate on and take care of their patients one at a time, whereas primary care physicians manage panels of patients. Both of these groups have a role in the health care system but when you combine the two, the result is inefficiency. Surgeons require well-equipped hospitals and trained support staff to be successful. As their care becomes more specialized, it should be centralized into centers of excellence.

When you move primary care out of the hospital and into the community, health maintenance … is more successful. At the same time, when primary care is taken out of the hospital, acute care thrives.

and health care resources in the United States, which has led to more expensive care in some regions. It was not particularly surprising that health care spending varied in different regions of the country, but the shocking revelation was that those parts of the country that spent the most did not get the best results. In fact, excessive spending in many situations correlated with, or led to, worse results. Furthermore, the regions that had invested heavily in primary care and that provided the least expensive care had the best overall health care results. In economic science parlance, they were “getting the most bang for the buck.”

professional life as a tertiary care, hospital-based surgeon, I have become a convert to this way of thinking. I now speak about it to groups of surgeons and, although in an auditorium I can’t see their eyes rolling up in their heads, the silence in the room gives the same message. But I think they are not hearing my complete message. Although health care should be primary care–centric and primary care–driven, there is still a very distinct and important role for secondary and tertiary care physicians, most notably the surgeons. The best way to practice acute care is to distinguish between acute and chronic care

Primary care physicians, on the other hand, should try to decentralize their efforts and keep their patients closest to home and out of the hospital. The concept of a general hospital that is “one-stop shopping,” where you can get all of your health care needs serviced, is outdated.

Chronic care is most effectively done in clinics, or even better, in the home, and the lesson for the acute care physician is this: When chronic care is not managed appropriately, chronically ill patients end up in the emergency rooms and ultimately in the hospitals, occupying beds that are intended for acute care needs. For example, a diabetic patient must have his

hemoglobin A1c followed and get proper counseling about diet and exercise. If that does not happen, his diabetic vasculopathy progresses and leads to ulcers, gangrene and ultimately amputation. We see the same scenario play out for coronary artery disease, COPD and other chronic illnesses. Poor primary care leads to overburdened secondary and tertiary care facilities that don’t have the manpower or resources to accomplish what they are best at, which is acute care.

The most effective way to treat any chronically ill patient is at the primary care stage, and this is why we should spend time and resources promoting care at that point. Furthermore, when you move primary care out of the hospital and into the community, health maintenance such as blood pressure and glucose control is more successful. At the same time, when primary care is taken out of the hospital, acute care thrives. The Veterans Affairs medical system provides a useful example.

In 1995, the VA recognized that care for chronic illnesses was its main problem and was not something to be managed in a hospital. The VA closed 29,000 beds from its 170-hospital network, and increased the number of outpatient facilities to 1,700. Although the VA had intentionally become one of the primary care leaders in the country, it had not foreseen the effect on acute care: Acute care thrived. Operative volumes increased by 10% immediately and have continued to increase every year since. The acuity of the inpatient population increased as ward beds were replaced by critical care beds. The lesson learned was that taking primary care out of the hospitals was good for primary care, but even better for secondary and tertiary care.

Another point I make to doubters comes from the surgical literature. It is well known that we have a workforce problem. The American College of Surgeons has devoted a lot of time to studying the present as well as projecting the future for our profession, and their reliable predictions are for extreme surgical workforce shortages in the near future.

There will be no lack of work for the inadequate numbers of general surgeons and surgical subspecialists we are currently training. We have regional shortages of surgeons now, but in the next decade, there will be global shortages. If primary care physicians can keep more people away from the hospitals and out of the operating rooms, this will be helpful for our depleted ranks. It is one of the few win–win situations in a zero-sum game.

So, how do ACOs fit in? Anyone who see ACOs, page 6

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

ACOs continued from page 5

has read the description of a Medicare ACO knows the rules are complicated.

There are contracts between multiple providers, and both savings and losses are distributed between CMS and the providers with complex formulas.

Although the details are complicated, the concept of an ACO is simple: It is just primary care and acute care providers working together to care for patients efficiently and effectively. If they save money doing it, they share in the profits. ACOs just realign incentives so that providers are rewarded less for treating illness and more for promoting health.

Primary, secondary and tertiary care physicians all have roles, and when they are all working toward a common goal, their efforts are more likely to be profitable for themselves as well as less expensive for the industry.

That last sentence seems to be a little accounting sophistry. How can something cost less, yet bring greater profits for the provider? The reason is buried in the reality that we have a redundant and inefficient system that has embarrassing excesses at the same time that it has glaring gaps in coverage. Resources are squandered on care that is often not indicated or even harmful. Nonintegrated care spends more money on unneeded care, unnecessary accounting, reduced efficiency, voluminous paperwork, and occasionally fraud. There is also a financial reality to pursuing the more expensive alternatives of secondary and tertiary

care instead of promoting primary care.

When we start to run out of resources, the primary care side of the equation loses out. For example, if our resources run low, our diabetic patients may not get proper counseling on management of their diets and blood sugars, but compassion dictates they will always get their gangrenous extremities amputated or revascularized. This kind of care is certainly not in the patient’s best interest.

need episodically. We should appreciate the role that we each play, integrate our efforts and learn to work together.

Thumb Wrestling Now, what’s the connection to thumb wrestling? Some years ago, I participated in a program about team building.

At the end of a day-long session with multiple lectures, the organizers had the participants pair up to play a game.

to pin them down, and then they pinned down their opponent. They did it as quickly as their thumbs could move and pinned each other more than 100 times during the minute, and both walked away with $50,000. Although the prize money was only virtual, the lesson was real: If you struggle against each other, you will have limited success; but when you work together toward a common goal, your results can be extraordinary.

‘Oklahoma!’

Although the details are complicated, the concept of an ACO is simple: It is just primary care and acute care providers working together to care for patients efficiently and effectively. If they save money doing it, they share in the profits.

So, although the incentive for an ACO for a primary care physician is obvious, there is an equally strong argument to be made for secondary and tertiary care physicians. When we don’t invest in primary care, we will be forced to manage more advanced acute care, which is the most expensive (and least effective) way to care for patients. Surgeons and primary care physicians should share a common goal to manage patients jointly, keep them out of the hospital, and have lean and efficient hospitals that are equipped for the complicated secondary and tertiary care that patients will

Each group was asked to thumb wrestle and the rules were simple. Everyone would thumb wrestle for one minute, and each time a wrestler pinned down his or her opponent, he or she would win $1,000. As soon as the game clock started, people began thumb wrestling and attempted to pin each other down.

About half of the groups had one winner earning $1,000, and the other groups earned $2,000 or had no winner at all.

One particular pair, who had obviously been paying attention to the teambuilding lectures, planned their strategy.

They took turns allowing their opponent

And what would Richard Rodgers and Oscar Hammerstein II have to say about ACOs? Part of their musical “Oklahoma!” dealt with the struggle between cowmen and farmers. In the early days of Oklahoma, the cowmen and the farmers were competitors for the same land. The farmers had their land fenced off to keep animals out of their crops, and the cowmen liked the open spaces to graze their herds.

One of the key scenes is a dance number, during which the point is made that there is enough land for everyone and that they were all Oklahomans and would do better if they would only help each other out.

The finale to the scene is this appeal: Territory folk should stick together, territory folk should all be pals; Cowmen dance with farmers’ daughters, farmers dance with the cowmen’s gals.

At our hospital, we have a very talented and competent chief of primary care. At this year’s Christmas party, I think I’ll ask her to dance.

■

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

From Private Practice to Hospital Employee Physicians Describe Loss of Autonomy, Among Other Problems

BY KATE O’ROURKE BOSTON—Throughout the United States, private medical practices are being snapped up by hospitals. So, what is it like to go from being a physician business owner to a hospital employee? At the recent National Oncology Conference, two oncologists discussed the pros and cons.

“There are a lot of pitfalls. The most important thing is to try to remain focused on patient care,” Terrence Cescon, MD, said. He was the executive vice president of the nine-physician practice Berks HematologyOncology Associates, in Reading, Pa., before it was sold to Reading Health Care System. Dr. Cescon became a hospital employee in January 2013. Given the chance, he would not do it again, and he likened being a hospital employee to being a raindrop in an ocean. “You have no say, no control over anything,” he said.

According to Dr. Cescon, Berks sold because of political pressure, not fiscal woes.

“Our practice was doing well. I think the partners were getting wary about what the future was going to hold. We got a lot of pressure from the [hospital],” he said. He cautioned about letting a hospital pay for a private practice evaluation. Berks did this, and Dr. Cescon believes the practice evaluation was erroneous.

Dr. Cescon has been overwhelmed by the number of hospital staff issuing edicts on administrative day-today operations and on patient care. For example, he no longer is able to give patients copies of their pathology and laboratory reports, which was a routine practice at Berks. Accustomed to answering to one president of his private practice, he found he suddenly had “a million different bosses.”

According to Dr. Cescon, Reading changed numerous aspects of Berks when it acquired the practice, including the computers, electronic medical records and processes used to ensure patient identification.

“We had a lot of processes in place that worked extremely well,” he said. “They messed with everything. … You don’t make decisions anymore. If you are a physician and you want to buy a widget, you have to go and

get permission. It requires an act of Congress.”

Physicians transitioning to a hospital setting also may lose control over staff.

“One of the things you have [the] advantage of in private practice is you can hire good people and let them do their job and get out of their way. When the hospital comes in, their criteria are different. We had recent layoffs, based on seniority, and in many cases, those who have the lowest seniority might have been the best people,” Dr. Cescon said. “All our staff is slowly being picked away.”

Hyatt “Tracy” DeGreen III, DO, the managing partner of a four-physician practice, Lancaster Cancer Center in Lancaster, Pa., agreed that physicians making the transition to hospital employees need to prepare themselves for loss of control.

“You definitely lose autonomy,” he said. “From my previous experiences, it is more difficult to practice medicine when there are so many to answer to. In my practice, I answer only to the patient and the insurances.”

Before practicing at Lancaster Cancer Center, Dr. DeGreen worked at Penn State Hershey Medical Center; he still treats some patients at local hospitals.

“I treat many patients at the local hospital, and it is much more difficult in many ways,” he said. For example, insurances accepted by a hospital may not be accepted by the outpatient infusion center. Patients arrive for appointments, expecting to be seen and treated, and are told that their insurance is not taken at the infusion center. According to Dr. DeGreen, Lancaster Cancer Center was recently approached by a hospital and decided not to sell.

Many physicians transitioning to a hospital setting have problems with loss of autonomy, according to a recent white paper on oncologist–hospital integration.

The white paper, “Opportunities and New Realities in Cancer Care,” was the product of an Institute for the Future of Oncology forum involving 40 participants, oncologists and cancer program executives from hospitals, practices and health care systems across the United States. Forum participants said physicians transitioning to the hospital might have difficulty with the loss of dayto-day control over administrative matters, the need to

‘They messed with everything. … You don’t make decisions anymore. If you are a physician and you want to buy a widget, you have to go and get permission. It requires an act of Congress.’

—Terrence Cescon, MD

be accountable to institutional policies and procedures, and the need to meet accreditation requirements for the Joint Commission and the American College of Surgeons. This report also stated that “merging or migrating IT from a physician office setting to a hospital can be an enormous task,” and that patients transitioning to a hospital setting may encounter more time in the waiting room and higher copays.

Dr. Cescon said that in his hospital setting, patient copays have doubled and wait times have increased.

Patients also have been inconvenienced by the loss of an outpatient pharmacy.

“A hospital is not interested in having an outpatient pharmacy,” Dr. Cescon said. “There is a certain convenience factor that just disappears for the patients, because you can’t go and hand them their dexamethasone for the next cycle of chemotherapy.”

Dr. DeGreen agreed that when a private practice transitions to a hospital setting, the loss of a dispensary can have big implications.

“It’s very nice to have a dispensary, because patients get the teaching not just from myself but from the pharmacists and nurses,” Dr. DeGreen said. Studies have shown that when patients buy from mail order companies, education about adverse drug reactions is lacking, and this increases emergency room visits and hospitalizations.

Dr. Cescon also complained that patients were inconvenienced by the loss of a laboratory in their office, which provided lab results in 15 minutes.

“Right now, it can take easily an hour for us to get lab-reported data back, so patients just sit there,” he said.

According to Dr. DeGreen, the increased wait times caused by the loss of a laboratory is frustrating but understandable, given that a hospital laboratory is caring for a varied patient base.

One benefit of being affiliated with a hospital is reducing the high cost of drugs. Nonprofit hospitals benefit from 340B pricing. Dr. DeGreen added that it is difficult for private practices to absorb drug costs when a patient cannot pay. Hospitals are in a better position to do this, because they have other profit centers. The Institute for the Future of Oncology white paper concluded that many of the private practices that consolidated “were satisfied with the additional resources and improved operational efficiencies of a hospital.”

Dr. Cescon had several recommendations for private practices considering selling to a hospital: Leave negotiations to the lawyers and get all promises in writing.

“When you ask them to put [an item] in writing and they won’t do it, that is because they are not going to keep that promise,” Dr. Cescon said. Even with a contract on paper, however, nothing is set in stone. “Your contract is definitely not guaranteed. The hospital can come back and say, ‘I’m sorry, I know we have a contract but we don’t have the money to pay you, so we are going to have to adjust this contract.’ You can either sign the new contract or you can leave.”

Instead of hospital direct employment, Dr. Cescon recommended that private practices enter into a professional services agreement with a hospital.

“That keeps everyone separate enough that physicians are going to be happier,” he said.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

Eradication continued from page 1

researchers in the field, David Graham, MD, professor of medicine at Baylor College of Medicine, Houston.

“In my lifetime we should see this cancer disappear,” Dr. Graham said in a lecture at the 2014 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. “We know how, we are starting the process. Now, we just have to do it!”

Nearly all gastric cancers begin with H. pylorii infection, which causes inflammation and progressive gastric mucosal damage. Sporadic gastric cancer results from a combination of chronic inflammation and direct H. pylori–induced genetic instability.

At least five distinct genetic mechanisms have been identified, including H. pylori infection–associated DNA double-strand breaks, impaired DNA mismatch repair, aberrant activation-induced cytidine deaminase expression (which induces nucleotide alterations involved in DNA mutations), aberrant methylation in gene promoters within the gastric mucosa and aberrant microRNA expression.

Risk for gastric cancer is influenced by the virulence of the organism, plus environmental factors such as diet.

Given the right environment, H. pylori infection leads to atrophic gastritis, which progresses to metaplastic epithelium, “and the cancer risk skyrockets,” Dr. Graham said.

H. pylorii eradication quells the inflammation, and halts the risk for damage to the gastric mucosa and cancer.

Japanese Studies Confirm H. pylorii Link Gastric cancer risk correlates with the degree and severity of gastric atrophy, as eloquently demonstrated in several important studies from Japan. One early study comprised 4,655 men, aged 40 to 59 years, who were screened for the presence of H. pylorii infection and atrophic gastritis. Men who did not have H. pylori infection did not develop gastric cancer, whereas those with atrophic gastritis progressed to gastric cancer at a rate of 1% per year (Ohata H et al. Int J Cancer 2004;109:138-143).

Another Japanese study followed 1,382 patients who were stratified according to baseline presence and severity of atrophic gastritis and eradicated H. pylorii for a median of four years. Patients with mild atrophic gastritis developed cancer at the low rate of less than 0.05% per year, whereas the risk increased linearly with increasing severity and extent of atrophy, reaching 0.66% per year for severe cases (Take et al. J Gastroenterol 2007;42[suppl 17]:21-27).

Call for Eradication Gastric cancer was first linked to atrophic gastritis in the late 19th century. Research on the link progressed rapidly through the first half of the 20th century, but then stalled, Dr. Graham explained.

“In the mid-20th century, the discovery that gastritis, and thus gastric cancer, was caused by infection with a microorganism would have likely led to calls for a worldwide eradication program,” he said. “Instead … proof that [H. pylori]] causes gastritis was followed by an additional 30-year delay, until finally in early 2013, Japan became the first country to approve H. pylori eradication to prevent gastric cancer. Hopefully, the world will follow Japan’s lead.”

Prevention should begin in childhood, when infection occurs, Dr. Graham said.

“If children don’t become infected, then there’s no gastric cancer.”

For individuals who are already infected, the aim of

‘If you want to eliminate cancer, you eliminate H. pylori.’

—David Graham, MD

Gastric Cancer Risk Assessment treatment is to eliminate H. pylori before it causes atrophic gastritis. “That will allow healing and some reversibility of changes that have occurred, although we have to recognize that in some patients irreversible damage has already occurred,” Dr. Graham said. This means that eradication programs will have a delayed effect in highrisk countries.

The study that validated the benefits of H. pylori eradication and “changed our thinking,” he said, involved 544 Japanese patients who were randomized to undergo H. pylori eradication or no eradication after endoscopic treatment for early gastric cancer (Fukase K et al. Lancet 2008;372:392-397). After three years, metachronous gastric cancer had developed in nine patients in the H. pylori eradication group and in 24 patients in the control group (odds ratio, 0.353; P P=0.009). Untreated patients developed cancer at the high rate of 4% per year, but eradication resulted in a rapid and marked reduction in the development of additional tumors.

“This very high risk is related to the existing extensive genetic changes that occur with infection. After eradication, the risk fell about fourfold. Something happened simply by eradicating the infection, which eliminates inflammation, allows acid secretion to return and stops the bacterial–host interactions that produce genomic instability,” Dr. Graham explained.

Research is now focused on understanding these interactions and determining whether they are reversible, Dr. Graham added.

Determining Risk The risk for progression from H. pylorii infection to atrophic gastritis to gastric cancer can be estimated noninvasively, and action taken to halt the process, Dr. Graham said.

“Even in the worst risk population, eradication has benefits. If you want to eliminate cancer, you eliminate H. pylori. If you have no atrophy, cancer is very rare, but with atrophy present there is some risk and it is related to the extent and severity of the atrophy. Eradication likely reduces the [risk for progression].”

In high-risk countries and high-risk patients, H. pylori eradication should be coupled with risk assessment. In general, Dr. Graham recommends eradication of H. pylori “from everyone,” identifying those still at

• Test for H. pylorii noninvasively (e.g., urea breath test) in adults and in children of infected parents.

• Eradicate H. pylori; confirm cure and noninvasively test for gastric atrophy (e.g., serum pepsinogen level, histology or both).

• Assess risk based on serum pepsinogen ratio.

• For pepsinogen I <70 and for pepsinogen I:II <3, perform endoscopy to look for atrophic changes.

• Assess gastric cancer risk according to the Operative Link for Gastritis Assessment (OLGA) staging system.

• For OLGA stages 0-2, no follow-up is required; for OLGA stages 3-4, develop a surveillance plan.

risk for cancer and determining their need for surveillance. It remains unclear how to conduct surveillance and for how long, but data from the Japanese eradication program may be informative, Dr. Graham said.

Jaffer Ajani, MD, professor of medicine at the University of Texas MD Anderson Cancer Center in Houston, who co-chaired the ASCO session on gastric cancer, agreed with Dr. Graham that a widespread H. pylori eradication program is warranted.

“It’s very appropriate because H. pylorii has been established as a carcinogen for gastric cancer,” Dr. Ajani said.

“In many countries, most adults are infected. The only thing we don’t know is who is susceptible and who is not.

It is host susceptibility that determines who gets gastric cancer, but since we don’t know who that is and it’s easy to eradicate the organism, we should consider that.”

Dr. Ajani added that the eradication of H. pylorii also relieves gastric symptoms, and this alone is reason to treat.

“It’s simple, inexpensive and reinfection is uncommon,” Dr. Ajani concluded. “But the next problem to emerge is resistance of the bacteria to treatment. That’s another research frontier.”

■ Dr. Graham has served as a consultant and advisor for Otsuka Pharmaceutical Company.

Dr. Ajani reported no conflicts of interest.

10

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ MAY 2014

Sphincterotomy Not Superior to Sham Treatment For Sphincter of Oddi Dysfunction Type III

BY MONICA J. SMITH SAN DIEGOâ&#x20AC;&#x201D;Although many patients enrolled in the sham-controlled EPISOD trial of sphincterotomy for the treatment of post-cholecystectomy pain experienced significant relief initially, those who underwent treatment eventually fared no

better than those in the sham arm. â&#x20AC;&#x153;The problem with suspected sphincter of Oddi dysfunction [SOD] type IIIâ&#x20AC;&#x201D;patients with pain onlyâ&#x20AC;&#x201D;is that the results of ERCP [endoscopic retrograde cholangiopancreatography] management are unimpressive, manometry has unproven value in this context and the risks of these procedures is substantial,â&#x20AC;?

said study author Peter Cotton, MD, who presented the findings of the trial at the 2013 American College of Gastroenterology Annual Scientific Meeting. â&#x20AC;&#x153;The pancreatitis rate is at least 15%, and perhaps even more important, patients who are unhappy with their progress often undergo multiple further ERCP procedures and even surgical resections,â&#x20AC;? added

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Dr. Cotton, who is professor of medicine at the Medical University of South Carolina, in Charleston.

EPISOD Trial The goal of the EPISOD (Evaluating the Predictors and Interventions of Sphincter of Oddi Dysfunction) trial was to identify which patients with SOD type III, if any, responded to biliary and/or pancreatic sphincterotomy, and whether any clinical characteristics (e.g., type of pain, reason for cholecystectomy, psychological status) were predictive of outcomes. The researchers also evaluated the effectiveness of sphincter manometry in predicting outcomes.

â&#x20AC;&#x2DC;The problem with suspected sphincter of Oddi dysfunction type IIIâ&#x20AC;&#x201D;patients with pain onlyâ&#x20AC;&#x201D;is that the results of ERCP management are unimpressive, manometry has unproven value in this context and the risks of these procedures is substantial.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Peter Cotton, MD

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The trial included 214 patients from seven U.S. centers. The patients, most of whom were women, had severe post-cholecystectomy pain. None of the patients had evidence of pancreatitis (past or present), and none had undergone previous sphincter intervention; all had normal endoscopies and scans, and all had bile ducts less than 10 mm.

The researchers assessed patients for the presence or absence of other functional gastrointestinal disorders, and also assessed psychological status, quality of life, coping and catastrophizing scores. â&#x20AC;&#x153;We were surprised to find they were less psychologically distressed than we had expected, actually less so than patients with irritable bowel syndrome [IBS],â&#x20AC;? Dr. Cotton said, noting that 34% of patients had symptoms consistent with IBS as well.

Slightly more than one-fourth (26%) of patients in the study used narcotics occasionally, and 38% were taking antidepressant medication. Patients who used narcotics daily and those with severe depression, suicidal ideation and/or psychosis were excluded from the trial.

Patients underwent ERCP with

11

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

both biliary and pancreatic manometry and were randomized 2:1, regardless of manometry results, to undergo sphincterotomy (n=114) or a sham procedure (n=74). Patients who underwent sphincterotomy who had elevated pancreatic sphincter pressures were randomized again to undergo biliary or dual biliary and pancreatic sphincterotomy. All patients received a temporary stent to reduce the risk for pancreatitis.

Researchers followed the patients monthly for one year, and all patients, caregivers and research staff were blinded to treatment allocation. Success was defined as a reduction in pain-related disability to less than six days during a three-month period as measured at nine and 12 months in patients who had not undergone reintervention and who did not take narcotic medication in the past three months.

“The initial results are gratifying— both biliary and dual sphincterotomytreated patients had a reduction in their pain scores at three months,” Dr. Cotton said. “What was surprising is that exactly the same applied to the sham-treated patients.”

However, by the end of the 12-month period, only 36% of patients in the sham arm and 22% of those treated with sphincterotomy achieved the criteria for success.

Comparing the different types of sphincterotomy, biliary sphincterotomy fared worst and was associated with successful outcomes in only 19% of patients, whereas dual sphincterotomy was successful in 28% of patients.

“One question that arises immediately is whether our outcome for success was too strict, so we looked at it in a number of different ways, one of which was reducing the reduction in the pain burden by half,” Dr. Cotton said. “Not surprisingly, the success rates increased, but there was no difference in terms of pattern—the sham patients still did as well if not better than the sphincterotomy-treated patients.”

Despite the expertise of the physicians involved in the procedures and the routine use of temporary pancreatic stents, pancreatitis occurred in 10% of patients in the sphincterotomy arm and 15% in the sham arm, with four episodes that were severe.

Two patients suffered post-sphincterotomy perforation; one required surgery. No patients died.

ERCP, Sphincterotomy Not Warranted for SOD Analysis of the results is ongoing, but at this point the researchers have not identified any characteristics predictive of success.

“We looked at pain patterns, the presence or absence of IBS, the presence or absence of minor lab abnormalities, psychological status, why the gallbladder

‘Many subjects improved initially, regardless of the treatment allocation. But at one year, sphincterotomy treatment was not superior to sham treatment; manometry did not predict the primary outcome; and it’s clear that alternative approaches are needed for these challenging patients.’

—Peter Cotton, MD was removed etc, and none of those things seem to correlate with a good or a bad outcome,” Dr. Cotton said. “Most

importantly, we found that the results of sphincter manometry did not predict outcome.”

“Our conclusion is fairly straightforward. Many subjects improved initially, regardless of the treatment allocation,” Dr. Cotton said. “But at one year, sphincterotomy treatment was not superior to sham treatment; manometry did not predict the primary outcome; and it’s clear that alternative approaches are needed for these challenging patients.”

John R. Saltzman, MD, director of endoscopy at Brigham and Women’s see Sphincterotomy, page 24

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

Risk for Skin Cancer From IBD, Thiopurines May Warrant Development of Prevetion Guidelines

BY TED BOSWORTH BERLIN—The body of evidence linking inflammatory bowel disease (IBD) and its treatments with an increased risk for nonmelanoma skin cancer is sufficient to support more rigorous prevention efforts, according to a recent review of the data. Although some but not all therapies for IBD are associated with an exacerbation of risk, IBD alone poses an increased likelihood for developing skin cancer and warrants a more aggressive approach toward prophylaxis.

encourage more ambitious strategies to prevent skin cancer in patients with IBD, regardless of the therapy they are taking.

Until recently, most published recommendations for reducing the risk for skin cancer in patients with IBD were generic. These included the use of broad-spectrum sun protection and other steps that are appropriate for the general population. Recently, the European Crohn’s and Colitis Organisation (ECCO) recommended annual screening for dermatologic cancers in patients taking immunomodulators for IBD (Magro F et al. J Crohns Colitiss 2014;8:31-44), but Dr. Jess suggested that

transplant, so there is a precedent. However, transplant patients receive a greater degree of immunosuppression, and may have increased risks. Dr. Long, who has written on this topic and recently evaluated the challenges of a national surveillance program for IBD (Long MD et al.

Inflamm Bowel Diss 2014;20:398-415), agreed that skin cancer screening guidelines are “reasonable” to consider in patients with IBD. The value of screening guidelines are not only supported by the association of immunomodulators for IBD with increased risk for nonmelanoma skin cancer but also for the association of TNF inhibitors with risk

‘The data raise the issue of whether some type of guidelines for preventing skin cancer are needed in IBD patients.’

—Tine Jess, MD

“The data raise the issue of whether some type of guidelines for preventing skin cancer are needed in IBD patients,” said Tine Jess, MD, of Statens Serum Institut in Copenhagen, Denmark, in a presentation at the 2013 United European Gastroenterology Week meeting.

Drawing on data from patient registries and metaanalyses, Dr. Jess estimated the risk for nonmelanoma skin cancer is about twice as great in patients with IBD relative to background rates. Furthermore, treatment with thiopurines, such as azathioprine or 6-mercaptopurine, may double the risk over that posed by IBD alone.

Although there is less consistency among studies linking thiopurines to nonmelanoma skin cancer, the likelihood for some increase appears to be substantial. Dr. Jess noted that tumor necrosis factor (TNF) inhibitors and other biologic medications appear to be associated with no risk or a relatively small additional risk associated with IBD alone.

According to Dr. Jess, there is biologic plausibility linking skin cancer with use of thiopurines, which have been shown to increase the DNA damage caused by ultraviolet light in an experimental setting; however, these data should not affect clinical treatment decisions, as association does not establish causation and thiopurines are highly effective for IBD. Rather, the data

the data may support broader inclusion criteria.

Dr. Jess conceded that the cost efficacy of more stringent measures of skin cancer prevention, such as annual screening, has not been established and may vary regionally according to such factors as underlying rates of skin cancer, cost of screening and cost of cancer treatment within a given health care system. It may be reasonable to limit annual screening to those IBD patients taking thiopurines, but this is a question that requires further discussion.

“If we decide to create international evidence-based guidelines for reducing the risk for skin cancer in patients with IBD, such guidelines also need to focus on the baseline risk for melanoma in patients with IBD,” Dr. Jess contended.

Although guidelines may direct more attention to the relationship between IBD and skin cancer and may increase the frequency with which clinicians recommend preventive strategies, skin cancer is readily treated in its early stages.

Asked to comment, Millie D. Long, MD, of the Division of Gastroenterology and Hepatology at the University of North Carolina, Chapel Hill, noted that guidelines regarding screening for skin cancer are already in place for those who have received a solid organ

for melanoma, which also could be caught early with screening, Dr. Long noted. However, she cautioned that one reason the U.S. Preventive Task Force Services has not advocated broad skin cancer screening programs is the lack of evidence that screening, despite early recognition of skin cancers, leads to a reduction in mortality.

“We also are lacking these mortality data in patients with IBD,” she noted. “However, the growing data on skin cancer risks in IBD patients may justify the development of such guidelines.”

In the absence of guidelines, she recommended that “clinicians educate patients on the increased risk for skin cancer at the initiation of immunosuppression and counsel them on sun protection strategies.”

But she thinks the data are there to support guideline development.

“I agree with Dr. Jess that a process of evidence-based guideline development is warranted for IBD patients to consider whether screening skin examinations are warranted, which subsets of IBD patients would most benefit and at what intervals these examinations might be recommended,” Dr. Long concluded.

■ Dr. Jess reported no relevant conflicts of interest. Dr. Long has served as an advisory board member for UCB Pharma.

13

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

Continuation of Immunomodulators in IBD Patients Starting Anti-TNFs Evaluated in Meta-Analysis

BY TED BOSWORTH

for infection but a lower risk for infusion site reactions; adalimumab and certolizumab were not associated with any increased risk for AEs. Although these findings provide some objective data with which to address the controversy of whether to keep patients on immunomodulator therapy after biologics are started, Dr. Peyrin-Biroulet noted that this was a retrospective analysis with some limitations. For example, the data do not control for the period of time that patients were on taking immunomodulators prior to starting an anti-TNF agent; timing of this combination may be important.

BERLIN—The benefit of keeping patients with Crohn’s disease on an immunomodulator after starting an antitumor necrosis factor (TNF) agent appears to differ based on the specific anti-TNF agent used, according to a meta-analysis designed to address this question.

The differences were observed in a subgroup analysis when clinical remissions were compared at six months: Outcomes were improved when immunomodulator therapy was continued in patients initiating infliximab but not in those initiating adalimumab mab or certolizumab.

The meta-analysis comprised 11 ran‘The fact that the authors of this metadomized trials with 1,601 patients, inclu uding analysis did not see differences in efficacy five trials of infliximab, four of adalimu umab and two of certolizumab. Among thesee, 625 in post hoc analyses of subgroups of patients remained on immunomodu ulator patients with and without concomitant therapy when an anti-TNF agent was initiated; 976 did not. The study, presentted at immunosuppression in the PRECiSE 2 the 2013 United European Gastroentteroltrial should tell us that there are powerful ogy Week meeting, addressed the ongoconfounders that make it difficult to ing debate of whether immunomodu ulator therapy should be continued once anti-T -TNF impossible to determine the effect of therapies are initiated. The overall results combination versus monotherapy on showed no advantage.

“The odds ratio [OR] for clinical reemisefficacy in post hoc analyses.’ sion at six months was 1.06 for thosee who —William J. Sandborn, MD remained on immunomodulators compared with those who did not, bu ut the confidence interval [CI] included 1” (95% CI, 081-1.4), reported Laurent PeeyrinBiroulet, MD, head of the Inflamm matory Bowel Diseases Unit, Centre Hospiitalier Universitaire, Nancy, France. When n the outcome of induction or maintenan nce of response was considered, CIs were wider and the relative advantage of remaiining on an immunomodulator remained d statistically insignificant (OR, 1.46; 95% % CI, 0.7-3.05). There also was no advan ntage observed for remaining on immunom modulators to achieve fistula closure.

However, a subgroup analysis thatt looked at specific anti-TNF agents revealed differences in the advantages of immunomodulators. For infliximab, there was a substantial and statistically significant advantagee for remaining on an immunomodulattor (OR, 1.79; 95% CI, 1.06-3.01). How wever, It would be useful to have “data on there was no advantage with adalimum mab (OR, patients who started and then remained on an 0.97; 95% CI, 0.65-1.37) or certolizumab (OR, immunomodulator for six months prior to starting 0.84; 95% CI, 0.55-1.27). anti-TNF therapy, [because] in my experience it takes Overall, the risk for significant adverse events (AEs), time to respond to immunomodulator therapy,” Dr. defined as infection, malignancy or death, was not Peyrin-Biroulet noted. increased by remaining on an immunomodulator after Prospective studies are needed to provide a more initiation of anti-TNF therapy (OR, 1.11; 95% CI; rigorous evaluation of whether improvement in dis0.86-2.2). Notably, patients on combination therapy did ease control can be achieved when one drug is added have a significantly lower risk for infusion site reactions to the other, Dr. Peyrin-Biroulet said. This is particu(OR, 0.43; 95% CI, 0.19-0.98). Stratification based larly important when a suboptimal response is achieved on anti-TNF agent revealed that combination therapy with an immunomodulator before adding a biologic. that included infliximab did result in an increased risk As these agents have different mechanisms of action,

some additive effect is a reasonable expectation. The potential for a combination to induce healing before stepping down to a single agent for maintenance also deserves formal trials.

The need for prospective controlled trials to explore the hypotheses of this post hoc analysis was strongly reiterated by William J. Sandborn, MD, chief of the Division of Gastroenterology, University of California, San Diego. He identified several potential problems and specifically suggested that the results “should not be used to guide clinical practice.”

Indeed, Dr. Sandborn said that the conclusions are “likely incorrect,” based on several observations, one stemming from data from the PRECiSE (Pegylated Antibody Fragment Evalu uation in Crohn’s Disease: Safety and E Efficacy) 2 trial (Schrieber S et al. N Engl J Med 2007;357:239-250), which was includ ded in this meta-analysis. In the PRECiSE E 2 trial, anti-certolizumab antibody formation was significantly lower in the group p that received certolizumab plus an immu unomodulator relative to certolizumab alonee. Past studies have demonstrated that antti-drug antibody formation reduces efficacy by increasing drug clearance.

“The fact that the authors of this meta-analysis did not see differences in efficacy in post hoc analyses of subgroups of patients with and without concomitant immunosuppression in the PRECiSE 2 triial should tell us that there are powerfull confounders that make it difficult to impoossible to determine the effect of combinatiion versus monotherapy on efficacy in post-h hoc analyses,” Dr. Sandborn said.

Mooreover, the anti-drug antibody formation n rates in the PRECiSE 2 trial with certoliizumab were very similar to those that have b been reported previously for infliximab, accord ding to Dr. Sandborn. Noting that immu unogenicity may be the best measure of ben nefit for combination versus a monotherap py in a withdrawal trial like PRECiSE E 2, Dr. Sandborn indicated that the similaar rates of anti-drug antibody formation p predict better efficacy for both agents when n they are combined with an immunomodu ulator. No immunogenicity data were colleccted in the Phase III trial with adalimumab, so relativve effect on this measure is unknown.

