Dec 2014 by McMahon Group

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as SG Us e Vi E B at sit oo th #1 02

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Alarming Trend: Colorectal Cancer Surging in Younger Patients

ENDOSCOPY SUITE

New Algorithm Boosts Endoscope Cleanliness

PHILADELPHIA—A growing number of younger patients are being diagnosed with aggressive colorectal cancer, even as the incidence of the disease among older patients is declining, new research shows. The incidence of early-onset colorectal cancer (CRC) among patients younger than age 50 has been rising at an annual rate of 1.5% per year, compared with an annual decrease of 3.1% among older individuals over the past decade, according to the study. Individuals with earlyonset disease tend to have larger tumors that are more likely to metastasize. “Although the incidence in younger patients is still low compared with colorectal cancers in older populations, the trend is alarming and calls for more investigation and appropriate intervention,” said Xi Emily Zheng, MD, PhD, a study investigator and fellow in the Department of Healthcare Policy and Research

Modified protocol produces pass rates above 90% CHICAGO—A change in the cleaning algorithm for endoscopes can dramatically improve pass rates when the devices are reprocessed after use. see Algorithm, page 36

For Acute GI Bleeds, Hitting Care Metrics Cuts Hospital Stays CHICAGO—In patients with acute gastrointestinal bleeding, meeting quality-of-care indicators reduces length of stay in the hospital, a study has found. The retrospective study, involving 700 patients, is consistent with a series of other initiatives suggesting that adhering to and documenting quality indicators improves outcome in gastroenterology practice.

at Weill Cornell Medical College, in New York City. Dr. Zheng’s group presented its findings at the 2014 annual meeting of the American College of Gastroenterology (abstract 7). see Younger, page 12

see Bleed, page 27

I N S I D E

Elderly Patients Often Receive Too Much Anesthesia for Endoscopy NEW ORLEANS—Elderly patients undergoing ambulatory gastrointestinal procedures often receive inappropriately high doses of anesthesia at induction, researchers have found. The study, a review of the anesthetic management of patients

EXPERTS’ PICKS The Best of The American College of Gastroenterology annual meeting...............page 22

undergoing upper endoscopy and colonoscopy at Yale School of Medicine, in New Haven, Conn., found that even with ageadjusted dosing, significant drops in mean arterial pressure occur. “The elderly population may be more

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Michel Kahaleh, MD, AGAF, FACG, FASGE Chief of Endoscopy and Medical Director, Pancreas Program Division of Gastroenterology and Hepatology Department of Medicine Weill Cornell Cancer Center NewYork-Presbyterian/Weill Cornell Medical Center, and Professor of Medicine, Weill Cornell Medical College

Yvonne Saenger, MD Director, Melanoma Immunotherapy Department of Medicine Herbert Irving Comprehensive Cancer Center NewYork-Presbyterian Hospital/Columbia University Medical Center, and Assistant Professor, Columbia University College of Physicians and Surgeons

The Target: Pancreatic Cancer

See page 8

Pancreatic cancer typically develops without early symptoms and presents no dependable, clinically available means of early detection, so diagnosis is often delayed until an advanced stage and lethality is heightened.1 Surgical resection of the tumor, radiation therapy, and chemotherapy may prolong survival but rarely produce a cure.1 Novel, molecularly targeted therapies have generally failed to improve survival2 when added to chemotherapy (with the possible exception of the addition of the epidermal growth factor receptor [EGFR] inhibitor erlotinib to gemcitabine3). The result: Pancreatic cancer, with a projected incidence of 46,420 new cases in 2014, will cause 39,590 deaths.1 Relative 5-year survival rate is a scant 6%.4 Clearly there are vast, unmet needs in the diagnosis and management of pancreatic cancer. The challenge is considerable, but two research teams at NewYork-Presbyterian Hospital are advancing the medical science in two key areas: definitive diagnosis, via the use of sophisticated imaging technology, and the development of immunotherapy to combat pancreatic cancer. The goal: improve clinical outcomes.

Reimagining the Workup Michel Kahaleh, MD, leads a team investigating the imaging of pancreatic cancer with probe-based confocal laser endomicroscopy (pCLE).5,6 This technique is especially suited to visualize difficult-to-access visceral regions, such as bile and pancreatic ducts.5 Therefore, pCLE has important applications for pancreatic cancer, which typically involves pancreatic ductal tissues and may extend to the bile duct.2 “Until the advent of pCLE,” Dr. Kahaleh said, “we were not always able to image pancreaticobiliary areas as thoroughly as we would like for definitive diagnosis and surgical planning.” A number of imaging modalities are used in the workup of pancreatic cancer—including computed tomography, magnetic resonance imaging, endoscopic ultrasonography, and endoscopic retrograde cholangiopancreatography (ERCP)5,7—but

definitive diagnosis, even with a combination of techniques, tissue pathology.5 When ERCP and pCLE were combined, accuracy was 90%—significantly higher than the 73% accuis difficult.8 For example,ERCP provides valuable, direct visualization of racy of ERCP plus tissue acquisition (P=0.001). This research led to the so-called Miami Classification—a ductal epithelium but cannot offer images of sufficient precision for planning surgery, radiation therapy, or chemother- uniform and reproducible description of findings from panapy.5 The clinician is often compelled to round out the profile creaticobiliary pCLE.9 Miami criteria most suggestive of canwith histologic confirmation, a technique that cer on pCLE include thick dark bands, thick white itself confers limited accuracy.5 bands, dark clumps, or epithelial struc“pCLE tures.9 A further classification The use of pCLE resolves this problem; it verifies the presence schema—the Paris Classificais a way to confirm of pancreatic cancer while tion— expanded the criteria diagnosis, but even more, it is generating distinct images to improve pCLE accuracy in a technique that beautifully maps of great utility to the surdistinguishing benign from geon contemplating resecinflammatory pathology.10 pancreatic cancer, telling the surgeon tion. Dr. Kahaleh described A study conducted by Dr. exactly what to remove.” pCLE as “a way to confirm diagKahaleh and his team showed —Michel Kahaleh, MD nosis, but even more, a technique the importance of proper training that beautifully maps the cancer, tellto ensure interrater reliability when ing the surgeon exactly what to remove.” using pCLE.11 Because NewYork-Presbyterian/ Weill Cornell Medical Center is one of the first centers in the pCLE Methodology United States to use pCLE actively, affiliated clinicians are pCLE employs a miniaturized probe designed for use dur- among the best trained in the technology. ing the ERCP procedure.5 By funneling light through a confocal opening, the pCLE probe views the tissue subsurface with pCLE Linked to Better Management no interference from solid residues or secretion (bile or panDr. Kahaleh and his team recently completed a study of the 5 creatic juice). For convenience, the probe can be inserted utility of pCLE of the pancreatic duct compared with cytologic via catheter or cholangioscope as a standard ERCP accessory and histologic results.6 The study has been accepted for pubdevice.5 lication in Digestive and Liver Disease. An important finding of Once the probe is placed in direct contact with the mucosa the study was that pCLE resulted in a favorable change in surat a selected pancreaticobiliary site, a solution of 10% fluo- gical management from total resection to partial resection.6 rescein sodium (2.5 mL) is injected intravenously.5 A scanning The study was conducted at 2 tertiary care centers: laser is then activated, and the site is microscopically evalu- NewYork-Presbyterian/Weill Cornell in New York City and Instiated, generating real-time, microscopic video sequences. tut Paoli-Calmettes in Marseilles, France. Clinicians conducted Images produced by pCLE are remarkably informative. “On pCLE via placement of the confocal probe through a pancrepCLE,” Dr. Kahaleh noted, “normal cells look organized and atoscope or catheter, advancing the probe into the pancreatic clear, but cancer is disorganized and dark. The images are duct. After obtaining real-time video images, endoscopists high contrast.” performed immediate interpretation according to the Miami Prior comparative research demonstrated that, in the Classification. These pCLE interpretations were compared detection of cancerous pancreaticobiliary strictures, pCLE with available cytologic and histopathologic material. attained an overall accuracy of 81% versus 75% for index Use of pCLE differentiated cases of benign (ie, inflammatory) disease, malignant neoplasm, intraductal papillary mucinous neoplasm of the pancreas, and normal tissue. Agreement between the cytology/histopathology and pCLE results was nearly perfect. Most importantly, pancreatic pCLE altered management for some patients in this study, changing the choice of surgery from total resection to partial resection (pancreaticoduodenectomy). “The study shows we can confirm cancer with pCLE,” Dr. Kahaleh said. “But in some patients, pCLE enabled us to guide the surgeon to a partial resection of the pancreas, sparing the patient a more extensive procedure. This is a meaningful clinical advance.”

Immunotherapy: The New Frontier Confocal imaging in pancreas cancer: Dark cells with disorganized architecture confirm the diagnosis of pancreatic cancer. Courtesy of Dr. Michel Kahaleh

12 ("4530&/5&30-0(: &/%04$01: /&84 t %&$&.#&3

NewYork-Presbyterian/Columbia University Medical Center is participating in ECLIPSE (Efficacy of Combination Listeria/ GVAX Immunotherapy in the Pancreatic Cancer Setting),12 an ongoing, multicenter, Phase IIb study that compares immunotherapy with chemotherapy in metastatic pancreatic cancer.

Gary Li Lichtenstein, ht t i MD

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES Brought to you by

Pancreatic Cancer Research Update: Advancements in Diagnosis and Immunotherapy

Pancreatic Cancer Research Update: Advancements in Diagnosis And Immunotherapy

Peter P t Hi Higgins, i MD

see Overdose, page 34

Supported by

December 2014

The Role of Technology in Optimizing Colonoscopy Quality and Efficiency Faculty

The Role of Technology in Optimizing Colonoscopy Quality and Efficiency See insert after page 54

Seth A. Gross, MD, FACG Chair

Steven A. Gorcey, MD

Steven Lichtenstein, DO

Amit Rastogi, MD, FASGE

Andreas M. Stefan, MD

Assistant Professor of Medicine Director of Endoscopy Tisch Hospital Division of Gastroenterology NYU Langone Medical Center New York, New York

Chief, Division of Gastroenterology Monmouth Medical Center Monmouth Gastroenterology Eatontown, New Jersey Assistant Clinical Professor Drexel University College of Medicine Philadelphia, Pennsylvania

Director, Division of Gastroenterology Medical Director Endoscopy/GI Lab Mercy Fitzgerald Hospital Clinical Associate Professor of Medicine Philadelphia College of Osteopathic Medicine Philadelphia, Pennsylvania

Associate Professor of Medicine University of Kansas Medical Center Kansas City VA Medical Center Kansas City, Kansas

Chief, Division of Gastroenterology Maine Medical Center Associate Director The Pancreaticobiliary Center Portland, Maine

Introduction With ongoing efforts to reform health care and contain related costs, steps have been taken to implement quality measures that optimize outcomes while ensuring efficiency. As part of the health reform initiative, preventative and procedural measures, such as colonoscopy, are considered a gateway to managing patient care more effectively. Considered the most effective screening and surveillance test for colorectal cancer (CRC), colonoscopy has been associated with a reduced mortality rate.1-4 Colonoscopy, however, is a highly technical procedure with significant risks and complications (eg, loop formation) that can cause patient discomfort and increase expenses.5,6 A successful colonoscopy depends on a number of variables, including patient- and disease-related factors, but particularly the clinician’s expertise and the technology being used.6-8 In an effort to reduce variability, improve colonoscopy outcomes, and maximize efficiency, quality measures, including cecal intubation rate and adenoma detection rate (ADR), have been implemented.1,3,7 In the future, these measures will be used to determine a clinician’s level of reimbursement; success in achieving these quality measures will result in higher reimbursement, whereas failure to achieve these marks will subject clinicians to penalties.1,9 An assessment of the available technology for colonoscopy demonstrates the benefits of using devices that enhance visualization and control to improve outcomes. The Olympus EVIS EXERA III system offers clinicians advanced technology that optimizes visualization and maneuverability, while reducing patient discomfort using a new generation of innovative colonoscopes, along with ScopeGuide and the UCR Endoscopic CO2 Regulation Unit.