Although Dr. S Sandborn challenged the conclusions drawn from this meta-analysis, he agreed that post hoc analyses are hypothesis generating and provide “the basis for conducting additional clinical trials to best determine the truth.”

■ Dr. Peyrin-Biroulet has served as a consultant for Abbott Laboratories and UCB Pharma. Dr. Sandborn has received research funding and/or honoraria from Abbott, Centocor, Elan, Procter & Gamble, Prometheus Laboratories, Salix Pharmaceuticals, Shire and UCB Pharma.

14

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

Noninvasive Liver Fibrosis Scores Fall Sho ort In Children With NAFLD

BY MONICA J. SMITH SAN DIEGO—The same noninvasive fibrosis scores that work excellently in the adult population fall short or fail to detect fibrosis in children with nonalcoholic fatty liver disease (NAFLD), according to recent research. Scores developed specifically for the pediatric population are desperately needed, researchers said.

NAFLD is the most common form of chronic liver disease in children and it can progress, even in childhood, to fibrosis or cirrhosis. Although liver biopsy remains the gold standard for diagnosing the presence and degree of fibrosis, it comes with a risk for complications and other problems, which led to the development of noninvasive fibrosis scores, such as those based

on the aspartate aminotransferase (AST)– alanine aminotransferase (ALT) ratio, the AST/platelet ratio index (APRI), the FIB-4 index and the NAFLD fibrosis score (NFS). All of these, however, were developed based on use in adults.

“Since none of these scores were developed in the pediatric population, we sought to assess the utility of the noninvasive scores in children with NAFLD,” said study author Sana Mansoor, MD, who presented the research at the 2013 American College of Gastroenterology Annual Scientific Meeting.

Dr. Mansoor, of the Cleveland Clinic Foundation in Ohio, and her colleagues from other centers in the United States, Canada and Italy conducted a retrospective cohort study to investigate the utility of noninvasive fibrosis scores in children.

‘Since none of these scores were developed in the pediatric population, we sought to assess the utility of the noninvasive scores in children with NAFLD.’ —Sana Mansoor, MD

The study sample con nsisted of 92 children n from five large tertiary care centers in whom biopsy evaluated by expert hepatic pathologists tested positive for NAFLD between 1995 and 2007.

The researchers tabulated noninvasivve fibrosis scores for eaach child using AST/A ALT ratio, APRI, FIB-4 index and NFS, and assessed the performance of each score using C statistics and receiver-operating r-operating characteristic curves.

Among the children in the study, 30% were girls, 50% were white, mean age was 13.3 years and mean body mass index was 32 kg/m2.

“Of the total of 92 children, 15% had no fibrosis, 35% had stage I fibrosis, 26% had stage II fibrosis and 24% had stage III fibrosis,” Dr. Mansoor said. None of the children had stage IV fibrosis.

She and her colleagues further classified the children into three categories: presence of any fibrosis (defined as stage I-III), which included 84% of the children; clinically significant fibrosis (defined as stage II or III), which included 50%; and advanced fibrosis (defined as stage III), which included 24%. “All scores were then applied to these three categories,” Dr. Mansoor said.

Comparing the calculated fibrosis scores with the stages of fibrosis among the children, the researchers found extensive overlap between groups. “We had values significantly higher in the group with any disease, although the overlap was still present,” Dr. Mansoor said.

In terms of identifying any significant or advanced fibrosis, AST/ALT, FIB-4 index and NFS all either had subpar diagnostic accuracy or failed completely. The APRI score had an area under the curve of 0.8, suggesting fair diagnostic accuracy for distinguishing the presence of fibrosis from the absence of fibrosis in children; however, further evaluation revealed poor diagnostic accuracy for significant or advanced disease.

“We concluded that the hepatic fibrosis scores developed in the adult population, which have shown excellent outcomes [in that population], are not appropriate for the pediatric population,” Dr. Mansoor said. “What we would like to stress is the urgent need to develop more noninvasive fibrosis markers that would be appropriate

specifically for the pediatric population.”

The findings of the study were somewhat surprising to Samra Blanchard, MD, chief of pediatric gastroenterology, University of Maryland School of Medicine, Baltimore.

“If there is any scarring in the liver, whether adult or pediatric, it should be predictable, so I expected the pediatric results to follow the adult results. But the study shows that they do not correlate,” Dr. Blanchard said.

“On the other hand, pediatric medicine is not medicine for little adults. There are some situations where children differ from adults, and I think this is one of those cases. The markers used in the adult population, such as INR [international normalized ratio] levels, you don’t see in children unless you have significant fibrosis or cirrhosis,” she said.

“Currently we do not have any way to assess [fibrosis] other than liver biopsy,” Dr. Blanchard said, noting the discomfort that parents express at the notion of their children having to undergo a procedure that carries a risk for infection, bleeding and perforation. “There is a lot of research investigating serologic, radiologic or special ultrasound [methods] for predicting fibrosis in the liver, so I think we can go further into those arenas,” Dr. Blanchard said.

Dr. Mansoor and her colleagues are currently developing a model that they hope will serve as an effective marker for predicting liver fibrosis in children.

“We have again included a large cohort of children with biopsy-proven NAFLD, and using multivariable logistic analysis, we’ve developed a new model consisting of a few variables,” Dr. Mansoor explained.

“These are laboratory values that pediatricians can easily obtain in their offices without any advance testing or referral.”

■

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

H E PAT O L O G Y I N F O C U S

15

Emergency Room Testing Chips Away at Hidden HCV Epidemic

BY KATE O’ROURKE WASHINGTON—A recent study suggests that testing baby boomers who visit the emergency department (ED) could go a long way in combatting the hidden epidemic of hepatitis C virus (HCV) in the United States. Although the study involved only one center over a six-week period, it has garnered much attention from health care officials.

“We identified a high prevalence—12%—of unaware HCV antibody–positive baby boomers, and confirmed infection in 8.7% overall,” said study author James Galbraith, MD, associate professor, Department of Emergency Medicine, University of Alabama, Birmingham (UAB). He presented the study at the Liver Meeting 2013.

Baby boomers, individuals born between 1945 and 1965, account for

We identified a high prevalence—12%—of unaware HCV antibody– positive baby boomers, and confirmed infection in 8.7% overall.’

—James Galbraith, MD

approximately 75% of HCV infections in the United States—50% of them are unaware they are infected. In the past two years, the Centers for Disease Control and Prevention (CDC) and the U.S. Preventive Services Task Force released recommendations that all baby boomers should undergo one-time screening for HCV infection.

Populations that are disproportionately affected by HCV—e.g., non-whites, Medicaid recipients, the

uninsured—are the same populations that disproportionately use the ED for health care, said Dr. Galbraith. Studies have shown that traditional HCV screening efforts, such as through primary care physicians (PCPs), may not be successful in reaching many individuals at the highest risk (Denniston MM et al.

Hepatology 2012;55:1652-1661).

In the current study, HCV screening was conducted at the UAB ED. This 51-bed, Level 1 trauma center has more

than 65,000 visits annually, including an average of 12,337 unique baby-boomer visits. As part of the study, ED nurses administered a short questionnaire to all baby boomers to ascertain whether they had been tested for HCV. The nurses educated patients about CDC recommendations for HCV testing for all baby boomers, and then informed patients that free, confidential HCV testing would be conducted unless they see HCV Testing, page 22

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H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

From the Literature

Liver Transplantation Leads to Surprising Improvements In Young Patient With Lathosterolosis

BY CHRISTINA FRANGOU A young girl with a rare metabolic disease that causes liver failure and autistic behavior experienced remarkable improvements in her mental and physical health after receiving a liver transplant, according to a case report in the American Journal of Transplantation (Calvo PL et al.

2014;14:960-965).

The investigators said they were surprised by the girl’s developmental improvements after the surgery, which was performed to resolve the liver disease associated with her lathosterolosis, a defect of cholesterol biosynthesis characterized by high lathosterol levels and associated with progressive cholestasis, multiple congenital anomalies and mental retardation. The unexpected findings suggest a possible link between metabolic conditions and some forms of autism, the authors said.

‘We were dealing with a unique case—literally, as

Remarkable Results In this case report, Dr. Calvo and his colleagues described the only patient alive today with the disease. No other treatment has been shown to markedly benefit a patient with this disease.

When the girl was diagnosed with lathosterolosis at the age of 2, she exhibited autistic behavior, was unable to walk without aid and developed cataracts that impaired her vision. At age 7, she was diagnosed with end-stage liver disease.

One year later, the girl underwent a liver transplant. Within 12 hours of surgery, blood tests showed increases in serum cholesterol levels and a drop in lathosterol levels. One year after transplantation, her cholesterol synthesis was normal. The girl gradually began

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the child is the only known surviving patient with the condition—so it is difficult drawing inferences of broader significance.’

—Pier Luigi Calvo, MD

The investigators hypothesize that, although established structural defects in the patient’s brain could not be reversed, a degree of residual plasticity in her central nervous system (CNS) may have benefited from the normalization of cholesterol levels that occurred after liver transplantation. They stressed that this is the only case of liver transplantation for lathosterolosis. The broader implications are yet unknown, they said.

“We were dealing with a unique case— literally, as the child is the only known surviving patient with the condition— so it is difficult drawing inferences of broader significance,” said lead author Pier Luigi Calvo, MD, of the Città della Salute e della Scienza in Torino, Italy, in a press statement.

“We described this case on its own merits and also as a possible model for other, more common defects of cholesterol biosynthesis.”

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exploring her environment and learned to walk independently. Five years after transplantation, she experienced complete biochemical recovery, arrest of CNS lesions and partial improvements in neurodevelopment and behavior. She is alert, thrives on a normal diet and has had no further hospital admissions.

“One cannot but wonder what the evolution of her disease might have been if her metabolic imbalance had been corrected at age 1, when her brain

MRI [magnetic resonance imaging] was reported as ‘normal,’” the authors said.

The investigators suggested that liver transplantation “might be considered for patients with [defects of cholesterol biosynthesis], even in absence of end-stage liver disease with the aim of preventing further neurologic deterioration.”

Questions Raised However, other experts pointed to another possible explanation for the

H E PAT O L O G Y I N F O C U S

19

child’s developmental improvement, an explanation unrelated to neuroplasticity.

The data reported in the study indicate that the child had ammonia levels more than twice normal levels before transplantation, said Carlos O. Esquivel, MD, PhD, the Arnold and Barbara Silverman Professor in Pediatric Transplantation, Stanford University, in Palo Alto, Calif.

Excessive levels of ammonia in see Transplantation, page 20

‘We have seen this in other metabolic disorders in children and adults. If you replace the liver and the ammonia goes back down to normal, like in this particular case, the child’s neurologic impairment returns to baseline.’

—Carlos O. Esquivel, MD, PhD

20

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

HCC continued from page 1

Survival ‘Dismal’ “At a time when the incidence is rapidly increasing, the five-year survival rate is dismally low—about 10% to 15%,” Dr. El-Serag noted.

Globally, more than half of all cases of HCC result from hepatitis B virus (HBV) infection, while 30% of cases are related to hepatitis C virus (HCV) infection; in the United States, those rates are 15% and 47%, respectively. In regions where HBV is the primary etiology of HCC, HCC incidence is highest in the third or fourth decade of life; where HCV predominates, HCC incidence peaks in the fifth or sixth decade of life.

“Interestingly, in countries where HCC rates are increasing, incidence is shifting from the old to the young. In the United States, we are shifting from HCC occurring at 70 to 80 years of age to mostly 60 years of age,” he said.

men with HCV-related HCC dies, we begin to see HCC in age groups and gender groups that are not typical for HCC,” he said. “The last wave to present in the HCC epidemic will be older women.”

Risk Factors for Progression To HCC The relative risk for developing HCC is 25 times higher among HCV-infected persons compared with individuals who are not infected. The absolute risk is one per 100 after 30 years of HCV infection, rising to 3.5 per 100 in the setting of HCV-related cirrhosis.

Several factors render HCV-infected persons more likely to develop HCC: older age, longer duration of HCV infection, male gender and race. Potentially

modifiable risk factors include alcohol consumption (40-50 g/day), obesity, type 2 diabetes and coinfection with HBV or HIV. Testing positive for HCV RNA, and possibly HCV genotypes 1 and 3, are related to increased risk as well. The REACH-B (Risk estimation for hepatocellular carcinoma in chronic hepatitis B) model incorporates these risk factors to calculate a score that is prognostic for the development of HCC at three, five and 10 years of infection (Yang HI et al.

Lancet Oncoll 2011;12:568-574).

The risk for progression of HBV to HCC also can be estimated: Risk factors include male gender; alcohol consumption; and coinfection with HCV, hepatitis D virus or HIV. In patients who are hepatitis B e antigen see HCC, page 22

Tracing the Worldwide HCV Epidemic There are three regions of the world with a similar prevalence of HCV, yet considerable differences in the incidence of HCC: Japan, southern Europe and the United States. The annual mortality rate per 100,000 persons due to HCC is apprroximately 30 in Japan, 15 in Europe and 5 in the Uniited States.

“This puzzles epidemioologists,” Dr. ElSerag said. “It may have to do with the time at which HCV wass introduced into the region: in the 1920s in Japan, in the 1940s in Europe and in the 1960s in the United States. Thee implication of this is that it’s only a maatter of time for regions of low incidence to catch up with those of higher incidence, although this may or may noot be true, especially in lieu of recent developments in the treatment of H HCV.” This pattern reflects a ““cohort phenomenon,” Dr. El--Serag explained, in which HCV infeci tion occurs in young ad dulthood and HCC emerges a few decades later.

“As the cohort of youn ng

Transplantation continued from page 19

children significantly impair neurologic function, causing walking difficulties, lethargy and in extreme cases, coma.

Interventions to address the ammonia levels have been shown to improve these impairments, Dr. Esquivel explained.

He believes in this case, the child’s neurologic function improved as a result of the drop in ammonia levels after transplantation.

“We have seen this in other metabolic disorders in children and adults,” Dr. Esquivel said. “If you replace the liver and the ammonia goes back down

to normal, like in this particular case, the child’s neurologic impairment returns to baseline.”

He added that the study highlights a difficult ethical dilemma that many transplant centers struggle with: Should organs in limited supply be given to developmentally impaired patients?

“That’s an ethical issue. For me, and the rest of our team here, we do transplants on kids who are developmentally delayed, but other centers might see it in a different light.”

Emily R. Perito, MD, assistant professor of pediatrics at the University of California, San Francisco, who specializes in the treatment of pediatric liver disease,

‘The southern part of Texas has a [liver-related mortality] rate that is close to some parts of China.’

—Hashem El-Serag, MD, MPH

said that in this case, the mechanism behind the child’s improved neurologic function may be multifactorial, including more normalized cholesterol synthesis and normalized overall hepatic function.

“This is an intriguing case and an amazing outcome for this unique child and her family,” she said.

“At this point, her case raises fascinating questions for future research, and possibly a treatment consideration for a very few children with exceedingly rare disorders, but does not provide enough information to recommend liver transplant for most cholesterol synthesis defects.”

This is the latest study to demonstrate that patients with mental

disabilities—which were once considered a contraindication for liver transplantation—can benefit from a transplant and can manage complicated immunosuppressive regimens with help of their families and friends.

“This case raises the question of performing early liver transplantation in these patients, before the development of permanent neurologic damage,” said Naim Alkhouri, MD, a pediatric gastroenterologist with an interest in transplant hepatology at the Cleveland Clinic.

Lathosterolosis should be added to a growing list of inherited metabolic disorders that potentially could be cured by a timely liver transplantation, he said. ■

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

H E PAT O L O G Y I N F O C U S

21

From the Literature

Trial of Sunitinib in Patients With HCC Halted for Futility Vincent Chung, MD Associate Clinical Professor Medical Oncology City of Hope Duarte, California A trial comparing outcomes of patients with hepatocellular cancer (HCC) treated with sunitinib (Sutent, Pfizer) with outcomes of those treated with sorafenib (Nexavar, Bayer/Onyx) was terminated for futility when overall survival (OS) with sunitinib proved inferior.

The current recommended treatment for unresectable HCC is sorafenib, a vascular endothelial growth factor (VEGF) inhibitor. Investigators sought to compare sorafenib with sunitinib, which has similar properties, in an international, open-label, Phase III trial. Patient selection focused on Asia; 75.6% of enrolled study participants (812 of 1,074) originated from nine Asian countries. Among the other patient characteristics in the study were the presence of esophageal varices in 27.7% of those in the sunitinib group versus 28.7% in the sorafenib group; hepatitis B virus (HBV) infection in 54.7% versus 52.9%, respectively; hepatitis C virus (HCV) infection in 21.3% versus 21.9%, respectively; vascular invasion and/or extrahepatic spread in 78.9% versus 76.3%, respectively; and underlying cirrhosis in 50.0% versus 45.4%, respectively.

The international group of investigators published its findings in the Journal of Clinical Oncologyy (Cheng AL et al.

2013;31:4067-4075). There were 544 patients in the sorafenib arm (400 mg twice daily) and 530 in the sunitinib arm (37.5 mg once daily). The primary end point was OS; secondary end points were progression-free survival, time to progression (TTP) and safety.

Median OS was 7.9 and 10.2 months for those in the sunitinib and sorafenib arms, respectively (hazard ratio [HR], 1.30; one-sided P=0.9990, two-sided P=0.0014).

Median OS for patients from Asia was 7.7 and 8.8 months with sunitinib and sorafenib, respectively (HR, 1.21; onesided P=0.9829), whereas median OS for patients enrolled from non-Asian countries was 9.3 versus 15.1 months with sunitinib and sorafenib, respectively (HR, 1.64; 95% confidence interval, 1.20-2.26; P=0.9964).

TTP was 4.1 months with sunitinib versus 3.8 months with sorafenib (HR 1.13; one-sided P=0.8312; two-sided P=0.3082).

TTP rates differed between Asian and nonAsian populations, as well as in subgroups of patients with HBV and HCV. Adverse events (AEs), primarily of grades 1 and 2, were frequent in both

groups. Nonetheless, grade 3 and 4 AEs occurred in 432 (82.1%) of patients receiving sunitinib and 402 (74.2%) of patients receiving sorafenib. The most common AEs of grades 3 and 4 were thrombocytopenia (29.7%) and neutropenia (25.7%) in the sunitinib group and hand–foot syndrome (21.2%) in the sorafenib group.

Treatment discontinuations caused by AEs were recorded in 13.3% of patients in the sunitinib arm and 12.7% of patients in the sorafenib arm.

Commentary by Dr. Chung HCC is a leading cause of death worldwide, with the incidence continuing to increase.1 Caught in the early stages, cure is still possible with liver transplant or resection, but in the advanced stages treatments are only palliative. Sorafenib

group having more advanced disease. In non-Asian patients treated with sorafenib, 68.7% had Barcelona Clinic Liver Cancer stage C disease compared with 78.1% in the sunitinib-treated group, but this could not account for such a large difference in survival: 15.1 versus 9.3 months, respectively. As seen in previous studies, the behavior of HCC in Asian and nonAsian patients is different and exhibits a different biology. In the Asia-Pacific study, sorafenib still improved survival over placebo, with median OS increasing from 4.2 to 6.5 months (P=0.014).

P However, this OS was much shorter than demonstrated in the results of the SHARP (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol) trial, which improved survival from 7.9 to 10.7 months (P<0.001).3

‘We need to establish biomarkers that can help guide treatment decisions to maximize effectiveness while minimizing toxicities.’

—Vincent Chung, MD

was the first molecular targeted therapy to improve survival in patients with advanced HCC. By targeting the RafMEK-ERK signaling pathway, VEGF receptors 1, 2 and 3 and platelet-derived growth factor receptor-β, which play an important role in the pathogenesis of HCC, survival was improved by three months over placebo.2 Because HCC is a vascular tumor and high VEGF expression has been associated with a poor prognosis, several studies have been conducted targeting VEGF. This study, published by Cheng et al, evaluated whether sunitinib was superior or equivalent to sorafenib.

Sunitinib is an oral multikinase inhibitor targeting VEGFR1, VEGFR2, PDGFR-a/b, c-kit, FLT3 and RET. Prior trials tested multiple dosing schedules with encouraging results, but toxicity was limiting. This Phase III trial used continuous daily dosing of 37.5 mg; more than 1,000 patients were randomized between the two arms. Surprisingly, the trial was terminated early due to futility and safety reasons.

Across all groups, survival was worse in the sunitinib group, with non-Asian patients faring particularly poorly when compared with patients who were administered sorafenib. Overall, the trial was well conducted, accruing patients from 23 countries (nine Asian countries). Between the two arms, differences were seen in the patient characteristics, with Asian patients and patients in the sunitinib

If we look at the etiology of the cancer, we find that a majority of patients in Asian countries develop HCC from HBV infection compared with HCV infection.

In tissues infected with hepatitis C, there is activation of the Raf-1-MEK-ERK pathway leading to cell proliferation.

Sorafenib inhibits the Raf-1 kinase at nanomolar concentrations, giving it a comparative advantage over sunitinib, which does not hit this target. Additional research is being proposed to evaluate the effects of sorafenib on HCV replication (ClinicalTrials.gov: NCT01849588).

The drive for personalized medicine has led to an explosion of knowledge about the signaling pathways important for HCC pathogenesis. In addition to VEGF, it has been determined that fibroblast growth factor (FGF) receptor also is an important driver of angiogenesis. Although other clinical trials with VEGF inhibitors have met a fate similar to that of sunitinib in HCC, there was particular interest in brivanib, a smallmolecule inhibitor of VEGF and FGF. The BRISK-FL study (Brivanib Study in HCC Patients at Risk—First-Line) randomized patients with advanced unresectable HCC to either brivanib or sorafenib.

The primary end point of OS noninferiority was not met and brivanib was less well tolerated compared with sorafenib although both agents had similar antitumor activity. The discontinuation rate due to AEs was 33% for sorafenib and 43% for brivanib. In the subset analysis,

there was also a slightly longer survival in HCV patients treated with sorafenib, which may reflect the importance of Raf inhibition.4 For patients failing or being intolerant of sorafenib, the BRISK-PS (Brivanib Study in HCC Patients at Risk—Post Sorafenib) study randomized patients in a 2:1 fashion to either brivanib or best supportive care. Unfortunately, brivanib did not improve OS.5 As we learn more about potential driver pathways leading to cell proliferation, clinical trials of rational combinations are being conducted. AZD6244 in combination with sorafenib was tested in HCC, but as we have seen with other combinations of small-molecule inhibitors, the toxicities can be quite significant, limiting their use. In the first dose level of the trial, AZD6244 at 50 mg twice daily and sorafenib at 400 mg twice daily, there were two dose-limiting toxicities in six patients. The recommended Phase II dose was 75 mg daily of AZD6244 and 400 mg twice daily of sorafenib (ClinicalTrials.gov: NCT01029418).

Many other VEGF inhibitors have been tested with varying degrees of activity, but so far, none has been able to surpass sorafenib. Going forward, we need to establish biomarkers that can help guide treatment decisions to maximize effectiveness while minimizing toxicities.

■

References 1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer.

2010;127:2893-2917.

2. Llovet JM, Ricci S, Mazzaferro V, et al.

Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. d 2008;359:378-390.

3. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25-34.

4. Johnson PJ, Qin S, Park JW, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.

J Clin Oncol. l 2013;31:3517-3524.

5. Llovet JM, Decaens T, Raoul JL, et al.

Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. l 2013;31:3509-3516.

Dr. Chung reported no relevant financial disclosures.

22

H E PAT O L O G Y I N F O C U S

‘Alcohol can cause alcoholic cirrhosis, which may lead to

HCC

HCC on its own, but it is a virulent player in the presence of

continued from page 20

(HBeAg)-positive, the risk for HCC is increased by a prolonged interval before seroconversion, age older than 40 years, mildly and persistently abnormal alanine aminotransferase (ALT) levels and viral genotype C (more so than B). For HBeAg-negative patients, persistent viral replication, high level of HBV DNA, abnormal ALT levels and presence of HBV precore and basal core promoter mutations are risk factors.

An understanding of the HCV–HCC connection led to the recent recommendation by the Centers for Disease Control and Prevention that individuals born between 1945 and 1965 be screened for HCV, thus potentially providing protection from progression to HCC. But although eradication of HCV reduces a person’s risk for HCC, if cirrhosis has developed, the risk does not fall back to baseline. Age is also important: Older individuals with cirrhosis who are cured of HCV have a higher risk for HCC than younger people.

“This information has important implications for what will happen after the HCC epidemic is over,” Dr. El-Serag noted. “The risk for HCC is unlikely to return to baseline.”

Similarly, adequate suppression of HBV DNA by antiviral medications is believed to reduce the risk for HCC, but this theory is based largely on observational studies only.

Dr. El-Serag cautioned that even the newest agents targeting HBV and HCV may not completely eliminate liver cancer.

“There is great discrepancy between the extremely high efficacy of these medications and their effectiveness in community practice,” he said.

Also, there are other risk factors that are especially potent when they occur in combination.

“Alcohol can cause alcoholic cirrhosis, which may lead to HCC on its own, but it is a virulent player in the presence of HCV or HBV,” he said.

Data regarding tobacco use are inconsistent. Smoking is not likely to be a risk factor on its own, but in the

HCV Testing continued from page 15

chose to decline. The study also encouraged testing in individuals who abused drugs, those with newly diagnosed HIV infection and those with new symptoms of liver disease; however, at the Liver Meeting, only data from the babyboomer population was presented.

Patients were informed that the rapid HCV test would not delay their treatment in the ED, and that results would be disclosed to them before they were discharged. Clinicians used the ARCHITECT Anti-HCV assay (Abbott) and HCV RNA quantitative analysis for testing. Individuals with confirmed HCV infection were linked with appropriate antiviral treatment services with the help of the Liver Center, Liver Transplant Clinic and the 1917 Liver Clinic, all part of UAB. The linkage coordinator also helped HCV-positive individuals establish a PCP, so they were able to maintain

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

HCV or HBV.’ —Hashem El-Serag, MD, MPH —Hashe

presence of HBV infection the effect is “more than additive,” and in the presence of HCV infection the interaction is “multiplicative,” Dr. El-Serag noted.

Of increasing importance in the risk for development of HCC are obesity and insulin resistance. A body mass index of 35 kg/m2 or greater is associated with a 4.5-fold increased risk for liver cancer. Insulin resistance can lead to diabetes, which doubles the risk for HCC. Insulin resistance also predisposes individuals to nonalcoholic fatty liver disease (NAFLD), which in 20% of patients may progress to nonalcoholic steatohepatitis; this, in turn, leads to cirrhosis in 10% to 15% of patients.

“Hepatologists believe that NAFLD increases the risk for HCC, but as a relatively new entity, there are no population-based studies,” Dr. El-Serag noted. “We don’t know the magnitude of risk, but what’s clear is that cirrhosis-related NAFLD is associated with increased risk for HCC, although the risk is less than that associated with HCV. The risk factors that compound that

consistent health care throughout progression of their disease.

In a six-week period during 2013, the UAB ED had 2,363 unique visits by baby boomers. Of the 1,721 individuals who completed questionnaires, 74.8%

risk are obesity and cirrhosis [White D et al. Clin Gastroenterol Hepatol 2012;10:1342-1359],” he said.

Is Prevention Possible?

Conversely, coffee consumption and metformin use (in diabetic patients) appear protective against HCC. Meta-analyses suggest that each cup of coffee is associated with an approximately 25% reduction in risk, whereas metformin use reduces risk by 76% (Zhang H et al. Scand J Gastroenteroll 2013;48:78-87). Additionally, observational studies suggest that statins are associated with a 47% risk reduction; however, this association has not been supported by clinical trials.

In summary, Dr. El-Serag concluded: “HCC is a global problem that continues to increase. Prevention is largely through HBV vaccination and antiviral treatments, but there are major gaps in effectiveness for all our prevention measures. Although there is a possibility that coffee, statins and metformin are protective, we need trials before we implement these strategies.”

■

were unaware of their HCV status and 90.8% agreed to testing. Of the patients who underwent testing, 12% had a positive anti-HCV test and 72.5% of those also tested positive for HCV RNA. HCV was more likely to be found in

‘The ED may be an important venue for HCV screening of the baby-boomer birth cohort.’

—James Galbraith, MD

men, blacks, individuals on Medicaid and uninsured patients.

“The ED may be an important venue for HCV screening of the baby-boomer birth cohort,” said Dr. Galbraith.

According to J. Gregory Fitz, MD, past president of the American Association for the Study of Liver Diseases, the study underscores the hidden hepatitis C epidemic.

“You have an enormous reservoir of disease out there,” said Dr. Fitz, who is provost and dean of the University of Texas Southwestern Medical School, in Dallas. “This is a quick study and an early study, and it is consistent with my own experience, but it really does need to be reproduced in a much larger population over a much longer period of time.”

He said the study is a validation of the CDC recommendation that all patients born between 1945 and 1965 be tested for HCV infection.

■ Drs. Galbraith and Fitz reported no conflicts of interest.

23

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

Telemedicine continued from page 1

Despite this, the nurse was successful— thanks to telemedicine, a doctor was able to make a confirmatory diagnosis from more than 100 miles away.

The level of detail afforded by telemedicine is a far cry from grainy black-andwhite security camera footage, thanks to advances in video conferencing technology and data streaming capabilities. As the technological barriers fall, telemedicine is poised to become increasingly widespread; however, several hurdles remain, particularly with respect to reimbursement and clinician adoption.

“I think we are at step 1 of a very, very long race,” said Brendan Carr, MD, assistant professor of emergency medicine at the University of Pennsylvania’s Perelman School of Medicine, in Philadelphia.

Even in these early stages, telemedicine’s lens can capture a wide range of

cardiology procedure performed in Missouri; via telemedicine, he was able to have a postoperative visit in his hometown.

“When we asked him about it afterward,” Ms. Deibert said, “he was almost in tears, saying: ‘My daughter just got chemotherapy yesterday, and if I would have had to go to St. Louis, I would have been away from her for two to three days.’”

A recent study published in Critical Care Medicine evaluated the quality of care for pediatric patients who visited five rural emergency departments (Dharmar M et al. 2013;41:2388-2395).

Through a chart review, the investigators found that quality of care was highest for patients who received consultation by telemedicine, intermediate for patients who received consultation by telephone and lowest for patients who did not receive consultation. Likewise, a survey of the patients’ parents revealed that parental satisfaction was highest for the telemedicine consultations.

unique licensing and credentialing problems. “We never think about where [patients] are when they’re on the phone,” Dr. Carr said. But with telemedicine, state lines may come sharply into focus.

Mercy Telehealth Services covers five states: Arkansas, Kansas, Missouri, Oklahoma and South Carolina. Some of those states, such as Arkansas, Missouri and South Carolina, recognize out-of-state nursing licenses. Still, “you’ve always got to pay attention to the state lines,” Ms. Deibert said. “It takes a lot of work to get a physician licensed in a different state, anywhere from three months to a year,” she said. Both Ms. Deibert and Dr. Dharmar noted that proponents of telemedicine comprise some of the voices in the call for universal medical licensing.

Telemedicine also raises issues of privacy for the patient and the physician.

“We’re pretty far away from figuring out how you make this HIPAA-compliant on both sides,” Dr. Carr said.

Better Outcomes Telemedicine also can save money in other ways, such as decreasing errors or length of stay. Dr. Dharmar and his colleagues evaluated physicianrelated medication errors by analyzing the charts of 234 pediatric patients.

They compared the rates of medication errors based on the type of consultation: phone, telemedicine or no consultation (Dharmar M et al. Pediatrics 2013;132:1090-1097). Pediatric patients who received telemedicine consultation as part of their care had lower odds of medication errors than patients receiving phone consultation (odds ratio [OR], 0.19; P<0.05) or no consultation (OR, 0.13; P<0.05).

Implementing telemedicine can increase efficient use of resources at health care systems. Preliminary study findings, Dr. Dharmar said, indicate that telemedicine could save tens of thousands of dollars due to more

Telemedicine ‘changed how we are able to deliver our medical care’ by helping to close the gap ‘between an underserved population and a medically served population.’

—Madan Dharmar, MBBS, PhD

specialties. At Mercy Hospital St. Louis, the telemedicine program includes areas of care such as pediatric neurology and endocrinology, as well as pulmonology and dermatology.

“We are using telemedicine across the continuum of care, from the inpatient setting to the outpatient clinic setting and then into the home setting,” said Wendy Deibert, RN, BSN, vice president of Mercy Telehealth Services. “You can create all kinds of paths down the telemedicine road.”

“In our experience, patients are very satisfied with the consultation [through] telemedicine,” said Madan Dharmar, MBBS, PhD, a pediatric telemedicine specialist at the University of California, Davis Children’s Hospital, and an author of the study. “Overall, patients seem to receive telemedicine very well.”

Telemedicine, Dr. Dharmar said, “changed how we are able to deliver our medical care” by helping to close the gap “between an underserved population and a medically served population.”

Patient Satisfaction

Challenges for Clinicians

Patients seem to be responding positively. “The patients are the easy ones,” Ms. Deibert said. “They love being able to go to their hometown to see a doctor from wherever. They really don’t mind the video perspective.”

Ms. Deibert offered the example of a patient who lived in Arkansas and had a

In contrast to patients, winning over clinicians may prove to be a more difficult challenge. “Anecdotally, we have had plenty of resistance because [telemedicine] is new and change is hard,” Dr. Carr said.

Clinicians who frequently consult patients using telemedicine may encounter

Consultation Compensation Another aspect of physician resistance stems from the uncertainty of compensation for telemedicine calls. On the website of the American Telemedicine Association (ATA), CEO Jonathan Linkous wrote that a question he has been asked most frequently during his 20-year experience is: “How do we get paid for telemedicine?”

Reimbursement for telemedicine consultation, from an insurance perspective, varies from state to state. As of February 2014, 21 states have introduced bills that would mandate provider coverage for telemedicine, according to the ATA, which tracks the state legislature addressing telemedicine reimbursement.

Medicaid coverage of telemedicine, which also differs by state, depends on where the consultation occurs—a health care system on the receiving end of the video conference must be deemed “rural” to be eligible for coverage.

informed transfer decisions. From the perspective of a tertiary care hospital with limited ICU beds, he said, “telemedicine can enable health care systems to prioritize ICU care to those who need the higher level of care, and also help local hospitals in caring for those admitted in their facility.”

A critical component of telemedicine is that the technology enables information to spread from clinician to clinician. It can take up to 17 years for a medical discovery to transition into common practice, Dr. Carr said, referring to a review that assessed the lag time between research and integration (Balas EA. Pediatr Ann 1998;27:581-584).

“Waiting two decades to get the word out is probably not the goal,” Dr. Carr said. By offering their expertise to other physicians via telemedicine, specialists can help “bend the dissemination and implementation curve.”

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24

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

EHRs continued from page 1

A spate of recent studies reflects just how varied physician responses have been to EHRs. Last November, IDC Health Insights surveyed 212 clinicians and found that 58% felt neutral, dissatisfied or very dissatisfied with EHRs. Additionally, RAND Corporation reported in October on several factors contributing to physician dissatisfaction with EHRs, such as interference with patient care, poor usability and the large amount of time consumed by data entry.

“An EHR is a source of both promise and frustration, which stems from a mismatch of expectation and reality,” said Anil Makam, MD, assistant professor in the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, who specializes in health care information technology. “It’s not like installing Microsoft Windows,” he said. “These things are not ready out of the box.”

For users who are learning how to implement EHRs in practice, the adoption process can be costly and disruptive.

For many physicians, the switch from paper records to electronic equivalents can be “very, very difficult,” said Lawrence Kosinski, MD, chair of the American Gastroenterological Association’s Practice Management and Economics Committee. Of more than half of the health care providers who reported being neutral or dissatisfied in the IDC Health Insights survey, 85% reported that EHRs result in a loss of productivity and 66% said the diminished time cut into patient visits.

At his practice in Elgin, Ill., Dr. Kosinski can see up to four patients per hour while simultaneously entering data into EHRs. The key is to position the computer and the patient to form a tight line of sight, he said, and to maintain frequent eye contact. And as he types, he will read back information to his patients.

Dr. Kosinski’s interest in medical databases spans 30 years. He designed his own electronic medical system in 2003. When the meaningful use requirements of the Medicare and Medicaid EHR Incentive Program were established in 2010, Dr. Kosinski and his colleagues at Illinois Gastroenterology Group switched to a commercial system, NextGen Ambulatory EHR. Although commercial systems enable physicians to meet the requirements for meaningful use incentives, vendors do not always design EHR systems with gastroenterologists in mind. Instead, Dr. Kosinski said, many systems are aimed at primary care doctors, who make up the largest slice of the EHR market. For gastroenterologists, whose records often require a higher level of detail, using these systems can be like trying “to fit a round peg in a square hole,” he said.

In some cases, physicians may overlook features that can optimize EHR use. With systems such as Epic, clinicians can optimize the EHR system by customizing their own note templates and order sets. “This reduces the number of clicks or words you have to type,” Dr. Makam noted.

“Instead of reinventing the wheel,” he said, a gastroenterologist who frequently sees patients with peptic ulcer disease, gastrointestinal bleeding or inflammatory bowel disease, for example, could create templates that automatically populate with the necessary information.

In the future, EHRs will emphasize configurability over customizability, Dr. Kosinski said.

‘An EHR is a source of both promise and frustration, which stems from a mismatch of expectation and reality.’

—Anil Makam, MD

‘The successful evolution of the EHR is dependent on physicians’ input.’

—Ellen J. Scherl, MD

“Vendors are moving toward a one-size-fits-all product,” he said, to stay competitive.

The 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD10), which Dr. Kosinski called “the big elephant in the room,” may pose problems for EHR developers. By Oct. 1, 2014, all EHR systems must support ICD-10 codes to remain compliant with meaningful use. For EHR vendors scrambling to update their systems, he said, “2014 will be like Y2K.” Beyond 2014, however, the outlook for EHRs trends toward the positive.

“The potential for EHR technology to enhance communication between physicians, patients and health care teams is unparalleled,” said Ellen J. Scherl, MD, associate professor in the Division of Gastroenterology and Hepatology at Weill Cornell Medical College, New York City.

And if clinicians can turn data in EHRs into actionable information through decision-support systems and predictive analytics, Dr. Makam said, the functionality of these systems could greatly improve. This is “a huge advantage we’re just beginning to tap into,” he said.

But without increased interaction between clinicians and vendors, the promising future of EHRs may never come to fruition. “The successful evolution of the EHR is dependent on physicians’ input,” Dr. Scherl said.

■

Hospital, and associate professor of medicine at Harvard Medical School, both in Boston, noted: “Dr. Cotton and colleagues are to be congratulated for performing this study and providing answers to some of the common clinical questions confronting clinicians. The results from the EPISOD trial have been long awaited by gastroenterologists and those who care for patients with SOD,” he said.

“Given the high rate of complications with ERCP in this patient group and the potential for further harmful interventions, I think the EPISOD study has provided direction for clinicians who care for and patients with biliary type III SOD,” Dr. Saltzman concluded. “Based on these results, we should no longer offer ERCP with manometry and/ or sphincterotomy in these patients. Further research is clearly needed in patients with SOD to better define subgroups and to elucidate alternative therapies that improve patient outcomes.”

■

Drs. Kosinski, Makam and Scherl reported no conflicts of interest.

The study was funded by National Institute of Diabetes and Digestive and Kidney Diseases.

Sphincterotomy continued from page 11

Lowest volume of active prep solution— only 10 oz.

Superior

cleansing *

…that

patients preferred in clinical trials

†

*Demonstrated non-inferiority with both split-dose and day-before regimens, evaluated in randomized trials using the validated Aronchick scale. Superior cleansing efficacy of split-dose regimen demonstrated vs day-before regimen comparator (84% vs 74%, respectively, achieving “excellent or good” visualization). The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efficacy endpoint was the proportion of patients with successful colon cleansing defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists.

[Prepopik: n=256/304; comparator: n=221/297].1-3 SUPERIOR CLEANSING

PATIENT PREFERENCE

with the ACG-recommended split-dose regimen, assessed using validated scales*‡1,2

reported in clinical trials†1-3

Percentage of patients achieving excellent or good visualization in the split-dose trial

Patient reactions to bowel prep regimens in the split-dose trial

Colon segment

Prepopik

2L PEG+E plus 2x 5 mg bisacodyl tablets

Overall

84%

74%

(n=256/304)

Ascending Mid (Transverse and Descending)

Rectosigmoid

90%

(n=272/304)

92%

(n=221/297)

79%

10%

86%

(n=255/297)

92%

87%

Completed preparation

DIFFERENCE

(n=234/297)

(n=281/304) (n=281/304)

Patient perspective

(n=259/297)

Prepopik

99%

(n=304/305)

96%

Would ask for the prep again in the future

(n=290/302)

Was very easy or easy to take

(n=270/302)

89%

2L PEG+E plus 2x 5 mg bisacodyl tablets

91%

(n=267/292)

55%

(n=162/296)

29%

(n=86/296)

SPLIT-DOSE OR DAY-BEFORE REGIMEN4

INDICATION AND IMPORTANT SAFETY INFORMATION Prepopik ® for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults.

• Prepopik is contraindicated in the following conditions: patients with severely reduced renal function, gastrointestinal obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should be advised on the importance of adequate hydration, and post-colonoscopy lab tests should be considered if a patient develops significant vomiting or signs of dehydration after taking Prepopik • Patients with electrolyte abnormalities should have them corrected before treatment. Use caution when prescribing for patients who are at risk for seizures, or arrhythmias, including those patients with a history of prolonged QT, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy.

Caution should also be used in patients with impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function, electrolyte imbalance and/or water retention • Oral medication administered within one hour of the start of administration of Prepopik solution may be flushed from the GI tract and the medication may not be absorbed. Prior or concomitant use of antibiotics with Prepopik may reduce its efficacy. Tetracycline and fluoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of Prepopik to avoid chelation with magnesium. Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization.

Concurrent use of additional stimulant laxatives with Prepopik may increase this risk • Prepopik should not be used if gastrointestinal obstruction or perforation is suspected. Prepopik is not for direct ingestion. Each packet must be dissolved in 5 ounces of cold water and administered at separate times, in addition to additional clear fluids, according to the dosing regimen. In randomized, multicenter, controlled clinical trials, nausea, headache, and vomiting were the most common treatment-emergent adverse reactions (>1%) following Prepopik administration

Please see brief summary of Prescribing Information following this advertisement. †

The SEE CLEAR I and SEE CLEAR II studies were phase 3, randomized, multicenter, assessor-blinded, noninferiority studies in patients preparing for colonoscopy. The primary endpoints were evaluation of overall colon cleansing with Prepopik vs a comparator using modified Aronchick and Ottawa scales. Patients were also required to complete a questionnaire, which included the questions: “How easy or difficult was it to consume the prescribed bowel preparation?” and “Would you ask your doctor for this preparation again if you needed another colonoscopy in the future?”1,3

‡

The Ottawa bowel preparation scale assesses bowel cleanliness by section, based on numeric scores of 0-4. A score of 0 denotes “excellent” cleansing with ascending numbers denoting “good,” “fair,” “poor,” and “inadequate.” Additional numeric value is assigned based on the amount of fluid present (small, moderate, or large). [Prepopik: n=272/304; comparator: n=234/297].1,2

Visit prepopik.com/testimonials to hear what patients and healthcare professionals have to say about Prepopik!

References: 1. Rex DK, Katz PO, Bertiger G, et al. Split-dose administration of a dual-action, low-volume bowel cleanser for colonoscopy: the SEE CLEAR I study [published online ahead of print]. Gastrointest Endosc. 2013. http://dx.doi.org/10.1016/j.gie.2013.02.024. 2. Data on file. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA. 3. Katz PO, Rex DK, Epstein M, et al. A dual-action, low-volume bowel cleanser administered the day before colonoscopy: results from the SEE CLEAR II study. Am J Gastroenterol. 2013;108:401-409. http//dx.doi. org/10.1038/ajg.2012.441. 4. Prepopik® Prescribing Information, July 2012. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA. PREPOPIK® is a registered trademark of Ferring B.V. © 2013 Ferring B.V. All rights reserved.

PK/1219/2013/US(1)

26

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

Do You Need a Medical Scribe?

Frederick L. Greene, MD Clinical Professor of Surgery UNC School of Medicine Chapel Hill, North Carolina Over the past several decades, new and interesting medical and paramedical occupations have been created to reflect the changing complexities of our health care system. We have seen the proliferation of hospitalists, surgicalists

and laborists (in-hospital obstetrical specialists) on the physician side, and patient navigators, physician extenders and patient ombudsmen in the nonphysician cadre.

Now, there is an additional and intriguing job title that may gain some traction even in the high-tech era of the electronic medical record (EMR): the “medical scribe.”

The medical scribe, also known as a “clinical scribe,” “ER scribe” or “ED scribe,” is a trained medical information

Aspiration Patients with impaired gag reÀex and patients prone to regurgitation or aspiration should be observed during the administration of PREPOPIK. Use with caution in these patients.

Not for Direct Ingestion Each packet must be dissolved in 5 ounces of cold water and administered at separate times according to the dosing regimen.

The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information. ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances.

INDICATIONS AND USAGE PREPOPIK® (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults.

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, CONTRAINDICATIONS adverse reaction rates observed in the clinical trials of a drug cannot PREPOPIK is contraindicated in the following conditions: be directly compared to rates in clinical trials of another drug and may • Patients with severely reduced renal function (creatinine clearance not reÀect the rates observed in practice. less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium and vomiting were the most common adverse reactions (>1%) • Gastrointestinal obstruction or ileus following PREPOPIK administration. The patients were not blinded to • Bowel perforation the study drug. Since abdominal bloating, distension, pain/cramping, • Toxic colitis or toxic megacolon and watery diarrhea are known to occur in response to colon cleansing • Gastric retention preparations, these effects were documented as adverse events in • An allergy to any of the ingredients in PREPOPIK the clinical trials only if they required medical intervention (such as a change in study drug or led to study discontinuation, therapeutic or WARNINGS AND PRECAUTIONS diagnostic procedures, met the criteria for a serious adverse event), Serious Fluid and Serum Chemistry Abnormalities or showed clinically signi¿cant worsening during the study that was Advise patients to hydrate adequately before, during, and after the not in the frame of the usual clinical course, as determined by the use of PREPOPIK. Use caution in patients with congestive heart investigator. failure when replacing Àuids. If a patient develops signi¿cant vomiting PREPOPIK was compared for colon cleansing effectiveness with or signs of dehydration including signs of orthostatic hypotension a preparation containing two liters (2L) of polyethylene glycol plus after taking PREPOPIK, consider performing post-colonoscopy electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets, all lab tests (electrolytes, creatinine, and BUN) and treat accordingly. administered the day before the procedure. Table 1 displays the most Approximately 20% of patients in both arms (PREPOPIK, 2L of PEG common adverse reactions in Study 1 and Study 2 for the PREPOPIK + E plus two x 5-mg bisacodyl tablets) of clinical trials of PREPOPIK Split-Dose and Day-Before dosing regimens, respectively, each as had orthostatic changes (changes in blood pressure and/or heart rate) compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were documented out to seven days post colonoscopy.

Table 1: Treatment-Emergent Adverse Reactions observed in at Fluid and electrolyte disturbances can lead to serious adverse events Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** and electrolyte abnormalities should be corrected before treatment with PREPOPIK. In addition, use caution when prescribing PREPOPIK Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen for patients who have conditions or who are using medications that Reaction increase the risk for Àuid and electrolyte disturbances or that may PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* increase the risk of adverse events of seizure, arrhythmia, and renal with 2 x (N=296) with 2 x 5-mg (N=305) impairment. n (% = n/N) 5-mg n (% = n/N) bisacodyl Seizures There have been reports of generalized tonic-clonic seizures with the use of bowel preparation products in patients with no prior history of seizures. The seizure cases were associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. The neurologic abnormalities resolved with correction of Àuid and electrolyte abnormalities.

Use caution when prescribing PREPOPIK for patients with a history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with known or suspected hyponatremia.

Use in Patients with Renal Impairment As in other magnesium containing bowel preparations, use caution when prescribing PREPOPIK for patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or non-steroidal anti-inÀammatory drugs). These patients may be at increased risk for renal injury. Advise these patients of the importance of adequate hydration before during and after the use of PREPOPIK. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur.

bisacodyl tablets (N=302) n (% = n/N) Nausea 8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3) Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7) Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0) * 2L PEG + E = two liters polyethylene glycol plus electrolytes solution. **abdominal bloating, distension, pain/cramping, and watery diarrhea not requiring an intervention were not collected tablets (N=298) n (% = n/N)

arrhythmias, and prolonged QT in the setting of Àuid and electrolyte abnormalities. This includes patients receiving drugs which may be associated with hypokalemia (such as diuretics or corticosteroids, or drugs where hypokalemia is a particular risk, such as cardiac glycosides) or hyponatremia. Use caution when PREPOPIK is used in patients on nonsteroidal anti-inÀammatory drugs (NSAIDS) or drugs known to induce Antidiuretic Hormone Secretion (SIADH), such as tricyclic antidepressants, selective serotonin re-uptake inhibitors, antipsychotic drugs and carbamazepine, as these drugs may increase the risk of water retention and/or electrolyte imbalance. Consider additional patient evaluations as appropriate.

Potential for Altered Drug Absorption Oral medication administered within one hour of the start of administration of PREPOPIK solution may be Àushed from the GI tract and the medication may not be absorbed.

Tetracycline and Àuoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of PREPOPIK to avoid chelation with magnesium.

Antibiotics Prior or concomitant use of antibiotics with PREPOPIK may reduce ef¿ f cacy of PREPOPIK as conversion of sodium picosulfate to its active metabolite BHPM is mediated by colonic bacteria.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Reproduction studies with PREPOPIK have been performed in pregnant rats at oral doses up to 2000 mg/kg/day (about 1.2 times the recommended human dose based on the body surface area), and did not reveal any evidence of impaired fertility or harm to the fetus due to PREPOPIK. The reproduction study in rabbits was not adequate, as treatment-related mortalities were observed at all doses.

A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses up to 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on the body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, PREPOPIK should be used during pregnancy only if clearly needed.

Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PREPOPIK is administered to a nursing woman.

Pediatric Use The safety and effectiveness of PREPOPIK in pediatric patients has not been established.

Geriatric Use In controlled clinical trials of PREPOPIK, 215 of 1201 (18%) patients were 65 years of age or older. The overall incidence of treatmentemergent adverse events was similar among patients 65 years of age ( 3%) and patients <65 years of age ( 1%). Among all patients 65 years of age, the proportion of patients with successful colon cleansing Electrolyte abnormalities was greater in the PREPOPIK group (81.1%) than in the comparator In general, PREPOPIK was associated with numerically higher rates group (70.9%). of abnormal electrolyte shifts on the day of colonoscopy compared to the preparation containing 2L of PEG + E plus two x 5-mg bisacodyl Renal InsufÀ f ciency tablets. These shifts were transient in nature and numerically similar Patients with impaired renal function or patients taking concomitant between treatment arms at the Day 30 visit. medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor Postmarketing Experience blockers, or non-steroidal anti-inÀammatory drugs) may be at The following foreign spontaneous reports have been identi¿ed during increased risk for further renal injury. Advise these patients of the use of formulations similar to PREPOPIK. Because these events are importance of adequate hydration before during and after the use reported voluntarily from a population of uncertain size, it is not always of PREPOPIK. Consider performing baseline and post-colonoscopy possible to reliably estimate their frequency or establish a causal laboratory tests (electrolytes, creatinine, and BUN) in these patients. relationship to drug exposure.

In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur. The Allergic reactions signs and symptoms of hypermagnesemia may include, but are not Cases of hypersensitivity reactions including rash, urticaria, and limited to, diminished or absent deep tendon reÀexes, somnolence, purpura have been reported. hypocalcemia, hypotension, bradycardia, muscle, respiratory paralysis, complete heart block, and cardiac arrest.

Electrolyte abnormalities There have been reports of hypokalemia, hyponatremia and OVERDOSAGE hypermagnesemia with the use of PREPOPIK for colon preparation The patient who has taken an overdose should be monitored carefully, prior to colonoscopy. and treated symptomatically for complications.

Cardiac Arrhythmias There have been rare reports of serious arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation. Use caution when prescribing PREPOPIK for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy Gastrointestinal ECGs should be considered in patients at increased risk of serious Abdominal pain, diarrhea, fecal incontinence, and proctalgia have been reported with the use of PREPOPIK for colon preparation cardiac arrhythmias. prior to colonoscopy. There have been isolated reports of reversible Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis aphthoid ileal ulcers. Ischemic colitis has been reported with the use Osmotic laxatives may produce colonic mucosal aphthous ulcerations of PREPOPIK for colon preparation prior to colonoscopy. However, a and there have been reports of more serious cases of ischemic colitis causal relationship between these ischemic colitis cases and the use requiring hospitalization. Concurrent use of additional stimulant of PREPOPIK has not been established. laxatives with PREPOPIK may increase this risk. The potential for mucosal ulcerations should be considered when interpreting Neurologic colonoscopy ¿ndings in patients with known or suspected inÀammatory There have been reports of generalized tonic-clonic seizures associated with and without hyponatremia in epileptic patients. bowel disease.

Use in Patients with SigniÀcant Gastrointestinal Disease If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering PREPOPIK. Use with caution in patients with severe active ulcerative colitis.

manager who specializes in charting physician–patient encounters in real time.

Although originally spawned as an adjunct in the emergency medicine environment, this clerical resource has been introduced now into the inpatient and office settings.

Traditionally, physicians would complete their history gathering, physical examination and discussion with patients before writing or dictating notes that eventually would be included in the paper

DRUG INTERACTIONS

Manufactured by: Ferring Pharmaceuticals (China) Co., Ltd. No. 6 HuiLing Lu (Ferring Road) National Health Technology Park Zhongshan City, Guangdong Province, CHINA Manufactured for: Ferring Pharmaceuticals Inc. Parsippany, N.J. 07054

www.ferringusa.com 1-888-FERRING Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities Use caution when prescribing PREPOPIK for patients with conditions ©2014 Ferring Pharmaceuticals Inc. or who are using medications that increase the risk for Àuid and All rights reserved. Printed in USA. electrolyte disturbances or may increase the risk of seizure, PK/069/2014/US

file. With the advent of the EMR, data are usually prepopulated by nursing personnel and then completed either during or after a patient encounter.

One of the unintended and unfortunate consequences of electronic data recording is scenarios in which physicians literally face the computer screen rather than their patients in order to populate data in the EMR. The time that physicians spend during a patient visit capturing and entering data rather than focusing on the patient can be a major hindrance to the overall quality of care. Here is where the medical scribe may play a very important role. The medical scribe is an unlicensed individual hired to enter information into the EMR or chart at the direction of the physician or licensed independent practitioner. In-depth guidelines were released by the Joint Commission in 2011, and include the duties and supervisory issues of the medical scribe (www.jointcommission.org/mobile/standards_information).

In my opinion, this concept may help correct some of the negative consequences foisted on all of us by the EMR. I sense that in the inpatient setting, the time that physicians, and especially physicians-in-training, are spending at the patient bedside has been drastically reduced in order to spend more time with EMR entry and review. In deciding whether to actually see patients or to complete the EMR entries before going to the OR each morning, the lure of the EMR frequently, and unfortunately, wins.

It would be a true benefit to have clerical support to document and transcribe, in a real-time fashion, the events of physician–patient interaction on rounds and to enter the data accordingly.

The same concepts apply to the office setting where our time should be spent interacting face-to-face with our patients, while having office notes completed by the medical scribe in real time during patient encounters. This may improve the overall quality of documentation for both granularity and specificity. Such granularity might be translated into improved billing codes and remuneration. This also would reduce the necessity of finalizing notes and EMR data after a busy clinic day. Think of the wonderful possibilities in terms of time management!

The positive results created by working with a medical scribe are legion.

These benefits may become more apparent especially as physicians continue to face the morass of data acquisition created by the launching and promulgation of the EMR and the real barriers that this disruptive technology creates for patients and physicians alike.

■

Q & A

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

27

A D V E R T I S E M E N T

Improve Mucosa Viewing With ENDOCUFF™ Endoscopic Overtube

Q.

What is the ENDOCUFF Endoscopic Overtube?

A. ENDOCUFF Endoscopic Overtube is a single-use, disposable device that fits on the tip of the endoscope to improve the physician’s ability to visualize and examine the mucosa, and improves tip control during extubation.

does not occlude the working channel of the endoscope, so no change is required for biopsies or polypectomies. The ENDOCUFF Endoscopic Overtube may provide additional stability during polyp removal, allowing for greater control during the procedure.

Q.

Q.

A.

A.

Does the ENDOCUFF Overtube fit all endoscope models?

The ENDOCUFF Endoscopic Overtube is available in different sizes to fit most Olympus, Pentax and Fujinon colonoscopes.

How do I add this product to my practice?

To schedule a product consultation and evaluation, visit www.medivators.com/ endocuff, or contact Medivators at (800) 444-4729, option 1.

Q.

How does the ENDOCUFF Endoscopic Overtube help improve colon visualization?

A.

During withdrawal, the ENDOCUFF Overtube’s flexible arms open the bowel for inspection, everting large mucosal folds to provide clear views of mucosa previously difficult to visualize.

INCREASE YOUR ADENOMA DETECTION RATE

Q.

Can ENDOCUFF Overtube improve adenoma detection rates and procedural outcomes?

A. Yes, studies have shown that use of the ENDOCUFF Endoscopic Overtube significantly improves adenoma detection rates and provides a higher standard of patient care through improved screening and polyp detection.

Studies show ENDOCUFF™ Endoscopic Overtube assisted colonoscopy significantly increases ADR and assists in complex polyp removal.

Q.

Will use of the ENDOCUFF Overtube increase procedure time?

Provide the highest standard of care for your patients.

A.

No. During intubation, the arms fall flush with the colonoscope, allowing for unimpeded forward motion. During extubation, the arms gently center the endoscope tip within the colonic lumen, stabilizing the scope while reducing red-out and the need for reintubation. This stability creates an environment that can improve outcomes while not increasing procedure time.

MEDIVATORS A Cantel Medical Company

Q.

How will usage affect the “feel” of the endoscope?

A. The ENDOCUFF Endoscopic Overtube reduces slippage and assists the physician by maintaining a steady view while instruments are fed through the biopsy channel.

The hinged arms fall flush with the colonoscope to not interfere with forward motion.

No ENDOCUFF Endoscopic Overtube Unable to control tip of colonoscope

Q.

Does usage require a change in technique?

A.

No. However, with increased experience, physicians can use the flexible arms to manipulate mucosa folds, polyps or debris to gain a better view without losing field of view. With increased usage, physicians have found greater value in the device’s ability to improve visualization and tip control.

Q.

How do I remove a polyp with ENDOCUFF Endoscopic Overtube on the endoscope tip?

A. The ENDOCUFF Endoscopic Overtube

ENDOCUFF Endoscopic Overtube attached Same scar evaluation

MEDIVATORS.COM © 2014 Medivators Inc. P/N 50098-498 ENDOCUFF™ is a trademark of Arc Medical Design Limited

Your Best Practice is Our Promise. &/%04$01: 130$&%63& r &/%04$01: 3&130$&44*/(

28

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

Digital Distraction: Signs of Improvement, But More Focus Needed Peter Papadakos, MD Professor of Anesthesiology, Neurology, Neurosurgery and Surgery University of Rochester Medical Center Rochester, New York In November 2011, I wrote an article outlining my observations of the growing addiction of hospital staff to their smartphones. Not long after the piece appeared (“Electronic Distraction: An Unmeasured Variable in Modern Medicine,” Anesthesiology News November 2011;37:8), I received a call from a reporter for The New York Times, which ran its own article about digital distractions—what the paper dubbed “digital doctoring”—on the front page some weeks later (“As Doctors Use More Devices, Potential for Distraction Grows” by Matt Richtel. Dec. 14, 2011).

The Timess story, and subsequent media coverage, served as a call to action in the fields of professionalism and patient safety. Professional societies in the United States and beyond began to address the issue through their annual meetings, safety committees, guidelines and studies. The issue was widely addressed in the newsletters of many health care groups including the ECRI Institute, the Association of periOperative Registered Nurses (AORN), the American Academy of Orthopaedic Surgeons (AAOS), Canadian and American respiratory therapists and the Congress of Neurological Surgeons.

Table. University of Rochester Modified CAGE Questions Have you ever felt you needed to cut down on the use of your PED?

So, where do we stand? The signs are encouraging. Medical centers throughout the country have started to develop guidelines and recommendations on the use of electronic devices and professional behavior. Hospitals, medical schools and clinical departments have addressed the issue thorough grand rounds and staff education. It is being addressed in

operating rooms throughout the United States through the recommendations of AORN. ECRI even listed electronic distraction as one of the top 10 technology hazards for 2013.

We have made strides to at least address this issue of addiction with health care workers. One of the tools that has become popular during these

educational programs is the University of Rochester Modified CAGE Questions (Table). CAGE is a highly validated survey of alcohol addiction, which has been modified and replaces drinks with personal electronic devices (PEDs).

This survey self-validates to the participant his or her own shortcomings with PEDs and is a springboard to starting a

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Have people annoyed you by criticizing your use of your PED?

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

dialogue and correction of behavior in the professional environment. Organized medicine has thus started to self-correct and educate its practitioners at all levels of technical staff.

But as we train ourselves in electronic etiquette and the proper way to interact with technology in both our personal and professional lives, we must look at society as a whole. Health professionals should be at the forefront of educating the general public in the many dangers of electronic intrusion. These devices are rapidly changing how humans interact with and

behave toward each other.

The ever-rising figures of mortality and morbidity by texting while driving— a reporter earlier this year said texting at the wheel now kills 3,000 American teens per year, making it the leading cause of death in this age group—and the tens of thousands of brain-injured survivors and the millions of dollars required for their care will, of course, increase costs and burden the already strained rehabilitation system.

New mental illnesses identified as an addiction to PEDs and to the Internet

are reshaping our understanding of how the human brain functions. And virtual relationships like cyber-bullying, pornography and online gaming are altering our society in ways we have not yet begun to fully comprehend. Medicine also is identifying physical conditions that can cause lifelong disabilities such as injury due to repetitive use of the thumbs and back deformities such as “Game Boy back” from prolonged hours of texting.

As health professionals, we already have become leaders in self-correction

29

of this behavior and developing ways of addressing these technology issues. I call on each of us to begin educating both our families and communities. Hospitals and health professionals should educate young people in the schools of the dangers of overuse of this technology. We should educate our elected officials on the dangers of not only texting and driving, but on distracted pedestrians and their other psychological and physical problems.

Through education, we can effect great, positive change in how we interact with these new technologies.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

Bariatric Surgery May Stunt Aging Mechanism

BY CHRISTINA FRANGOU Bariatric surgery may reverse the shrinkage of telomeres, the caps on the ends of each strand of DNA that are considered markers for biological aging, according to a small, preliminary study presented at Obesity Week 2013.

“This is the first study to demonstrate that surgical weight loss leads to decreased aging by increasing telomere length,” said lead author John M. Morton, MD, MPH, director of bariatric surgery, Stanford University in Stanford, Calif.

He and his colleagues presented the findings at the first annual joint meeting of the American Society for Metabolic and Bariatric Surgery and The Obesity Society.

Over the past decade, there has been increased attention focused on telomeres.

Often likened to the tips on the ends of shoelaces, telomeres are responsible for maintaining chromosome stability. Every time cells replicate, the telomere frays and shortens, losing some genetic material in the process. Shortened telomeres have been linked to higher rates of cancer, neurodegenerative diseases and mortality.

But although researchers understand more about what happens as telomeres lose integrity, little is known about how to prevent it. It is believed that interventions to prevent telomere shortening could increase longevity

and decrease incidence of age-related dementia (Honig LS et al. Arch Neurol 2012;69:1332-1339).

Obesity is one of the drivers of telomere shortening and experiments in mice suggest that obesity increases the formation of reactive oxygen species in fat cells and shortens telomeres (Ahima RS. Nat Med 2009;15:996-997). Based on these findings, Dr. Morton and his colleagues set out to look at whether weight loss induced by bariatric surgery could influence telomere length.

They studied 55 patients (mean age, 48.5 years) who underwent laparoscopic gastric bypass for obesity and telomere analysis by Telomere Diagnostics, Inc. Overall, patients’ telomere length remained relatively stable, measuring 0.987 (relative to 1.0) preoperatively and 0.982 one year after surgery (P=0.764).

P But specific groups of patients showed remarkable improvements in telomere length, particularly those with the highest preoperative levels of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP).

Patients with high preoperative CRP, defined as 7 at baseline, demonstrated a 2.83% increase in telomere length one year after surgery. Patients with high LDL-C preoperatively, defined as greater than 140 at baseline, showed a 1.62% increase in telomere length.

“I look at it this way: It’s the sickest patients—those with the worst

cholesterol, the most inflammatiion— who got the mostt benefit, benefit,” said Dr. Morton.

The findin ngs suggest that theree may be a way to determine who will have the best results from bariatric surgery, an issue that willl become even more important in the next few years under health h lh care reform, said Bruce Wolfe, MD, professor of surgery at Oregon Health & Science University in Portland, who was not involved with the study.

“A fundamental question in bariatric surgery is how to determine beforehand who will have a very good operation so we can focus the selection of patients,” he said.

“What this study showed, as I interpret it, is that the gastric bypass and resultant weight loss led to restoration of telomere function and chromosomal preservation. If indeed the weight loss does have a positive effect on preservation of DNA and how it functions, that is a remarkable finding.”

Dr. Wolfe cautioned that although the study provides proof of concept, more information is needed.

Currently, the investigators have expanded the study and plan to conduct

Telomeres (highlighted in red) are responsible for maintaining chromosome stability and are considered markers for biological aging.

Source: NASA

telomere analysis on more than 1,500 patients who underwent gastric bypass as part of the National Institutes of Health research consortium on bariatric surgery, known as LABS. Such a study would provide more information about what happens to the telomeres of bariatric surgery patients, particularly in the long term. Dr. Wolfe is co-chair of LABS. It is unknown if telomere erosion itself contributes to aging or if it is a reflection of the aging process. That’s a question for future research, said Dr. Morton.

■ Dr. Morton has served as a consultant for Covidien and Ethicon. Dr. Wolfe reported no relevant conflicts of interest.

Study Provides Snapshot of Recent Bariatric Demographics, Outcomes Stability Seen; More Current Data May Alter Patterns

BY CHRISTINA FRANGOU Despite major shake-ups in insurance coverage of bariatric surgery since 2007, the demographics of patients who undergo these procedures have not changed, a new study shows.

Also stable throughout the study period were patient safety outcomes, measured in terms of morbidity and mortality. These remain virtually unmoved since 2007, with major complications reported in around 2% of patients and deaths in 0.1%.

“We’ve reached a certain stability where both morbidity and mortality are unchanged from year to year. These statistics now represent what would be considered average for these types of cases,” said Ranjan Sudan, MD, a bariatric and robotic surgeon and vice chair of education, Duke University Health System, Durham, N.C. Dr. Sudan presented the study on behalf of the research committee and the executive council of the

American Society for Metabolic and Bariatric Surgery at Obesity Week 2013.

The study paints a picture of bariatric surgery at U.S. centers of excellence by gender, ethnicity, age, procedure, rate of complications and outcomes. It shows very little change between 2007 and 2011. Overall, there were no significant increases in the percentage of minoriities, males or individuals with diabetes wh ho underwent bariatric surgery.

Of the more than 364,000 patients in the study, 1.75% experienced a serious adverse event (AE) within the first 30 days, and 2.02% experienced a serious AE within one year. The one-year serious AE rate stayed close to that average throughout the six years of data collection, peaking at 2.18% in 2009 and dropping to 1.66% in 2011.

The data are not risk-adjusted so it is impossible to compare complication or death rates across procedures.

Generally, patients with a higher body mass index, more

excess body weight and more comorbidities bd tended d d to undergo d more extensive reconstructive bariatric procedures, such as gastric bypass or biliopancreatic diversion with duodenal switch. For this reason, the investigators caution against comparing complication rates across different procedures.

But, they added, the complication and mortality rates within procedures could be used for benchmarking.

One-year mortality rates were 0.84% for biliopancreatic diversion with duodenal switch, 0.26% for Roux-en-Y see Bariatric Demographics, page 32

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

Bariatric Procedures Decline Despite Rise In Rates of Obesity, Diabetes Why This Is, and What We Should Do About It Mitchell S. Roslin, MD Chief, Bariatric and Metabolic Surgery Lenox Hill Hospital/NSLIJ New York, New York Northern Westchester Hospital Center Mt. Kisco, New York Imagine there is an investment opportunity for a product in the medical space that treats a condition that is growing in prevalence, is increasingly associated with premature morbidity and mortality, has little competition, and has years of data documenting safety and efficacy.

Sounds like a great investment and the chance to invest in the next Intuitive Surgical. Intuitive Surgical is the darling of Wall Street. Its share price has increased 400% in the past five years.1 This growth has been achieved despite the fact that the daVinci system has never shown better outcomes in any area over standard laparoscopy, while being a good deal more expensive.2 That is why the story of bariatric surgery is so confounding. Despite data that have shown remission of diabetes, cardiac risk reduction, improved quality of life and weight loss results that cannot be challenged by any other treatment for obesity, the number of procedures performed in the United States has, at best, remained stable since 2010.3 In all probability, the total number of cases performed has declined by approximately 10%.

If revisions are subtracted, the number of people having bariatric surgery has declined even further.

These statistics are even harder to understand when you add the documented safety improvements that have reduced mortality from 0.5% to less than 0.1%.4 Furthermore, each year numerous fellows complete outstanding minimally invasive training programs that emphasize bariatric surgery. As a relatively young field, the number of people entering bariatric surgery practice far exceeds the number of surgeons with large bariatric practices who are retiring. The purpose of this article is to examine the factors and propose potential solutions for this issue.

Some may believe this is inconsequential. Some may think, “My practice is fine, so why be concerned?” To

Bariatric Demographics continued from page 31

gastric bypass, 0.11% for sleeve gastrectomy and 0.05% for gastric banding.

“The study provides real-life benchmarks for common bariatric procedures, benchmarks that surgeons and credentialing bodies can use to compare a surgeon’s outcomes,” said Dr. Sudan.

The study showed a trend toward more blacks and Hispanics undergoing bariatric surgery. The percentage of black patients rose from 10.11% in 2007 to 13.43% in 2011, and the percentage of Hispanic patients increased from 5.84% to 8.44%.

However, the increase in these minority

the contrary, I believe that this is the most sentinel issue facing the field. Absence of growth and penetration of an exceedingly low percentage of the potential population that could benefit from bariatric surgery is a strong indicator that our message is still not being heard, and as health care reform moves forward, bariatric surgery will be a low priority. With increasing economic pressure, further decline is inevitable.

Returning to my corporate analogy, if bariatric surgery was a company, shareholders would be questioning current executives and the board of trustees. As specialists, we are not a company or corporation, but it is imperative that part of the mission of our national specialty society, journals and publications be to disseminate the outstanding data accumulated and to improve access for these life-

For the past year, Allergan’s total revenue for its bariatric unit was $160 million. This is down from $269 million the year before.6 For simplicity, assume that the revenue per band-patient is $3,000. This would include cost of needles, accessory ports and so on. The amount of cases done with the Allergan system was around 53,000 in 2011. At maximum, it was approximately 85,000.