This article reviews the use of the Olympus EVIS EXERA III system, ScopeGuide, and the UCR Endoscopic CO2 Regulation Unit as an encompassing approach to meeting quality measures and improving the success rate of colonoscopy.

NEW PRODUCT Vizballoons™ Airless Colonic Intubation

Essential Quality Measures In 2006, the American College of Gastroenterology (ACG) and the American Society of Gastrointestinal Endoscopy (ASGE) formed a task force to develop quality indicators for endoscopy,7,10 which were then incorporated into a voluntary reporting program known as the Gastroenterology Quality Improvement Consortium (GIQuIC).11 This program is a quality metrics registry approved by the Centers for Medicare & Medicaid Services (CMS) and qualified by the Physician Quality Reporting System (PQRS). GIQuIC provides endoscopists with a mechanism to meet quality documentation standards to avoid future reimbursement penalties and adjustments.1,9,12 The quality measures, including cecal intubation rate and ADR, for colonoscopy screening and surveillance are listed in TTable 1.11

Cecal Intubation Rate As the initiating point of a colonoscopy, cecal intubation refers to the complete passage of the colonoscope tip in the cecal caput with visualization of the medial wall between the appendiceal orifice and the ileocecal valve.1,7 Cecal intubation improves overall sensitivity, eliminating the need for radiographic procedures or repeat colonoscopy, thus reducing associated costs.7 According to GIQuIC recommendations, clinicians should be able to achieve cecal intubation in at least 90% of all colonoscopies and 95% of screening colonoscopies.9

See ads on page 16 and 23

Rajiv R ji Chh Chhabra, b MD

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Heard Here First

Happy Holidays

See page 32

from the team at Gastroenterology & Endoscopy News

We have seen a move toward

serologic

diagnosis without confirmatory

duodenal biopsy, in contrast to what is suggested in all the

guidelines and espoused by nearly all experts.

Brian, Matt, Jeanette, Adam & Dan

Vol. 65, No. 12

December 2014

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Elizabeth City, North Carolina

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Cleveland, Ohio

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FRANK G. GRESS, MD New York, New York

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NIRMAL S. MANN, MD, PhD Sacramento, California

PETER R. MCNALLY, DO

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Wide View.

Slim Profile. Slim Colonoscope The biggest advancement in GI just got smaller. Colonoscopy and gastroscopy are widely accepted as the gold standards for screening, surveillance and diagnosis of GI diseases. However, endoscope technology has not changed significantly in decades and, as a result, clinicians are constrained by current technology. The revolutionary Fuse Endoscopy System enables physicians to see nearly twice the anatomy as Traditional Forward-Viewing (TFV) scopes. The Fuse C38s Slim Colonoscope is the latest advancement in the Fuse portfolio and provides physicians the benefits of a slim scope coupled with an unparalleled 330° field of view – all while maintaining a large 3.8mm instrument channel, typically found only in adult colonoscopes.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

The Day Medicine Stood Still Facing the challenge of a tech-failure event Peter J. Papadakos, MD, FCCM, FAARC

n the classic science fiction film, “The Day the Earth Stood Still,” the planet comes to a panic-stricken stop when electricity is shut off by an advanced alien force. Hospitals and health care facilities for the past several decades have developed backup electrical generation and protocols that are regularly drilled in the event of power emergencies. Over the

past several years, however, major natural disasters, such as Hurricane Sandy, and major regional power and computer failures have identified a new danger. As medicine in just the past five years has become more dependent on computer-based systems such as electronic medical records (EMRs), automated vital sign downloads, central lab data and

Most health care facilities and hospitals do not have a well-developed protocol for what to do for such system failures, nor do they regularly drill staff to prepare them.

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digital image libraries, and computerbased pharmacy ordering, a new Achilles’ heel has been identified in patient care and safety—the fragile nature of this digital infrastructure. Most health care facilities and hospitals do not have a well-developed protocol for what to do for such system failures, nor do they regularly drill staff to prepare them. No internal emergency backup technology exists for such events. Staff is crippled without these instruments and “smart” devices. Younger staff who have been trained in today’s technology-based world are the most vulnerable. Such disasters have brought to the forefront how these tech-savvy individuals cannot adapt and provide quality, safe care without appropriate alternative training. Indeed, in certain scenarios, they would be crippled. For example, how does one get a patient history without an EMR problem list? How does one record vital signs nondigitally? What is the dosage of a commonly used drug without a computer-based checklist or pharmacologic ordering library? Care providers are unable to know the history or medical care received by critically ill patients when they may need transfer to a safer area out of reach of a natural event, such as a tornado or flood. Hospitals may not even be able to call in emergency help or hospital leadership because emergency phone contact algorithms may be stored in the computer software or on the Internet, both of which would be down. Such

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

environment. Staff should be taught how to gather data by phone from labs, radiology, etc.; protocols on how to communicate information without computers should be taught, along with the use of paper-based record keeping and ordering. Patient interactions for gathering history and recording physical findings without computer-stored data and checklists should be practiced. Hospital- and department-based preparation and regular drills, including brainstorming sessions, should allow for improvement and growth. Staff will thus

feel comfortable in a tech-failure event and be able to communicate professionalism with patients and their families, who will also be affected by area-wide disasters. Through such training, communities will know that, like other basic emergency services that provide aid in times of crisis, the provision of health care will remain intact. Dr. Papadakos is director of critical care medicine at the University of Rochester Medical Center, in Rochester, N.Y. He lectures on the impact of technology on medical care.

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amarcus@mcmahonmed.com

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UCERIS® (budesonide) rectal foam basic things as contacting the families of patients to inform them of transfers grind to a halt when the screen turns blue. How can we safeguard our patients and health care infrastructure from the threat of such natural and technologybased disasters? The keystone is developing an emergency plan to react to such events, and develop and carry out regular training and drills. Each patient care area should have unit-specific supplies, such as order sheets, progress notes and reference books to make dosing and pharmacologic data available in the event of such emergencies. One computer and printer should be plugged into the emergency power system; on this device, a summary Word document containing key sign-out information, history and family contact data should be kept so that care and possible transfer information can be generated seamlessly. The hospital and each specific medical unit should also keep a log with emergency contact information of key staff who can be reached by landline or cell phone to aid in the emergency. Hospitals and technology companies should develop devices that will provide emergency backup to these Internet-based medical technologies, so that EMRs can function in emergency mode, ideally on backup power. Regarding staff education, because new young staff may not be versed in pre-technology patient care, regular education and drills should reinforce how to safely care for patients in a low-tech

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

‘Silent Epidemic’ From Herbal and Dietary Supplements?

10-year study by investigators tasked with tracking the primary causes of liver injury has found that although conventional medications continue to be a major contributing factor, the proportion of cases tied to herbal and dietary supplements (HDS) is growing at a nearly threefold faster pace. Products marketed for bodybuilding were a common type of HDS causing liver abnormalities, the investigators reported (Hepatology 2014;60:1399-1408). But the

most severe outcomes—liver transplantation and death—were seen in patients who ingested non-bodybuilding formulations. Middle-aged women were among the most at risk for such outcomes. “Contrary to widespread belief, this study demonstrates that HDS products are not always safe,” reported Victor J. Navarro, MD, the first author of the study and a contributor to the DrugInduced Liver Injury Network (DILIN), which helped coordinate the decade-long

investigation. Part of the blame, he noted, goes to government regulations such as the Dietary Supplement Health and Education Act of 1994 that “require less safety evidence to market products than what is required for conventional pharmaceuticals.” Cathy Rosenbaum, PharmD, MBA, a holistic clinical pharmacist and CEO of Rx Integrative Solutions, who was not involved in the study, praised the researchers for using the DILIN databank

with the best-read gastroenterology publication.

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to measure the extent of HDS-induced liver injury. The research tool, Dr. Rosenbaum noted, “is a much-needed resource to rigorously quantify clinical patterns in this suspected ‘silent epidemic.’” The prospective study, conducted between 2004 and 2013, included patients with signs of having developed DILI within the preceding six months. Inclusion criteria included common markers for DILI, such as jaundice (total bilirubin >2.5 mg/dL) and coagulopathy (international normalized ratio >1.5). In all, 839 patientss with liver injury were included in n the final analysis; 709 (85%) of the cases were attributed to med dications and 130 (15.5%) to HDS. Of the latter group, 45 (35%) had taken bodybuilding HDS and 85 (65%) haad ingested non-bodyybuilding supplements. During the first two years of the study, 7% of DILIN cases were attributed to the supplements. Ten years later, that num mber nearly tripled, to 20% (P=00.0007), when all types of HDS products cts were combined. Although bodybuilding supplements caused prolonged jaundice (median, 91 days) in the men included in the study, no fatalities or liver transplants (LTs) occurred in that group. Those severe outcomes were only observed in patients taking non-bodybuilding products, and they occurred far more frequently in patients taking those supplements versus conventional medications (13% vs. 3%, respectively; P<0.05). All 13 of the patients who underwent LTs or died were middle-aged women.

Weighing the Evidence

Based on data from Kantar Media, June 2013

Given the fact that the study was based on data from only eight DILIN centers, Dr. Navarro and his colleagues stopped short of concluding that the observed rise in liver injury from HDS is truly a nationwide problem. But they came close, noting that the potentially severe adverse event “not only occurs, but also may be increasing in frequency over time in the populations surrounding the DILIN centers and, probably, in the United States as a whole.” Dr. Rosenbaum added that “it’s too soon to tell from these regional results” whether HDS-induced liver injury is a nationwide problem. Outside of this study, she added, there are many other challenges in quantifying the extent of the risks posed by HDS. For one, “we lack an accurate tally of the number of Americans who consume dietary supplements, of

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Experimental Drug May Shield Liver From Ischemia

novel complement inhibitor appears to not only protect the liver from injury after surgery but may spur regeneration of the organ, researchers have found. There is presently no approved treatment for ischemia reperfusion injury (IRI), the inflammation that occurs when blood flow is returned to healthy liver tissue after diseased tissue has been surgically removed. IRI results in part from the deposition of complement, a protein

which there are an estimated 60,000 on the world worldwide market,” she said. Moreover, “adverse reactions and causality related to supplements are difficult to quantify.” But the adverse events are likely far more common than currently appreciated, she stressed, in part because “these reactions are underreported to the FDA, to supplement manufacturers and to health care professionals.” Dr. Rosenbaum stressed that it is also important to remember a key cause of liver injury not covered by the current Hepatologyy study: accidental overdoses of acetaminophen. Dr. Navarro agreed that clinicians should heed the painkiller’s potential to cause liver injury. As for why it was excluded from his study, he explained in an email that hepatic damage caused by acetaminophen far outstrips cases attributed to other drugs and thus would have skewed the results. He added that the National Institutes of Health, which supports DILIN, “needed to focus its resources on the less understood (and studied) agents” contributing to liver disease. Study methods aside, Dr. Navarro stressed the central challenge raised by his team’s research. “All stakeholders, including the dietary supplement industry, regulatory agencies, health care providers and consumers, must take note of these findings if a culture of safety for HDS use is to be established.” —David Bronstein None of the sources in this article reported any relevant financial conflicts of interest.

that kills liver cells and impairs regeneration. Complement inhibition therefore has been recognized as a potential way to prevent IRI. However, some complement proteins deposited early signal cells involved in hepatic proliferation and are essential to the regeneration of liver tissue. Researchers from the Medical University of South Carolina, in Charleston, treated mice with a site-targeted murine complement inhibitor, CR2CD59, to investigate the balance between

complement-dependent injury and regeneration. They found that the novel agent not only protected against IRI, but also enhanced the proliferation of hepatocytes significantly. Long-term survival in the mice that received the treatment directly after surgery—just before the skin was closed— reached 70%, even in animals from whom as much as 90% of the liver had been removed, compared with 0% survival in untreated mice.

The researchers concluded that unlike other available complement inhibitors, which disrupt the early essential component of the complement pathway, CR2CD59 may offer a nontoxic approach to preventing liver injury and promoting regeneration in a variety of liver injuries in humans. The researchers reported their findings in the Journal of Experimental Medicine (2014;211:1793-1801). —Monica J. Smith

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Pancreatic Cancer Research Update: Advancements in Diagnosis and Immunotherapy Michel Kahaleh, MD, AGAF, FACG, FASGE Chief of Endoscopy and Medical Director, Pancreas Program Division of Gastroenterology and Hepatology Department of Medicine NewYork-Presbyterian/Weill Cornell Medical Center Center for Advanced Digestive Care, and Professor of Medicine, Weill Cornell Medical College

Yvonne Saenger, MD Director, Melanoma Immunotherapy Department of Medicine NewYork-Presbyterian/Columbia University Medical Center NCI-Designated Herbert Irving Comprehensive Cancer Center, and Assistant Professor, Columbia University College of Physicians and Surgeons

The Target: Pancreatic Cancer Pancreatic cancer typically develops without early symptoms and presents no dependable, clinically available means of early detection, so diagnosis is often delayed until an advanced stage and lethality is heightened.1 Surgical resection of the tumor, radiation therapy, and chemotherapy may prolong survival but rarely produce a cure.1 Novel, molecularly targeted therapies have generally failed to improve survival2 when added to chemotherapy (with the possible exception of the addition of the epidermal growth factor receptor [EGFR] inhibitor erlotinib to gemcitabine3). The result: Pancreatic cancer, with a projected incidence of 46,420 new cases in 2014, will cause 39,590 deaths.1 Relative 5-year survival rate is a scant 6%.4 Clearly there are vast, unmet needs in the diagnosis and management of pancreatic cancer. The challenge is considerable, but two research teams at NewYork-Presbyterian Hospital are advancing the medical science in two key areas: definitive diagnosis, via the use of sophisticated imaging technology, and the development of immunotherapy to combat pancreatic cancer. The goal: improve clinical outcomes.

definitive diagnosis, even with a combination of techniques, tissue pathology.5 When ERCP and pCLE were combined, is difficult.8 accuracy was 90%—significantly higher than the 73% accuFor example,ERCP provides valuable, direct visualization of racy of ERCP plus tissue acquisition (P=0.001). ductal epithelium but cannot offer images of sufficient preThis research led to the so-called Miami Classification—a cision for planning surgery, radiation therapy, or chemother- uniform and reproducible description of findings from panapy.5 The clinician is often compelled to round out the profile creaticobiliary pCLE.9 Miami criteria most suggestive of canwith histologic confirmation, a technique that cer on pCLE include thick dark bands, thick white itself confers limited accuracy.5 bands, dark clumps, or epithelial struc“pCLE The use of pCLE resolves this tures.9 A further classification problem; it verifies the presence schema—the Paris Classificais a way to confirm of pancreatic cancer while tion— expanded the criteria diagnosis, but even more, it is generating distinct images to improve pCLE accuracy in a technique that beautifully maps of great utility to the surdistinguishing benign from geon contemplating resecinflammatory pathology.10 pancreatic cancer, telling the surgeon tion. Dr. Kahaleh described A study conducted by Dr. exactly what to remove.” pCLE as “a way to confirm diagKahaleh and his team showed —Michel Kahaleh, MD nosis, but even more, a technique the importance of proper training that beautifully maps the cancer, tellto ensure interrater reliability when ing the surgeon exactly what to remove.” using pCLE.11 Because NewYork-Presbyterian/ Weill Cornell Medical Center is one of the first centers in the pCLE Methodology United States to use pCLE actively, affiliated clinicians are pCLE employs a miniaturized probe designed for use dur- among the best trained in the technology. ing the ERCP procedure.5 By funneling light through a confocal opening, the pCLE probe views the tissue subsurface with pCLE Linked to Better Management no interference from solid residues or secretion (bile or panDr. Kahaleh and his team recently completed a study of the creatic juice).5 For convenience, the probe can be inserted utility of pCLE of the pancreatic duct compared with cytologic via catheter or cholangioscope as a standard ERCP accessory and histologic results.6 The study has been accepted for pubdevice.5 lication in Digestive and Liver Disease. An important finding of Once the probe is placed in direct contact with the mucosa the study was that pCLE resulted in a favorable change in surat a selected pancreaticobiliary site, a solution of 10% fluo- gical management from total resection to partial resection.6 rescein sodium (2.5 mL) is injected intravenously.5 A scanning The study was conducted at 2 tertiary care centers: laser is then activated, and the site is microscopically evalu- NewYork-Presbyterian/Weill Cornell in New York City and Instiated, generating real-time, microscopic video sequences. tut Paoli-Calmettes in Marseilles, France. Clinicians conducted Images produced by pCLE are remarkably informative. “On pCLE via placement of the confocal probe through a pancrepCLE,” Dr. Kahaleh noted, “normal cells look organized and atoscope or catheter, advancing the probe into the pancreatic clear, but cancer is disorganized and dark. The images are duct. After obtaining real-time video images, endoscopists high contrast.” performed immediate interpretation according to the Miami Prior comparative research demonstrated that, in the Classification. These pCLE interpretations were compared detection of cancerous pancreaticobiliary strictures, pCLE with available cytologic and histopathologic material. attained an overall accuracy of 81% versus 75% for index Use of pCLE differentiated cases of benign (ie, inflammatory) disease, malignant neoplasm, intraductal papillary mucinous neoplasm of the pancreas, and normal tissue. Agreement between the cytology/histopathology and pCLE results was nearly perfect. Most importantly, pancreatic pCLE altered management for some patients in this study, changing the choice of surgery from total resection to partial resection (pancreaticoduodenectomy). “The study shows we can confirm cancer with pCLE,” Dr. Kahaleh said. “But in some patients, pCLE enabled us to guide the surgeon to a partial resection of the pancreas, sparing the patient a more extensive procedure. This is a meaningful clinical advance.”

Immunotherapy: The New Frontier Confocal imaging in pancreas cancer: Dark cells with disorganized architecture confirm the diagnosis of pancreatic cancer. Courtesy of Dr. Michel Kahaleh

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Supported by

Two-Part Immunotherapy

expression on pancreatic cancer cells, coupled with minimal expression on normal tissues, makes mesothelin a good choice for tumor-selective immunotherapy.17 “The concept of CRS-207,” Dr. Saenger explained, “is that the mesothelin-expressing Listeria will trigger the immune system to pump out inflammatory mediators in response to a bacterium associated with the same protein that is present on cancer cells. In essence, the vaccine trains the immune system to attack when confronted with mesothelin.” The immune system is therefore more likely to attack pancreatic cancer cells, which express mesothelin. A Phase I study demonstrated both the safety and immune activation of CRS-207.17 The other component of this approach to immunotherapy is GVAX-irradiated pancreatic cell lines. GVAX relies on a classic vaccination model. The irradiated tumor cells enter the body and express granulocyte-monocyte colony-stimulating factor (GM-CSF) before they die.13 This elicits a broad immune response,13 triggering the immune system to target cells associated with GM-CSF. The immune system attacks not only the vaccine cells, but also the patient’s own GM-CSF–producing pancreatic cancer cells. GM-CSF is upregulated in pancreatic cancer, and may help to “mask” the tumor from the immune system.19 “In pancreatic cancer,” Dr. Saenger said, “the immune system has decided to accept the malignancy. We want to change that with GVAX, by creating strong signals to attack the cells associated with GM-CSF.”

Live attenuated Listeria monocytogenes vaccine is one component of the immunotherapy regimen.14 The use of bacteria to reduce solid tumors has a lengthy and fascinating history, dating back to at least the 1890s, when William Coley Phase II and IIb Studies injected bacterial mixtures called Coley’s toxins to In a Phase II study,13 patients with metastatic pan15 treat cancer. creatic cancer received either of 2 regimens: Listeria vaccines were evaluated GVAX/CRS-207—2 doses of GVAX (with “GVAX in a mouse model of pancreatic low-dose cyclophosphamide for plus mesothelinintraepithelial neoplasms in T-regulatory cell depletion) folexpressing Listeria is the most the Jaffee laboratory at Johns lowed by 4 doses of CRS-207 Hopkins. Dr. Saenger particievery 3 weeks; or GVAX alone—6 advanced treatment under study for pated in these earlier studies doses of GVAX/low-dose cyclopancreatic cancer right now.” before arriving at NewYorkphosphamide every 3 weeks. —Yvonne Saenger, MD Presbyterian/Columbia. The bacFor the full cohort assessed after terium was genetically engineered a median follow-up of 7.8 months, to express Kras—hence the name of median overall survival (OS) was 6.1 the bacterium is LM-Kras. Study animals were months with GVAX/CRS-207 versus 3.9 months with bred for mutations KrasG12DD/Trp53R172HH/Pdx-1-Cre (KPC mice) GVAX alone (P=0.011). Among per-protocol patients, who or KrasG12D and Pdx-1-Cre.14 The mutant Kras was targeted received at least 3 doses of immunotherapy, median OS because it is a very common oncogene in human pancre- was 9.7 months with GVAX/CRS-207 versus 4.6 months with atic cancer.14,16 Mice received LM-Kras alone or LM-Kras in GVAX alone (P=0.0074). Adverse events included injection sequence with an anti-CD25 antibody and cyclophospha- site reactions after GVAX and transient fevers, rigors, and mide to deplete T-regulatory cells.14 lymphopenia after CRS-207. Results were auspicious: Immunization of KPC mice with The Phase IIb ECLIPSE study20 compares the combination LM-Kras, when accompanied by depletion of T-regulatory of GVAX/CRS-207 to a physician’s choice of single-agent checells, reduced progression of early-stage pancreatic intraepi- motherapy or to CRS-207 alone in previously treated metathelial neoplasms.14 LM-Kras sequenced with cyclophospha- static pancreatic adenocarcinoma. The primary end point of mide increased infiltration of lesions by inflammatory cells.14 the study is OS in patients treated with GVAX/CRS-207 verThis study provided a proof of concept that Listeria-based sus OS in those treated with chemotherapy. The study is still immunotherapy might be useful in slowing progression of recruiting patients.12 If final results of ECLIPSE are favorable, pancreatic cancer.14 the next step may be submission to the FDA for approval. In preparation for clinical studies, the Listeria bacterium “Immunotherapy offers great promise, giving us the potenwas manipulated to express the protein mesothelin, cre- tial for a durable response not seen with chemotherapy,” Dr. ating the vaccine now known as CRS-207.17 Mesothelin is Saenger said. “GVAX plus mesothelin-expressing Listeria is the highly expressed by pancreatic cancer cells, but not by nor- most advanced treatment under study for pancreatic cancer mal pancreatic cells or the cells of chronic pancreatitis.18 High right now.”