Several years ago it was estimated that bands replaced, or nearly equaled gastric bypass as the most prevalent procedure. Add at most 10% market share for the Realize band, and the maximum number of cases performed was 200,000. Lap-Band revenue has declined more than 30% in the past two years. Some have argued that stapling procedures have stayed the same and the number of band procedures has declined. If that is true, then the

Despite data that have shown remission of diabetes, cardiac risk reduction, improved quality of life and weight loss results that cannot be challenged by any other treatment for obesity, the amount of procedures performed in the United States has, at best, remained stable since 2010. saving procedures. As our data have improved, we need to begin the difficult task of questioning our strategy and see how, collectively, our field can succeed, even in the current economic decline.

Penetration and the Numbers The exact number of bariatric procedures performed in the United States has been estimated to be as high as 250,000. Although all agree that the number has stabilized or plateaued after rapid growth from 2000 to 2008, the actual number is one of debate, and, by my calculation, frequently overestimated.5 I believe that the most accurate way to determine the number of bariatric procedures is to use the revenue reported by Allergan for its obesity unit.

As a publicly traded company, it is easy to determine the maximum number of gastric bands that Allergan has sold.

From these data, we can estimate the percentage of bands representative of the total market, as well as the percentage of total bands that the Lap-Band comprises.

patients is still less than what would be expected based on the prevalence of obesity in this population, Dr. Sudan said.

The most common comorbid condition among bariatric patients was hypertension, roughly twice the rates of diabetes, sleep apnea, gastroesophageal reflux disease and musculoskeletal disorder. Notably, about one-fourth of bariatric patients between 2007 and 2011 had been diagnosed with diabetes.

Surgeons said they expect a greater percentage of patients with diabetes to undergo bariatric surgery in 2013 specifically to treat their disease. Multiple studies have shown that overweight and obese patients with type 2 diabetes improve or

total number of cases performed in the United States is approximately 170,000, which I believe is reasonably accurate. It is not likely that all the patients who would have had bands have had a sleeve gastrectomy or gastric bypass instead. What is far more likely is a significant decline for the total market.

This has occurred as the prevalence of obesity and diabetes has continued to increase. It is now estimated that 6.6% of the U.S. population has a body mass index (BMI) greater than 40 kg/m2. This percentage more than doubles if one includes individuals with severe obesity, or BMI greater than 35 kg/m2. Furthermore, the American Diabetes Association estimates that there are 25 million individuals with diabetes in the United States and another 79 million with prediabetes. The most recent estimate of the U.S. population is 311 million. So, there are at least 20 million individuals with a BMI greater than 40 kg/m2.

If we conservatively estimate the potential target market

reverse their condition, as well as reduce their cardiovascular risk factors, years after the surgery (Brethauer SA et al. Ann Surg 2013;258:628-636). In 2011, the International Diabetes Federation Taskforce on Epidemiology and Prevention of Diabetes issued a statement that bariatric surgery can be considered an appropriate treatment for people with type 2 diabetes and obesity who are not achieving recommended treatment targets with medical therapies (Dixon JB et al. Diabet Med 2011;28:628-642).

Vivek N. Prachand, MD, director of the University of Chicago Medicine Center for the Surgical Treatment of Obesity, said the study provides a “very nice snapshot”

see Procedure Rates, page 34

of bariatric surgery in the United States during an important period for the field, but he expects that things have shifted since 2012.

“These data don’t reflect the impact of recent high-quality data published in the nonsurgical literature demonstrating the profound impact of these operations on diabetes,” he said.

“The overall message from this study is that bariatric surgery is remarkably safe, and despite the absence of published clinical guidelines for procedure selection, it is encouraging to see that patients are generally undergoing procedures proportionate to the burden of their obesity and comorbidities.”

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

Despite widespread

Procedure Rates continued from page 32

for bariatric surgery as 30 million people, we have a penetration of only 0.5%. Thus, despite widespread media attention that has highlighted strong advantages for surgical therapy for obese individuals with diabetes, we treat less than 1% of those individuals. I know of no other area in medicine where the data and the penetration are this discordant.

Our challenge is to be critical and determine how we can better present our

message. We need to determine what data are most critical to assemble, and how we can accumulate them in a cost-effective manner. Finally, we have to realize the relevance of these facts.

For medical device manufacturers, bariatric and metabolic surgery represented growth. As a result, they became our partners battling for insurance approval for novel procedures such as sleeve gastrectomy. They provided financial support for our educational meetings, research grants and fellowship programs. It was a win–win situation. We were treating

an undertreated deadly condition using equipment they manufactured, such as staplers and bands. Growth was expected to continue, and more than justify their investment in our field.

But the numbers are vastly different today. The anticipated market potential for obesity and diabetes has not approached even conservative estimates. As a result, we can expect a reduction in industry support and investment. Recently, Johnson & Johnson eliminated its bariatric specialty sales unit. Instead, it has combined with hernia and thoracic surgery. In my

media attention that has highlighted strong advantages for surgical therapy for obese individuals with diabetes, we treat less than 1% of afflicted individuals.

I know of no other area in medicine where the data and the penetration are this discordant.

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opinion, this is not a trivial change.

We all know that the better financed lobbies and fields are going to fare best with health care reform. Although the Obesity Action Coalition has done a great job, its task is complicated by the present diversity of opinion regarding obesity. As opposed to the National Multiple Sclerosis Society, the Arthritis Foundation, the American Heart Association and the American Cancer Society, there is little uniformity regarding the mission of the obesity lobby. Are they fighting for cure, treatment or tolerance? It is thus essential that we continue to gain support from our industry partners, until our lobby becomes stronger. W also can join forces with other key players, such as the American Diabetes Association.

Prejudice Against Obesity A common rationale for the aforementioned data is discrimination against obesity and obese individuals. George Cowan, MD, a retired bariatric surgeon from Tennessee liked to say, “obesity was [the] last bastion of accepted prejudice in the USA.” Certainly, when states, unions or employers reduce coverage for bariatric surgery, many blog posts are supportive. But if we had a referendum on what is covered, few things other than child care and vaccinations would be popular. In all probability, the popularity of coverage would vary directly with the number afflicted. This should be promising, because if current growth rates continue, virtually the entire population will be obese by 2040.7 As a result, it would seem logical that prejudice against obese individuals will decline as more people and their family members desire treatment. This will be offset by the difference between an individual’s actual level of obesity and their perception. Frequently, many underestimate their degree of obesity. Additionally, there is the widespread belief that obesity is a condition of choice, caused

35

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ MAY 2014

treatment of obesity. The development of Obesity Week and the combined meeting of the American Society for Metabolic and Bariatric Surgery with the Obesity Society hopefully will initiate this process.

The Economy It is the opinion of many that an important cause of the decline or stabilization in bariatric surgery is the downturn of the economy. Certainly, one cannot discount the effect of the current economic condition. Unemployment levels have been approximately 10%. Not counted are many

by an absence of personal responsibility.

The argument continues: Why should I pay for coverage for a condition that is self-inflicted? There are limitations to this argument. Certainly, cigarette smoking causes the majority of lung cancers, and there are no limitations on treatment.

Similarly, even liver transplant in reformed IV drug addicts and alcoholics is a covered procedure. It is doubtful that this discrepancy can be explained by the fact that alcoholics, smokers and drug addicts are more popular than obese individuals.

Then what is the difference? In my estimation, it is the fact that there is consensus that the treatment of choice for end-stage liver failure is liver transplantation. All would agree that without treatment, lung cancer is a terminal disease. Even with treatment, the prognosis often is dismal.

In contrast, for obesity, there is no mandatory treatment level. The patient determines whether his or her obesity requires treatment. There is no accepted pathway.

For example, for hypertension, the firstlevel treatment may include behavioral changes followed by reexamination. If severe, medical therapy will be started.

If appropriate metrics are not reached, then the dose will be raised or additional agents will be started. For obesity, this metric does not exist. Thus, although bariatric surgery is considered the treatment for refractory morbid obesity, there is no accepted medical definition of what constitutes refractory morbid obesity. It is akin to being at the top of a nonexistent food chain. If there were an accepted treatment threshold, then those who do not respond would go up the chain. Many would ultimately be referred for surgery.

The existence of prejudice is an unfortunate fact of life. However, what limits treatment is the lack of consensus and a level that mandates treatment. It is essential that we understand this complex issue and work with other societies to develop an accepted clinical pathway for the

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people who have given up even searching for jobs. Struggling companies have had to reduce or at least stabilize their contribution for health insurance. Wages have been stagnant, yet health care costs and insurance rates have risen. Both employers and employees have been reluctant to increase their level of contribution for health insurance. To keep costs stable, covered benefits have been reduced. Individual and family deductibles, as well as copays have been raised. The net result is that the cost to an individual for elective surgery has increased. To reduce

expenditures, less robust benefit packages are being purchased. Often these contain riders or exclusions for services that are deemed not essential. Unfortunately, riders that exclude coverage for the treatment of obesity and surgical treatment for morbid obesity are not uncommon. The importance of this point cannot be overstated. Thus, although recent data have resulted in virtually all national insurance companies covering bariatric surgery, many of their clients purchase programs that exclude this coverage. see Procedure Rates, page 36

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For almost four decades, Gastroenterology & Endoscopy News has been providing gastroenterology health care professionals with specialty-specific news and reviews, offering comprehensive and objective information for the practicing clinician.

We are proud to be the best-read gastroenterology publication in the marketplace, and we look forward to continuing to be your #1 source for gastroenterology news in decades to come.

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

There Is No Such Thing as ‘Healthy Obesity’!

Editor’s note: The following editorial was first published in the January/February 2014 issue of Missouri Medicine.

M. Javed Ashraf, MD, MPH Cardiologist University of Missouri–Kansas City School of Medicine Kansas City, Missouri Overweight and obesity are the fastestgrowing causes of morbidity and death in the United States. Obesity is a chronic metabolic disorder associated with increased cardiovascular morbidity and mortality. However, despite the fact that obesity is associated with increased health hazards, in recent years there have been some confusing and contradicting reports of “healthy obesity,” “benign obesity” and “obesity paradox.” These reports unfortunately have tried to undermine the severity of this alarming problem.

Dr. Caroline Kramer and her colleagues highlighted the worsening obesity issue in their meta-analysis published last year in the Annals of Internal Medicinee (2013;159:758-769). They reported increased incidences of cardiovascular disease and all-cause mortality among obese adults for both metabolically unhealthy and metabolically “healthy” people of various weights and emphasized “there is no such thing as healthy obesity.”

The authors compared the cardiovascular and all-cause mortality for healthy and unhealthy obese groups. In their

meta-analysis with a follow-up of 10 years, metabolically healthy obese adults had an increased risk for all-cause mortality and cardiovascular disease. The data for their study came from eight prospective studies published during the past decade. Metabolic health was defined by the presence or absence of metabolic

syndrome as per Adult Treatment Panel III (ATP III) criteria or by the International Diabetes Federation. Excess weight is associated initially with subclinical metabolic and vascular dysfunction that ultimately leads to increased cardiovascular events and mortality.

The concept of “benign obesity”

‘Normal-weight obese’ individuals have an increased risk for diabetes and cardiovascular disease compared with individuals who are metabolically healthy and of normal weight.

Procedure Rates continued from page 35

The combination of fewer people with health insurance and exclusions for coverage for those with health insurance is certainly a major issue. Another cause has been the decline in net worth and total assets of Americans. As people are less wealthy, with declining home values, they are reluctant to pay out of pocket for bariatric surgery. This has certainly been a major issue for laparoscopic adjustable gastric bands. The cash pay market has decreased significantly.

Although economic issues certainly play a role, they do not completely explain why market penetration is so low.

In fact, after a sharp reduction at the beginning of the economic crisis, most fields have recovered. Some areas such as joint replacement and spine surgery have flourished.

There are many essential messages. Rather than caused by the recession and economic turbulence, I believe these data demonstrate how vulnerable our field is. Why are exclusions for obesity so popular? What can we do about it? It seems clear to all that cost pressures are only going to increase, and all fields in medicine will be competing for a smaller pie. Where will bariatric and metabolic surgery land when we have struggled even before the fiscal cliff?

To combat exclusions, it has been suggested to insurers and employers that bariatric surgery will offer a return

on investment (ROI) in two to three years; thus, it is an excellent investment for health care plans and employers.

The problem is whether this is true. Recently, I met with leadership of the Optimum Division of United Healthcare. Even with low in-network rates, their clients failed to have an ROI. In fact, more than 30% of the covered lives who had bariatric surgery had revisional procedures in less than three years. The majority had laparoscopic adjustable bands.

An additional misnomer is the implication that all patients who have bariatric surgery or a BMI greater than 40 kg/m2 are actuarial disasters for their insurers. In fact, major portions of patients who have bariatric surgery are premenopausal women without life-threatening risk for heart disease. In order to see an ROI, patients selected for surgery would need to have advanced disease. Unfortunately, the same people may be more likely to have significant complications, thus increasing costs.

These issues should not be cause for concern. I doubt there is any surgical procedure that can clearly show an economic ROI. Probably immunizations can, but few other areas. Even screening programs for cancer are only cost-effective if you add improved quality of life and reduced mortality. In terms of medical costs, they probably result in an increased number of procedures, such as biopsies that are frequently negative. Thus, as bariatric

originated from reports that evaluated metabolically healthy obese individuals over a short period of time. The authors claim their results do not support this concept of benign obesity. I applaud Dr. Kramer and her colleagues on their excellent work to clarify that there is no healthy pattern of obesity. In fact, the metabolically unhealthy adults, including those of mild obesity, exhibited the highest relative risk for cardiovascular events and all-cause mortality.

My colleague and I also highlighted the increased cardiovascular risks in obesity as well as among “normal-weight obese” (NWO) individuals in our review article recently published in Missouri Medicine (2013;110:499-504). NWO adults have increased atherosclerotic plaques in their arteries and worse clinical outcomes than those who have normal or smaller waist-to-hip ratios. NWO individuals have an increased risk for diabetes and cardiovascular disease compared with individuals who are metabolically healthy and of normal weight.

I strongly suggest that clinicians pay more attention to this group of NWO individuals as they are likely to perceive themselves as healthy. Regardless of metabolic status, if someone is obese or has normal-weight obesity, he or she should be considered at risk. The data from Kramer et al’s meta-analysis further strengthen the fact that obesity at any level or severity is not a benign condition and is never healthy.

■

surgeons, we should stop being actuaries and investment advisors, and highlight the fact that we can offer reversal and remission of serious chronic health issues. In contrast, without surgery, stabilization is often the goal. The key point is that we need to convince people of the value of our procedures for their immediate health care needs. The long-term health of an individual is affected by so many things, it is doubtful that any procedure or treatment can offer a return in hard health care costs.

■

References 1. ISRG Historical Price; Yahoo Finance.

2. Jin LX, Ibrahim AM, Newman NA et al. Robotic surgery claims on United States hospital websites. J Healthc Qual.

2011;33:48-52.

3. Adams TD, Davidson LE, Litwin SE et al. Health benefits of gastric bypass surgery after 6 years. JAMA. 2012;308:1122-1131.

4. Kim JH, Wolfe B. Bariatric/metabolic surgery: short- and long-term safety. Curr Atheroscler Rep. 2012;14:597-605.

5. Livingston EH. The incidence of bariatric surgery has plateaued in the U.S. Am J Surg. 2010;200:378-385.

6. Allergan Inc. Yearly report, 2008-2011.

7. Ruhm CJ. Understanding overeating and obesity. J Health Econ. 2012;31:781-796.

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38

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

The Early Days of Laparoscopic Bariatric Surgery From ‘Voodoo’ to Today’s Best Weapon Against Obesity and Metabolic Syndrome, Laparoscopic Surgery Hits Stride in Past Decade

BY VICTORIA STERN Alan Wittgrove, MD, became intrigued by laparoscopy during his surgical residency at San Diego Naval Hospital in the late 1970s. Jerry Ragland, MD, a staff

surgeon at the hospital, felt that operating with scopes would be the future of general surgery. His prediction turned out to be correct.

In the early 1990s, after laparoscopic cholecystectomy had gained a foothold in the United States, surgeons

began investigating minimally invasive approaches for a range of procedures. At the time, Dr. Wittgrove was exploring ways to reduce the high rate of incisional hernia complications (16%) associated with open gastric bypass, a procedure initially described in the late 1960s by

Advances in Probiotic Therapy For Diarrhea-Associated Illness To participate in this FREE CME activity, log on to

www.CMEZone.com

Release Date: February 10, 2014 Chair William D. Chey, MD Professor of Internal Medicine Director, Gastrointestinal Physiology Laboratory Co-Director, Michigan Bowel Control Program H. Marvin Pollard Institute Scholar Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

Faculty Brooks Cash, MD

Statement of Need

Intended Audience

Probiotics can be powerful tools in managing a number of medical conditions. However, effi fficacy may be suboptimal if these agents are not used appropriately. As public interest in the benefits fi of probiotics increases, so does the need for clinical education.

Many physicians and patients are unfamiliar with the nuances of probiotic pharmacology, or—with many probiotics available for over-the-counter purchase— may not be aware that their patients are selecting ineffective ff therapies. Thus, it is important for health care professionals to familiarize themselves with the latest research data on probiotic use.

Gastroenterologists, primary care physicians, nurse practitioners, nurses, physician assistants, pharmacists, and other health care professionals involved in the care of patients who may benefit fi from the use of probiotic therapy.

Professor of Medicine Division of Gastroenterology University of South Alabama Mobile, Alabama

Goal

Shanti Eswaran, MD

Learning Objectives

Clinical Assistant Professor Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

Expiration Date: February 10, 2015

The goal of this educational activity is to provide clinicians with current evidence and strategies for effecff tive probiotic therapy in a variety of disease states.

Upon completion of this activity, the participant will be better prepared to do the following: 1 Review key diff fferentiating characteristics of various probiotic therapies, including mechanism of action.

2 Describe the importance of strain specificity fi in the clinical applicability of probiotic therapies.

Estimated Time for Completion 1 hour

Course Format Monograph

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of AKH Inc., Advancing Knowledge in Healthcare, and Applied Clinical Education. AKH Inc. is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation AKH Inc. designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should claim only the credit commensurate with the extent of their participation in the activity.

3 Discuss the role of probiotic therapy in clinical digestive ailments.

4 Review strategies for appropriate patient selection and education in the use of probiotic therapies.

Jointly sponsored by AKH Inc. and Applied Clinical Education

Supported via an educational grant from Procter & Gamble

Distributed via CMEZone and Gastroenterology and Endoscopy News

surgeons Edward Mason, MD, and Chikashi Ito, MD (Surg Clin North Am 1967;47:1345-1351).

During Dr. Wittgrove’s travels to Belgium to learn laparoscopic Nissen fundoplication, he realized that he could turn an open gastric bypass into a laparoscopic technique. Upon his return to California in 1992, Dr. Wittgrove and G. Wesley Clark, MD, co-directors of a private practice bariatric surgery program in San Diego, began investigating ways to mimic the open procedure laparoscopically in the animal lab. The duo teamed up with Ethicon EndoSurgery to help develop new stapling technology. Once the circular stapler was approved, the surgeons had everything in place. In 1993, they performed the first laparoscopic Rouxen-Y gastric bypass in a patient.

Next, Drs. Wittgrove and Clark reported a case series of five laparoscopic Roux-en-Y gastric bypasses (Wittgrove AC et al. Obes Surg 1994;4:353-357).

They hand-selected patients with body mass indexes (BMIs) between 35 and 40 kg/m2 to ensure the best possible outcomes, given the early stage of the technique. The procedure was free for the patients: The anesthesiologist didn’t bill, Ethicon EndoSurgery donated equipment and follow-up was free.

“Bariatric surgery was still a bit of voodoo in early 1990s,” said Dr. Wittgrove.

“We were very attuned to the fact that this procedure might be controversial, so it was important for us to keep track of our patients’ data to refute any malicious attacks.”

Initially, Drs. Wittgrove and Clark were training surgeons at their primary facility but hospital administration became concerned that the facility might run into legal troubles if a patient had complications. The surgeons then began holding courses with a company named Vista, and later partnered with the American Society for Metabolic and Bariatric Surgery (ASMBS), then the ASBS, to run a laparoscopic gastric bypass program, in which they trained a select group of bariatric surgeons with laparoscopic experience to perform their technique on human cadavers.

During this time, the procedure began to spread, mostly among surgeons in private practice, and some surgeons, including Michel Gagner, MD, Philip Schauer, MD and James Ken Champion, MD, started bariatric programs and courses to help train surgeons throughout the United States.

Over the next few years, Drs. Wittgrove and Clark reported outcomes on a growing series of patients. By 1996, they had completed a series of 100 laparoscopic Roux-en-Y gastric bypasses (Wittgrove AC et al. Obes Surg 1996;6:500-504), and by 2000, the series had grown to 500

39

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

patients (Wittgrove AC et al. Obes Surg 2000;10:233-239). In this later series, the authors found that the average percent excess body weight loss at five years was 75%, and the procedure appeared to be safe, with few complications and no mortalities. Additionally, 96% of preoperative comorbidities, including gastroesophageal reflux disease, sleep apnea and diabetes had resolved after surgery.

But even before Drs. Wittgrove and Clark had performed a laparoscopic gastric bypass, Belgian general surgeon Guy-Bernard Cadière, MD, PhD, had done the first adjustable gastric banding procedure laparoscopically in 1992 (Delbro DS. Br J Surg 1994;81:1529).

Dr. Cadière had used a Kuzmak adjustable silicon gastric band, designed for open procedures, so credit for the first laparoscopic adjustable gastric banding procedure initially went to Belgian surgeon Mitiku Belachew, MD, who did the procedure with a lap band on Sept.

1, 1993 (Belachew M et al. World J Surg 1998;22:955-963). This lap band had been modified from the Kuzmak adjustable silicon gastric band for laparoscopic applications. Subsequently, Dr. Cadière performed the procedure with the lap band one week later (Cadière GB et al. J Celio Chir 1994;10:27-31).

‘Bariatric surgery was still a bit of voodoo in early 1990s.

We were very attuned to the fact that this procedure might be controversial, so it was important for us to keep track of our patients’ data to refute any malicious attacks.’

—Alan Wittgrove, MD with clinical fellow Gregg Jossart, MD, and surgical resident John de Csepel, MD, performed laparoscopic biliopancreatic diversion with a duodenal switch on six 50-kg pigs, restricting

see Laparoscopy, page 40

Optimizing the Prevention and Management of Postsurgical Adhesions To participate in this FREE CME activity, log on to

Duodenal Switch and Sleeve Gastrectomy Intrigued by the possibility of more minimally invasive approaches to bariatric surgery, Dr. Gagner established a laparoscopic program at the University of Montreal, Hotel-Dieu, where he was assistant professor of surgery. Despite experiencing staunch resistance from the chief of surgery there, Dr. Gagner set up a pig lab at Hotel-Dieu in July 1990, and for the next five years worked on various laparoscopic techniques, including adrenalectomy, pancreatectomy and Rouxen-Y gastric bypass (Potvin M et al. Surg Laparosc Endosc 1997;7:294-297).

Eventually, however, the administrative roadblocks proved too intrusive, and Dr. Gagner relocated to the Cleveland Clinic in summer 1995 where he established the Minimally Invasive Surgery Center, and in early 1996, initiated a course on laparoscopic gastric bypass.

Two years later, Dr. Gagner moved to the Icahn Medical School at Mount Sinai in New York City, and took on the role of chief of laparoscopy, starting a minimally invasive surgery program that later became one of the biggest in the United States. After hearing about the success of an emerging open bariatric procedure—a biliopancreatic diversion with a duodenal switch—Dr. Gagner wondered whether he could perform the procedure laparoscopically.

In spring 1999, Dr. Gagner, along

food intake with a sleeve gastrectomy and achieving malabsorption with Roux-en-Y (de Csepel J et al. J Laparoendosc Adv Surg Tech A 2001;11:79-83).

On July 2, 1999, Dr. Gagner performed

the first laparoscopic duodenal switch in a severely obese patient with a BMI greater than 60 kg/m2.

“This was a very difficult patient, and soon we conducted a series using this technique on 40 morbidly obese patients,” Dr. Gagner said. “After presenting our results at the 2000 ASBS meeting, people took notice. We showed that gastric bypass was not the only bariatric surgery we could do laparoscopically.”

In the 40-patient series, patients showed significant excess weight loss

www.CMEZone.com and enter keyword “MN125” Release date: December 1, 2012

Chair

Jon Gould, MD Chief, Division of General Surgery Alonzo P. Walker Chair in Surgery Associate Professor of Surgery Medical College of Wisconsin Senior Medical Director of Clinical Affairs Froedtert Hospital Milwaukee, Wisconsin

Faculty

Michael J. Rosen, MD Associate Professor of Surgery Division Chief, General Surgery University Hospitals Case Medical Center Cleveland, Ohio

Statement of Need Adhesions are the most common complication of abdominopelvic surgery, developing postoperatively in 50% to 100% of all such interventions. They can lead to serious medical complications, substantial morbidity, high monetary costs, large surgical workloads, dangerous and difficult reoperations, and an increasing number of medicolegal claims. An official definition of the Sponsored by

Expiration date: September 1, 2014 condition has not been established, and an unequivocally effective prevention method has not been identified. A standardized classification for adhesion assessment and scoring also is lacking, as are guidelines for diagnosis and management. To close these gaps, clinician education is necessary.

Goal The goal of this educational activity is to provide surgeons with up-to-date, clinically useful information concerning the prevention and management of postoperative adhesions.

Learning Objectives 1 Review the pathophysiology and complications of postoperative adhesion formation.

2 Summarize current strategies used to prevent postoperative adhesion formation.

3 Describe the various types of barrier materials used to prevent postoperative adhesion formation.

Intended Audience The intended audience for this educational activity includes general surgeons, vascular surgeons, colon and rectal surgeons, critical care surgeons, surgical oncologists, trauma surgeons, and thoracic surgeons.

Supported by an Educational Grant from

Estimated Time for Completion: 60 minutes Course Format Monograph (print and online)

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical College of Wisconsin and Applied Clinical Education. The Medical College of Wisconsin is accredited by the ACCME to provide continuing medical education for physicians.

Designation of Credit Statement The Medical College of Wisconsin designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should only claim credit commensurate with the extent of their participation in the activity.

Method of Participation There are no fees for participating in or receiving credit for this activity. To receive CME credit, participants should read the preamble and the monograph and complete the post-test and evaluation. A score of at least 70% is required to complete this activity successfully.

Distributed via

40

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

Laparoscopy continued from page 39

of 46% after six months and 58% after nine months (Ren CJ et al. Obes Surg 2000;10:514-523). However, Dr. Gagner also found high rates of complications, including one anastomotic leak, four staple-line hemorrhages and one mortality.

“In my introspection, I realized that the problems were a result of performing this surgery on such severely obese patients,” Dr. Gagner said. “If such patients have a leak or infection, they are

at high risk for severe complications.”

A solution soon emerged. One day, Dr. Gagner was performing a duodenal switch on a morbidly obese patient.

The surgical team had begun the sleeve gastrectomy, but because the patient was severely obese, the anesthesiologist was finding it difficult to maintain hemodynamics. The team finished the sleeve gastrectomy and stopped the operation.

“At that moment, we had done the first isolated sleeve gastrectomy,” Dr. Gagner said.

The patient lost more than 100

pounds after undergoing the sleeve gastrectomy. Dr. Gagner realized that they could reduce the rate of complications associated with laparoscopic duodenal switch by dividing the procedure into two parts, initially performing a sleeve gastrectomy and then performing the duodenal switch months later, after the patient had lost weight.

Dr. Gagner began conducting a series of sleeve gastrectomies in these highrisk patients, which he followed up with duodenal switches months later.

He soon realized that some patients did

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Three ways to download: 1. Go to the iTunes App Store and search for Gastroenterology & Endoscopy News.

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The laparoscopic sleeve gastrectomy, originally done as the first part of a duodenal switch, was shown to produce good results as a stand-alone operation.

Image courtesy of Michel Gagner, MD.

so well after the sleeve gastrectomy that they did not require the second part of the operation.

However, after presenting results of a small series of laparoscopic sleeve gastrectomies at several meetings, the paper was rejected by Surgical Endoscopyy because, according to the editors, the follow-up time was too limited.

“It can be difficult to get publication on first concept, which infuriates me,” Dr. Gagner said. “Insurance companies in the United States were refusing duodenal switch so we started doing laparoscopic gastric bypass instead as the second part of the procedure,” added Dr. Gagner, noting that the results of a two-phase sleeve gastrectomy and gastric bypass procedure were published earlier with co-authors Alfons Pomp, MD, and William B. Inabnet, MD (Regan JP et al.

Obes Surg 2003;13:861-864).

Dr. Gagner also began leading courses on sleeve gastrectomy in New York every six to 12 months, and interest grew exponentially.

“During the first course, about 25 to 30 people came, but then the audience started doubling in subsequent courses,” Dr. Gagner recalled.

Michael McMahon, MD, a general surgeon from the University of Leeds, United Kingdom, for example, was also an early pioneer of sleeve gastrectomy,

41

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

“Initially, the available technology limited us and perhaps that’s why we had higher complication rates early on,” he said. “However, industry responded by making better flexible, long staplers for super obese patients as well new suture material to do running sutures, more intelligently designed, smaller bougies and balloons with holes for leak tests.”

By 2005, the number of bariatric procedures performed laparoscopically surpassed that of the open approach nationwide.

“It took time to become more

mainstream, but by the mid-2000s, about 60% of all weight loss surgeries were done laparoscopically and today the percentage is closer to 90%,” said Dr. Pomp, Leon C. Hirsch Professor and vice chairman, Department of Surgery, chief, Section of Laparoscopic and Bariatric Surgery, Weill Medical College of Cornell University, NewYork-Presbyterian Hospital, New York City. “Although some practices still perform open bariatric surgery with good results, most of the time, there’s significant patient-driven demand to do minimally invasive surgery.”

Dr. Nguyen recently mapped the changing landscape of bariatric operations performed in the United States (Nguyen NT et al. J Am Coll Surg 2013;216:252257). He and his colleagues found that of 60,738 bariatric procedures performed between Oct. 1 2008 and Sept. 20 2012, laparoscopic sleeve gastrectomy rose from the third most popular procedure to the second, accounting for 36.3% of all bariatric procedures done in 2012. This increase in laparoscopic sleeve gastrectomy accompanied a significant decline see Laparoscopy, page 42

ASGE Endoscopic Learning Library With over 30 titles, ASGE’s Endoscopic Learning Library represents the field’s most complete collection of high-quality CME videos on endoscopy. ASGE’s titles feature live-action endoscopic procedure videos complemented by expert instruction on the latest topics. The Endoscopic Learning Library continues to expand each year with valuable titles. Learn more about the new releases for 2014. developed from the concept of Magenstrasse and Mill in 2000. The procedure also started to take off abroad in France, Belgium, Austria and Germany.

“This was the beginning of sleeve gastrectomy, which is fast becoming one of the most popular bariatric operations worldwide,” Dr. Gagner said.

Four New DVDs for 2014!

Rise of Laparoscopy When laparoscopic techniques for bariatric surgery were introduced, critics complained the operations were unsafe and associated with high morbidity compared with the open approach.

Although a proponent of the laparoscopic approach, Ninh Nguyen, MD, chief of gastrointestinal surgery at UC Irvine Medical Center, in California, recognized safety issues in the early days of the procedure. “I reviewed my initial experience of laparoscopic gastric bypass and found that it took 75 cases to overcome the steep learning curve,” he said.

The criticism prompted Dr. Nguyen to conduct a randomized trial comparing open versus laparoscopic gastric bypass.

He and his colleagues found a significant benefit for the laparoscopic approach, including less postoperative pain, lower rate of wound-related complications and a quicker recovery (Nguyen NT et al. J Am Coll Surgg 2001;192:469-476).

Over the years, an emphasis on surgical education and fellowship training in bariatrics allowed the procedures to mature and resulted in significantly fewer risks and complications as well as a decline in the mortality rate. Dr. Gagner believes this improvement in outcomes is due in great part to changes in technology.

Esophageal Introitus (DV061) (2014 AV Award Winner) Shou-jiang Tang, MD, FASGE and Ruonan Wu, MSE In this DVD, the definition of esophageal introitus (EI) is broadened to cover the lower part of the hypopharynx posterior to the larynx, the esophageal h l opening i posterior t i to t the th cricoid i id prominence, i and d the th area between the bilateral pyriform fossae and the cervical esophagus. Benefit from valuable insight as the authors demonstrate EI anatomy, endoscopic findings and pathologies within EI and their management. Plus, learn to diagnose common endoscopic findings such as gastric mucosa heterotopia, web, radiation stricture, cricopharyngeal bar, mucositis, foreign body impaction, and more.

1.00 AMA PRA Category 1 Credits™

Per-Oral Endoscopic Myotomy (POEM) for Achalasia (DV062) (2014 AV Award Winner) Jun-Hyung Cho, MD, Joo Young Cho, MD, Tae Hee Lee, MD, Su Jin Hong, MD and Won Kyung Cho, MD This DVD focuses on delivering a comprehensive, evidence-based review of the advantages of POEM, international POEM survey data and learning curve. Specific content covered includes examinations and preparation before POEM, procedural techniques, and post-procedure care. In the chapter on POEM procedure, endoscopic technique is demonstrated with detailed video clips. As a result, you will learn more about how POEM procedure consists of five cardinal steps: creation of mucosal entry, creation of submucosal tunnel, identification of the esophagogastric junction, endoscopic myotomy and closure of mucosal entry.

0.50 AMA PRA Category 1 Credits™

The Detection, Diagnosis and Treatment of Superficial Nonpolypoid Barrett’s Neoplasia – A Potential New Approach (DV063) Roy Soetikno, MD, FASGE, Tonya Kaltenbach, MD, FASGE, Noriya Uedo, MD and Takuji Gotoda MD, FASGE Through this DVD, you will gain insight on new concepts of the detection, diagnosis and treatment of superficial nonpolypoid Barrett’s neoplasia.

This includes detection of neoplasia using white light endoscopy and image enhanced endoscopy, as well as a new concept of the diagnosis of superficial Barrett’s neoplasia using the microvessels and surface findings.

This DVD also covers the technique of using indigo carmine to help define the border of the neoplasia.

0.50 AMA PRA Category 1 Credits™

ABCs of EUS: A Complete Roadmap (DV064) John Meenan, MD, PhD, FRCPI, FRCP, Charles Vu, MD, and Sabina DeMartino, MD (2014 AV Award Winner) This DVD is a primer to the common problems experienced by beginner and intermediate trainees in Linear and Radial EUS, both Diagnostic and Therapeutic. Through this title, you will be provided with a road-map to the understanding and practice of all the major areas of EUS. Benefit from 17 narrated video clips that include: EUS videos; literature discussion with slides of key points; diagrams and CT scans of regional anatomy along with animation to explain scope position and view orientation.

4.00 AMA PRA Category 1 Credits™

Continuing Medical Education – ASGE is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

ASGE designates these enduring materials for the stated maximum number of AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. For more information about claiming AMA PRA Category 1 Credit™ for activities in the Endoscopic Learning Library, visit www.asge.org.

If Endoscopy is Your Practice, ASGE is Your Partner!

42

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

FDA Proposes Updates to Nutrition Facts Label on Food Packages The FDA has proposed updating the nutrition facts label for packaged foods to reflect the latest scientific information, including the link between diet and chronic diseases such as obesity and heart disease.