Leadership in Research NewYork-Presbyterian Hospital is a recognized leader in pancreatic cancer research, working to improve the dire outcome from this lethal disease. The comprehensive study and implementation of pCLE technology and Listeria-plus-GVAX immunotherapy together place this institution at the forefront of innovation in both diagnostic technology and clinical treatment. It is hoped that this culture of innovation will soon change the narrative for patients suffering from cancer of the pancreas.

References 1. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Pancreatic Adenocarcinoma. Version 2. 2014. www.nccn.org. Accessed November 9, 2014. 3. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960-1966. 4. SEER Cancer Statistics Review 1975-2010. Age-adjusted SEER incidence and U.S. death rates and 5-year relative survival (percent) by primary cancer site, sex and time period. www. http://seer.cancer.gov/statfacts/ html/all.html. Accessed November 10, 2014. 5. Meining A, Chen YK, Pleskow D, et al. Direct visualization of indeterminate pancreaticobiliary strictures with probe-based confocal laser endomicroscopy: a multicenter experience. Gastrointest Endosc. 2011;74:961-968. 6. Kahaleh M, et al. Probe-based confocal laser endomicroscopy in the pancreatic duct provides direct visualization of ductal structures and aids in clinical management. Dig Liver Dis (in press). 7. Coté GA, Smith J, Sherman S, Kelly K. Technologies for imaging the normal and diseased pancreas. Gastroenterology. 2013;144:1262-1271. 8. Anderson CD, Pinson CW, Berlin J, et al. Diagnosis and treatment of cholangiocarcinoma. Oncologist. 2004;9:43-47. 9. Meining A. Shah RJ, Slivka A, et al. Classification of probe-based confocal laser endomicroscopy findings in pancreaticobiliary strictures. Endoscopy. 2012;44:251-257. 10. Caillol F, Filoche B, Gaidhane M, Kahaleh M. Refined probe-based confocal laser endomicroscopy classification for biliary strictures: the Paris Classification. Dig Dis Sci. 2013;58:1784-1789. 11. Talreja JP, Sethi A, Jamidar PA, et al. Interpretation of probe-based confocal laser endomicroscopy of indeterminate biliary strictures: is there any interobserver agreement? Dig Dis Sci. 2012;57:3299-3302. 12. A phase 2B, randomized, controlled, multicenter, open-label study of the efficacy and immune response of GVAX pancreas vaccine (with cyclophosphamide) and CRS-207 compared to chemotherapy or to CRS-207 alone in adults with previously-treated metastatic pancreatic adenocarcinoma. (NCT02004262). www.clinicaltrials.gov. Accessed November 10, 2014. 13. Dung TL, Wang-Gillam A, Picozzi V, et al. A phase 2, randomized trial of GVAX pancreas and CRS-207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma: Updated results. J Clin Oncol. 2014;32 (suppl 3). Abstract 177. 14. Keenen BP, Saenger Y, Kafrouni MI, et al. A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology. 2014;146:1784-1794. 15. Shahabi V, Maciag PC, Rivera S, Wallecha A. Live, attenuated strains of Listeria and Salmonella as vaccine vectors in cancer treatment. Bioengineered Bugs. 2010;1:235-239. 16. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008; 32:1801-1806. 17. Dung TL, Brockstedt DG, Nir-Paz R, et al. A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Clin Cancer Res. 2012;18:858-868. 18. Hassan R, Laszik ZG, Lerner M, et al. Mesothelin is overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis. Am J Clin Pathol. 2005;124:838-845. 19. Greenhill C. Pancreatic cancer: the role of GM-CSF in pancreatic cancer unveiled. Nature Rev Gastroenterol Hepatol. 2012;9:426. 20. Dung TL, Wang-Gillam A, Picozzi V, et al. A phase 2b, randomized, controlled, multicenter, open-label study of the efficacy and immune response of GVAX pancreas vaccine and CRS-207 compared to chemotherapy or to CRS-207 alone in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE study). J Clin Oncol. 2014;32(suppl 5s). Abstract TPS4159. BB1426

The immunotherapy studied is a novel combination vaccine: GVAX-irradiated pancreatic tumor cells plus live, attenuated Listeria monocytogenes (CRS-207). This study was initiated by Elizabeth Jaffee, MD, at Johns Hopkins Medical Center, Baltimore, Maryland, and is based on years of basic immunology research in several laboratories around the country. According to Yvonne Saenger, MD, NewYork-Presbyterian/ Columbia researcher, findings to date in a Phase II trial of metastatic pancreatic cancer have already given “a positive signal that GVAX plus Listeria as immunotherapy is clinically superior to GVAX alone.”13 Dr. Saenger declared that this finding “brings hope to the setting of pancreatic cancer, where, as we know, chemotherapy is often not very effective.” If the Phase IIb ECLIPSE trial produces favorable outcomes for the GVAX-plus-Listeria vaccine in comparison to chemotherapy, researchers will be even more encouraged. The term vaccine should not be confused in this case with precancer prevention; GVAX plus Listeria is an immunotherapeutic intervention for patients diagnosed with pancreatic cancer. “A fully preventive vaccine, along the lines of human papillomavirus vaccine, is not feasible in pancreatic cancer,” Dr. Saenger said, “given the complex etiology of the disease and the small population of high-risk patients who might be candidates for prevention.”

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Study Hints Gut Microbiome Plays A Role in Multiple Sclerosis BOSTON— —The gastrointestinal tract may seem like an odd place to look for insight into a neurologic disease, but a small study has identified an association between two types of bacteria found in the gut and the development of multiple sclerosis. The work is the first in humans to map the microbiome in patients with MS, and may provide clues to causes of some cases, according to the researchers. Changes in the gut microbiome have been linked to other autoimmune disorders, including inflammatory bowel disease and rheumatoid arthritis (Inflamm Bowel Dis 2006;12:106-111; Curr Opin Rheumatol 2014;26:410-415), said Sushrut Jangi, MD, an instructor in medicine at Harvard Medical School, in Boston, who led the latest study. “MS has more in common with inflammatory bowel disease, rheumatoid arthritis, lupus and some of the other immune diseases than neurodegenerative diseases,” Dr. Jangi said. “In all of those autoimmune diseases, the immune system is attacking its own tissues because it has been activated by some bacteria, virus or environmental trigger. We don’t know what causes MS, and one thought is that there is a bacteria in your body that may predispose you or contribute to you getting MS. The gut has more bacteria than any other part of the body, so it makes sense to look there.” In the new study, the investigators obtained fecal samples from 61 patients with MS and 43 healthy people. The study included untreated MS patients

(n=19) as well as those treated with interferon β-1a (n=21), interferon β-1b (n=2), glatiramer acetate (n=18) and natalizumab (n=1). The researchers performed genetic sequencing on the samples to determine the specific microbial taxa of all study participants. The two cohorts had similar baseline characteristics in terms of factors that are known to influence gut bacteria, such as body mass index. The investigators found that the average abundance of Methanobrevibacterr was seven times greater in patients with MS than in the control group, but not every MS patient had the bacteria. Methanobrevibacterr has been increasingly linked to multiple inflammatory states, but its ability to drive immune responses is not well understood, according to Dr. Jangi. “Methanobrevibacterr also live in the healthy gut, but they seem to be increased in MS patients,” he said. “Is that because in MS, the gut is not working that well that it lets the Methanobrevibacterr grow more readily or is the bug somehow associated with causing the disease? It is a chicken-and-egg problem.” The investigators also found that the average abundance of Butyricimonass was three times lower in untreated patients with MS than in healthy controls. But the levels of Butyricimonass in treated patients and healthy controls did not differ significantly, suggesting that treatment has an effect on this bacteria. The possible role of Butyricimonass in

the immune system is better understood. When Butyricimonas digests dietary fiber, butyrate is produced. Butyrate influences the production of regulatory T cells in the gut (Naturee 2013;504:446-450). Previous studies have shown that patients with autoimmune conditions such as type 1 diabetes and inflammatory bowel disease have lower levels of butyrate-producing bacteria (Rev Diabet Studd 2012;9:251-259; Nestle Nutr Inst Workshop Serr 2014;79:2939). “Butyrate probably helps to dampen the immune response,” Dr. Jangi said. Emeran Mayer, MD, director of the Center for Neurobiology of Stress, in the Division of Digestive Diseases at the University of California, Los Angeles, said the findings were interesting. “I think the study is important as alterations in the gut microbiome have previously been implicated in the pathophysiology of MS,” Dr. Mayer said. “However, even though conceivable that an altered gut

microbial state may play some role in fully developed MS, the observed microbial differences could be a consequence of the disease—altered neurovisceral regulation of GI [gastrointestinal] transit, secretion or the stress associated with the disease—or it could be related in some way to the altered function of the immune system in autoimmune disorders.” The Boston-based researchers say they plan to validate their findings in a larger cohort of 250 patients. “We are finding changes, and it will take some time to figure out if these changes can be reproduced and what they mean for the biology of the patient,” Dr. Jangi said. The researchers presented their findings at the 2014 Probiotics Throughout the Lifespan symposium (poster 8). —Kate O’Rourke Dr. Jangi reported no relevant financial conflicts of interest. Dr. Mayer is a member of the advisory board for Dannon.

Delivery Mode Alters Newborn’s First Bacteriial Exposure How microbiome develops after birth could affect later-life immuniity

baby’s first exposure to bacteria varies by the method of delivery, researchers have found. These differences could have health implications later in life, according to an emerging body of evidence that suggests gut bacteria may be important to the development of a healthy immune system (Arrieta MC et al. Front Immunoll 2014;5:427). For example, evidence shows that alterations in gut bacteria early in life may increase the incidence of allergies later on (Bendiks M, Kopp MV. Curr Allergy Asthma Rep 2013;13:487-494). In the new study, presented at the 2014 annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, a group at the University of Colorado School of Medicine, in Aurora, compared oropharyngeal aspirates taken from 12 infants born by cesarean delivery and 11 born vaginally, and their bacterial content by sequencing the bacterial genes in the samples (abstract 7). Samples taken from the mothers’ vaginal and rectal areas, and samples of the infants’ stool, were also analyzed for bacterial genes.

Bacteria in aspirates from newborns delivered vaginally were more similar to the bacteria found in samples from their mothers than the aspirates from infants born by cesarean delivery, the investigators found. Infants born vaginally had higher numbers of firmicutes (62.6% vs. 30.1%; P P=0.0013), particularly lactobacilli typically found in the vagina. Aspirates from infants born by cesarean delivery, in contrast, had higher levels of Actinobacteria (20.1% vs. 3.8%; P P=0.045), which are found on the skin. Stool samples from vaginally delivered newborns also had greater numbers of Bacteroidetes than stool samples from infants born by cesarean delivery. This difference persisted through six weeks of life, the researchers said. David Brumbaugh, MD, assistant professor of pediatrics at the University of Colorado School of Medicine, in Aurora, said the finding of fewer Bacteroidetes in cesarean newborns is potentially alarming. Studies of mice raised in sterile conditions have shown that exposure to a specific type of Bacteroidetes, Bacteroides

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Study Clears Gum Chewing Before Endoscopy NEW ORLEANS—Patients who are fasting before upper endoscopy can safely chew gum up until the time of the procedure, researchers have found. Guidelines on preoperative fasting from the American Society of Anesthesiologists do not explicitly address gum chewing. However, many anesthesia departments prohibit sedation in such patients because gum chewing is considered the ingestion of a clear liquid. As a result, many patients end up having procedures delayed or cancelled when they report having chewed gum—unnecessarily, the new data suggest. “The effect of chewing gum on fasting has been a subject of debate. We found that although chewing gum does increase the production of saliva and thus the residual gastric volume, it does not increase pH,” said Basavana Goudra, MD, assistant professor of anesthesiology and critical care medicine at the Hospital of the University of Pennsylvania, in Philadelphia, who led the study. “We think that gum chewing before a procedure may help to allay anxiety in patients and increase their comfort and satisfaction. Patients who have chewed gum inadvertently should not face delays or cancellations.” The findings were presented at the 2014 annual meeting of the American Society of Anesthesiologists (ASA) by Augustus Carlin, a clinical research assistant to Dr. Goudra and a student at Drexel University, in Philadelphia. The

study appeared in the journal Digesstive Diseases and Sciencess (Nov. 2). The prospective randomized controlled study evaluated the effect of gum chewing on volume and pH of gasstric contents in 67 patients scheduled too receive IV conscious sedation for upper endoscopy. The night before the procedure, patients were randomly assigned to chew gum until the start of sedation—using fentanyl, midazolam and occasionally diphenhydramine—or to not chew w gum, with no limit on the number of pieces or how long they could chew. “The aim was to reflect real-life gu umchewing habits,” Mr. Carlin said. After insertion of the endoscoope, stomach contents were suctioned coompletely under direct vision and the volume and pH of stomach contents were measured. “We found a significant differencee in gastric volume,” Mr. Carlin reported, “however, the increase in residual volume was smaller than what we expected and therefore it failed to achieve clinical significance that would alter practice.” The median volume suctioned from the gum chewers was 13 mL, compared with 6 mL for non-gum chewers. Similarly, gastric fluid also was greater for gum chewers—0.35 versus 0.11 mL/ kg for patients who did not chew gum. “The 0.35 mL/kg is still under 0.4 mL/ kg, which is where the risk for aspiration comes into effect,” he noted.

The mean pH value was 2.84 2.8 for gum chewers and 3.79 for non-gum chewers, a difference that did not reach statistical significance (P=0.141). P “There was little to no change, and therefore no increased risk [for aspiration],” Mr. Carlin said. Anthony Absalom, MD, professor of anesthesia at University Medical Center Groningen, in The Netherlands, said concerns about gum chewing are based on fears that the regurgitation of gastric contents into an unprotected airway will damage the lungs, and the degree of potential damage is related to the volume,

fragilis, suppresses the animals’ inflammatory response (Mazmanian SK et al. Nature 2008;453:620-625), he said. Dr. Brumbaugh said he and his colleagues hypothesize that exposure to lactobacilli in a vaginal birth may help the Bacteroidetes to become established in the gut. “The fact that this bacteria never gets established early in life [in babies born by cesarean delivery] is concerning,” he said. Some studies have suggested that infants born by cesarean delivery may be at greater risk for developing conditions such as asthma, type 1 diabetes and celiac disease (Cho CE, Norman M. Am J Obstet Gynecoll 2013;208:249-254). But not all studies have supported such risks; other studies suggest that genetic factors or the reason for the cesarean delivery itself may contribute to disease later in the child’s life (Almqvist C et al. Clin Exp Allergyy 2012;42:1369-1376). Jean-Eric Ghia, PhD, assistant professor of immunology and internal medicine at the University of Manitoba, in Winnipeg, Canada, said the findings add to a body of evidence suggesting that gut bacterial colonization is affected by mode of delivery, and these altered

nature and pH of the contents. Lower pH equates to more acid and potentially more damage, he said. “Although the study found that gum chewing causes a slight increase in gastric volume, this was clinically insignificant and insufficient for causing lung injury if aspirated into the lungs. The pH also did not change,” Dr. Absalom noted. “All said, the study showed no evidence that gum chewing during fasting is bad; and on this basis, I personally would not delay anesthesia because a patient chewed gum while fasting.” —Caroline Helwick

gut bacteria might contribute to immune system–related disease later in life (Neu J, Rushing J. Clin Perinatol 2011;38:321-331). “The first colonization of the gut happens when the baby comes out,” he said. But he noted that long-term studies are needed to assess the effect of these gut differences on health in the long term. He noted that a multitude of exposures before and after birth can also influence gut biota (Munyaka PM et al. Front Pediatr. doi:10.3389/fped.2014.00109 [published online October 9, 2014]). “It’s really, really complicated,” he said. Dr. Brumbaugh suggested that, in the future, a single oral dose of bacteria such as lactobacilli might be administered to infants born by cesarean delivery to promote more physiologic colonization with bacteria such as the Bacteroidetes. Such an intervention might help to ward off future inflammatory and allergic diseases, he said, because normal gut bacteria help to “educate” the developing immune system. “We think the gut is critical to the overall allergic milieu later in life,” he said. —Bridget M. Kuehn

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Over the past decade, new cases of earlyonset CRC have been rising at an annual rate of 1.5% per year. Among patients older than 50, the rate has been declining by 3.1% annually.

Younger Using the Surveillance, Epidemiology, and End Results database from 2000 to 2011 (Figure), the researchers compared the incidence and characteristics of CRC among patients younger than age 50 (n=39,787) with those of CRC patients who were older than 50 (n=330,009). The New York researchers also found that younger CRC patients were more likely to be male (odds ratio, 1.13; 95% confidence interval [CI], 1.11-1.16) and black or Hispanic rather than white. Blacks had a 1.6-fold higher risk for CRC than whites (95% CI, 1.57-1.67) and Hispanics had a 2.1-fold higher risk than whites (95% CI, 2.07-2.21), Dr. Zheng said. In addition to the trends in cancer incidence, they also found that the rate of distant disease has increased 3% per year, whereas cases of localized or regional tumors have risen 1%. This trend, which is being seen in clinical practice, is disturbing, said Al B. Benson III, MD, professor of medicine and associate director for clinical investigations at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, in Chicago. “We are seeing increasing numbers of younger patients and many are presenting with more advanced disease,” said Dr. Benson, who was not part of the study. The tumors are more advanced in stage, of higher grade, larger size with more neural invasion compared with CRC in older patients. They also are more likely to metastasize, according to Dr. Zheng. “The young-onset CRC is more likely to present with aggressive clinicopathologic characteristics compared with old-onset CRC. And the rising incidence of young-onset CRC stratified by stage shows greatest uptrend for the advanced/distant disease,” Dr. Zheng said, postulating that it could be due to the distinct underlying biology of this cancer in younger patients and/or a delay in diagnosis. “It is not clear why this is happening and whether any of the associated risks for developing colon cancer are an issue, including diet, exercise, obesity, etc. This will have potential impact on how we screen patients for colorectal cancer and push a research agenda to find out how to precisely identify patients at risk to inform screening strategies,” Dr. Benson added. Both doctors said more data are needed before baseline-screening policies can be changed. However, it would be reasonable to consider colonoscopy in younger black or Hispanic individuals with a family history of CRC, Dr. Benson said.

Rate of Young-Onset Disease (per 100,000 population)

continued from page 1

20-49 years regional local distant

50+ years 100

Overall: 1.5% increase

Overall: 3.1% decrease 75

4 50 2 25

0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Figure. Colorectal cancer incidence by stage, 2000-2011. “Screening colonoscopies and removing polyps starting at a younger age would undoubtedly be helpful if we set aside cost,” Dr. Zheng told Gastroenterology & Endoscopy News. “Our study shows CRC diagnosed between 40 and 50 years of age accounts for more than 50% of young-onset CRC.”

However, expanding screening to this population would be cost-prohibitive and risk stratification would be needed to determine which people should be screened earlier. Dr. Zheng and her colleagues are trying to determine if young-onset CRC has a unique genetic profile. —Marie Rosenthal

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Treatment-experienced patients who failed treatment with either peginterferon (Peg-IFN) alfa + ribavirin (RBV) or an HCV protease inhibitor + Peg-IFN + RBV.1

HCV = hepatitis C virus

HARVONI is the ﬁrst and only IFN- and RBV-free regimen available in one tablet taken once a day1 • HARVONI is IFN- and RBV-free for GT 1 treatment-naïve and treatment-experienced patients with or without cirrhosis, regardless of GT 1a or 1b subtype1 • Each HARVONI tablet contains 90 mg of ledipasvir and 400 mg of sofosbuvir1 • HARVONI can be taken with or without food1 • Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups1 • No dose adjustments are required based on advanced age, mild or moderate renal impairment, or mild, moderate, or severe hepatic impairment. The safety and efficacy of HARVONI have not been established in patients with decompensated cirrhosis1 • No dose recommendation can be given for patients with severe renal impairment (estimated glomerular ﬁltration rate [eGFR] <30 mL/min/1.73 m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite1

APPROVED

ONE IS HERE

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS • Risk of Reduced Therapeutic Effect of HARVONI Due to P-gp Inducers: Rifampin and St. John’s wort are not recommended for use with HARVONI as they may signiﬁcantly decrease ledipasvir and sofosbuvir plasma concentrations. • Related Products Not Recommended: HARVONI is not recommended for use with other products containing sofosbuvir (SOVALDI®).

ADVERSE REACTIONS Most common (*10%, all grades) adverse reactions were fatigue and headache.

DRUG INTERACTIONS • In addition to rifampin and St. John’s wort, coadministration of HARVONI is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of HARVONI. • Coadministration of HARVONI is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively. Consult the full Prescribing Information for HARVONI for more information on potentially signiﬁcant drug interactions, including clinical comments.