The proposed label also would replace out-of-date serving sizes to better align with how much people really eat, and would feature a fresh design to highlight key parts of the label, such as calories and serving sizes.

“Our guiding principle here is very simple: that you as a parent and a consumer should be able to walk into your local grocery store, pick up an item off the shelf, and be able to tell whether it’s good for your family,” said first lady Michelle Obama. “So this is a big deal, and it’s going to make a big difference for families all across this country.”

The nutrition facts label has been required on food packages for 20 years and has not changed significantly since 2006 when information on trans fat was added to labels, prompting manufacturers to reduce partially hydrogenated oils, the main source of trans fat, in many of their products.

“For 20 years, consumers have come to rely on the iconic nutrition label to help them make healthier food choices,” said FDA Commissioner Margaret A. Hamburg, MD. “To remain relevant, the FDA’s newly proposed nutrition facts label incorporates the latest in nutrition science as more has been learned about the connection between what we eat and the development of serious chronic diseases impacting millions of Americans.”

“To help address obesity, one of the most important public health problems facing our country, the proposed label would drive attention to calories and serving sizes,” added Michael R. Taylor, the FDA’s deputy commissioner for foods and veterinary medicine.

The proposed updates reflect new dietary recommendations, consensus reports and national survey data, such as the 2010 Dietary Guidelines for Americans, nutrient intake recommendations from the Institute of Medicine and intake data from the National Health and Nutrition Examination Survey.

The FDA also considered extensive input and comments from a wide range of stakeholders.

Some of the proposed changes would: • Require information about the amount of “added sugars” in a food product. The 2010 Dietary

Laparoscopy continued from page 41

in laparoscopic gastric banding (23.8% in 2008 to 4.1% in 2012) as well as a reduction in laparoscopic gastric bypass (66.8% in 2008 to 56.4% in 2012), which continues to be the most commonly performed bariatric procedure.

Part of the reason laparoscopic sleeve gastrectomy outstripped laparoscopic gastric banding in popularity is because it affords better weight loss (55% vs. 47% excess weight) with fewer reoperations down the road, said Dr. Pomp.

More importantly, Dr. Wittgrove noted, laparoscopic gastric banding doesn’t alter

Nutrition facts label: Current format

•

•

•

•

Nutrition facts label: Proposed format

Guidelines for Americans states that intake of added sugar is too high in the U.S. population and should be reduced.

Update serving size requirements to reflect the amounts people currently eat. What and how much people eat and drink has changed since serving sizes were first put in place in 1994. By law, serving sizes must be based on what people actually eat, not on what people “should” be eating.

Present calorie and nutrition information for the whole package of certain food products that could be consumed in one sitting.

Present “dual-column” labels to indicate both “per-serving” and “per-package” calorie and nutrition information for larger packages that could be consumed in one sitting or multiple sittings.

Require the declaration of potassium and vitamin D, nutrients that some in the U.S. population are not getting enough of, which puts them at higher risk for chronic disease. Vitamin D is important for its role in bone health. Potassium is beneficial in lowering blood pressure. Vitamins A and C would

patients’ hormone levels like laparoscopic gastric bypass or sleeve gastrectomy does.

“Now we’re really understanding that to get a durable, predictable response, the procedure has to manipulate our hormones in a beneficial and lasting way,” he said. In other words, patients need a metabolic operation, not just a weight loss one.

Down the Road A major concern for the future is that obesity has become the “new norm,” according to Dr. Pomp.

“This is the first generation that won’t live as long due to accumulating cardiovascular problems and diabetes,” he said.

All images courtesy of the FDA

no longer be required on the label, although manufacturers could declare them voluntarily.

• Revise the daily values for a variety of nutrients, such as sodium, dietary fiber and vitamin D. • Continue to detail “total fat,” “saturated fat” and “trans fat” on the label, while “calories from fat” would be removed because research shows that type of fat is more important than the amount.

• Refresh the format to emphasize certain elements, such as calories, serving sizes and percent daily value, which are important in addressing current public health problems like obesity and heart disease.

The proposed changes would affect all packaged foods except certain meat, poultry and processed egg products, which are regulated by the U.S. Department of Agriculture’s Food Safety and Inspection Service.

The FDA is accepting public comments on the proposed changes through June 2 online at www. regulations.gov.

Despite a growing obese population, patients have limited access to preventative and surgical care, largely due to social stigma and inadequate insurance coverage.

“People tend to perceive this as radical surgery and every time a complication occurs, it gets a headline,” Dr. Pomp said.

“However, 99.7% of patients live through this operation, with a 3% to 4% likelihood of a major complication.”

Dr. Wittgrove agreed, noting that surgery is clearly the best treatment for metabolic syndrome and for the serious comorbidities that accompany it, including diabetes, hypertension, dyslipidemia and obstructive sleep apnea. Arthritis,

—Based on a press release from the FDA

depression and many other comorbidities of morbid obesity also can be treated effectively.

Looking to the future, Kelvin Higa, MD, director of Minimally Invasive and Bariatric Surgery, Fresno Heart and Surgical Hospital, in California, defined where the focus of attention should be (Higa KD. Medscape J Med 2008;10:101).

“It’s about time that we recognize the disease of obesity for the multifaceted killer that it is, understand better why it has become so prevalent in today’s society, work on preventative measures, and treat those already afflicted.”

■

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F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • MAY 2014

FDA Advisory Committee Recommends Ap pproval of Stool-Based DNA Test for Colorectal Canceer On March 27, an FDA advisory committee unanimously recommended the approval of Exact Sciences’ Cologuard, a noninvasive, stool-based DNA screening test for colorectal cancer (CRC). The committee determined that the test is safe, effective and has a favorable risk–benefit profile.

Data in support of Cologuard comes from the DeeP-C (Detection of Colorectal Advanced Adenomatous Polyps and Cancer) trial, one of the most extensive CRC screening studies ever conducted in the United States, according to Exact Sciences, comprising approximately 10,000 patients and 90 sites. In the trial, the sensitivity for detecting CRC with Cologuard was 92.3%, based on a combination of DNA and hemoglobin markers. Full results of the study were published in the April 3 issue of The New England

Journal of Medicine (Imperiale TF et al. 2014;370:1287-1297).

“We look forward to continuing our work with the FDA to complete its review of Cologuard and remain committed to addressing the growing unmet needs in CRC screening. … We

are pleased the Committee strongly supported Cologuard’s approval,” said Kevin T. Conroy, chairman and CEO of Exact Sciences.

The FDA is not bound by the recommendation of its advisory committee, but will consider the committee’s

guidance as it evaluates the data on Cologuard.

For more information about Exact Sciences, visit www.exactsciences. com.

—Based on a press release from Exact Sciences

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Quest Diagnostics Introduces Blood and Biopsy Testing For Lynch Syndrome Quest Diagnostics recently made available new diagnostic tests for Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, an inherited genetic disorder that significantly increases an individual’s risk for colorectal cancer (CRC).

Quest’s Lynch syndrome blood test offering includes a comprehensive blood test panel that evaluates genes ((MLH1, MSH2 [and EPCAM terminal deletions], MSH6 and PMS2) for inherited mutations that are responsible for the majority of Lynch syndrome cases.

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Quest services are available in all 50

1978 —

at

35th Anniversary — 2013

H E PAT O L O G Y IN F O C U S

Guidance Equivocal On HCV Screening Of Baby Boomers

Despite Above Average Income, Gastros Report Job Dissatisfaction

BY VICTORIA STERN

BOSTON—Recent evidence suggests that nonalcoholic fatty liver disease (NAFLD) is emerging as a significant public health problem. One study revealed an “alarming” rate of HCC related to NAFLD, even among

Gastroenterologists are the fourth most highly compensated physicians compared with doctors in 24 other medical specialties, according to an online survey conducted by Medscape in February 2013. Average annual income for gastroenterologists was up 13% in 2012 compared with 2011, coming in at $342,000. The three specialties that beat out gastroenterology in average yearly compensation were orthopedists at $405,000, cardiologists at $357,000 and radiologists at $349,000 (see Figure 1, page 28).

But despite robust earnings, less than half (48%) of the gastroenterologists surveyed said they felt fairly compensated, the same percentage as that of physicians of all specialties who said they felt fairly compensated.

The findings were based on responses collected in a third-party online survey of 21,878 U.S. physicians, 2% of whom were gastroenterologists. Most gastroenterologists who responded were men (84%) and board certified (96%), and 62% were aged 45 years or older.

see NAFLD, page 14

see Income, page 28

BY CHRISTINA FRANGOU Hepatologists have added their voices to the debate over screening for hepatitis C virus (HCV) infection and are urging the U.S. Preventive Services Task Force (USPSTF) to upgrade its current recommendation

BY KATE O’ROURKE

I N S I D E

Cost Sharing for Polyp Removal During Colonoscopy Waived for Some Patients

H E PAT O L O G Y

I N

FOCUS

Investigational Device Prolongs Survival of Livers For Transplantation .................................................page 8

BY MONICA J. SMITH

tor

Effect of Preexisting Cardiovascular Disease On Outcomes After Liver Transplantation May Be Underestimated..........................................page 9

Patients with private insurance will no longer be responsible for any cost sharing in the event that a polyp is removed during a screening colonoscopy, according to a recent clarification, issued by the federal government, on preventive screening benefits under the Affordable Care Act (ACA).

“This is very good news,” said Durado Brooks, MD, MPH, direcof Prostate and Colorectal Cancers at the American Cancer Society in

Retreatment of Hepatitis C With Interferon Alone May Increase Mortality ..........................................«>}iÊ£È Statins Linked to Reduction in Mortality From Liver Cancer.................................................«>}iÊÓ{

see Cost Sharing, page 32 PRINTER FRIENDLY VERSION AT GASTROENDONEWS.COM

CLINICAL REVIEW see insert between pages 20 and 21

Ulcerative Colitis: Treatment Strategies

By Ellen J. Scherl, MD, Arun Swaminath, MD, Brian Bosworth, MD, and Vinita Jacob, MD

Director, Jill Roberts Center for Inflammatory Bowel Diseasea Jill Roberts Center for Inflammatory Bowel Disease Director of Researchb Jill Roberts Associate Professor of Inflammatory Bowel Diseaseb Associate Professor of Clinical Medicineb Adjunct Associate Professor of Medicinec

ch hallenge for clinicians who

treat patients with inflamma atory bowel disease (IBD) is to move from symptomoriented (step--up) strategies toward preventio on-orie ented (early intervention) strategies aimed

ARUN SWAMINATH, MD

at tight inflammation control and alteration of the natural history of IBD. This review focuses on a personalized

BRIAN BOSWORTH, MD

acid (5-ASA) agents.

approach to the treatment of IBD using 5-aminosalicylic

Assistant Attending Physiciana Assistant Professor of Medicineb Anne and Ken Estabrook Clinical Scholar in Gastroenterologyb

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

NewYork-Presbyterian Hospital/ Weill Cornell Medical Center New York, New York Weill Cornell Medical College New York, New York Columbia University College of Physicians and Surgeons New York, New York

Challenging the Traditional IBD Diagnosis Traditionally, IBD has been divided into 2 distinct entities: ulcerative colitis (UC) and Crohn’s disease (CD). A nuanced view presents IBD as an immunoinflammatory spectrum of chronic and recurring diseases of the intestines defined by individual molecular signatures. This newly gained perspective holds the promise of moving treatment in a more proactive, personalized direction, toward targeting molecules and risk assessment, rather than treating symptoms of the disease.

One of the major questions facing clinicians is whether IBD is a single entity or a spectrum of multiple disorders. This distinction becomes particularly difficult to make when attempting to

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS •

the U.S. Food and Drug Administration.

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T

he e greatest

Assistant Attending Physiciana Assistant Professor of Clinical Medicinec

b

on press releases from manufacturers and

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Ulcerative Colitis: Optimizing Mesalamine Strategies ELLEN J. SCHERL, MD

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column is compiled by the editors based

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see HCV Screening, page 18

FDA Update & Product News

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states and include clinician access to genetic counselors who can help simplify test selection and interpretation of results. Additional information is available at www.QuestDiagnostics.com.

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REPORT PENTAX Medical i-SCAN™ Technology for Improved Endoscopic Evaluations E

ndoscopy plays a vital role in the diagnosis and clinical management of diseases of the gastrointestinal (GI) tract, among other organ systems. Despite advances in technology, the adenoma detection rate remains suboptimal in many cases, at least partly due to the limitations of standard endoscopic imaging modalities.1,2 “Although white light endoscopy [WLE] has come a long way, there are still limitations in detecting subtle lesions.

For instance, if a lesion is flat rather than the classic pedunculated polyp, it can be missed with white light endoscopy

because the borders are not quite as defined and the surface of the lesion is not quite as defined,” said Steven Naymagon, MD, Department of Gastroenterology at the Icahn School of Medicine at Mount Sinai in New York City.

“The limitations of conventional white light video endoscopy are potentially that you’re not necessarily accentuating the surface characteristics and vascular changes that are associated with the progression to cancer,” said Sharmila Anandasabapathy, MD, medical director, Mount Sinai Endoscopy Center and an

Faculty Sharmila Anandasabapathy, MD Medical Director Mount Sinai Endoscopy Center Associate Professor of Medicine Icahn School of Medicine at Mount Sinai New York, New York

Steven Naymagon, MD

Carlos Robles-Medranda, MD

Department of Medicine Division of Gastroenterology Icahn School of Medicine at Mount Sinai New York, New York

Head of the Endoscopy Division Instituto Ecuatoriano de Enfermedades Digestivas–IECED OMNI Hospital Guayaquil, Guayas, Ecuador

Supported by

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associate professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City.

Adjunctive techniques to enhance the utility of conventional high-definition white light endoscopy (HDWLE) are available, such as dye-based and spray chromoendoscopy.

These techniques apply stains to the mucosal surfaces during endoscopy to highlight mucosal differences as well as to detect dysplastic and malignant changes that are not apparent in white light. However, chromoendoscopy has important drawbacks that limit its overall utility.3 “Application of the dyes to the large areas of the mucosal surfaces can be time consuming in addition to being expensive. Sometimes, you might even run out of your supply of the dye and not have it available when you need it. Also, like any drug, some patients can have an allergic reaction to the dye,” said Carlos Robles-Medranda, MD, head of the Endoscopy Division at Instituto Ecuatoriano de Enfermedades Digestivas at OMNI Hospital in Guayas, Ecuador. The dyes are inhomogeneous, which can cause unevenly coated mucosal areas that affect clinicians’ ability to assess lesions.3 “Interpreting chromoendoscopic findings is a learned process that can lead to a lot of variability in diagnosis, so it’s inconsistent,” added Dr. Anandasabapathy.

Fortunately, several high-tech approaches have been developed to approximate similar data generated by chromoendoscopy without the use of dyes, thereby facilitating the accurate detection of malignant and premalignant lesions in general endoscopic practice. These “virtual chromoendoscopic” approaches are known as image-enhanced endoscopy and include narrow band imaging (NBI; Olympus), Fuji intelligent color enhancement (Fujinon; currently not FDA-approved), and PENTAX i-SCAN™ (PENTAX Medical) technology.3

i-SCAN™ Technology i-SCAN is a software-based, image-enhancement technology that is classified as a digital contrast method among endoscopic imaging techniques.4,5 The technology works by conducting per-pixel modifications of white light images. Although i-SCAN is technically a post-imaging technology, all processing is done in real time, allowing instant, real-time visualization of processed images during endoscopy.5,6 Image enhancement of blood vessels and mucosal surfaces allows recognition of pathologic lesions that otherwise are not visible with conventional white light imaging without digital enhancement.3 “i-SCAN is basically an attempt to give the effect of chromoendoscopy without using dyes or stains, so it is what we call ‘virtual chromoendoscopy.’ Instead of using a liquid dye or stain, which is sprayed on the lining of the GI tract and used with white light endoscopy, with i-SCAN you push a button to change the post-image processing on the scope. Basically, it is a software-based processing method of visualizing the same surface changes and, possibly, the same vascular changes that you get with chromoendoscopy, but without using a dye,” said Dr. Anandasabapathy. i-SCAN technology offers 3 different modes of image enhancement: surface enhancement (SE), contrast enhancement (CE), and tone enhancement (TE), which can be used

2

sequentially or in any combination. Switching between levels or enhancement modes can be done on a real-time basis, with zero delay, by pushing a relevant button, thus offering clinicians efficient endoscopic observation.6 The SE mode analyzes differences in luminance intensity between target pixels and surrounding ones, enhancing the edges by augmenting light–dark contrast. Compared with normal images, SE images do not differ in brightness and show only minor color variations. This mode also offers improved observation of tiny glandular structures.6 The SE mode contains low, medium, and high enhancement levels. “Surface enhancement, in general, can help you identify the borders of lesions, meaning that it helps bring out the mucosal surface and thereby allows you to delineate exactly where the lesion is,” said Dr. Naymagon.

The CE mode uses pixel-wise luminance intensity data to identify areas that are lower in luminance intensity than surrounding pixels, followed by relative enhancement of the blue component through slight suppression of red and green components in this low luminance area.6 As a result, a blue color is added to relatively dark areas, and tiny irregularities on the mucosal surface are enhanced. The minute glandular structure can be enhanced even with flat mucosa because the change in color reflects very minute depressions at the opening of the gland duct. Image processing with CE does not result in changes to image brightness, and causes only slight bluish-white staining of depressed areas.6 Like the SE mode, the CE mode contains the same 3 enhancement levels. “Contrast enhancement can bring out the subtle irregularities around the surface and allow you to inspect it in a more detailed manner. It may also help bring out some of the blood vessels and allow you to inspect the vascular pattern in the lesions,” Dr. Naymagon added.

During conventional endoscopy, white reflective rays from the mucosa are captured at the tip of the endoscope and appear on the monitor. However, i-SCAN TE mode deconstructs each component of the red-blue-green color spectrum and independently adjusts them along a tone curve before reintroducing them into an image that enhances tiny mucosal structures with subtle color changes.6 Additionally, the tone curve can be modified to enhance individual red, green, or blue components as well as to adjust image contrast. As a result, different parameters can be used that are specifically suited to characterize individual portions of the GI tract. Three types of TE have been established: TE-e for the esophagus, TE-g for the stomach, and TE-c for the colon.6

i-SCAN™ Settings Use of the i-SCAN modes in different combinations can enable targeted imaging functions. Thus far, 3 default combination modes have been established and approved by the FDA for use during endoscopy: i-SCAN 1, 2, and 3. Switching between HDWLE and the 3 i-SCAN settings can be performed on a real-time basis with no delay, which offers efficient endoscopic observation. These modes allow the user to visualize more mucosal and vascular details compared with white light imaging.4

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i-SCAN combines a variety of parameters to produce the effect of each default mode: brightness of light (off, –5 to +5), red (off, –5 to +5), blue (off, –5 to +5), light-measuring mode (ave, peak) enhancement (off, low, medium, high), SE (off, +1 to +6), CE (off, +1 to +6), TE (off, c, g, r, e, b, d), and noise reduction (off, low, medium, high).4 For example, i-SCAN 1 uses a combination of SE, CE, and a fast Fourier transform analysis to sharpen surface vessels and enhance the texture of surface mucosa while maintaining an image as bright as a conventional white light image.4,5 This setting provides the user with a sharper view of the HDWLE images and enhances areas of the mucosa that are depressed or elevated; vessels retain their natural red coloration (Figure 1).4 By comparison, i-SCAN 2 adopts a combination of CE, SE, and TE-c enhancement to sharpen surface vessels, enhance surface texture, and improve the contrast of blood vessels and mucosa.4 In fact, this setting results in a 147% to more than 300% improvement in contrast between blood vessels and mucosa when compared with HDWLE images.4 Furthermore, this setting allows increased visualization of microvascularity and the peripheral capillary network and an enhanced view of the mucosa while retaining tissue color throughout use.4 Finally, the i-SCAN 3 setting mimics the same levels of CE and SE as i-SCAN 1, resulting in the sharpening of surface vessels and enhancement of surface texture.4 Additionally, i-SCAN 3 improves contrasts between blood vessels and mucosa through engagement of the TE-g mode. The main difference between i-SCAN 2 and 3 is one of brightness due to the different tone curves employed. Although i-SCAN 2 improves contrast in vessels, it may reduce the brightness of low-intensity regions of the image.5 i-SCAN 3 maintains visibility within dimly illuminated distal regions by balancing tonal alterations and image brightness to avoid excessive darkening. As a result, i-SCAN 3 generates a contrast-enhanced image while maintaining uniform brightness. As with all i-SCAN modes, vessels maintain a natural red coloration when i-SCAN 3 is engaged.5 “Within the individual default i-SCAN modes, the settings on brightness and tone enhancement, surface enhancement, and contrast enhancement are all specifically up-regulated and down-regulated to help you achieve certain goals.

For instance, i-SCAN 1 can help you detect lesions and that uses the surface enhancement more than anything,” said Dr. Naymagon. “i-SCAN 2 is more about characterizing lesions, and that uses both surface enhancement and tone enhancement. i-SCAN 3 is a modality that I would use to help demarcate lesions, to tell where a lesion begins and ends. That mode uses contrast enhancement, tone enhancement, and surface enhancement.” Figure 2 depicts differences in the images provided by the HDWLE and the 3 default i-SCAN modes.

Clinical Use of i-SCAN As Dr. Robles-Medranda explained, “the ability of i-SCAN to enhance the images of the mucosal surface and vascularity of the lesion means that it can be used as a ‘red flag’ indicator.

There are certain mucosal patterns or vascular patterns that can be detected by this technology that would help you target a lesion for biopsy. Going further, in our group’s experience, the features revealed by this image enhancement also allow you to predict histology with good degree of confidence. We have data to show that i-SCAN can detect organic disease in patients who were otherwise thought to have only functional GI disease based on characterization by standard white light endoscopy.”

Dr. Anandasabapathy echoed this sentiment about i-SCAN as a “red flag” technology: “i-SCAN is a good detection technology that may better help you identify areas of abnormality.

For example, the technology is very good at accentuating what we call the mucosal pit pattern, or Kudo pit pattern, which has been shown to differentiate benign polyps from those that are adenomatous or precancerous.”

Figure 1. Colonic adenoma visualized with i-SCAN 1 (top) and i-SCAN 2 settings (bottom).

Images courtesy of Carlos Robles-Medranda, MD.

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Figure 2. Adenomatous polyp detected under HDWLE with increased definition using i-SCAN 1, 2, and 3.

HDWLE, high-definition white light endoscopy Images provided by PENTAX Medical Company.

4

In addition to pit patterns, i-SCAN image enhancement is useful for detecting and characterizing other correlates of clinical lesions, including margin details, vascular patterns, angiogenesis, and early mucosal changes. In fact, several groups of investigators have published reviews of endoscopic findings with i-SCAN and how they correlate with specific clinical lesions. For example, Hong and colleagues performed a prospective, randomized trial that used a modified, back-toback colonoscopy to assess the efficacy of i-SCAN application during screening colonoscopy in 389 consecutive asymptomatic, average-risk patients.7 Analysis demonstrated that the prediction of neoplastic and non-neoplastic colorectal lesions was more precise in the i-SCAN 2 group compared with the conventional WLE group (accuracy, 88.1% vs 75.5%; P=0.29; sensitivity, 86.5% vs 72.6%; P= 0.02; specificity, 91.4% vs 80.6%; P=0.40).7 Similarly, Bouwens and colleagues investigated the use of i-SCAN technology for the prediction of polyp histology by 11 endoscopists across 550 images (396 adenomatous, 154 non-adenomatous).8 Mean sensitivity, specificity, and accuracy for diagnosing adenomas were 79.3%, 85.7%, and 81.1%, respectively.8 Researchers also have investigated the use of the i-SCAN system for endoscopic diagnostics and management.

For example, Hancock and colleagues reviewed data from 20 consecutive patients who underwent endoscopic procedures and compared mucosal lesions with HDWLE and i-SCAN. A positive end point was defined as cases in which i-SCAN imaging highlighted mucosal abnormalities not as clearly seen with WLE and where i-SCAN data subsequently affected management.5 The investigators reported that for upper GI tract pathology, i-SCAN assisted in diagnosis or therapy for Barrett’s esophagus with dysplasia, esophageal adenocarcinoma, viral esophagitis, gastric mucosa-associated lymphoid tissue lymphoma, gastric antral intestinal metaplasia with dysplasia, duodenal follicular lymphoma, and a flat duodenal adenoma.5 For lower GI tract pathology, i-SCAN assisted in diagnosis or therapy of right-sided serrated adenomas, flat tubular adenoma, rectal adenocarcinoma, anal squamous cell cancer, solitary rectal ulcer, and radiation proctitis.5 Hoffman and colleagues studied the utility of i-SCAN– enhanced endoscopy versus conventional WLE in 200 patients undergoing screening colonoscopy for the prediction of histology from biopsy or resected samples.9 These investigators reported that i-SCAN detected significantly more patients with colorectal neoplasia (38%) compared with standard resolution endoscopy (13%). Furthermore, significantly more neoplastic (adenomatous and cancerous) lesions and more flat adenomas could be detected using i-SCAN, and final histology could be predicted with high accuracy (98.6%).9 Clinical scenarios where i-SCAN potentially has advantages over conventional white light video endoscopy include the detection and characterization of lesions of the esophagus (eg, early squamous cell cancer, gastric inlet patch, minimal change gastroesophageal reflux disease, Barrett’s esophagus, early adenocarcinoma), stomach (eg, atrophic gastritis,

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gastric antral vascular ectasia, early gastric cancer), duodenum (eg, celiac disease, Whippleâ&#x20AC;&#x2122;s disease), and large colon/rectum (eg, polyps, inflammatory bowel disease; Figures 3 and 4), among others.3 An overview of i-SCANâ&#x20AC;&#x2122;s ability to detect adenomatous polyps and lesions is provided in the Table.7-10 Investigators also have reported good inter- and intraobserver agreement when using i-SCAN for the discernment of pathologic GI lesions: Pigo and colleagues found that using the i-SCAN enhancement produced strong inter- and intraobserver agreement in evaluating colorectal polyps in 78 patients undergoing colonoscopy.10 First, a skilled endoscopist used

the high-resolution technology to predict the histology of polyps in real time with subsequent analyses performed by a pathologist. Afterward, 4 other endoscopists were asked to predict polyp histology from digital images taken with i-SCAN enhancement; 6 months later, the 4 endoscopists repeated the assessment.10 Overall, kappa values for inter- and intraobserver agreement were 0.462 (95% confidence interval [CI], 0.373-0.537) and 0.657 (95% CI, 0.373-0.941), respectively.10 Similar results were obtained in a study performed by Masci and colleagues using 400 previously recorded images of colorectal polyps captured with different i-SCAN settings.11

Figure 3. Upper gastrointestinal tract with HDWLE (top left); microvascularity intensifies using the 3 different modes of i-SCAN (top right and bottom row).

HDWLE, high-definition white light endoscopy Images courtesy of Carlos Robles-Medranda, MD.

5

REPORT Eight endoscopists evaluated whether the polyps were neoplastic or non-neoplastic with a moderate interobserver Fleiss’ kappa value of 0.446 (P<0.001).11 Kodashima and colleagues reviewed the utility of NBI compared with i-SCAN. They noted that images on NBI were much darker than conventional white light images, particularly in large luminal diameter regions of the GI tract. In comparison, i-SCAN images were as bright as conventional white light images, thereby enabling observation of much larger areas in a distant view compared with NBI.6 Moreover, the researchers noted that i-SCAN did not need magnifying endoscopy to observe the demarcation of the lesion.6

“In inflammatory bowel disease, most of the dysplasia that we find is flat rather than a classic pedunculated polyp that you will see in the average-risk population. i-SCAN 1 might be a good way to survey the colon and to help your eye spot abnormalities in the mucosal surface that might tell you that a lesion is there. You may then want to switch to i-SCAN 2 and 3 to help better characterize the lesion. i-SCAN 2 might help bring out the vascular pattern; if the vascular pattern looks normal, it suggests that the lesion is benign,” said Dr. Naymagon.

“On the other hand, cancerous and precancerous lesions often alter the vascular pattern of the mucosa, so that is a red flag for us. Finally, i-SCAN 3 in concert with i-SCAN 2 can be used

Figure 4. Upper gastrointestinal retroflexion while using i-SCAN modalities (HDWLE, top left; i-SCAN 1, top right; i-SCAN 2 and 3, bottom row).

HDWLE, high-definition white light endoscopy Images provided by PENTAX Medical Company.

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Table. Accuracy of i-SCAN for Diagnosing Adenomas Authors

Target

Sensitivity, %

Specificity, %

PPV, %

NPV, %

Bouwens et al, 2013

Colorectal polyps

79.3

85.7

84.7

80.5

Hoffman et al, 2010

Colorectal lesions

98

100

100

97

Hong et al, 2012

Colorectal polyps

86.5

91.4

95.5

76.2

Pigo et al, 2013

Colorectal lesions

95

82

—

93

NPV, negative predictive value; PPV, positive predictive value Based on references 7-10.

to demarcate the lesion’s borders and guide where we should begin and end our resection.”

Practical Considerations Several of the faculty commented on the economics of i-SCAN image enhancement technology. For example, Dr. Robles-Medranda said, “i-SCAN is quite cost-effective when compared with other endoscopic enhancement technology. There are no recurring costs for consumable reagents, as is the case with chromoendoscopy. Also, you save a great deal of time with i-SCAN, which you can use by just pressing a button, compared with the time-consuming burden of applying large volumes of stain to the extensive mucosal surfaces of the stomach and colon.”

“If the negative predictive value of i-SCAN technology for tissue histology is borne out in prospective trials, then there could be marked cost savings: It would likely reduce the number of samples that we’re sending for histopathologic examination. For example, if i-SCAN image enhancements can predict with good confidence that a lesion is not malignant, then we could simply avoid biopsy or discard these samples. However, we need additional studies before we reach that point,” Dr. Anandasabapathy said.

Dr. Naymagon commented on the ease of i-SCAN use during endoscopy: “It is the click of a button technology that makes it very simple. Having the ability to toggle between the various different modes, high-definition white light, i-SCAN 1, 2, and 3, within seconds, is very convenient. Compared with narrow band imaging, which often can be very dark and therefore interfere with lesion detection, i-SCAN modes allow you to enhance the image while maintaining brightness. With the 3 different i-SCAN modes, you can go back from one to the other to get exactly what you need and what you are looking for.”

Dr. Robles-Medranda noted the potential for customization beyond the FDA-approved modes. “Although i-SCAN settings 1, 2, and 3 are the default modes, clinicians can change any setting individually to suit their needs. Our group already has experience establishing different settings that we feel are useful, and I think it’s likely that additional default modes will be established that use these new combinations of settings,” Dr. Robles-Medranda said. In fact, Dr. Robles-Medranda and his colleagues presented data from a prospective study on the use of new combination settings at the 2013 Digestive Disease Week meeting. The authors found that compared with the 3 default i-SCAN modes, their new combination settings were more effective for diagnosing neoplastic and non-neoplastic colonic lesions.12

Conclusion Recognition of pathologic lesions under conventional WLE remains suboptimal. i-SCAN is a novel image-enhancement technology that allows improved recognition of pathologic lesions throughout the GI tract. For example, it can help improve polyp characterization, adenoma detection, and visualization of architectural subtleties in the mucosal lining. The system is easy to use, quickly engages with the touch of a button, and offers rapid imaging results. It is a software-based program with free upgrades, thereby enhancing cost-effectiveness. “i-SCAN addresses many aspects of diagnostic endoscopy that we are trying to achieve. It is software-driven, meaning that a computer processor enhances a white light image captured by the scope to help us find whatever it is that we are looking for. The endoscopist flips a switch on the scope and it goes from white light to i-SCAN, and you don’t need any of the other equipment that conventional chromoendoscopy requires,” said Dr. Naymagon.

7

REPORT

References 1. Dik VK, Moons LMG, Siersema PD. Endoscopic innovations to increase the adenoma detection rate during colonoscopy. World J Gastroenterol. 2014;20(9):2200-2211.

8. Bouwens MWE, de Ridder R, Masclee AA, et al. Optical diagnosis of colorectal polyps using high-definition i-scan: an educational experience. World J Gastroenterol. 2013;19(27):4334-4343.

2. Rex DK, Petrini JL, Baron TH, et al; ASGE/ACG Taskforce on Quality in Endoscopy. Quality indicators for colonoscopy. Am J Gastroenterol. 2006;101(4):873-885.

9. Hoffman A, Sar F, Goetz M, et al. High definition colonoscopy combined with i-Scan is superior in the detection of colorectal neoplasias compared with standard video colonoscopy: a prospective randomized controlled trial. Endoscopy.

2010;42(10):827-833.

3. Neumann H, Fujishiro M, Wilcox CM, et al. Present and future perspectives of virtual chromoendoscopy with i-scan and optical enhancement technology. Dig Endosc. 2014;26(suppl 1):S43-S51.

4. PENTAX Medical. PENTAX i-SCANTM Functionality, application, and technical analysis: technical whitepaper. Montvale, NJ: PENTAX Medical; 2013.

10. Pigò F, Bertani H, Manno M, et al. i-Scan high-definition white light endoscopy and colorectal polyps: prediction of histology, interobserver and intraobserver agreement. Int J Colorectal Dis. 2013;28(3):399-406.

5. Hancock S, Bowman E, Prabakaran J. Use of i-Scan endoscopic image enhancement technology in clinical practice to assist in diagnostic and therapeutic endoscopy: a case series and review of the literature. Diagn Ther Endosc. 2012;2012:1-9.

11. Masci E, Mangiavillano B, Crosta C, et al. Interobserver agreement among endoscopists on evaluation of polypoid colorectal lesions visualized with the Pentax i-Scan technique. Dig Liver Dis. 2013;45(3):207-210.

6. Kodashima S, Fujishiro M. Novel image-enhanced endoscopy with i-scan technology. World J Gastroenterol. 2010;16(9):1043-1049.

12. Robles-Medranda C, Del Valle RS, Lukashok HP, et al. Mo1662 Pentax I-SCAN with electronic magnification for the real-time histological prediction of colonic polyps: a prospective study using a new digital chromoendoscopy setting. Gastrointest Endosc.

2013;5(suppl 1):S1-S612.

MK-518 Rev: A

7. Hong SN, Choe WH, Lee JH, et al. Prospective, randomized, back-to-back trial evaluating the usefulness of i-SCAN in screening colonoscopy. Gastrointest Endosc. 2012;75(5):1011-1021.

Disclosures: Dr. Robles-Medranda reported that he serves as a consultant for and on the speakers’ bureau of Mauna Kea Technologies and PENTAX Medical.

Drs. Anandasbapathy and Naymagon reported no relevant financial conflicts of interest.

Copyright © 2014, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

8

SR148

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, PENTAX Medical, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

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MAY 2014

REPORT DDW 2014: Using IBD Diagnostics To Help Manage and Personalize Biologic Therapy nflammatory bowel disease treatment.3,5 In addition to high (IBD) is a common, chronbaseline levels of TNFα and Faculty ic disease that is often signifiC-reactive protein (CRP), one Corey A. Siegel, MD, MS cantly detrimental to patients’ major factor associated with quality of life. Both subtypes of LOR is the presence of antidrug Associate Professor of Medicine and of IBD, Crohn’s disease (CD) and antibodies, including antibodies The Dartmouth Institute for Health Policy ulcerative colitis (UC), occur to infliximab (ATI) and antibodand Clinical Practice frequently in the United States ies to adalimumab (ATA).3 Up Geisel School of Medicine at Dartmouth and share similar symptoms. to 59% of patients on IFX may Director, Dartmouth-Hitchcock Inflammatory Therefore, determining whethdevelop ATI; patients with susBowel Disease Center er a patient has CD or UC may tained ATI often discontinue IFX Lebanon, New Hampshire be difficult and often requires due to hypersensitivity or LOR6 ; extensive laboratory testing and up to 44% of patients who and invasive exams in addition develop an LOR to ADA have to assessing the patient’s clinical presentation.1 There are ATA present.7 The presence of antidrug antibodies may effective biologic therapies for IBD currently available, sevlead to increased drug clearance and decreased drug eral of which target tumor necrosis factor-alpha (TNFα). binding, thus reducing treatment efficacy.5 Commonly used anti-TNFα agents include infliximab (IFX) In the field of therapeutic drug monitoring, assays, and adalimumab (ADA). These agents have been shown including enzyme-linked immunosorbent assays (ELISAs) to be effective in managing IBD cases that do not require and electrochemiluminescence immunoassays (ECLIA), surgery.2-4 use solid-phase binding. However, these tests can be problematic because they are unable to detect ATI and However, up to 54% of patients initially responsive to IFX ATA when the drug itself is present.7,8 may experience a subsequent loss of response (LOR) to

I

Supported by

REPORT To address this limitation, liquid-phase homogeneous mobility shift assays (HMSAs) were recently developed and made commercially available. These assays, such as the PROMETHEUS ® Anser™ IFX and PROMETHEUS ® Anser™ ADA, may provide clinicians clinically actionable results for each patient to help assess LOR and aid in the development of appropriate, proactive management strategies.

To help in the diagnosis of IBD, tests have been employed to examine biologic markers related to IBD subtypes. These biomarkers include the first-generation serologic markers anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic antibodies (pANCA),1,9,10 as well as the newer antibody to outer membrane porin C (anti-OmpC) and anti-flagellin antibodies (anti-CBir1, antiFlaX, and anti-Fla2).9-12 Earlier generations of IBD diagnostic testing relied on serologic markers alone; however, the

newest-generation test (PROMETHEUS® IBD sgi Diagnostic™) takes into account the various factors that are associated with the pathophysiology of IBD, combining serologic, genetic, and inflammatory markers to add additional clarity to the diagnosis of IBD and the differentiation between CD and UC. Information regarding these biomarkers may shed light on both the patient’s IBD diagnosis as well as the future severity of their disease course.

This review highlights the latest research investigating the role of serologic, genetic, and inflammatory markers in the diagnosis of IBD and for assessing long-term patient prognoses, as well as the clinical utility of the new-generation HMSAs for measuring serum drug and drug antibody levels during biologic therapy. All of the abstracts included here were accepted and presented at Digestive Disease Week 2014.13-20

Higher 6-thioguanine nucleotide concentrations are associated with higher trough levels of infliximab in patients on combination therapy Yarur A, Kubiliun M, Drake K, Hauenstein S, Barkin JS, Sussman DA, Deshpande AR, Quintero MA, Singh S, Abreu MT

Background The treatment of IBD includes drugs such as IFX and thiopurines. The combination of both drugs has been shown to be more effective than monotherapy through several mechanisms including higher anti-tumor necrosis factor (TNF) levels and decreased immunogenicity against the drug. 6-Thioguanine (6TGN) is a thiopurine metabolite and higher levels are linked with better clinical outcomes. The aim of this study was to assess if there is a correlation between 6TGN and IFX levels and ATIs.

Methods This was a cross-sectional study of patients with IBD receiving maintenance therapy with IFX in combination with a thiopurine (azathioprine or 6-mercaptopurine) for at least 4 months and in whom levels of both were measured within 2 weeks of each draw. Predictive variables included demographics, IBD phenotype, laboratories (including a complete blood count and CRP), the dose of thiopurine the patient was taking, and metabolite levels (6TGN and 6-methylmercaptopurine [6-MMP]). The primary outcome was the IFX trough level and the presence of ATIs measured using a mobility shift assay, which allows the detection of ATIs in the presence of IFX (Prometheus Labs, San Diego, CA). Spearman’s rho (ρ) was used to correlate levels. Quartile analysis and receiver operating curves (ROC) were performed to identify the best cutoff 6TGN concentration that predicted higher anti-TNF levels.

Results Seventy-two patients were included. Baseline characteristics are shown in Table 1. There was a significant positive

2

Table 1. Baseline Characteristics of the Population Age, mean y (SD)

36 (14)

Female gender, n (%)

31 (56.9)

Diagnosis of Crohn’s disease (vs ulcerative colitis), n (%)

45 (62.5)

Receiving aminosalicylates, n (%)

20 (27.8)

Presence of antidrug antibodies, n (%)

8 (11.1)

Detectable infliximab, n (%)

65 (90.2)

Receiving azathioprine (vs mercaptopurine), n (%)

55 (76.4)

Crohn’s disease phenotype Ileal, n (%a)

25 (56)

Ileo-colonic, n (%a)

15 (34.1)

Colonic disease, n (%a)

5 (11.4)

Fistulizing disease, n (%a)

16 (36.4)

Stricturing phenotype, n (%)

8 (18.2)

Ulcerative colitis phenotype Proctitis, n (%b)

0

Left colitis, n (%b)

10 (43.5)

Pancolitis, n (%b)

13 (56.5)

a b

Percent of patients with Crohn’s disease.

Percent of patients with ulcerative colitis.

REPORT correlation between 6TGN levels and IFX levels (ρ=0.477, P<0.0001) but there was no correlation between thiopurine dose or lymphocyte count and IFX level (ρ=–0.05, P=0.71; ρ=0.12, P=0.3, respectively). A 6TGN level >125 pmol/8×108 red blood cell (RBC) best predicted higher antiTNF levels (ROC=0.82, P=0.002). There was a positive correlation between 6TGN and 6MMP levels (ρ=0.42, P<0.001) and a negative correlation between 6TGN and lymphocyte count (ρ=–0.36, P=0.002). Although there was a correlation between 6-MMP concentrations and IFX levels, in the multiple regression analysis, only 6TGN level was predictive of IFX measurements (P<0.001). Only 8 patients had detectable ATIs (11%); the differences between groups with and without ATI are shown in Table 2. Those patients with 6TGN levels <125 pmol/8×108 RBC had a higher chance of having detectable ATIs (odds ratio [OR], 1.3; 95% confidence interval [CI], 2.3-72.5; P<0.01).

Conclusions 6TGN metabolite levels, rather than weight-based dosing, may assist clinicians in optimizing treatment when using thiopurines in combination with IFX. Therapeutic levels of 6-TGN (>232) were not necessary to achieve higher trough levels of IFX. Thus, in patients on combination therapy, lower target 6TGN levels (125 pmol/8×108 RBC) may maximize IFX levels while minimizing toxicity.

Table 2. Comparison Between Groups With and Without Detectable ATIs (+) ATIs

(–) ATIs

P value

Female gender, n (%)

7 (87.5)

34 (53.1)

0.06

Age, mean y (SD)

41 (12)

36 (14)

0.26

Thiopurine dose, mean mg (SD)

112 (44)

142 (60)

0.12

Lymphocyte count, mean cell × 10 3/mL (SD)

1.7 (0.8)

1.8 (0.7)

0.81

WBC, mean cell × 10 3/mL (SD)

7.1 (1.7)

6.8 (2.2)

0.66

6-thioguanine, pmol/8×10 8 RBC (SD)

116.7 (75)

193 (88)

0.024a

6-methylmercaptopurine, pmol/8×10 8 RBC (SD)

1,419 (3,135)

3,661 (4,942)

0.1

ATI, antibodies to infliximab; RBC, red blood cell; WBC, white blood cell a

P<0.05

Infliximab and antibody to infliximab concentrations in 7,613 patients shows indication for testing, association with loss of response, and provides new insights into binding characteristics of anti-drug antibodies Vande Casteele N, Drake KA, Hauenstein S, Levesque B, Singh S, Sandborn WJ

Introduction

Results

Therapeutic drug monitoring of IFX and ATI concentrations in patients with IBD may help to guide treatment decisions and further increase efficacy. Here we explore the reason for ordering IFX and ATI concentrations in clinical practice. A clinically validated HMSA (AnserTM IFX) was used to measure IFX and ATI concentrations and provided insights into the binding characteristics of ATI.

Clinicians’ reported indications for testing in each of the 8,281 samples are designated in Table 3. Of 8,281 samples, 5,591 had IFX >3 mcg/mL (67%) and 1,575 (19%) had detectable ATI. IFX concentration was higher in ATI-negative samples than in ATI-positive samples (median 10.3 vs <1.0 mcg/mL; P<0.001). Of the samples, 73% (293) had no detectable drug even when ATI was present at low concentrations (<10 U/mL) compared with 21% (1,392) with no detectable drug in ATI-negative samples (P<0.001). Analysis of chromatograms revealed that in samples with ATI <40 U/mL, complexes had 1:1 molar ratios of ATI to IFX (molecular weight [MW] ~300 kDa). Samples with ATI >40 U/mL also contained larger complexes indicative of 1:2 molar ratios of ATI to IFX (MW ~450 kDa). Of the 290 samples sent in for reason of adverse events (AEs), 143 (49%) were ATI-positive versus only 17% to 20% of the other groups (P<0.001). In this same AE group, 72 of 143 ATI-positive samples (51%) had ATI >40 U/mL compared with 7 of 56 (13%) in the disease monitoring group (P<0.001) and

Methods IFX and ATI concentrations were available for 8,281 serum samples from 7,613 patients. Samples collected since July 30, 2012 were analyzed using previously described AnserTM IFX assay (Wang S et al, 2012; Prometheus Laboratories Inc., San Diego, CA). Reason for testing was known for 3,888 of the 8,281 samples from the order request form completed by the treating clinician. ATI-binding characteristics were determined using proprietary software analysis of high-performance liquid chromatography chromatograms.

3

REPORT 116 of 551 (21%) for LOR or flare (P<0.001). Of the samples sent in for flare or LOR (2,965), 551 (18%) contained ATI, 587 (23%) contained no ATI and low IFX (<5 mcg/mL), and 1,727 (58%) contained no ATI and high IFX (>5 mcg/mL).

Conclusion Low concentrations of ATI (range, 3.1-40 U/mL) influence drug clearance and correlate with lower concentrations of

drug, whereas high concentrations of ATI (>40 U/mL) also lead to the formation of high molecular mass IFX to ATI complexes.

The results presented here indicate that not only the concentration but also the size of IFX to ATI complexes might be correlated with AEs. The majority of samples analyzed for reasons of LOR and flare contained an adequate IFX concentration and absence of ATI, indicating a possible alternate disease mechanism in those patients.

Table 3. Clinical Reason for Ordering the ATI Test Proportion

N

% ATI (+) a

Adverse Event

3.5%

290

50%

Disease Monitoring

3.9%

323

17%

Flare

15.1%

1247

18%

Loss of Response

20.7%

1718

19%

Ongoing Disease Activity

2.0%

169

18%

Restarting IFX

0.9%

77

17%

Other

0.7%

64

20%

Missing

53.0%

4393

18%

ATI, antibodies to infliximab; IFX, infliximab a

Positive results were defined as >3.1 U/mL.

Antibodies to adalimumab predict inflammation in Crohn’s patients on maintenance adalimumab therapy Baert F, Lockton S, Drake K, Hauenstein S, Singh S, Gils A, Vermeire S

Introduction During IFX therapy for IBD, antidrug antibody formation can lead to LOR to the drug. Data for ADA is limited. Karmiris and colleagues demonstrated that ADA resulted in sustained clinical benefit in two-thirds of patients with CD during 2-year follow-up. We performed additional analyses on this cohort using the HMSA, focusing on the interrelationship of serum concentrations of ADA, ATA, and CRP.

Methods Five hundred thirty-six prospectively collected serum samples were available from 148 of 168 patients in the Karmiris cohort for additional analysis. Serum ADA and ATA at predefined time points were measured using HMSA. Samples

4

were classified as ATA-negative, ATA-detectable (non-zero ATA levels below the lower limit of quantitation [LLOQ] of 1.7 U/mL), or ATA-positive (ATA ≥LLOQ). The LLOQ for ADA was ≥1.0 mcg/mL. We studied the role of week 4 ADA levels on ATA formation with a Cox proportional hazards model of time to ATA versus ADA. Repeated-measures mixed-regression modeling was performed to assess the independent effects of ATA and ADA on CRP.

Results ATA were positive (above LLOQ) in 20.2% of patients (30 of 148) after a median of 34 weeks (interquartile range [IQR], 12.4-60.5 weeks). Samples with ADA in the lower 2 quartiles were more often ATA-positive than samples in the third and fourth ADA quartiles (P<0.0001; Figure 1). ATA-positive samples (both detectable and above LLOQ) were associated with lower median ADA levels than ATA-negative samples (P<0.001;

REPORT Figure 2). Cox regression modeling showed that week 4 ADA <5 mcg/mL significantly increased the future ATA formation risk compared with >5 mcg/mL (hazard ratio [HR], 11.13; P=0.0002). Regression modeling showed a negative correlation between CRP and ADA levels (P=0.0013) and a positive association with ATA (P=0.042). When the model was used to predict CRP on observation in the future, ATA was strongly associated with future CRP increase (P=0.002; median 7.8 weeks between samples; IQR, 4.0-15.8), although ADA levels were not (P=0.176). Per-patient median CRP was significantly higher in those who eventually failed ADA therapy (median 8.34 vs 4.35 mg/L; P=0.026).

ATA Positive False True

120

Count

100

60 40 20

Conclusion

0

Using HMSA, ATA were detected in 20% of patients in this cohort on ADA maintenance therapy, compared with 9% as previously reported by Karmiris and colleagues. Risk for ATA formation increased with lower early drug levels. Interestingly, ATA was strongly associated with CRP in the future, whereas drug levels were only informative of present CRP levels.

These data suggest that early drug and antibody-level monitoring and subsequent dose optimization would help prevent ATA and improve patient outcomes.

Median HMSA Adalimumab, mcg/mL

80

First

Second

Fourth

ADA Quartile Figure 1. Relationship between serum ADA and presence of ATI across time.

ADA, adalimumab; ATA, antibodies to adalimumab

19

20

Third

26

5

15

ATA Group High ATA Detectable ATA No ATA

81 77

10

7 10

5

20

8 14

99

0

6

8

1

0

4

8

12

16

20

24

28

32

36

40

44

48

52

Weeks Since Adalimumab Start Figure 2. Relationship between detectable ATA levels and median adalimumab levels.

ATA, antibodies to adalimumab; HMSA, homogeneous mobility shift assay

5

REPORT Is there a higher rate of infliximab dose optimization in initial responders between UC and CD cases?

O’Donnell S, Stempak J, Silverberg M

Aims

Methods All cases receiving IFX for treatment of IBD between January 2008 and October 2013 were identified. Cases receiving 4 or more infusions were included. Details of infusion dosing and timing were obtained from a central database. Dose increase from 5 to 10 mg/kg or a reduction in the dosing interval to less than 8 weeks were considered dose optimization. Alterations in doses to account for weight changes were not considered dose optimization. Where available, results of Prometheus Anser assay for IFX levels and ATI were evaluated.

Results There were 211 cases identified. Of these cases, 50% were women, 66.8% had CD, and 32.7% had UC. Average age at diagnosis was 19.9 years and the median time from diagnosis to treatment with IFX was 7.9 years (IQR, 2-11.5). By October 2013, 69.7% of cases receiving maintenance IFX during the study period continued on therapy. The median duration of IFX treatment during the study period was 23 months (IQR, 12-53). Nearly half (48.5%) of the cases required dose optimization during the study period. Dose optimization was more common in cases with UC than CD (66.7% vs 48.9%; P=0.015). This reflected more dose increases in UC than CD (37.7% vs 18.4%; P=0.002) with no significant difference in frequency of interval reduction (56.5% vs 44.7%; P=0.107). IFX TLs were available on 26 UC and 51 CD

Survival Functions 1.0

Cumulative Survival

Dose optimization is frequently required in IBD cases treated with IFX. Factors affecting the pharmacokinetics of IFX include body weight, albumin, CRP, and antibodies to IFX. It has been hypothesized that a high inflammatory burden and high levels of TNF at induction may lead to rapid clearance. The aim of this study was to examine the differences in need for dose optimization between CD and UC patients who have had an initial response to IFX therapy.

Diagnosis CD UC CD-Censored UC-Censored

0.8 0.6 0.4 0.2 0.0 0

20

40

60

80

100

Time to Dose Optimization, mo

Figure 3. Time to effective doses among patients with IBD. CD, Crohn’s disease; UC, ulcerative colitis

patients with no difference in mean levels observed (10.14 vs 9.18 mcg/mL; P=0.666). Patients with UC required a higher mean dose of 350 mg per month versus 285 mg per month for those with CD (P=0.001). Time-to-dose optimization was significantly lower in UC compared with CD (log rank P=0.002; Figure 3).

Conclusion These results show that higher doses of IFX are being used in UC than CD cases with comparable IFX TLs, suggesting higher drug clearance. This may reflect a higher burden of inflammation in UC than in CD cases.

Anti-tumor necrosis factor drug levels and antibodies are associated with Crohn’s disease recurrence at the level of the ileocolonic anastomosis after ileal resection Yarur A, Trivella JP, Sussman DA, Drake KA, Barkin JS, Hauenstein S, Deshpande AR, Quintero MA, Singh S, Abreu MT

Background Endoscopic and clinical recurrence of CD after small bowel resection (SBR) and ileocolonic anastomosis (ICA) is common.

Anti-TNFs have been shown to decrease the rate of recurrence,

6

although the relationship between drug levels and disease activity at the level of the ICA is unknown. The aim of this study was to assess if there is an association between anti-TNF drug levels and postoperative disease recurrence.

REPORT Methods This is a cross-sectional study of patients with CD who underwent SBR and ICA and received maintenance doses of infliximab or ADA, starting within 12 months of the surgery. Predictive variables included demographics, CD phenotype at the time of the surgery, concomitant medications for CD, and anti-TNF levels, and ADAs (Prometheus Labs, San Diego, CA). Infliximab levels of ≥3 mcg/mL and ADA levels of ≥5 mcg/mL were considered therapeutic as per previous reports in patients without a surgical anastomosis. The primary outcome was an endoscopic Rutgeerts score (RS) ≥i2 (>5 aphthous ulcers at the site of the anastomosis), which was chosen based on the worse prognosis of these patients compared with those with a score of i0 to i1. The χ2 test and the Mann–Whitney test were used to compare categorical and quantitative variables. Receiver operating characteristic (ROC) analysis was also performed using the RS, presence of stenosis and microscopic disease activity as classification variables.

Results Twenty-nine patients were included. Mean age was 39 (SD 11), 13 (45%) were women, 15 (52%) were receiving IFX

(vs ADA), 11 (38%) had ileal disease at the time of the surgery (vs ileocolonic), 15 patients had an RS of i0 to i1 (52%), and 14 had an RS ≥i2 (48%; Table 4). Time from the surgery to colonoscopy was 3.1 years (range 1-6). Those with an RS ≥2 had a significantly higher level of anti-TNF. The differences between those with an RS of i0 to i1 and those with an RS ≥i2 are shown in Table 5. Patients with an RS ≥i2 were more likely to have anti-TNF antibodies (P<0.01) and undetectable drug levels (P= 0.03; Figure 4). The area under the curve on the association between an RS ≥i2 and anti-TNF levels was 0.84 (P= 0.011). Six (21%) and 16 (55%) had stenosis at the level of the anastomosis and microscopically active disease, respectively. Lower drug levels were predictive of microscopic disease activity in the anastomosis (ROC, 0.74; P= 0.02) but not for stenosis of the anastomosis (ROC, 0.71; P= 0.13).

Conclusion Low anti-TNF drug levels and the presence of anti-drug antibodies were associated with endoscopically significant disease recurrence after surgery for CD. Monitoring anti-TNF drug levels in patients receiving these drugs for postoperative prevention may be useful in proactively minimizing disease recurrence.

Table 4. Baseline Characteristics Age, mean y (standard deviation)

39 (11)

Female gender, n (%)

13 (44.8)

Receiving infliximab, n (%)

15 (51.7)

Aminosalicylates, n (%)

1 (34.5)

Thiopurines, n (%)

21 (72.4)

Methotrexate, n (%)

1 (34.5)

Antibiotics, n (%)

none

Had ileal disease at the time of surgery, n (%)

11 (37.9)

Had ileocolonic disease at the time of surgery, n (%)

18 (62.1)

Had fistulizing disease at the time of surgery, n (%)

9 (31)

Had stricturing disease at the time of surgery, n (%)

9 (31)

Had a Rutgeerts score ≥i2, n (%)

14 (48.3)

7

REPORT

Table 5. Comparison of Patients Found to have a Rutgeerts i0-i1 Compared With i2-i4a Rutgeerts i0-i1

Rutgeerts i2-i4

P value

Age, mean y (SD)

39 (12)

39 (12)

0.89

Male gender, n (%)

9 (60)

7 (50)

0.6

CRP, mean in mg/dL (SD)

0.44 (0.7)

2.12 (2.7)

0.01b

Albumin, mean in mg/dL (SD)

4.47 (0.6)

3.69 (1.1)

0.03 b

Time surgery-colonoscopy, mean in years (SD)

3.2 (2.1)

3.0 (2.3)

0.81

Anti-TNF level (mean in mcg/mL)

12.2 (8.4)

4.1 (5.6)

0.002b

Detectable anti-TNF level, n (%)

14 (93)

8 (57)

0.023 b

Anti-TNF level therapeutic, a n (%)

15 (75)

5 (35)

<0.001

Anti-drug antibodies, n (%)

none

3 (21.4)

0.03 b

On aminosalicylates, n (%)

1 (6.7)

none

0.33

Thiopurines, n (%)

10 (66.7)

11 (78.6)

0.47

Ileal disease at the time of surgery, n (%)

8 (53.3)

3 (21.4)

0.08

Ileocolonic disease at the time of surgery, n (%)

7 (46.7)

11 (78.6)

0.07

Fistulizing disease, n (%)

3 (20)

6 (42.9)

0.18

Stenotic disease, n (%)

4 (26.7)

5 (35.7)

0.6

CRP, C-reactive protein; TNF, tumor necrosis factor a

Infliximab levels â&#x2030;Ľ3 mcg/mL and adalimumab levels â&#x2030;Ľ5 mcg/mL were defined as therapeutic.

b

P<0.05

P<0.01 Mean Anti-TNF Level 4.1 mcg/mL

Mean Anti-TNF Level 12.2 mcg/mL

16

Number of Patients

14 12 10 8 6 4 2 0 i0 or i1

i2

i3

Endoscopic Rutgeerts Score Figure 4. Anti-TNF levels based on endoscopic Rutgeerts score.

TNF, tumor necrosis factor

8

i4

REPORT

Preoperative serologic markers may predict postoperative Crohn’s disease recurrence: results from a prospective monocentric trial Ferrante M, Noben M, De Buck Van Overstraeten A, Lockton S, De Hertogh G, Princen F, Wolthuis A, Van Assche GA, Vermeire S, Singh S, D’Hoore A

Background and Aims Preventing postoperative endoscopic (ER) and clinical recurrence (CR) remains a challenging issue in patients with CD undergoing an intestinal resection. Several clinical and histologic risk factors have been identified, and may guide selection of appropriate candidates for postoperative prophylactic CD therapy. We evaluated if a set of preoperative serologic markers could strengthen the prediction of postoperative ER and CR.

Methods Our study population consisted of 100 consecutive patients (41 men, 27 active smokers, and median age 41.7 years) undergoing an ileal resection with ileocolonic anastomosis for refractory CD, in whom a serum sample was collected ≤1 week before surgery. All patients were followed prospectively and underwent a postoperative endoscopic evaluation at 6 months. The primary end point was defined as a postoperative ER score of i3 or i4. Secondary end points included time to clinical recurrence. Sera were analyzed blindly at Prometheus laboratories for the expression of ASCA-IgA and ASCA-IgG antibodies, 3 different anti-flagellin antibodies (CBir1, Fla2, and FlaX), OmpC, and atypical pANCA. The Q3 value of each individual marker in this dataset was defined as the cutoff point. Predictors of both ER and CR in univariate

analyses were included in the binary logistic and Cox regression analysis.

Results Twenty-five patients developed ER at 6 months. Fla2 >66 EU (odds ratio [OR], 3; 95% confidence interval [CI], 1.1-8.7; P= 0.037), and active smoking (OR, 3.1; 95% CI, 1.1-8.8; P= 0.029), were independently associated with ER. During a median follow-up of 23.6 months, 29 patients developed a CR, with Fla2 >66 EU (OR, 2.2; 95% CI, 1.04.6; P= 0.041), pANCA positivity (OR, 2.5; 95% CI, 1.2-5.4; P= 0.016), and active smoking (OR, 2.6; 95% CI, 1.2-5.5; P= 0.011) as independent risk factors. A cumulative risk score was developed by combining 3 risk factors (Fla2 >66 EU, pANCA positivity, and active smoking). Based on this cumulative risk score, we could observe a significant and gradual increased risk for both ER and CR.

Conclusion Preoperative serologic markers, including anti-flagellin Fla2 antibodies, were independently associated with postoperative ER and CR. We identified a risk panel of clinical and serologic markers that may guide postoperative prophylactic therapy. Validation of these results in an independent cohort is warranted.

Prediction of sustained remission after discontinuation of infliximab in patients with Crohn’s disease Papamichail K, Vande Casteele N, Hauenstein S, Princen F, Singh S, Ferrante M, Van Assche G, Rutgeerts P, Gils A, Vermeire S

Background and Aim

Material and Methods

The STORI (Stop Infliximab in Patients With Crohn’s Disease) trial showed that biologic and endoscopic features of persistent inflammation were predictors of relapse in patients with CD who stopped IFX for remission and continued on immunomodulators (IMMs). Predictive markers that assist in identifying patients at low risk for relapse after discontinuation of anti-TNF are needed before this strategy can find wide acceptance. A serology panel against microbial peptides was shown to predict disease progression and hence could also help in identifying patients at risk for relapse. We studied clinical, biological, mucosal, and serologic predictors for sustained clinical remission (SCR) after cessation of IFX.

In an observational retrospective single-center study, we identified 100 patients with CD who discontinued IFX therapy for clinical remission. SCR was defined as maintained disease remission without the need to reintroduce medical therapy (biologics, corticosteroids, thiopurines, or methotrexate) or surgical interventions (ileocolonic resection, stricturoplasty, fistulotomy) until end of follow-up. IFX trough levels (TL) were analyzed using an in-house developed and clinically validated ELISA, the serology panel containing ASCA, anti-bacterial flagellins (CBir1, Fla2, and FlaX), and OmpC and circulating inflammatory markers such as intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), and serum amyloid A (SSA) were

9

REPORT evaluated (Prometheus Laboratories Inc., San Diego, CA) in serum samples taken from the time of cessation.

Results One hundred patients with CD (40 men; median age at diagnosis 25 years (IQR, 18-34]; 43 treated mainly for fistulizing disease; 65 treated with episodic, 15 induction only, and 20 with maintenance IFX therapy) discontinued IFX therapy for remission after a median of 7.3 months (IQR, 1.4-16.2) and a median number of 3.5 infusions (IQR, 2-6). After stopping IFX, 84 patients continued on IMM while 16 received 5-aminosalicylic acid or no therapy. With a median followup of 9.9 years (IQR, 7.9-11.7), 52 had SCR. Univariate analysis showed age at diagnosis >25 years (log-rank, P= 0.013)

and IFX TL <6 mcg/mL (n=19; log-rank, P= 0.031); complete mucosal healing (n=18; log-rank, P= 0.048); VCAM >0.67 mcg/mL (n=71; log-rank, P= 0.044) at the time of IFX cessation predicted SCR.

Conclusion In this single-center study, 52% of patients with CD who discontinued IFX therapy due to clinical remission remained in SCR and mainly with continued IMM treatment. We have confirmed the results of the STORI trial indicating that low IFX TL and mucosal healing at the time of IFX cessation can predict SCR, whereas the role of serologic factors as predictors of remission after IFX discontinuation deserves further investigation.

Classification of non-IBD, Crohnâ&#x20AC;&#x2122;s disease, and ulcerative colitis in a young patient population using a multimarker diagnostic panel Lockton S, Princen F, Singh S

Background Approximately 10% to 15% of IBD cases occur in individuals younger than 18 years old. A combination of a clinical examination, imaging, endoscopy with histopathology, and laboratory testing is conventionally used to diagnose pediatric IBD. Less-invasive testing methods can be especially valuable for younger patients. The use of serology to assist in IBD diagnosis has been extensively described in the literature for adult patients. In addition to the auto- and antimicrobial antibodies typically associated with IBD, genetic variants as well as angiogenesis and inflammation molecules may better help identify IBD. A recent study (Plevy et al., Inflamm Bowel Dis 2013;19:1139-1148) demonstrated the benefit of biomarker combinations to aid in diagnosing adult IBD. However, the diagnostic value of this biomarker test to classify and stratify IBD in younger patients is not as well established. The aim of this study was to evaluate the diagnostic performance of a biomarker test that can identify and stratify young patients with IBD.

Methods Samples from well-characterized patients were collected from 15 North American gastroenterology centers. Median age of patients was 15 years (IQR, 13-16). Samples from 251 patients were used: 147 CD, 47 UC, and 57 non-IBD disease controls. A combination of serologic markers (ASCAIgA, ASCA-IgG, ANCA, pANCA, anti-OmpC, anti-Fla2, anti-FlaX, and anti-CBir1), 4 gene variants (ATG16L1, NKX2-3, ECM1, and STAT3), and 5 inflammatory markers (CRP, SAA, ICAM, VCAM, and vascular endothelial growth factor) were used in this evaluation. Identification of IBD, CD, and UC was made with the aid of a machine-learning model. Sensitivity,

10

specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy statistics were calculated for both the IBD and non-IBD components of the diagnostic model, and separately for the CD and UC components (for patients called IBD by the model).

Table 6. Performance of the Prometheus SGI for Diagnosing IBD and Its Subtypes %

IBD

CD

UC

Sensitivity

86.1

91.9

82.1

Specificity

86.0

75.8

90.5

PPV

95.4

92.7

67.6

NPV

64.5

73.5

95.5

Accuracy

86.1

88.2

88.9

CD, Crohnâ&#x20AC;&#x2122;s disease; IBD, inflammatory bowel disease; NPV, negative predictive value; PPV, positive predictive value; UC, ulcerative colitis

REPORT Results The multimarker biomarker diagnostic model performed in classifying IBD, CD, and UC in pediatric patients is reported in Table 6. We observed a sensitivity of 86.1% and a specificity of 86% for identifying young adults with IBD. The sensitivity and specificity for classifying CD in patients called IBD by the model were 91.9% and 75.8%, respectively. UC sensitivity and specificity were 82.1% and 90.5%, respectively. Diagnostic accuracy of the biomarkers was 86.1% for IBD versus non-IBD, 88.2% for CD, and 88.9% for UC. The IBD NPV and

PPV were 64.5% and 95.4%, respectively. CD NPV and PPV were 73.5% and 92.7%, respectively. UC NPV and PPV were 95.5% and 67.6%, respectively.

Conclusion Our results demonstrate that a combination of serologic, genetic, and inflammatory markers may be used for classifying non-IBD, CD, and UC in the young adult patient population. More studies are required to further investigate the clinical utility of this biomarker test.

Discussion The research presented here may ultimately guide the diagnosis and treatment of IBD and its subtypes, as well as give insight into potential patient outcomes. These findings also provide important information regarding the development of LOR to currently available biologic treatments, highlighting the important role of newly available liquid-phase assays in uncovering the contributing factors, such as drug clearance and immunogenicity.

The addition of liquid-phase HMSAs to measure drug and antidrug levels suggests that more personalized treatment approaches for biologic therapies may be on the horizon.

Oâ&#x20AC;&#x2122;Donnell and colleagues showed that although IFX trough levels were similar between UC and CD patients, higher doses were used in UC cases.13 This suggests that UC cases present with higher drug clearance, possibly due to a higher inflammatory burden.

Prevalent LOR to IFX and ADA represents a limitation in biologic therapy; the data presented here shed light on some potential mechanisms behind these limitations. This information may be used to identify particular populations at increased risk for developing LOR, thus giving clinicians a head start to potentially help avoid it. Additionally, research from Vande Casteele and colleagues indicates that both the concentration

and the size of ATI/IFX complexes are important factors in developing LOR. Their data show that in cases where the concentration of ATI is greater, the molecular mass of ATI/IFX complexes increases.14 Furthermore, Baert and colleagues found that monitoring initial ADA drug serum levels in using HMSAs in CD patients suggested that low levels of ADA early in treatment could increase the likelihood of ATA developing.15 Finally, this research shows the value of using the HMSA to provide important insight into predicting patientsâ&#x20AC;&#x2122; outlook for remission. Papamichail and colleagues monitored remission results in CD patients as they discontinued IFX treatment.

Results showed that patients with low IFX trough levels who achieved mucosal healing at the time of IFX cessation were likely to see sustained clinical remission. Their results also suggest that the serologic inflammatory marker VCAM may be useful as a predictor of remission.16 Yarur and colleagues were also able to predict the recurrence of CD after small bowel resection and ICA using drug and antidrug antibody levels measured by HMSAs. They found that lower drug levels and the presence of antidrug antibodies were associated with significant CD recurrence after surgery.17 Furthermore, Ferrante and colleagues showed that serologic markers, specifically anti-OmpC and anti-Fla2, were associated with postoperative CD recurrence.18

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REPORT References 1.

Wolf DS, Bincy BP, Afzali A, et al. Community perspectives: combining serology, genetics, and inflammation markers for the diagnosis of IBD and differentiation between CD and UC. Gastroenterol Hepatol. 2012;8(6 suppl 2):S1-S16.

12. Targan SR, Landers CJ, Yang H, et al. Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn’s disease.

Gastroenterology. 2005;128(7):2020-2028.

2.

Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn‘s disease: results of the CLASSIC II trial. Gut. 2007;58(9):1232-1239.

3.

Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn‘s disease: the ACCENT I randomised trial.

Lancet. 2002;359(9317):1541-1549.

13. O’Donnell S, Stempak J, Silverberg M. Is there a higher rate of infliximab dose optimization in initial responders between UC and CD cases? Presented at: 2014 Digestive Disease Week; May 3-6, 2014; Chicago, IL.

5.

Regueiro M, Siemanowski B, Kip KE, et al. Infliximab dose intensification in Crohn’s disease. Inflamm Bowel Dis. 2007; 13(9):1093-1099.

6.

Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient.

Am J Gastroenterol. 2013;108(6):926-971.

7.

Wang SL, Hauenstein S, Ohrmund L, et al. Monitoring of adalimumab and antibodies-to-adalimumab levels in patient serum by the homogeneous mobility shift assay. J Pharm Biomed Anal. 2013;78-79;39-44.

8.

Wang SL, Ohrmund L, Hauenstein S, et al. Development and validation of a homogeneous mobility shift assay for the measurement of infliximab and antibodies-to-infliximab levels in patient serum. J Immunol Methods. 2012;382(1-2):177-188.

9.

Ferrante M, Henckaerts L, Joossens M, et al. New serological markers in inflammatory bowel disease are associated with complicated disease behavior. Gut. 2007;56(10):1394-1403.

15. Baert F, Lockton S, Hauenstein S, et al. Antibodies to adalimumab predict inflammation in Crohn’s patients on maintenance adalimumab therapy. Presented at: 2014 Digestive Disease Week; May 3-6, 2014; Chicago, IL. 16. Papamichail K, Vande Casteele N, Hauenstein S, et al. Prediction of sustained remission after discontinuation of infliximab in patients with Crohn’s disease. Presented at: 2014 Digestive Disease Week; May 3-6, 2014; Chicago, IL. 17. Yarur A, Trivella JP, Sussman DA, et al. Anti-tumor necrosis factor drug levels and antibodies are associated with Crohn’s disease recurrence at the level of the ileo-colonic anastomosis after ileal resection. Presented at: 2014 Digestive Disease Week; May 3-6, 2014; Chicago, IL. 18. Ferrante M, Noben M, De Buck A, et al. Pre-operative serological markers may predict postoperative Crohn’s disease recurrence: results from a prospective mono-centric trial. Presented at: 2014 Digestive Disease Week; May 3-6, 2014; Chicago, IL.