Please see Brief Summary of full Prescribing Information on the following pages.

harvoni.com/hcp

HARVONI® (ledipasvir 90 mg and sofosbuvir 400 mg) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only. INDICATIONS AND USAGE: HARVONI is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS: Risk of Reduced Therapeutic Effect Due to P-gp Inducers: Concomitant use may significantly decrease ledipasvir and sofosbuvir concentrations and may lead to a reduced HARVONI effect. Use of HARVONI with P-gp inducers (e.g., rifampin or St. John’s wort) is not recommended. Related Products Not Recommended: Use of HARVONI with products containing sofosbuvir (SOVALDI®) is not recommended. ADVERSE REACTIONS: The safety assessment of HARVONI was based on pooled data from three Phase 3 clinical trials in subjects with genotype 1 CHC with compensated liver disease (with and without cirrhosis) who received HARVONI for 8 (N=215), 12 (N=539) and 24 (N=326) weeks. Adverse events led to permanent treatment discontinuation in 0%, <1% and 1% of subjects receiving HARVONI for 8, 12 and 24 weeks, respectively. Adverse Reactions (adverse events assessed as causally related by the investigator): The most common adverse reactions (≥10%; all grades) were fatigue and headache. Adverse reactions (all grades; majority Grade 1) observed in ≥5% of subjects by treatment duration were: • HARVONI for 8 weeks: fatigue (16%); headache (11%); nausea (6%); diarrhea (4%); and insomnia (3%) • HARVONI for 12 weeks: fatigue (13%); headache (14%); nausea (7%); diarrhea (3%); and insomnia (5%) • HARVONI for 24 weeks: fatigue (18%); headache (17%); nausea (9%); diarrhea (7%); and insomnia (6%)

reported in subjects treated with sofosbuvir in combination with ribavirin or peginterferon/ribavirin in other clinical trials. DRUG INTERACTIONS: Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir and sofosbuvir are substrates of P-gp and BCRP while the inactive sofosbuvir metabolite GS-331007 is not. P-gp inducers (e.g. rifampin or St. John’s wort) may decrease ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect; use of HARVONI with P-gp inducers is not recommended. Established and Potentially Significant Drug Interactions: The drug interactions described are based on studies conducted in healthy adults with either HARVONI, the components of HARVONI as individual agents, or are predicted drug interactions that may occur with HARVONI. This list includes potentially significant interactions but is not all inclusive. An alteration in dose or regimen may be recommended for the following drugs when coadministered with HARVONI: • Acid Reducing Agents: Ledipasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease ledipasvir concentration. • Antacids: Separate HARVONI and antacid administration by 4 hours. • H2-receptor antagonists: Doses comparable to famotidine 40 mg twice daily or lower may be administered simultaneously with or 12 hours apart from HARVONI. • Proton-pump inhibitors: Doses comparable to omeprazole 20 mg or lower can be administered simultaneously with HARVONI under fasted conditions. • Antiarrhythmics (digoxin): Increased digoxin concentration. Monitor digoxin therapeutic concentration during coadministration with HARVONI. • Anticonvulsants (carbamazepine; phenytoin; phenobarbital; oxcarbazepine): Decreased ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect. Coadministration is not recommended.

Direct comparison across trials should not be made due to differing trial designs.

• Antimycobacterials (rifabutin; rifampin; rifapentine): Decreased ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect. Coadministration is not recommended.

Laboratory y Abnormalities: Bilirubin Elevations: Bilirubin elevations of greater than 1.5x ULN were observed in 3%, <1% and 2% of subjects treated with HARVONI for 8, 12 and 24 weeks, respectively. Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3x ULN were observed in <1%, 2% and 3% of subjects treated with HARVONI for 8, 12 and 24 weeks, respectively. Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials of HARVONI. Isolated, asymptomatic creatine kinase elevations (Grade 3 or 4) have been previously

• HIV Antiretrovirals • Regimens containing tenofovir disoproxil fumarate (DF) and an HIV protease inhibitor/ritonavir (emtricitabine/ tenofovir DF plus atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir): The safety of increased tenofovir concentrations has not been established. Consider alternative HCV or antiretroviral therapy. If coadministration is necessary, monitor for tenofovir-associated adverse reactions. Refer to VIREAD or TRUVADA prescribing information for renal monitoring recommendations.

• Efavirenz/emtricitabine/tenofovir DF: Monitor for tenofovirassociated adverse reactions. Refer to VIREAD, TRUVADA or ATRIPLA prescribing information for renal monitoring recommendations. • Elvitegravir/cobicistat/emtricitabine/tenofovir DF: The safety of increased tenofovir concentrations has not been established. Coadministration is not recommended. • Tipranavir/ritonavir: Decreased ledipasvir and sofosbuvir concentrations leading to reduced HARVONI effect. Coadministration is not recommended. • HCV Products (simeprevir): Increased ledipasvir and simeprevir concentrations. Coadministration is not recommended. • Herbal Supplements (St. John’s wort): Decreased ledipasvir and sofosbuvir concentrations. Coadministration is not recommended.

older individuals cannot be ruled out. No dosage adjustment of HARVONI is warranted in geriatric patients. Renal Impairment: No dosage adjustment of HARVONI is required for patients with mild or moderate renal impairment. The safety and efficacy of HARVONI have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD. Hepatic Impairment: No dosage adjustment of HARVONI is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C). Safety and efficacy of HARVONI have not been established in patients with decompensated cirrhosis.

• HMG-CoA Reductase Inhibitors (rosuvastatin): Significant increase in rosuvastatin concentrations and risk of rosuvastatin associated myopathy, including rhabdomyolysis. Coadministration is not recommended. Drugs without Clinically Significant Interactions with HARVONI: Based on drug interaction studies conducted with HARVONI or its components, no clinically significant drug interactions have been observed or are expected when used with the following drugs individually: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, lamivudine, methadone, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, tenofovir DF or verapamil. Consult the full Prescribing Information prior to and during treatment with HARVONI for potential drug interactions; this list is not all inclusive. USE IN SPECIFIC POPULATIONS: Pregnancy: HARVONI is Pregnancy Category B; there are no adequate and well-controlled studies in pregnant women. HARVONI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Studies in rats have demonstrated that ledipasvir and GS-331007 are secreted in milk but had no effect on nursing pups. It is not known if HARVONI and its metabolites are secreted in human breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HARVONI and any potential adverse effects on the nursing child from the drug or from the underlying maternal condition. Pediatric Use: Safety and effectiveness of HARVONI have not been established in pediatric patients. Geriatric Use: Clinical trials of HARVONI included 117 subjects aged 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some

Reference: 1. HARVONI US full Prescribing Information. Gilead Sciences, Inc. Foster City, CA. October 2014.

HARVONI, the HARVONI logo, SOVALDI, TRUVADA, VIREAD, GILEAD and the GILEAD logo are trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. ©2014 Gilead Sciences, Inc. All rights reserved. HVNP0101 12/14

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Past Exposure to Thiopurines for IBD Linked to Increased Leukemia Risk

ast exposure to a thiopurine for the treatment of inflammatory bowel disease (IBD) is associated with a sevenfold increased risk for leukemia or myelodysplastic disorders, according to a prospective observational study that included more than 19,000 patients. The risk for cancer appears to be unique to the treatment and not the presence of bowel disease, judging by a comparison of the study cohort with the general population, according to the researchers. Why thiopurines might trigger leukemia is unclear. One proposed mechanism is that the drugs produce accumulation of 6-thioguanine in cell DNA, which appears to be responsible both for its therapeutic cytotoxicity as well as the generation of errors in coding that yield mutations and abnormal cell replication. “These findings should be considered” when initiating a thiopurine, such as azathioprine or 6-mercaptopurine, in patients with IBD, according to the

‘The risk–benefit considerations for thiopurine monotherapy may favor not using [the drugs], given their relative lack of efficacy. Conversely, because of the clear benefit of coadministering thiopurines with anti-TNF agents, the risk and benefit considerations do favor the use of thiopurines as part of combination therapy.’ —William J. Sandborn, MD

researchers, who published their findings in Clinical Gastroenterology and Hepatology (2014;12:1324-1239). The study was led by Laurent PeyrinBiroulet, MD, of the Department of Hepato-Gastroenterology at the University of Nancy-Brabois, in France. Dr. Peyrin-Biroulet and his colleagues performed a prospective observational study of 19,486 IBD patients participating in a French registry. They were enrolled over a 12-month period (May 2004 to June 2005) and then followed through December 2007. In addition to comparing the incidence of myeloid disorders in those who did or did not receive thiopurines, the researchers also looked at relative rates of these cancers in the general population through data from the French Network of Cancer Registries. The absolute rate of myeloid disorders in patients with IBD on thiopurines was modest. Five cases were identified in 49,736 years of follow-up, but four of the see Exposure, page 20

NAFLD May Be More Common in IBD Patients

atients with inflammatory bowel disease (IBD) appear to be significantly more likely to also have nonalcoholic fatty liver disease (NAFLD) than those without the colon disorder, new research found. The single-center, retrospective analysis of 140 patients reported more than 41% patients with IBD had NAFLD compared with approximately 16% of those without the condition. Senior investigator Rajiv Chhabra, MD, assistant professor of medicine at the University of MissouriKansas City and a consultant gastroenterologist at St. Luke’s Health System in Kansas City, Mo., called the disparity in NAFLD rates “striking.” “As in the general population, NAFLD is becoming much more common among IBD patients and it will probably replace sclerosing cholangitis as the most common liver disease in this patient population,” Dr. Chhabra said. The investigators presented their findings at the 2014 annual meeting of the American College of Gastroenterology (abstract P830). Estimates of the prevalence of NAFLD in patients with IBD vary (see e.g., Bargiggia et al. J Clin Gastroenteroll 2003;36:417-420 and Sourianarayanane et al. J Crohns Colitiss 2013;7:e279-e285). Dr. Chhabra and his colleagues retrospectively examined records from all patients with IBD who presented to the emergency department between 2009 and 2014 with abdominal pain as their primary complaint. They examined computed tomography images taken at the time of presentation and established the presence of fatty liver. They did not include patients with a documented history of alcohol abuse or use of corticosteroids in the six months before the study.

Dr. Chhabra’s team also conducted statistical analyses controlling for age, body mass index (BMI), the presence of diabetes, differences between Crohn’s disease and ulcerative colitis patients, and the results of liver enzyme tests. Finally, NAFLD rates in patients with IBD were compared with a group of age- and BMI-matched patients who also presented to the emergency department during the same period and had abdominal pain as their chief complaint.

‘As in the general population, NAFLD is becoming much more common among IBD patients and it will probably replace sclerosing cholangitis as the most common liver disease in this patient population.’ —Rajiv Chhabra, MD Dr. Chhabra’s team reported that 70 patients with IBD and 70 controls met the study criteria. A review of their medical records revealed that 41.4% (29) of the patients with IBD had NAFLD compared with 15.7% (11) those without IBD (P<0.001). The only other parameters that were significantly different between the groups were serum albumin levels (4.3±0.5 g/dL for IBD vs. 3.8±0.6 g/dL for controls; P<0.001) and platelet counts (250±82 x 109/L for IBD

vs. 286±101 x 109/L for controls; P P=0.021). These biochemical abnormalities likely resulted from active IBD, Dr. Chhabra said. Liver expert Zobair Younossi, MD, MPH, vice president for research at Inova Health System, and chairman of the Department of Medicine at Inova Fairfax Hospital, both in Falls Church, Va., called the findings “intriguing,” but added that the results require validation in better-designed studies before a firm association can be established. “This study has some flaws related to its retrospective nature,” said Dr. Younossi, who was not involved in the work. “There are a number of possible confounding variables, like insulin resistance, visceral obesity and hyperlipidemia, that the analyses did not control for. Future studies designed to establish this potential association must carefully control for these and other important confounders.” Dr. Chhabra agreed with that assessment, but said clinicians should be aware of the possibility that the risk for NAFLD is elevated in patients with IBD and should consider screening this population for fatty liver. He noted several mechanisms that might predispose IBD patients to develop NAFLD. “We know IBD patients have systemic inflammation, which is also a risk factor for fatty liver,” Dr. Chhabra said. “Liver inflammation can also result from imbalances in gut microbiota, which IBD patient have, and elevated levels of proinflammatory cytokines, which we find in IBD patients. But these possible factors need to be studied in future research.” —David Wild Drs. Chhabra and Younossi reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Harefield May Best Boston for Bowel Prep Scoring But expert takes issue with conclusions PHILADELPHIA—Bowels, like Boy Scouts, should always be prepared—prior to colonoscopy, that is. But while scouts get badges as a mark of their readiness, how do clinicians best evaluate the cleanliness of a colon? In a comparison between the Boston Bowel Preparation Scale (BBPS) and the more conservative Harefield Cleansing Scale (HCS), researchers with the European pharmaceutical company Norgine, Ltd, suggest the HCS may be a more appropriate cleansing classification system. However, at least one expert questioned the methodology of the study, which was presented at the 2014 annual meeting of the American College of Gastroenterology (ACG; abstract P329). “Both are validated instruments, so I credit them for attempting to draw a comparison,” David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School, in Norfolk, told Gastroenterology & Endoscopy News. “But it’s very difficult for me to understand how they could be accurate in their interpretation with a retrospective, post-hoc analysis unless there was video analysis. They do assign a BBPS based on the HCS, which may not be accurate, as these scales are not validated to use one and reassign to another. The authors do acknowledge this in their poster presentation.” The purpose of the analysis was to compare BBPS, which assesses bowel cleanliness in three segments on a scale of 0 to 3, with success defined as an aggregate of at least a 6, and HCS, which assesses bowel cleanliness in five segments on a scale of

0 to 4. The HCS recognizes a bowel as successfully cleansed when one or more segments scores a 2, indicating removable stool, or between 3, indicating clear fluid, and 4, indicating an empty or clean bowel. The analysis of six clinical trials involved 1,865 patients undergoing colonoscopy, including a subset of 782 patients from two of the trials in which data on diagnostic yield were available. The research-

of the adenoma detection rate (ADR)— the number of patients with at least one adenoma, as confirmed by the pathologist, expressed as a percentage of the population tested—with an ADR of 30% in those with successful bowel prep scores compared with an ADR of 25% in those with unsuccessful scores. Patients who had discrepant system scores had an ADR of 24%, suggesting bowel prepara-

‘The data suggests HCS was the more conservative scoring approach, which led to a more appropriate cleansing classification.’ —Dave Walker

ers analyzed scores from both systems for each patient, cross-tabulated the scores and calculated a Pearson’s correlation coefficient to compare BBSP with HCS. The Pearson’s coefficient (r=0.78) suggested a strong correlation between the two systems. However, 122 patients whose bowel preparation was deemed successful by the BBPS were considered unsuccessful by the HCS. Both systems yielded similar scores in their assessment

tion was unsuccessful, according to the researchers. “Norgine does not claim the HCS is superior to BBPS, but that the data suggests HCS was the more conservative scoring approach, which led to a more appropriate cleansing classification,” said Dave Walker, senior director for clinical development at the company, in an email. Mr. Walker added that the study’s conclusion states that “satisfactory cleansing

in all segments is what is required to maximize adenoma detection rate, whichever scale is used.” But Dr. Johnson said reaching any conclusions from the study would be premature. “This data conflicts with other comparison studies in which BBPS seems to have better performance characteristics for kappa scores, meaning they have less intraobserver variation,” he said. “Other studies have shown HCS to be not as predictable, and to have higher intraobserver variability compared with systems like BBPS.” Dr. Johnson questioned the abstract’s conclusion given the design of the study. “To get a better definition of what they’re concluding here, they’d have to do a headto-head trial with a real-time, not retrospective, assessment,” he said. “Clearly, further validation of these reported findings is needed, hopefully from prospective comparisons.” Mr. Walker responded that there have been no published direct comparisons between the two scoring systems, and that the statistical methodology used and the outcomes assessed in validating the two scales are different, so direct comparison of the results is not possible. “However, the actual end result of cleansing evaluation from the use of each scale and subsequent resulting adenoma detection rates are what were compared,” he said, agreeing with Dr. Johnson that a head-to-head comparison between HCS and BBPS is required to further interpret the findings of this preliminary research. —Monica J. Smith

Exposure continued from page 18

five developed in patients taking a thiopurine. Of these, three developed in patients with prior exposure to a thiopurine and one in a patient currently taking a thiopurine. Patients with IBD were not at increased risk for myeloid disorders compared with the general population, nor were those taking thiopurines at the time of the study. However, IBD patients with past exposure to the drugs were 6.98 times more likely to develop leukemia than the other groups. Previous studies, including one performed by the same group from the same patient population (Gastroenterologyy 2011;141:1621-1628), linked thiopurines to a significantly increased risk for non-melanoma skin cancer. That work led some experts to advocate sunscreens in patients taking thiopurines (Clin Gastroenterol Hepatol 2014;12:274-276). The new data may suggest a more delicate risk–benefit ratio for thiopurines than previously appreciated. Although such calculations must consider the value of

thiopurines in controlling IBD, which itself is associated with an increased risk for colorectal cancer, a recently published meta-analysis that included Dr. Peyrin-Biroulet questioned whether thiopurines offer such protection. The review of 15 studies with long-term follow-up (Clin Gastroenterol Hepatoll 2014 June 4. [Epub ahead of print]) found no protection against colorectal neoplasia. Based on this accumulating evidence, Dr. PeyrinBiroulet expressed hope that “these findings encourage other researchers to investigate more about thiopurines and their potentially harmful effects.” However, thiopurines are not always offered as a single agent for IBD—a perspective not addressed in these studies, said William J. Sandborn, MD, chief of gastroenterology at the University of California, San Diego. “This paper presents a somewhat one-sided view, emphasizing the ‘relative risk’ of very rare toxicities and ignoring the large absolute benefits in terms of efficacy and prevention of immunogenicity when thiopurines

are coadministered with anti-TNF [tumor necrosis factor] agents,” Dr. Sandborn observed. He cited other studies from Europe that have suggested azathiopurine alone is not particularly effective in the treatment of early Crohn’s disease. “The risk–benefit considerations for thiopurine monotherapy may favor not using [the drugs] given their relative lack of efficacy,” Dr. Sandborn said. “Conversely, because of the clear benefit of coadministering thiopurines with anti-TNF agents, the risk and benefit considerations do favor the use of thiopurines as part of combination therapy.” —Ted Bosworth Dr. Peyrin-Biroulet has had financial relationships with Abbott Laboratories, Centocor and UCB Pharma. Dr. Sandborn has had financial relationships with Abbott Laboratories, Centocor, Elan, Procter & Gamble, Prometheus Laboratories, Salix, Shire and UCB Pharma.

ACG 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Best of ACG 2014 Gastroenterology & Endoscopy News asked three experts on inflammatory bowel disease to comment on several abstracts presented at the 2014 annual meeting of the American College of Gastroenterology that they believe are clinically significant and applicable.

Peter Higgins, MD Director of the Inflammatory Bowel Disease Program at the University of Michigan, in Ann Arbor

Postoperative Mortality for the Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis of Population-Based Studies (Singh S, et al)

18.

The investigators summarized an enormous amount of data from 52 studies, looking at death rates following surgery for both Crohn’s disease (CD) and ulcerative colitis (UC). They also broke down the data by elective versus emergent surgeries, which is where I think the real take-home message lies: There is a striking difference in 30-day postoperative mortality rates between elective and emergent surgery. Overall, the average 30-day mortality rate for UC was about 3.2%—or roughly one in 30. That sounds terrible, but if you break it down according to elective or emergent surgery, you see the 30-day mortality rate with elective surgery is only 0.7%, or roughly one in 140. If you wait until it’s an emergency, however, mortality increases to about 5.3% within 30 days of surgery for UC. That’s roughly a 7.5-fold increase in the risk for death. The same pattern emerged for CD, although the overall death rate was lower, at 1.8%. Again, with elective surgery, it was 0.6%, but it was 3.6% for emergency surgery. That’s a marked sixfold increase in the risk for death within 30 days after surgery. So, the message is clear: We really shouldn’t be waiting for things to get to an emergency situation. The facts about mortality risk with emergency surgery need to be communicated to physicians, and they in turn need to explain to their patients that they probably do not want to wait for emergency surgery, because it is much more likely to go badly. Association of Mean Vitamin D Level With Clinical Status in Inflammatory Bowel Disease: A 5-Year Prospective Study (Kabbani, TA, et al) This is one more piece in the vitamin D story, which really started with two studies presented at Digestive Disease Week 2013. In the first, patients with inflammatory bowel disease (IBD) were stratified according to their vitamin D levels, and those with lower vitamin D levels were found to be twice as likely as those with higher levels to be hospitalized and require surgery over the study period (DDW13; Ananthakrishnan A, et al; abstract 1). The second study was a small randomized controlled trial (RCT) from Dublin, Ireland. It showed that vitamin D supplementation in CD patients with

61.