10. Plevy S, Silverberg MS, Lockton S, et al. Combined serological, genetic, and inflammatory markers differentiate non-IBD, Crohn’s disease, and ulcerative colitis patients. Inflamm Bowel Dis. 2013;19(6):1139-1148.

19. Yarur A, Kubiliun M, Drake K, et al. Higher 6-thioguanine nucleotide concentrations are associated with higher trough levels of infliximab in patients on combination therapy. Presented at: 2014 Digestive Disease Week; May 3-6, 2014; Chicago, IL.

11.

20. Lockton S, Princen F, Singh S. Classification of non-IBD, Crohn’s disease and ulcerative colitis in a young patient population using a multimarker diagnostic panel. Presented at: 2014 Digestive Disease Week; May 3-6, 2014; Chicago, IL.

Landers CJ, Cohavy O, Misra R, et al. Selected loss of tolerance evidenced by Crohn’s disease-associated immune responses to auto- and microbial antigens. Gastroenterology.

2002;123(3)689-699.

Disclosures: Dr. Siegel reported that he serves as a consultant for AbbVie, BioLineRX, Elan Pharmaceuticals, Given Imaging, Janssen Pharmaceuticals, Pfizer, Prometheus Laboratories, Salix Pharmaceuticals, Takeda Pharmaceuticals, and UCB, Inc. He has also prepared and delivered CME for AbbVie, Janssen Pharmaceuticals, and Merck & Co., Inc. Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Prometheus Laboratories Inc., and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

Copyright © 2014, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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IBD14001

Ordás I, Mould DR, Feagan BG, et al. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokineticsbased dosing paradigms. Clin Pharmacol Ther. 2012;91(4): 635-646.

SR1415

4.

14. Vande Casteele N, Drake KA, Hauenstein S, et al. Infliximab and antibody to infliximab concentrations in 7,613 patients shows indication for testing, association with loss of response and provides new insights into binding characteristics of anti-drug antibodies. Presented at: 2014 Digestive Disease Week; May 3-6, 2014; Chicago, IL.

A BOS TON S C I E N TI F I C P UB L I C AT I O N

MAY/J U N E 2014 • I SSU E 1

E N H A N C I N G PATI EN T O U TC OMES. DELIVER IN G TOTAL VALU E.™

›

E ducation materials focus on the patient.

New Slimline Handle

The Making of a More Ergonomic Handle Expect™ Slimline (SL) Needle addresses physician preference.

Original Handle

A Message From Dave Pierce

Employees at Boston Scientific’s Costa Rica facility planted 250 trees on the property as part of a program designed to help reduce CO2.

The idea of green means different things to different people. For some, it’s about energy – alternatives, footprint and conservation. For others, it’s about waste management and recycling. There are many definitions.

For example, we are taking every opportunity to look at packaging improvements and what can be done to help reduce waste, use more recyclable materials, take up less shelf space, and improve operational and procedural efficiencies (p. 9).

Through our association with Practice Greenhealth, we’ve learned that many health care facilities have a fairly broad definition of green – one that includes managing waste, energy efficiency, health risks and safety. Green initiatives are not solely motivated by cost or compliance but by the potential impact to patients, employees and the community.

Tackling the challenges of sustainability is much like figuring out the changing health care landscape – it encompasses many things and there is no one right approach, no one right delivery-of-care model.

Customers like Kaiser and Geisinger Health (Read about Geisinger Health System in the October 2012 issue of ACCESS magazine) and others are taking action. They see the future – the challenges, the opportunities and the possibilities – and they are making changes to be successful in the evolving health care landscape. We are proud to be working with such customers and believe we have an important role to play in helping them achieve their goals.

Kaiser Permanente, headquartered in Oakland, California, is a great example. Through its Environmentally Preferred Purchasing program, Kaiser has reduced waste by approximately 2,400 tons, saved 87,000,000 kWh, switched to using dozens of chemically safer products at its campuses as well as made a number of improvements in its supply chain.* Kudos to Kaiser for its leadership and helping move the industry in this direction.

We too are addressing sustainability. We are incorporating LEED standards into the construction of new buildings and modification of existing facilities. We’ve achieved ISO14001 certification at all 14 of our major manufacturing and distribution facilities worldwide. We are working to find ways to help our customers achieve their sustainability goals.

Although the phrase “health care reform” is very much associated with the U.S., our customers around the world face similar cost, quality and delivery-ofcare challenges. Physician education to advance GI endoscopy is a key issue in many regions. That’s why we continue to focus our efforts in this area and work to create region-specific training. Read about a recent preceptorship held at St. Joseph’s Hospital in Marseille, France (p. 6), and our new endoscopy training offerings at Boston Scientific’s Institute for Advancing Science in Paris (p. 7).

Also in this issue, read about our Expect™ Slimline (SL) Needle – a version of our EUS needle with a new handle to accommodate physician preference.

Early feedback from physicians is impressive. See what they have to say and how their feedback made a difference (p. 2).

Dave Pierce Senior Vice President, Boston Scientific President, Endoscopy Division

*Source: “Rethinking Environmentally Preferred Purchasing: A case Study in Implementation at Kaiser Permanente,” Feb. 4, 2014, V. Lochner, Practice Greenhealth website (www.practicgreenhealth.org).

BOSTON SCIENTIFIC NEWS

Inside This Issue Articles 2

Designing the Expect™ Slimline (SL) Handle

8

An Interview with Maria Stewart, Director of Health Economics & Reimbursement

4

Improving Outcomes through Patient Education

8

Update on Endoscopy Gurukul

5

Working with the National Pancreas Foundation

9

Boston Scientific Green Initiatives – Making a Difference

6

Preceptorship Brings Master Class Training to Physicians in France

9

Close the Gap Initiative Works to Improve Patient Education and Access to Care

Eating After Esophageal Stent Placement

Colon Canc er

Risk Assessm ent Colorectal cancer affe cts an estimated 1 in 20 Am ericans.

WHAT’S YO LEVEL OF RI UR SK?

Take the Col orectal Can cer Risk Assessme nt Quiz to find out.

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Endoscopy Training Now Part of the Paris Institute for Advancing Science

7

Covered WallFlex™ Esophageal Stent Receives CE Mark in Europe for Refractory Benign Indication

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News and New Devices

Case Studies 10-11 E xpect™ Slimline (SL) Needle

for EUS FNA

12-14

WallFlex ™ Stents

15-16 SpyGlass™ Direct

Visualization System

17-20

21

Resolution™ Clip Device

TWISTER® PLUS Rotatable Retrieval Device and Captivator™ Snare

Opt-in to receive ACCESS magazine electronically and email updates on new products, indications and resources. Visit www.bostonscientfic.com/endo-access-subscribe. access

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Designing the Expect ™ Slimline (SL) Handle A novel approach to physician engagement yields new options for meeting their needs In its very first year on the market, the Expect™ Endoscopic Ultrasound Aspiration Needle commanded an impressive market share, and was widely praised for its superior needle penetration and ability to retain its sharpness and form through multiple passes.

But word came back from the marketing and field sales groups that not all customers had the same ergonomic and actuation preferences — and some were looking for a different shape or tactile feel to accommodate their individual techniques. That set Boston Scientific off on a unique journey to uncover and meet their customers’ needs.

The company had a novel idea: Instead of only engaging the company’s satisfied customers, what if they also reached out to physicians who preferred the competition? And what if they gave them a chance not only to suggest iterative changes, but to actually “blue sky” their idea of the perfect EUS Needle? “By engaging physicians who liked the original Expect needle, physicians who didn’t, physicians who regularly use our devices and physicians who didn’t, we hoped to get a variety of opinions and allow them to define their ideal EUS device,” explained Kurt Geitz, vice president of research and development at Boston Scientific.

Working with marketing and sales, we engaged more than 50 physicians from the U.S., Europe, Japan and Latin America to better understand what they liked and didn’t like about the current handle.

— Brandon Alexopolous

A FRESH APPROACH TO PHYSICIAN ENGAGEMENT Boston Scientific reached out to a wide range of thought-leading physicians, from the needle’s biggest fans to its toughest critics.

“Working with marketing and sales, we engaged more than 50 physicians from the U.S., Europe, Japan and Latin America to better understand what they liked and didn’t like about the current handle,” explains Brandon Alexopolous, R&D technical team lead on the Expect Slimline Handle design project.

The team promised to meet with these physicians consistently over a short period of time. “We held regular interviews and developed multiple rounds of prototypes based on their feedback, which they then used in animal labs to simulate real life experience,” Alexopolous says. “We worked with physicians in our R&D facility, in their hospitals, at conferences such as DDW and UEG, and at live courses held around the world.”

Dr. David Robbins, associate chief of endoscopy, Lenox Hill Hospital, recalls being particularly impressed with the integrity of the process.

“In the lab, we spent a lot of time trying to quantify things like resistance, tissue compliance and ergonomics,” he says. “It was a really well-designed analysis, not a one-size-fits-all proposition.”

R&D Technical Team Lead

What doctors are saying about the Expect™ Slimline Needle Early Clinical Outcomes

Enhanced Tissue Feedback and Tactile Feel

With this new needle, because it’s so sharp, you immediately go exactly

There’s an intimate connection between what you feel in the handle and

where you want to go. And in small lesions, we found in the early experience,

what’s happening at the tip. It translates into really amazing precision.

cases where I was pretty sure it was going to be very difficult to get a diagnosis,

we actually got a diagnosis.

— Anand Sahai, M.D.

Ergonomic Comfort step forward. The Slimline has several positions that I can assume during the course of a fine needle aspiration that will reduce fatigue and probably yield better samples. This is probably the most comfortable needle I’ve used.

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— David Robbins, M.D.

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Tactile feel allows you to feel the hardness of or softness of a lesion, and gives you a clue as to what that lesion could possibly be. The ability of the Slimline Needle to give us that nice one-to-one motion and to allow that

Ergonomics have been sort of a lost art in endoscopy and this needle is a

— Anand Sahai, M.D.

feel in the handle was a great improvement in the product.

— Adam Goodman, M.D.

“The team from Boston Scientific really took the time to listen. You can feel they have a passion for what they’re doing and, in the end, it produced amazing results,” said Dr. Anand V. Sahai, professor of medicine and chief, GI Division, Centre Hospitalier de l’Université de Montréal (CHUM).

PHYSICIAN INPUT YIELDS MEANINGFUL RESULTS Feedback was consistent from region to region: Physicians wanted a handle that was easy to grip, with minimal resistance during FNA. Thanks to the accelerated customer engagement and development process, a final design incorporating these features was available to them in less than a year.

They brought all of my thoughts back to the drawing board and were very innovative with the design, every step of the way.

— Dr. Ann Chen Director of Endoscopic Ultrasound Stanford University School of Medicine

“Physician preference matters,” said Bryan Bannon, senior product manager, Boston Scientific. “So much of GI endoscopy is about how a device feels in the physician’s hands. We wanted the Slimline Handle to accommodate these ergonomic and tactile feel preferences so the Expect Needle could be an option for them when performing EUS FNA.”

Dr. Ann Chen, director of endoscopic ultrasound at Stanford University School of Medicine

where their fingers can rest, to increase comfort and control as well as to accommodate different hand sizes and techniques. The new design also features lower profile locking knobs.

Physicians reported that the new handle design exceeded their expectations. “The improvement in the landing zone is significant,” said Dr. Chen. “You can place your thumb either on the top or the bottom depending on your preference. The groove in the middle can also serve as a resistance point, which allows you to easily move the needle to and fro within the tissue with simple up-and-down motion of the thumb. Lastly, the gliding mechanism has been improved significantly to allow a smoother movement of the needle during biopsy.”

Physicians also praised the Slimline Needle for enhancing tissue feedback. “I can get a sense of whether a lesion is solid or semi-soft or even cystic as I’m sampling,” said Dr. Robbins. “That’s an element that is unique to this needle.”

Physicians predict great success for the Slimline Needle. “You put the device in your hand and it just feels like quality, from beginning to end,” said Dr. Sahai. “I’m not an expert in marketing but I think that given the quality of the device, if you can just get it into physicians’ hands, it will speak for itself.”

The new Slimline Handle features a smaller handle profile and a low-friction gliding mechanism for a smoother actuation motion. The Control ZONE ™ gives physicians two ergonomically defined areas

Smooth Gliding Mechanism

Maintaining Shape and Sharpness

During EUS FNA, it’s very important to be able to move the needle to and fro

There’s very little bend in the needle, even after multiple passes. Its ability

very quickly within the target lesion to increase the areas being sampled so the

to get into difficult-to-access parts of the pancreas where there’s a lot of torque

gliding mechanism has to be almost frictionless. I can move the needle device

on the scope and stay true to its initial form will ultimately benefit

back and forth very quickly with just my thumb and my index finger, without a lot

our patients.

of resistance. This will aid in FNA tremendously.

— Ann Chen, M.D.

­

I was really struck by how easy the to-and-fro motion of the needle was

— David Robbins, M.D. Because the needle is so sharp, you immediately go exactly where you

want to go, and it maintains that sharpness. It works just as well the first time

in a variety of positions, short or long, and across all different needle gauge

as the last time.

sizes, between 19, 22 and 25. That’s a real step forward.

— Anand Sahai, M.D.

— Raman Muthusamy, M.D.

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BOSTON SCIENTIFIC NEWS

Dr. Ann Chen, director of endoscopic ultrasound at Stanford University School of Medicine, was similarly impressed. “My experience working with Boston Scientific was unexpected in many ways,” she says. “They brought all of my thoughts back to the drawing board and were very innovative with the design, every step of the way.”

Patient Education

For patients undergoing endoscopic stent placement, there are often many questions about post-procedure care. As a way to help physicians respond to the growing inquiries from patients looking for information, Boston Scientific developed three guides for patients living with a gastrointestinal stent. The guides will provide physicians with additional resources with which to help educate patients as well as caregivers. ▲

Eating Aft Esophag er eal Sten t Pl

acemen t

Eating After Esophageal Stent Placement – Working in conjunction with a nutritionist from the

University of Virginia, Boston Scientific developed a guide to provide information about diet and nutrition as well as recommendations on caring for an esophageal stent. The guide provides meal suggestions, tips and tricks for living with an esophageal stent (i.e., swallowing pills, maintaining weight, ways to avoid/reduce acid reflux, etc.) and contact information for additional third-party resources.

A Guide for ing with Patients Liv Stent an Enteral

▲ ▲

nts Patie for uide ith a tent G A g w al S Livin ry Met Bilia

A Guide for Patients Living with an Enteral Stent and A Guide for Patients Living with a Biliary Metal Stent

– These guides are designed to help patients understand what a metal stent is, and provide information about a stent placement procedure as well as questions to ask their physicians. Both the enteral and biliary stent guides include a plastic identification card that can be customized by the physician and staff, and is sized to fit in a wallet. The patient identification card includes information about magnetic-resonance compatibility for future medical treatment.

Copies are available for health care providers from their Boston Scientific representative.

Stent guides are also available at www.bostonscientific.com/endoscopy-resources.

e™ EndoVduivction

An Intro eding Fe to Tube with the Button EndoVive y Device om Gastrost

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DFU, Button

Patient

Care Guide,

EN, 907218

48-01A

▲ ▲

Patient care guides are available for patients living with a Boston Scientific tube feeding device.

An Introduction to Tube Feeding with EndoVive™ Gastrostomy Tube and

Boston

BOSTON SCIENTIFIC NEWS

Improving Outcomes through

An Introduction to Tube Feeding with the EndoVive Button Gastrostomy Device serve as a general guideline for patients to help them with care and use of their device. These guides provide information on the basics of tube feeding as well as the necessary steps required to ensure their stoma site is clean and properly cared for. In addition, the guide provides problem solving tips as well as suggestions for general patient care such as managing common oral and stomach conditions.

▲

The Resolution™ Clip Device MR Conditional Patient Card is for patients to take home with them after receiving clip(s). The card is intended to identify the anatomical location and placement date of a clip or clips for the patient, physicians and MR technicians. The card acknowledges that the Resolution Clip Device is indicated as MR Conditional according to ASTM F2503 and patients with Resolution Clip Devices can be scanned following the guidelines listed on the card such as Static Magnetic Field Tesla and Spatial Gradient Field parameters. A copy of the card should be used in patient records as well as given to the patient as a personal pocket card for medical reference.

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Resol

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Date Plac

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Anatom

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Clip D

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BOSTON SCIENTIFIC NEWS

Working with the National Pancreas Foundation to Provide Global Online Resources for Patients and Physicians

Boston Scientific is working with the National Pancreas Foundation to develop an interactive learning program for those seeking information on pancreatic disease states and procedures. The new program modules will be part of the foundation’s current website that works to provide easy-to-understand information for patients, and to enhance communication between patients and their physicians.

“Education is critical to helping patients manage the challenges of pancreatic disease and making informed medical decisions about their care,” said Dave Pierce, president of Boston Scientific Endoscopy. “We are proud to be leaders in helping create sections dedicated to EUS FNA and ERCP – two procedures that are playing an important role in helping diagnose pancreatic disease.”

Using a mix of animations, physician testimonials as well as downloadable information, the learning program will

Education is critical to helping patients manage the challenges of pancreatic disease and making informed medical

Animations web tool help patients learn about pancreatic diseases.

help patients understand complex medical terminology, disease states, diagnostic testing, procedures and clinical implications. With easy web access, the website’s learning programs could serve as an educational resource for health care professionals working with patients in a practice setting to help explain indications for the procedures, risks associated with the procedures, and the benefits of diagnostic and therapeutic pancreatic endoscopy, EUS FNA and ERCP. Boston Scientific is funding the project through an unrestricted education grant. The information will be co-hosted on www.pancreasfoundation.org and www.animatedpancreaspatient.com.

decisions about their care.

— Dave Pierce President, Boston Scientific

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BOSTON SCIENTIFIC NEWS

Preceptorship Brings Master Class Training to

Physicians in France In order to meet the ever-increasing need for specialized endoscopy training, St. Joseph Hospital in Marseille, France, implemented a preceptorship program to expand physicians’ skills in the areas of endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS). Developed by Dr. Christian Boustière, the two-day training is designed for physicians who are skilled endoscopists yet have limited experience in pancreatico-biliary endoscopy.

The first day includes a welcome for attendees and a review of patient cases to be treated. Each case is thoroughly reviewed, including pathologies, procedure indications and the types of devices to be used. Time is devoted for presentations, including videos to provide an update on technical innovations, guidelines or recent publications around major congresses related to the subject medical specialty. The day concludes with the schedule of cases for the next day and the pre-selected devices. The second day is fully dedicated to conducting procedures scheduled in two endoscopic rooms, one for ERCP and one for EUS. All procedures are performed under general anesthesia and intubation for ERCP. WORKING ALONGSIDE EXPERTS The expert starting the procedure is responsible for the case, and ensures the technique is performed adequately as discussed during the case presentation.

Depending on the level of difficulty of the procedure, one of the trainees will perform all or part of the procedure under direct supervision of the expert who can regain control at any time if deemed necessary.

The active participation of the trainee is a key element

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of this training. It allows for trainees to test their competency levels, and at the same time improve their techniques with step-by-step guidance from the experts. Trainees benefit from the theoretical exchange as well as learning from physicians’ experiences. The variety of cases allows trainees to learn about the diagnostic and technical issues often encountered in everyday practice.

T raining in therapeutic endoscopy and, more precisely, in biliary and pancreatic endoscopy requires rigorous training and learning which exceeds by far the environment of academic training in gastrointestinal endoscopy. Creating opportunities for continual education such as this master class is critical to furthering this practice,

The sessions at St. Joseph Hospital are part of Boston Scientific’s preceptorship program that is designed to support ongoing education and training at select medical facilities. Training of this sort is possible in hospitals like St. Josephs where there is a high volume of endoscopic procedures, the facility is well equipped and physician expertise is readily available. Having received positive feedback from participants, the hospital plans to pursue additional master classes in ERCP and pancreaticobiliary EUS training with two additional sessions in 2014.

— Dr. Boustière

Endoscopy professional training and education are now part of the multi-disciplinary programs available at the Boston Scientific Institute for Advancing Science in Paris, France. The Institute offers world-class training facilities designed to meet the educational needs of endoscopists, endosonographers and pulmonologists.

T he development of endoscopy training at the Institute for Advancing Science demonstrates Boston Scientific’s continued commitment to providing industry-leading training and education in partnership with physicians and societies to further the practice of endoscopy.

— Paraic Curtis Vice President of Endoscopy Europe, Boston Scientific

BOSTON SCIENTIFIC NEWS

Endoscopy Training Now Part of the Paris Institute for Advancing Science Boston Scientific offers a broad curriculum of training courses from basic to advanced levels in a range of specialties and techniques including ERCP, EUS, EMR/ ESD, cholangioscopy and bronchial thermoplasty.

“Hands-on training and peer-to-peer education are essential to maintaining good clinical practice and improving the quality of patient care. We hope that the endoscopy training at the Institute for Advancing Science will become an integral part of the training continuum of endoscopists and pulmonologists across Europe,” said Paraic Curtis, vice president of Endoscopy Europe, Boston Scientific.

The Institute is fully equipped to support integrated hands-on and didactic medical training in endoscopy.

It contains two endoscopic towers, two endoscopic ultrasound processors, a SpyGlass™ Direct Visualization System, a full range of endoscopes, and numerous biological and non-biological models to recreate and simulate adapted clinical conditions for training and education. Physicians have access to a complete catheterization lab fully equipped with fluoroscopy capabilities. In addition, training can be conducted in multiple languages via the onsite simultaneous translation facilities.

WallFlex™ Esophageal Stent Receives CE Mark in Europe The WallFlex Esophageal Fully Covered Stent received CE Mark approval in Europe for the treatment of refractory benign esophageal strictures. The fully covered metal stent provides a new treatment option for patients with malignant and benign refractory esophageal strictures.

“The advantage of the WallFlex Esophageal Fully Covered Stent is its ease-of-use and now removability, which allows me to treat patients with refractory benign strictures,” said Peter D. Siersema, M.D., PH.D., professor of gastroenterology, head, Department of Gastroenterology and Hepatology at University Medical Center in Utrecht, The Netherlands.

Previously, the fully covered and partially covered WallFlex Esophageal Stents received CE Mark and FDA clearance for the palliative treatment of malignant esophageal strictures.

T he advantage of the WallFlex Esophageal Fully Covered Stent is its ease-of-use and now removability, which allows me to treat patients with refractory benign strictures.

— Peter D. Siersema, M.D., Ph.D. Professor of Gastroenterology

Note: The WallFlex Esophageal Fully Covered Stent is not approved in the U.S. for the treatment of benign esophageal strictures.

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BOSTON SCIENTIFIC NEWS

AN INTERVIEW WITH Maria Stewart, director of Health Economics & Reimbursement, Boston Scientific, on changes impacting the U.S. health care industry.

Q

What do you see as the most pressing issue facing hospitals and physicians today?

Hospitals are being asked to improve quality of care and outcomes while demand is increasing and funding/payment is constrained. For example, health care reform is on the top of everyone’s mind. Hospitals are working to comply with all of the mandatory requirements associated with the value-based purchasing, hospital readmission reduction and hospitalacquired conditions programs. Hospitals must provide data on each of the specified parameters in order to receive their full payment update. In this environment, it will be critical for hospitals to increase efficiency while improving quality of care and patient satisfaction.

Q

Can you tell us about the impending ICD-9 to ICD-10 coding transition?

In the United States, hospitals are preparing for the implementation of the International Classification of Disease (ICD-10) coding system. The current ICD-9 code set used to report medical diagnoses and inpatient procedures is expected to be replaced by ICD-10 in October 2014. This will be a major change for hospitals. They will be going from using a system with approximately 13,000 diagnoses codes to a system with 68,000 diagnosis codes and from approximately 3,000 inpatient procedure codes to 87,000. To help ensure accurate coding, payment and claims processing, hospitals will need to train staff and coordinate a transition plan with the support of the coding, clinical, IT and finance departments. Physicians and their staff members will also need to familiarize themselves with new ICD-10 diagnosis coding. If the transition to ICD-10 is not properly implemented, they could have denied claims, delays in processing and payments, etc.

Q

How is the Boston Scientific Endoscopy Health

Economics & Reimbursement team supporting its health care partners in this changing environment?

Boston Scientific Endoscopy’s Health Economics & Reimbursement team is actively leading efforts to advocate for appropriate coverage and payment for GI and pulmonary endoscopy procedures, which we believe is critical if patients are to have access to all relevant treatment options.

In addition, through discussions with hospital administrators, we have learned that education for hospital staff on the changes associated with health care reform is needed. To support the education of our healthcare partners, the Boston Scientific Health Economics & Reimbursement Endoscopy team annually sponsors a complimentary reimbursement webinar during which an expert in the field reviews the impact of health reform and upcoming changes in coding and payment. This webinar receives positive reviews and draws approximately 300 attendees each year. In addition, the team provides onsite education for hospitals, ambulatory surgery centers and physicians on these important topics.

With respect to the transition to ICD-10, Boston Scientific has worked with coding experts to develop an ICD-10 educational webinar and coding cross-reference tools. These tools will be available on the Boston Scientific website, and will be an additional resource to our health care partners as they transition from the ICD-9-CM to ICD-10 coding system.

Q

How can a customer reach out to request reimbursement information or education?

To request information on reimbursement, U.S. customers may contact the Endoscopy Reimbursement Helpdesk at 1-800-876-9960 ext. 54145 or via email at: endoreimbursementhelpdesk@bsci.com.

Update on Endoscopy Gurukul Since its inception in 2011, the Boston Scientific School of Endoscopy in India, known as Endoscopy Gurukul, has quickly gained momentum and established itself as a center of expertise for gastrointestinal (GI) education and training.

More than 800 medical professionals have registered with Endoscopy Gurukul to take advantage of its many learning opportunities. The school offers a variety of ways to learn, including hands on, procedural video libraries at conferences, paramedical staff training for skill enhancement, patient education and more.

“Endoscopy Gurukul is an innovative initiative from Boston Scientific that has completely changed the landscape of training endoscopists in India.”

– Dr. D. Nageshwar Reddy, chief of gastroenterology and therapeutic endoscopy at the Asian Institute of Gastroenterology, Hyderabad, India.

“The Endoscopy Gurukul is a highly positive step taken by Boston Scientific to enhance endoscopic education in our country.”

– Dr. Amit Maydeo, chairman, Baldota Institute of Digestive Sciences, Global Hospitals, Mumbai, Maharashtra

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Left to right: Dr. T.S. Chandrasekar, MedIndia Hospitals (Chennai) moderates a discussion on ERCP with Dr. Randhir Sud, Medanta Institute of Digestive & Hepatobiliary Sciences (Gurgaon); Dr. D. Nageshwar Reddy; and Dr. Amit Maydeo at the Mumbai Live Endoscopy 2013 conference.

Look for Endoscopy Gurukul learning opportunities at conferences throughout India in 2014.

Boston Scientific’s Close the Gap is an ongoing program focused on initiatives to eliminate treatment disparities in high-risk, underserved patient populations suffering from gastrointestinal and pulmonary diseases by increasing awareness, sponsoring and developing educational programs, and improving access to care. Since its inception in 2013, the team has worked to raise awareness for colorectal and pancreatic cancers through a variety of awarenessgenerating and fund raising activities. The team raised

$20,000 that is being used to fund

the Colon Cancer Alliance’s new colorectal cancer Screening Assistance Program and more than $35,000 for The Lustgarten Foundation’s pancreatic cancer research initiatives. Close the Gap is also the primary sponsor of the Colon Cancer Prevention

Boston Scientific Green Initiatives – Making a Difference

BOSTON SCIENTIFIC NEWS

Close the Gap Initiative Works to Improve Patient Education and Access to Care

s members of Practice Greenhealth, A Boston Scientific is working to leverage the information, education and tools available on the best environmental practices for health care organizations as a way to meet the needs of its customers. Here are some of Boston Scientific’s accomplishments and ongoing initiatives: ENERGY AND SUSTAINABILITY � Incorporating LEED standards into the construction of new buildings and modification of existing facilities – seven facilities LEED certified. � Achieving ISO14001 certification – Certified at all 14 major manufacturing and distribution centers worldwide. � Leveraging solar – A 1.28 megawatt solar energy system will generate an average of 1,685,000 kilowatt hours a year, approximately 25 percent of the energy needs for Boston Scientific’s international distribution center in Quincy, Mass.

This 1.28 megawatt solar energy system will generate an average of 1,685,000 kilowatt hours a year, approximately 25% of the facility’s energy needs, or enough power to serve 145 average-sized American homes a year. This facility, located in Quincy, Massachusetts, is home to Boston Scientific’s international distribution center, which distributes more than 15.8 million medical device units per year to all 50 U.S. states and 46 countries.

PRODUCT PACKAGING Colon Canc er

Risk Assessm ent

Project’s pledge program.

Colorectal cancer affe cts an estimated 1 in 20 Am ericans.

WHAT’S YO LEVEL OF RI UR SK?

Take the Col orectal Can cer Risk Assessme nt Quiz to find out.

� Radial Jaw™ 4 Biopsy Forceps – Plastic packaging was made 13 percent smaller; a box of 5 was made smaller by 35 percent. The new packaging requires less shelf space (between 24-36% less) – helping decrease the task of restocking and improve efficiencies when moving product from the stock room to the procedure room. In addition, these packaging changes are expected to result in: • A reduction in overall packaging materials by 42,452 pounds per year

To learn more about how to get involved with colorectal and pancreatic cancer awareness activities, please visit our partners’ websites: � The Colon Cancer Alliance: www.ccalliance.org � T he Colon Cancer Prevention Project: www.coloncancerpreventionproject.org � T he Lustgarten Foundation: www.lustgarten.org

• 83 fewer trucks moving product from New York to the Boston Scientific distribution center in Quincy, Massachusetts • 1,653 fewer pallets per year moving from Costa Rica to the Massachusetts distribution center � Advanix™ Biliary Stent with NaviFlex™ RX Delivery System – Reduced by 28 percent. The new fully recyclable packaging uses 23 percent less material than the previous package. � CRE ™ Dilation Balloon – New packaging is made of fully recyclable REC-2-0 high-density polyethylene.

Boston Scientific has been certified to the FTSE4Good Corporate Social Responsibility index since 2004.

An investment index managed by the London Stock Exchange, it measures the performance of companies that meet globally recognized standards of corporate responsibility.

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GASTROENTEROLOGY

A Challenging Case of Endoscopic Ultrasound Fine-Needle Aspiration

CASE PRESENTED BY: ANAND V. SAHAI, M.D., MSC (EPID), FRCPC Professor of Medicine Chief, GI Division, Centre Hospitalier de l’Université de Montréal, CANADA

Dr. Sahai’s practice has been based

PATIENT HISTORY

solely on EUS since 1996. The Center

A 72-year-old female presented with obstructive jaundice due to a proximal bile duct lesion suspicious for cholangiocarcinoma upon magnetic resonance cholangiopancreatography. An endoscopic ultrasound (EUS) was requested to clarify the nature of the lesion and to perform fine needle aspiration (FNA), if possible, since the patient was not a surgical candidate.

Hospital, University of Montréal is one of the busiest EUS centers in the world, conducting approximately

PROCEDURE AND TECHNIQUE

2,800 cases per year and 12-14 cases

To visualize and biopsy hilar lesions, the echoendoscope must often be placed in a long scope position in the duodenal bulb with significant counter-clockwise torque. In this position, it may be very difficult to perform EUS-FNA because the needle may be difficult to insert into the scope, the endosonographer may be in an uncomfortable posture, and the needle may be hard to move. In this case, the lesion was particularly small. Therefore, very precise targeting was also required.

per day. Since 2000, Dr. Sahai has conducted EUS tutorials for more than 500 physician attendees.

In this case, the Expect™ Slimline (SL) Endoscopic Ultrasound Aspiration Needle performed extremely well. After identifying the lesion and site to biopsy (Figure 1) , the echoendoscope was withdrawn into the stomach in a more straight position. The 25g Expect SL Needle was then inserted into the operating channel and locked in place (Figure 2). (We recommend always inserting the needle into the scope when the scope is straight; this makes insertion easier and avoids trauma to the operating channel.)

The echoendoscope was then re-advanced into the bulb and the lesion was relocated.

Despite the long scope position and extreme counter-clockwise torque required, the needle exited easily from the operating channel (Figures 3 and 4). The needle was easily visible, and its sharpness made penetration of the duodenal wall exceptionally easy. The Expect Slimline FNA Needle also provides a very precise tactile response. As a result, we were able to precisely target the small, intra-ductal stricture while avoiding vascular structures posterior to the duct.

OUTCOME AND CONCLUSION

As is often the case, the first pass was positive for adenocarcinoma and there were no complications. This challenging case highlights how the ease of actuation, visibility, sharpness and exceptional tactile feel of the Expect-SL needle can help ensure success in cases of EUS-FNA of small lesions with difficult scope position.

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GASTROENTEROLOGY

EUS FNA-based Diagnosis of a Granular-cell Tumor in the Bile Duct

CASE PRESENTED BY: JOSÉ RAMÓN APARICIO, M.D. Endoscopy Unit Hospital General Universitario de Alicante Alicante, SPAIN

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PATIENT HISTORY

This patient is a 24-year-old male nursing student with recurrent episodes of abdominal pain during a one-year period. In one of these episodes, he went to the emergency room of another hospital where they detected a bilirubin level of 4 mg/dL together with a high level of hepatic enzymes. The abdominal ultrasound performed showed a gallbladder with cholesterolosis without stones and a normal-sized biliary tree (Figures 1a and 1b).

The patient was referred to his regular specialist for further study.

During a hospital examination, a doctor discovered conjunctival jaundice. He underwent magnetic resonance imaging that showed dilation of the intrahepatic bile duct secondary to a short stenosis of 7mm at the common hepatic duct that was suspicious for malignancy (Figures 2 and 3). The patient was referred for an endoscopic ultrasound (EUS) examination.

PROCEDURE

Under deep propofol sedation controlled by the endoscopist, EUS was performed showing dilation of the intrahepatic biliary duct. There was no presence of stones in the gallbladder and the pancreas was normal. At the level of the common bile duct (CBD) a regular thickening of the bile duct wall of a length of 13mm and 7mm was observed (Figures 1a and 1b). The distal area of the bile duct was normal. No lymphadenopathy or local hepatic lesions were observed.

A fine-needle aspiration (FNA) was performed using a 25 gauge Expect™ Slimline (SL) Needle (two passes), having previously administered a prophylactic intravenous dose of ciprofloxacino 400mg.

The cytology (Figure 4) showed the presence of a benign proliferative lesion of mesenchymal lineage consisting of sheets and plates of large round cells with granular eosinophilic cytoplasm and hyper­

chromatic oval eccentric nuclei. The biliary epithelium shows reactive hyperplasia papillary changes. No atypia, mitosis or malignancy signs were observed and an immunohistochemical study showed granular cytoplasmic positivity for S-100 protein. The cytologic findings were consistent with the existence of a granular-cell tumor.

SUMMARY AND DISCUSSION

A granular-cell tumor, or Abrikssoff’s tumor, is a benign mesenchymal tumor that is frequently located in the skeletal muscle of the tongue, skin and subcutaneous tissue. It originates in Schwann cells as evidenced by histological and immunohistochemical test results. Its location at the level of the biliary tract is rare, with only a few dozen cases reported in literature and this being the first case of cytologic diagnosis by EUS FNA. The preoperative diagnosis is difficult because benign tumors of the biliary tract are rare and usually not taken into account in the differential diagnosis of patients with obstructive jaundice. Brush cytology obtained by ERCP is rarely diagnostic because the tumor originates from the wall thickness of the common bile duct and not in the biliary epithelium. Most patients are young, with an average age of 34 years, and more often females of African heritage.

The ability of EUS FNA to properly evaluate the biliary system and the high performance of FNA in the context of biliary strictures make it an ideal and safe method to evaluate patients with obstructive jaundice. The 25 gauge Expect SL Needle is especially useful for puncturing small lesions and transduodenal use. The excellent ultrasound visualization and low deformability make the Expect™ SL Needle a very useful tool to puncture inaccessible lesions in which the scope is in a forced position.

References: 1) S aito J et al. Granular cell tumor of the common bile duct: a Japanese case. World J Gastroenterol 2012; 18: 6324-7.

2) F ritscher-Ravens A et al. EUS-guided fine-needle aspiration of suspected hilar cholangiocarcinoma in potentially operable patients with negative brush cytology.

Am J Gastroenterol 2004; 99:45-51.

3) E l Chafic AH et al. Impact of preoperative endoscopic ultrasound-guided fine needle aspiration on postoperative recurrence and survival in cholangiocarcinoma patients.

Endoscopy 2013; 45:883-9.

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GASTROENTEROLOGY

Bilateral Biliary Self-expanding Metal Stenting as Treatment for a Klatskin Tumor

CASE PRESENTED BY: PROFESSOR E.D. FEDOROV, E.V. IVANOVA, S.A. BUDZINSKIY, K.B. LUMMER, O.A. SHCHIPKOV, E.V. GORBACHEV Russia State Medical University N.I. Pirogov, Moscow University Hospital Medical Rehabilitation Center Moscow, RUSSIA

PATIENT HISTORY

A 78-year-old female was admitted to the emergency room with complaints of jaundice, fever, skin itch and dark urine for about ten days. Laboratory data showed a total bilirubin of 12.9 mg/dl, and conjugated bilirubin 6.3 mg/dl. A CT scan and ultrasonography showed a mass lesion at the confluence of the right and left hepatic bile ducts (Bismuth-IVC). Four months prior to admission, she underwent a percutaneous transhepatic cholangiography endoscopic retrograde cholangiopancreatography (ERCP) using the rendezvous cannulation technique (Figure 1) for biliary plastic stent placement into the right hepatic duct, followed by nasobiliary drainage for reactive cholangitis, and subsequent (on the 10th day) retrograde bilateral stenting with two plastic stents.

navigate the tip of the sphincterotome in the common bile duct, found the orifice of the left hepatic duct and selectively cannulated the left hepatic ducts by advancing the guidewire. Using the RX Locking Device, both guidewires were fixed in right and left hepatic ducts (Figure 2) and the sphincterotome was separated and removed.

We then performed a subsequent bilateral passage of fully uncovered metal stents (WallFlex™ Biliary RX Stent 8x100mm and WALLSTENT ™ RX Biliary Endoprosthesis Stent System 8x100mm) into the left and right biliary ducts (Figures 3, 4 and 5) followed by elimination of multiple stones and sludge from the left hepatic ducts.

POST-PROCEDURE

Within a short time, the patient improved and was discharged from the hospital on the fourth day.

PROCEDURE

During the ERCP, a partial obstruction of one stent and complete obstruction of the other stent was revealed as well as signs of cholangitis. The plastic stents were removed. A Dreamwire™ High Performance Guidewire 0.035" was placed via the working channel of a TJF-180 scope into the right duct, while successful placement of the second Dreamwire Guidewire into the left duct required use of an Autotome™ RX 44 Cannulating Sphincterotome. Using rotating capabilities of the Autotome Sphincterotome, we were able to

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DISCUSSION

This case represents the possibilities of endoscopic therapy using these types of devices to treat a difficult cholangiocarcinoma (Bismuth-IVC) situation. Gentle placement of self-expanding metal stents allows for adequate duct drainage, which plays a great role in effective palliation of a malignant biliary obstruction.

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NOTE: Use of the WallFlex Biliary RX Fully Covered Stent for the treatment of benign strictures or stenoses has not been cleared for use in the United States.

WARNING: The safety and effectiveness of the WallFlex Biliary Stent for use in the vascular system has not been established.

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ASHLEY T. EVANS, M.D. Digestive Health Clinic Boise, Idaho, USA

PATIENT HISTORY

OUTCOME / POST-PROCEDURE

A 62-year-old man was diagnosed with a nearly obstructing rectal mass after presenting with weight loss, tenesmus and rectal bleeding. A CT scan and biopsy of a liver lesion confirmed stage-IV disease. He received five months of palliative radiation and chemotherapy with plans to proceed with a low anterior resection once chemotherapy was optimized. Unfortunately, he presented to the hospital with nausea, vomiting, abdominal pain and distension six days before Christmas.

A CT scan showed distal colonic obstruction. A flexible sigmoidoscopy with enteral stent placement was planned to relieve the obstruction.

The patient tolerated the procedure well and had complete relief of his obstructive symptoms, passing multiple bowel movements within hours afterwards. He felt well enough that he asked for surgery to be delayed until after Christmas so he could spend the holiday with his family. He was discharged home on a low-residue diet.

Three weeks later, the patient completed a cleansing bowel prep and non-emergent, low anterior resection with diverting ileostomy was successfully performed.

PROCEDURE

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CASE PRESENTED BY:

Upon intubation of the rectum with the sigmoidoscope, an obstructing rectal mass was encountered at 8cm (Figure 1). With insufflation, a pinpoint lumen was visible within the mass with a small amount of air and liquid stool passing from above (Figure 2). A cannula was used to guide a .035 x 450 Hydra Jagwire™ Guidewire into the lumen, and under fluoroscopic guidance, advance across the stricture to the upstream bowel (Figure 3). Using a felt-tipped marker, the fluoroscopic image was marked to delineate the proximal and distal edges of the obstructing mass. A 25mm x 90mm through-the-scope (TTS) WallFlex™ Colonic Stent was passed over the guidewire and the on-screen markings were used to guide the ideal placement of the stent. The stent was easily deployed and upstream air and bowel contents immediately began flowing across the stricture (Figure 4). A fluoroscopic waist was visualized with good placement of the stent across the proximal and distal margins of the tumor (Figure 5).

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CONCLUSION

Colonic stents are an incredibly useful tool for both palliation of advanced disease and preoperative decompression. In this case, successful placement of an enteral stent across a malignant colonic stricture allowed for non-emergent resection of this patient’s tumor in a prepped bowel. In addition, decompression of the bowel allowed surgery to be postponed several weeks so that the patient could spend the holidays with his family.

There are several advantages to preoperative placement of expandable metal stents in the management of colonic obstruction. First, morbidity and mortality have been shown to be substantially lower in patients whose colonic resection can be performed on an elective basis1. In addition, patients with a primary anastomosis appear to have higher survival rates than those with emergent diverting colostomies2. It also seems that colonic stent insertion followed by elective surgery is more effective and less costly than emergent surgery 3. In this patient with stage IV rectal cancer, improved quality of life and time with family was also an important benefit of placement of a colonic stent.

References: 1) L eitman IM, Sullivan JD, Brams D, DeCosse JJ. Multivariate analysis of morbidity and mortality from the initial surgical management of obstruction carcinoma of the colon.

Surg Gynecol Obstet 1992; 174:513.

2) F ielding LP, Wells BW. Survival after primary and after stage resection for large bowel obstruction caused by cancer. Br J Surg 1974; 61:16.

3) T argownik LE , Spiegel BM, Sack J, et al. Colonic stent vs emergency surgery for management of acute left-sided malignant colonic obstruction: a decision analysis.

Gastrointes Endosc 2004;60:865.

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GASTROENTEROLOGY

Stenting Serves as Bridge to Surgery and Allows for Non-emergent Resection of a Malignant Colonic Neoplasm

GASTROENTEROLOGY

A Clinical Case of a Long-term Colonic Endoscopic Stent Placement Without Complications

CASE PRESENTED BY: ANTONIETTA LAMAZZA, M.D. University of Rome La Sapienza Policlinico Umberto I Department of Surgery “P. Valdoni” Digestive Endoscopy Unit Rome, ITALY

PATIENT HISTORY

A 74-year-old female underwent surgery in August 2005 for a left hemicolectomy caused by extrinsic neoplastic stenosis of the rectum caused by ovarian cancer for which she had undergone surgery a few years prior. In November 2008, after chemotherapy, she developed an intestinal obstruction by a new ab-extrinsic neoplastic stenosis of the colorectal anastomosis, as evidenced by an abdominal CT scan. A colonoscopy confirmed the presence of a neoplastic stenosis of the colorectal anastomosis, approximately 10-14cm from the anal verge.

A self-expanding uncovered WallFlex™ Single-Use Colonic Stent System (length 90mm - 25mm diameter) was placed that led to a complete resolution of the clinical obstruction. The stent remained patent for several years (Figure 1) and through several cycles of chemotherapy. In June 2013, after rectal bleeding, a colonoscopy showed stent neoplastic ingrowth; biopsies were then performed on the mucosa inside the stent that showed neoplastic epithelial proliferation, compatible with the diagnosis of colonic localization originating from ovarian cancer (Figure 2).

A CT scan confirmed the relapse of massive neoplastic disease, due to the presence of peritoneal carcinomatosis and liver metastases. It also showed a rectal metallic stent incorporated in the neoplastic tissue. Another colonoscopy was performed for the treatment of the neoplastic tissue within the stent using argon plasma coagulation (APC) (Figures 3 and 4).

Currently, the patient is undergoing chemotherapy without clinical signs of colonic obstruction or rectal bleeding, and her general condition is fair. The next endoscopic exam is scheduled for three months after the treatment with APC (Figure 5).

PROCEDURE

In order to treat the anastomotic stenosis, a self-expanding metal uncovered stent (WallFlex length 90mm, diameter 25mm) was used. The proper study of the stenosis occurred by performing a colonoscopy using a pediatric nasogastroscope exclusively designed for this procedure.

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The pediatric nasogastroscope allowed us to traverse the stenosis, measure the length of the lesion, and helped to reduce the angle, thereby allowing the colonoscopy in the upstream part; it also allowed the positioning of an Amplatz Super Stiff ™ Guidewire 70cm above, under direct endoscopic vision and radiologic control.

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OUTCOME / POST-PROCEDURE

The outcome of our treatment was the recanalization of the rectum without performing the definitive colostomy, otherwise indispensable, with the risk of neoplastic cutaneous implants due to the massive peritoneal carcinomatosis. From initial stent placement until June 2013, no immediate or late complications were observed, up to and including intestinal disorders.

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The interest of the clinical case described is in the longterm stent placement (five years), the absence of immediate and late complications (from November 2008 to June 2013), and the endoscopic APC treatment to resolve neoplastic infiltration within the stent (June 2013 – first late complication).

The choice of an uncovered stent has proved successful because it allowed the stent’s placement in the neoplastic stenosis without its dislocation, and when the slow growth of neoplastic tissue occurred (after five years), it was treated with a minimally invasive endoscopic technique (APC).

In our experience, the clinical case described demonstrates an optimal synergy among endoscopist, surgeon and oncologist. The choice of treatment favoring endoscopy and not surgery, the chemotherapy treatment and the biology of the tumor enabled palliation of the obstruction. The patient lived for about five years in fairly good general condition. Not having a permanent colostomy was a positive factor in the patient’s quality of life, both clinically and psychologically.

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CASE PRESENTED BY:

RAYBURN F. REGO, M.D.

MOHIT GIROTRA, M.D.

Director of Advanced Endoscopy and Associate Professor of Medicine Division of Gastroenterology and Hepatology Department of Medicine University of Arkansas for Medical Sciences (UAMS) Little Rock, Arkansas, USA

Gastroenterology and Hepatology Fellow Division of Gastroenterology and Hepatology Department of Medicine University of Arkansas for Medical Sciences (UAMS) Little Rock, Arkansas, USA

PATIENT HISTORY

OUTCOME

A 50-year-old man with hypertension and hypercholesterolemia was seen by a primary care physician in March 2012 for upper-mid abdominal pain radiating to the back. His laboratory workup was normal and he was treated for constipation, which relieved his symptoms partially. A CT scan showed his pancreas was atrophic with a dilated pancreatic duct from the neck distally toward the tail, with dilated side branches but a normal duct in the head. No obvious mass or cyst was noted and the rest of the CT was unremarkable.

The pancreatic fluid CEA level was < 5 ng/ml with high DNA quantity.

The SpyBite Biopsy Forceps pathology raised suspicion of dysplasia (Figure 5) and the patient was referred for surgery. Based on the above results and the fact that < 1.5cm of the normal pancreatic duct was seen in the head, the patient was deemed not a suitable candidate for subtotal pancreatectomy. He underwent a total pancreatectomy with splenectomy in May 2012 and did well postoperatively. The pathology of the resected tissue confirmed a focal invasive mucinous adenocarcinoma arising in the background of IPMN with extensive high-grade dysplasia.

The patient was referred to us for further management. He denied any past history of pancreatitis or similar abdominal pain, was completely asymptomatic and denied any weight changes or appetite loss. The laboratory work up revealed a normal hemogram, normal renal and liver function tests, amylase 49 IU/L, lipase 29 IU/L, IgG4 level 23 mg/dL, and CA19-9 < 0.8 U/ml. An MRCP was obtained which confirmed the CT findings and did not reveal any mass/cyst.

PROCEDURE

An ERCP showed a fish-mouthed ampulla (Figure 1) , but no mucus was seen extruding from it. Nevertheless, it raised concern for a possible intraductal papillary mucinous neoplasm (IPMN). The pancreaticogram showed the dilated pancreatic duct and side branches with extensive filling material suspicious of mucus (Figure 2).

Pancreatic fluid was aspirated for molecular analysis and carcinoembryonic antigen (CEA). A SpyScope™ Access and Delivery Catheter was used to access the pancreatic duct (Figure 3) , revealing very thick globs of mucus . Multiple random biopsies were obtained using the SpyBite™ Biopsy Forceps (Figure 4 ).

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The tumor size could not be assessed but pathological staging of a T1 tumor was ascertained based on the fact that the tumor was limited to the pancreas (with the invasive portion being < 2cm with negative margins absent lymphovascular or perineural invasion) there were 29 negative lymph nodes and there was no distant metastasis. The patient was then started on Gemcitabine chemotherapy which he did not tolerate beyond one cycle. Since then he is being followed by strict surveillance with a positron emission tomography/CT protocol and has remained metastasis and/or recurrence free.

CONCLUSION

This unique case illustrates the importance of the SpyGlass™ Direct Visualization System examination of highly suspicious pancreatic ductal abnormalities. With the use of SpyGlass System technology, we were able to detect pancreatic cancer at a stage when it was non-metastatic and operable, and when the patient’s overall life expectancy would be greater than otherwise expected with late-detected pancreatic adenocarcinoma. Therefore, we strongly suggest use of this available tool in detailed examination of abnormal pancreatic ducts.

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GASTROENTEROLOGY

Early Detection of Pancreatic Cancer Nidus in a Patient with Inconspicuous IPMN Lesion

GASTROENTEROLOGY

Usefulness of the SpyGlass Direct Visualization System for Difficult Stone Management

CASE PRESENTED BY: LUIGI GHEZZO, M.D. Santi Croce e Carle Hospital, Cuneo Piemonte, ITALY

PATIENT HISTORY

In this case, we treated a 60-year-old male with a 13mm stone that clogged his cystic duct after a cholecystectomy (Figure 1). In another hospital, the patient underwent three previous endoscopic retrograde cholangiopancreatography (ERCP) procedures. During the first ERCP, physicians performed a sphincterotomy and partially removed the stones.

They then placed a plastic stent. He underwent a cholecystectomy (without stone removal due to a thin common bile duct caliber) and a second ERCP that detected a big stone that was difficult to remove using a basket or extraction balloon. The patient again complained of cholangitis, so he underwent a third ERCP without success.

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PROCEDURE

In December 2013, the patient was assigned to our hospital and we performed an ERCP with the SpyGlass™ Direct Visualization System and holmium laser in order to destroy the stone under direct vision and remove it. After cholangiography and removal of the plastic stent, we confirmed the presence of two stones; the biggest one (13mm) was in a difficult position, clogging the cystic duct, without proximal common bile duct dilation or inflammation.

We introduced the SpyGlass System over-the-wire that easily allowed direct visualization of the stone (Figure 2). Using the SpyGlass System, we were able to perform holmium laser therapy under vision. This allowed us to obtain a partial stone fragmentation (Figure. 3) , making it easier for us to remove the fragments later with a basket (Figures 4 and 5).

CONCLUSION AND PATIENT OUTCOME

During choledocholithiasis procedures, there are often difficulties due to the number and position of stones. In these types of cases, it is not possible to remove the stones using only the standard techniques (sphincterotomy and extraction devices).

Sometimes it is not easy to capture the stone with a basket so we use external lithotripsy (extracorporeal shock wave lithotripsy); however, this technique can also be influenced by the position of the stone or the presence of fluid around the stones. These factors may decrease the wave’s energy. A good option can be the use of electrohydraulic lithotripsy or laser in order to apply the energy directly on the stone’s surface.

By using the SpyGlass Direct Visualization System, holmium laser can be applied directly on the stones. In this way, it is easier to destroy and remove the stones, managing difficult choledocholithiasis procedures in the best way.

Thanks to the SpyGlass System in combination with holmium laser, we were able to easily treat the patient and completely remove the stones. The final cholangiography showed the results (Figure 6) . The patient was discharged from the hospital the day after the procedure.

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GASTROENTEROLOGY

Endoscopic Clip Closure of a Gastrocutaneous Fistula in a Patient with History of Tucker Dilation via Gastrostomy

CASE PRESENTED BY: KIMBERLY J. KOLKHORST, D.O.

PATRICK BRADY, M.D.

Division of Digestive Diseases University of South Florida Tampa, FL, USA

Division of Digestive Diseases University of South Florida Tampa, FL, USA

PATIENT HISTORY

OUTCOME

A 56-year-old female with a history of laryngeal cancer (status post-neck radiation and total laryngectomy approximately 20 years prior), presented with complaints of dysphagia and was found to have a severe proximal esophagus radiation-induced stricture. A percutaneous radiological gastrostomy (PRG) was subsequently placed to improve nutrition.

Endoscopic evaluation four months after endoscopic clip placement revealed four clips in place and persistent closure of the GCF (Figure 4).

A repeat EGD 16 months after endoscopic clip placement revealed one clip in place with a well-healed gastric mucosa (Figure 5).

Over the course of 17 months, the patient underwent 18 esopha­ gogastroduodenoscopies (EGD) with Tucker dilation via the gastrostomy up to 38 Fr. Successful Savary dilation was eventually achieved and Tucker dilation was no longer required. The PRG was removed 10 months after placement. Fourteen days after PRG removal the patient was noted to have persistent leakage from a gastrocutaneous fistula (GCF) at prior gastrostomy (Figure 1). The EGD revealed a hole in the anterior wall of the stomach, approximating 8mm (Figure 2). Attempted closure of the fistula using internal and external interrupted silk sutures was unsuccessful.

PROCEDURE

An EGD with endoscopic clip placement using one Resolutionâ&#x201E;˘ Clip to approximate the margins of the fistulous tract was performed. A decreased fistula output was noted after clip placement but leakage persisted. An EGD was repeated one week later with placement of five endoscopic clips (Figure 3) resulting in immediate closure of the gastrocutaneous fistula.

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DISCUSSION

Refractory gastrocutaneous fistulas are a known consequence following gastrostomy removal that can be very difficult to manage.

Conservative management of GCFs has had limited success. Surgical laparotomy and excision of the fistulous tract is often required but results in increased morbidity and mortality, especially in debilitated patients.

Endoscopic clipping of GCFs involves grasping the mucosal and submucosal tissue layers at the fistulous tract edges and approximating the opposite walls, thus leading to macroscopic closure of the fistula opening. This case illustrates that endoscopic clip placement is a valuable modality for closing refractory gastrocutaneous fistulas and is a promising alternative to surgery.

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GASTROENTEROLOGY

Resolution Clip Devices Used to Close Duodenal Perforation after Endoscopic Submucosal Dissection

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CASE PRESENTED BY: ERIC C.S. LAM, M.D., FRCPC Clinical Associate Professor Division of Gastroenterology University of British Columbia Vancouver, British Columbia, CANADA

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PATIENT HISTORY

A 56-year-old man was found to have a 10mm subepithelial lesion in the junction between the first and second part of the duodenum when undergoing an upper endoscopy to screen for Barrett’s esophagus. He had a history of diabetes mellitus that was controlled with oral hypoglycemic agents. A radial endoscopic ultrasound was performed showing a 10mm hypoechoic lesion in the submucosa consistent with a duodenal carcinoid (Figures 1 and 2). Endoscopic biopsies confirmed carcinoid tumor cells. Because of the potential risk of metastatic disease and the possibility of requiring a more extensive resection, he was referred for endoscopic submucosal dissection.

PROCEDURE

The border of the endoscopic bulge in the duodenum was marked by applying superficial cautery to the mucosal surface. A solution of 1:10,000 epinephrine and methylene blue was injected into the submucosa. Using cap assistance, a submucosal dissection was carried out around the carcinoid tumor. Upon dissecting the proximal end of the carcinoid tumor, a 5mm duodenal perforation was identified (Figure 3).

The Sensation™ Single-Use 30mm Oval Polypectomy Snare was then used to resect the carcinoid tumor immediately after the perforation was identified. Unfortunately, the intraluminal air began to enter the peritoneal space and full distension of the duodenum could not be achieved. We then applied two Resolution™ Clip devices to the 5mm duodenal perforation and this re-established retention of intraluminal air. An additional five Resolution Clip devices were then used to close the remaining 2.5cm mucosal defect (Figure 4).

OUTCOME AND POST-PROCEDURE

The pathology of the removed lesion showed complete excision of the carcinoid tumor. The patient was discharged two days post procedure. Repeat upper endoscopy three months after the resection showed a well epithelialized scar with no recurrence of tumor (Figure 5).

This case demonstrates the usefulness of Resolution Clip Devices in the closure of luminal perforations of the duodenum. The initial two Resolution Clip Devices with their wide jaws and closing pressure were able to take the opposing sides of the luminal perforation and to provide an adequate seal. By utilizing the Resolution Clip to close the perforation during the endoscopy, the patient was able to avoid surgery.

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CASE PRESENTED BY: DAVID G. HEWETT, MBBS, MSC, PH.D., FRACP Associate Professor, University of Queensland School of Medicine Deputy Director (Endoscopy), Queen Elizabeth II Jubilee Hospital Brisbane, AUSTRALIA

PATIENT HISTORY AND ASSESSMENT

A 64-year-old female with serrated polyposis syndrome underwent a colonoscopy for endoscopic resection of the large proximal colon sessile serrated adenomas. This was her second colonoscopy for clearance of serrated lesions. Indigocarmine dyespray cap-fitted colonoscopy was used to facilitate detection, and a large sessile serrated adenoma/polyp (SSA/P) was identified at the hepatic flexure (Paris classification 0-IIa, 25mm, Figure 1).

PROCEDURE

Colonoscopic resection of the 25mm sessile serrated adenoma at the hepatic flexure was performed. An en bloc resection was attempted (Figure 2) following a submucosal injection of succinylated gelatin (Gelofusine) mixed with indigocarmine (80mg in 500mL solution), and using electrocautery (ERBE Vio 300D, EndocutQ effect 3). Carbon dioxide is used routinely for insufflation. After resection, a large concentric defect (approximately 10-15mm) in the muscularis propria was evident ( Figure 3, mirror target sign), with corresponding target sign on the resected specimen ( Figure 4, resected specimen ex-vivo, with a central white disk of muscularis propria surrounded by indigocarmine-stained blue submucosal tissue).

The defect was closed using Resolution™ Clip Devices (Figures 5 and 6). A total of 16 clips were applied sequentially from one side of the defect to the other in a “zipper” fashion. Each clip was placed immediately adjacent to the last to ensure complete closure in case of full thickness perforation.

Sequential clip closure required careful maneuvering of each clip to achieve a satisfactory position and acquire sufficient normal tissue

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within the clip to tightly appose the defect margins. To achieve closure, one arm of the clip can be used to grasp and lift normal tissue before then angulating the other arm into position on other side of the defect (again grasping a generous amount of normal tissue). Gentle application of suction can help bring the margins together, while minimally advancing the catheter, often with simultaneous down angulation of the instrument tip. Excessive tension on the colon wall from forward advancement of the clip should be avoided (to encourage generous tissue capture within the clip).

PATIENT OUTCOME

Intraprocedural intravenous antibiotics were administered, and the patient was admitted to hospital for observation on a clear fluid diet.

The patient reported no post-procedure abdominal pain. A CT of the abdomen excluded full thickness perforation, and the patient was discharged within 24 hours. Histology confirmed muscularis propria resection without serosa. Follow-up colonoscopy at four months demonstrated complete resection of neoplastic tissue, with a single clip remaining embedded within the scar (Figure 7).

CONCLUSIONS

Resolution Clip Devices are effective tools for closure of endoscopic perforations and deep muscle injury. During endoscopic resection, recognition of muscularis propria injury is important, and careful inspection of the base of the specimen (in vivo) and the mucosal defect for target/mirror target signs is essential. Caution with an en bloc resection of >20mm serrated lesions is warranted despite large volume submucosal injection and careful technique.

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GASTROENTEROLOGY

Resolution Clip Devices Closure of Muscularis Propria Injury during Colonoscopic Resection of a Large Serrated Polyp

GASTROENTEROLOGY

Successful Management of Immediate and Delayed Post-polypectomy Bleeding with the Resolution Clip Device

CASE PRESENTED BY: SHIVANGI KOTHARI, M.D. VIVEK KAUL, M.D., FACG Center For Advanced Therapeutic Endoscopy University of Rochester Medical Center Rochester, NY, USA

PATIENT HISTORY AND PROCEDURE DETAILS

A 61-year-old male with past medical history significant for hypertension and diabetes mellitus was referred for screening colonoscopy (average risk). During colonoscopy, eight 5-6mm polyps were resected and retrieved from the ascending and transverse colon using a hot snare. An approximately 5cm polyp on a short, broad-based stalk measuring about 1.5 cm was seen in the sigmoid colon. An endoloop was deployed at the base of the polyp and the polyp was resected in a piecemeal manner, in antegrade and retroflexed positions. The polyp base was then elevated with a submucosal saline injection and was resected with snare cautery (Figure 1).

Since the stalk was very short and broad based, the base of the polyp with the stalk was resected with the snare below the endoloop to ensure clear margins, and was submitted separately to pathology.

Immediately post-resection, significant brisk bleeding was seen from an arterial vessel in the polypectomy base. Epinephrine (1:10,000 x 20cc total) was injected at the site followed by deployment of eight Resolutionâ&#x201E;˘ Clip Devices (Figure 2). Direct application of the endoclips at the site of arterial bleeding (slightly less than 2mm) was done to achieve hemostasis and approximation of the edges of the 2.5cm resection site also was accomplished. Complete hemostasis was achieved at the end of the procedure (Figure 3). The patient was admitted for overnight observation. He remained stable with no further bleeding and he was discharged home the following day.

POST PROCEDURE FOLLOW UP

Two days after the procedure, the patient presented to the emergency room with hematochezia. His hematocrit had dropped from 34 to 31.

He was hemodynamically stable. Flexible sigmoidoscopy revealed a small amount of persistent bleeding from the arterial site where one clip appeared to have been dislodged (Figure 4). The remaining endoclips were still in place and there was no bleeding from those parts of the polypectomy site. Epinephrine (1:10,000 x 10 cc) was injected into the bleeding area and two additional clips were placed at the site of bleeding with complete hemostasis at the end of the

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procedure. The patient remained stable with no further episodes of bleeding. Pathology revealed the lesion to be a tubulovillous adenoma, completely resected with clear margins. A follow-up colonoscopy was performed three months after the initial procedure and no recurrence or residual adenoma was seen at the resection site or on surveillance biopsies of the healed polypectomy site (Figure 5).

DISCUSSION

Immediate post-polypectomy bleeding can occur in up to 1.5 to 3 percent of cases. Endoclips are being increasingly used to manage post-polypectomy bleeding. The clip can be placed across the base of the stalk of a pedunculated polyp prior to resection to minimize risk of post-polypectomy bleeding.

In our practice, we are placing endoclips for hemostasis when we feel there is an elevated risk of post-polypectomy bleeding. This could be patients with other co-morbidities and/or coagulopathy, defect sites with exposed blood vessels, or patients on anticoagulation.

When bleeding is encountered after resection of a pedunculated polyp, placing a clip across the stalk can help achieve durable hemostasis. In case of bleeding after resection of sessile polyps, the clip can be placed directly over the bleeding site, as in the above case. Additional clips can be placed to approximate the edges of the resection site in high risk situations, but the benefit of doing that has not been studied in a randomized trial design. Delayed postpolypectomy bleeding can occur from ulceration at the polypectomy site. In our patient, the relatively large caliber of the bleeding vessel, ulceration at the site and possible clip displacement led to recurrent bleeding. However, this was managed successfully with placement of additional endoclips at the site of the bleeding vessel. Our case illustrates successful management of immediate and delayed post-polypectomy arterial bleed with the use of the Resolution Clip Device.

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CASE PRESENTED BY: TARA CHALMERS-NIXON, M.D., FRCPC Clinical Assistant Professor University of Calgary, Rockyview Hospital Calgary, Alberta, CANADA

PATIENT HISTORY

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The patient was a 55-year-old male referred for nonspecific gastrointestinal complaints, including irregular bowel habits and abdominal discomfort. His past medical history was significant for obesity, diabetes, hypercholesterolemia, hypertension and hypothyroidism.

He previously had a cholecystectomy. Although his complaints were most likely a result of medication side effects, a colonoscopy was recommended to investigate further. This was the patient’s first colonoscopy.

PROCEDURE

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The patient was sedated with midazolam 5mg and fentanyl 50 mcg IV, and monitored with the appropriate monitoring equipment. Using a video colonoscope, the scope was advanced to the ileum. The bowel was well prepared with only clear liquid remaining. A 2.5cm polyp with a central depression was identified 5cm distal to the ileoceal valve. Because of concern for malignancy, the goal was to remove the polyp en bloc. Using an Interject™ Injection Therapy Needle Catheter the polyp was lifted and injected with 10cc of normal saline (Figure 1). The polyp was then removed using a large oval Captivator™ Single Use Snare with cautery applied (Figure 2). It was removed in one piece. The polypectomy site was clean and not bleeding, but rather large and in the proximal colon (Figure 3). As such, I felt that hemostasis was required and decided to close the post-polypectomy defect (approximately 2cm in length and 5-6mm wide) using Resolution™ Clip Devices.

Three Resolution Clip Devices were placed without difficulty to close the defect. The actual polyp site was in a good position, so the clips deployed very well without any torque applied to the scope, and very little rotation of the clip was needed (Figure 4).

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Before this polyp was retrieved, a second 1.0 cm polyp was identified just distal to the first polypectomy, so it was removed also with a snare cautery. Clips were not applied to this second site. Both polyps were then sitting in the lumen of the bowel.

Next, a TWISTER® PLUS Rotatable Retrieval Device was used to grab both of the large polyps together and remove them. The TWISTER PLUS Rotatable Retrieval Device fit around the two polyps without crushing them, allowing for the removal of both in one withdrawal (Figures 5 and 6). The polyps were then sent for pathology. The TWISTER PLUS Rotatable Retrieval Device retrieval net was easy to use and there was excellent visibility of the polyp tissue through the netting. The ‘spine’ (or third wire) in the TWISTER PLUS Rotatable Retrieval Device may have helped place the net over the polyps.

OUTCOME

The patient tolerated the procedure well and all the polyps were removed successfully during this single procedure. He had not experienced any post-polypectomy bleeding as discussed during his follow up more than 14 days post procedure. The largest polyp was a villous adenoma with high-grade dysplasia but no cancer. The second smaller polyp was a tubulovillous adenoma. The patient is scheduled for a follow-up colonoscopy within two weeks to be sure of complete removal given the size, pathology and saline lifting of the largest polyp, and to be sure no additional polyps were missed.

CONCLUSION

Proper polypectomy removal and retrieval is critical to performing a good-quality colonoscopy. Being able to send the polyp for pathological examination determines if the patient will or will not need resection, especially in the case of large polyps with worrisome features such as the one identified in this case: greater than 1cm, central depression, etc. Had it not been possible to remove the polyp and retrieve it properly, the patient may have had to have a resection of the area where the polyp was.

Information and in-services for the physicians and nurses in our endoscopy unit have been very helpful in using all of these Boston Scientific devices in appropriate situations.

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GASTROENTEROLOGY

Polypectomy Using the Interject Needle, Captivator Snare and TWISTER PLUS Rotatable Retrieval Device

News and New Devices ›

allFlex™ RX Biliary Stents are now available in Europe in 10cm and 12cm W lengths. The new stents will enable physicians to provide better treatment options for clinical indications, including anastomotic liver transplant strictures, altered anatomy and hilar strictures.

WARNING: The safety and effectiveness of the WallFlex Biliary Stent for use in the vascular system has not been established.

›

›

DirecTip™ Technology is what gives the Autotome™, TRUEtome™ and other Boston Scientific Cannulating Sphincterotomes their center-lumen design, allowing the guidewire to extend from the center of the sphincterotome to aid in positioning, and facilitate wireguided cannulation. DirecTip Technology enables the guidewire and contrast to be directed into the duct from the center of the tip, helping the physician inject contrast into the intended duct.

E xpect™ Slimline (SL) Needle for EUS FNA procedures offers a smaller handle profile and a smooth, low-friction gliding mechanism utilized during tissue sampling.

The Control ZONE ™ on its handle has two ergonomically defined areas to optimize control during the actuation motion and to accommodate different hand sizes and techniques. All Expect Needles have a sharp needle grind and highly visible echogenic pattern, providing precise guidance and helping to maintain tip visibility. Gauge sizes are 19, 19Flex, 22 and 25 for both the Expect and Expect SL Needles.

As Seen In

Online Global Resources For the latest news and information from Boston Scientific Endoscopy, visit www.bostonscientific.com/endo-resources

ACCESS Magazine was produced in cooperation with several physicians. The procedures discussed in this document are those of the physicians and do not necessarily reflect the opinion, policies or recommendations of Boston Scientific Corporation or any of its employees.

Results from case studies are not predictive of results in other cases. Results in other cases may vary.

Indications, Contraindications, Warnings and Instructions for Use can be found in the product labeling supplied with each device.

CAUTION: Federal (USA) law restricts this device to sale by or on the order of a physician.

WARNING: The safety and effectiveness of the WallFlex Biliary Stent for use in the vascular system has not been established.

Autotome, Advanix, Captivator, Control ZONE, CRE, DirecTip, Dreamwire, EndoVive, Expect, Jagwire, Interject, Resolution, Sensation, SpyBite, Spyscope, SpyGlass, WallFlex, and WALLSTENT are registered or unregistered trademarks of Boston Scientific Corporation or its affiliates. All other trademarks are property of their respective owners.

TWISTER ® PLUS is a trademark of Horizons International Corp. Distributed by Boston Scientific Corporation, Natick, Massachusetts; manufactured by Horizons International Corp., Heredia, Costa Rica. ©2014 Boston Scientific Corporation or its affiliates. All rights reserved.

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ENDO-236105-AA April 2013