Table 1. Are Gastroenterologists Meeting AGA IBD Quality Measures? IBD Quality Measures

Meeting AGA Criteria, %

Documentation of IBD type, anatomic location, and activity

44.6

Documentation that corticosteroid-sparing therapy was recommended for patients unable to taper off corticosteroids

69.2

Over a five-year period, patients with IBD and low vitamin D levels averaged 3.82 ED visits,

Documentation that bone loss assessment was recommended for patients at risk for corticosteroidrelated iatrogenic injury

17.3

Documentation that influenza immunization was recommended

26.4

Documentation that pneumococcal immunization was recommended

3.6

Documentation of screening for latent tuberculosis before initiating anti–tumor necrosis factor (TNF) therapy

21.7

Documentation of assessment of hepatitis B virus status before initiating anti-TNF therapy

20.3

Documentation of testing for Clostridium difficile

20.6

Documentation of prophylaxis for venous thrombembolism for inpatients with disease flare

13.9

Documentation of screening for tobacco use and cessation if relevant

2.7

compared with 1.7 visits for those with normal levels of the vitamin; 55.4% versus 44.1% of those with low and normal vitamin D levels, respectively, required surgery. surgeries and visits to the emergency room. This number of associations between vitamin D levels and use of health care suggests the correlation is indeed legitimate, instead of just a retrospective data-mining finding. The question that remains is whether vitamin D is simply a marker of disease activity and poor vitamin D absorption, or if vitamin D is directly involved in the disease process. These data suggest there might be an effect of vitamin D on disease activity; but to really answer the question, we need an RCT, which the Crohn’s and Colitis Foundation of America is sponsoring and is now in the pilot phase. At the very least, I think we should be checking vitamin D levels and worrying about those patients with low levels, since they clearly tend to have worse outcomes. Analysis of an Administrative Claims Database Suggests Poor Quality of Care for Inflammatory Bowel Disease (Melmed GY, et al) In 2012, the American Gastroenterological Association (AGA) released a series of IBD quality measures that are now used as markers of high-quality care. How well are we doing in meeting those measures? This analysis of a large claims database shows we’re doing remarkably poorly, all across the nation, at least in documenting high-quality care (Table 1). For example, we should be testing patients for tuberculosis and hepatitis B before they begin therapy with anti–tumor necrosis factor (TNF) agents, but that’s only happening in 20% of patients. We really should be bringing that up to at least 80%. Admittedly, most of the time when we’re seeing an IBD patient, it’s because he or she is very sick and we’re trying to get symptoms under control, and we’re not necessarily thinking about all these health maintenance measures. But we need to.

P1663.

AGA, American Gastroenterological Association; IBD, inflammatory bowel disease

low levels of the vitamin can actually increase their quality of life and muscle strength (DDW 2013; Raftery T, et al; abstract Sa1198). The current study looked at records from 944 patients with IBD over a five-year period, again stratifying them according to low and high vitamin D levels. Those with low vitamin D over a five-year period had greater use of steroids and narcotics, underwent more computed tomography (CT), and had more hospitalizations,

see ACG, page 24

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ACG 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

ACG continued from page 22

induction using vedolizumab (Entyvio; Millennium Overall, 57% of patients experienced clinical response; Pharmaceuticals) subsequently lose response. Sands, et 33% achieved remission and they had significant al found that serum drug levels could be increased by improvements in markers of inflammation and in quality Professor of Medicine and Director moving from the typical maintenance dose of 300 mg of life. Endoscopic response was seen in 68% of patients, of the Center for Inflammatory of vedolizumab every eight weeks to 300 mg every four and complete endoscopic remission occurred in 9%. Bowel Disease at the Raymond and Ruth Perelman School of Medicine, weeks. Indeed, in patients who had The outcomes are encouragof the University of Pennsylvania, in lost response, the switch led to signif- A single fecal microbiota trans- ing, particularly given that these Philadelphia icant improvements in disease activity patients had previously tried at plant effectively treats scores without an apparent increase in least one other anti-TNF agent. C. difficile infection in 80% of Three large, Phase III studies adverse events. The data are important but they patients with inflammatory are examining several induction Budesonide need to be validated in prospective and maintenance ustekinumab bowel disease (P454). Foam for trials, and the study raises some quesdosing regimens, both subcuUlcerative Proctitis (UP) and Ulcerative tions. One is whether there is any taneously and intravenously, in Proctosigmoiditis (UPS): Subgroup Analyses toxicity associated with higher drug levels. We know patients with CD. We are eager to see what level of of 2 Randomized, Placebo-Controlled, Phase from our experience with anti-TNF agents that high benefit those trials demonstrate, and what they suggest 3 Studies (Bosworth B, et al; poster 467) and drug levels place patients with certain genetic muta- the optimal dose might be. If they yield positive findEfficacy and Tolerability of Budesonide Foam tions at a higher risk for developing pustular psoriasis. ings, ustekinumab could get regulatory approval for With or Without Baseline 5-Aminosalicylic Acid To date, that has not been seen with vedolizumab, but treatment of CD, perhaps within two to three years. Use in Patients With Ulcerative Proctitis (UP) vigilance will be required to identify safety issues that It would be a nice addition to the medical armamenor Ulcerative Proctosigmoiditis (UPS): Results may arise in the future. tarium, because it can be administered subcutaneously; of 2 Randomized, Placebo-Controlled, Phase 3 Another question is whether one can use a lower dose it has a long half-life; and it seems to be effective in Studies (Sandborn WJ, et al P470) of the drug while staying within a therapeutic range. This patients who have failed prior anti-TNF therapy. We have several corticosteroid treatments for ulcer- has not been examined specifically with vedolizumab, In addition, unlike the anti-TNF agents, which can ative proctitis and proctosigmoidbut the TAXIT (Trough Level cause pustular psoriasis, ustekinumab treats psoriasis, itis. Despite their effectiveness, Two weeks of treatment with Adapted Infliximab Treatment) leaving open the possibility that it might be beneficial these agents have drawbacks. Some trial, which looked at infliximab in CD patients with comorbid psoriasis. rectally administered budesonide examples: Oral prednisone has sigdosing adjustments, showed foam induced clinical response in that there is a therapeutic winnificant potential systemic side effects, so we generally attempt 45.1% of patients with ulcerative dow that can be achieved even Rajiv Chhabra, MD to avoid using it. Oral budesonide with lower infliximab doses, proctosigmoiditis, compared with Assistant professor of medicine at the MMX (Uceris; Salix Pharmaceutimeaning patients can save University of Missouri Kansas City 26.9% with placebo. The treatment cals), approved for use in patients money (United European GasSchool of Medicine, and consultant with active UC, has less systemic produced a response in 30.6% of troenterology Week 2013; oral gastroenterologist at Saint Luke’s toxicity than conventional corticoplenary 001). A prospective, Hospital, in Kansas City, Kansas patients with ulcerative proctitis, steroids. Hydrocortisone enemas placebo-controlled, dose-escaversus 16% with placebo (P467). lation study with vedolizumab are hard to retain, particularly for people with active disease; hydrocould define what the optimal cortisone foam is a prednisone derivative that carries trough levels with this drug are, so that patients who some of the same systemic safety concerns associated have lost response can undergo appropriate dose optiOutcomes of Fecal Microbiota with prednisone; and hydrocortisone suppositories often mization and patients who have attained response might Transplantation for C. difficile deliver drug only to the rectum. use less of the drug while maintaining response. Infection in Patients With Inflammatory Bowel A recently FDA-approved, rectally administered form Disease (Fischer M, et al) Patients With Refractory of budesonide foam (Uceris) is a welcome new addition Crohn’s Disease for two reasons. First, it is associated with less systemic Fecal microbiota transplantation (FMT) is increasSuccessfully Treated With Ustekinumab ingly accepted as an effective and safe intervention toxicity than prednisone or hydrocortisone, thanks to the budesonide formulation. The second is that the foam (Harris KA, et al) in patients with recurrent Clostridium difficilee infeccoats the colon better than enemas or suppositories, and Since the publication of Phase II data suggesting tion. However, data regarding its efficacy and safety in reaches up to 40 cm from the anal verge. ustekinumab (Stelara; Janssen) may be effective in treat- patients with both C. difficile and IBD are lacking. TraThese two studies demonstrate superior efficacy ing some patients with CD (Sandborn WJ, et al. N Engl ditionally, these patients have had poor outcomes due to over placebo with a dose of 2 mg twice daily for two J Medd 2012;367:1519-1528), the drug has been used off- increased mortality from complications of both diseases, weeks, then once daily for four weeks. The benefit held label even though the ideal dosing regimen is unknown. particularly worsening colitis and toxic megacolon. regardless of age, disease duration and baseline use of This retrospective, multicenter chart review of Although this study was small, including 41 patients, 5-acetylsalicylic acid (ASA), and regardless of whether patients with refractory CD who received the drug sheds and had all the limitations of a retrospective trial, it is patients had ulcerative proctitis or proctosigmoiditis. light on the efficacy and safety of one possible dosing important in that it demonstrates that FMT is effective Importantly, it was effective in those with severe disease, regimen (Table 2). in more than 90% of these very challenging patients defined as Modified Mayo Score/Disease Activity Index with both conditions. Moreover, the treatment did not of 7 or higher, as well as those with established disease. lead to significant deterioration in the symptoms of Table 2. Possible Dosing Regimen for IBD. For several patients who were on immunosupUstekinumab in Crohn’s Patients Effects f of Increased pressive therapies, outcomes with FMT were not detVedolizumab Dosing Induction: 90 mg at 0, 4 and 12 wk rimentally affected, again highlighting the safety and Frequency on Disease Activity in Ulcerative efficacy of FMT. Booster dose: 270 mg at week 8 if no or limited Colitis and Crohn’s Disease (Sands BE, et al) These results need to be validated in a larger, prospective response As this post-hoc analysis suggests, low drug serum study, so that the benefit and safety profile of this intertrough concentrations may be why some patients who vention in IBD patients with C. difficile can be confirmed. Maintenance: 90 mg every 8 wk initially attain clinical response or remission with see ACG, page 26

Gary Lichtenstein, MD

P467/P470.

P454.

P1051.

P1054.

Q & A

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

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

Genii Recognized as Innovation Leader

How has Genii earned the title as the new leader in thermal therapy innovation?

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argon canister! This technology leap makes the gi4000 truly a compact all-inone natural choice for standardization. From a high flow rate lavage pump, to outputs perfect for everything from polypectomy to ESDâ&#x20AC;&#x201D;it goes everywhere and does it all for flexible endoscopy. We canâ&#x20AC;&#x2122;t forget the improved argon coagulation beam! The Linear ArC Smartâ&#x201E;˘ beam is ideal for flexible endoscopy. The beam ignites quickly. The linear beam is

predictably longer, and yet less aggressive than competitorsâ&#x20AC;&#x2122; amplified beams.b Another Genii advance is the Positive Pressure System. Controlled within our patented compact gas delivery mechanism, it has elegantly eliminated the need for external back flow filters. Since these filters add per-procedure cost, this is another way that Genii meets its continuing mission to provide innovation and value.

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A. The list is long, but starts with the user interface. Repeated testing has confirmed that staff learn to use the gi4000 in minutes and can set up the generator faster than older models. Users make significantly fewer setup errors.a Clinicians appreciate the way the interface makes the fundamentals of electrosurgery transparent. They are empowered with a clear understanding of the selection choices. Tissue sensed automatic power curves, and FDA-cleared default settings in every mode enhance confidence. The game-changing touch screen interface is extremely sophisticated in its simplicity. Of course, the innovation that gets immediate attention is the patented miniature

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ACG 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

ACG continued from page 24

Long-Term Efficacy of Vedolizumab Therapy for Crohn’s Disease (Hanauer SB, et al)

P1059.

These are very important and exciting data that present us with another treatment for successful management of some very complicated patients with CD. The safety and efficacy of up to 52 weeks of vedolizumab treatment in patients with CD was established in the GEMINI 2 trial (Sandborn WJ, et al. N Engl J Med 2013;369:711-721). Patients in GEMINI 2 were very difficult to treat, many having failed prior anti-TNF therapy. In addition, nearly half had a history of surgery and fistulizing disease, and approximately 17% had active, draining fistulae at the time of enrollment. This study examined outcomes at 104 weeks in 295 patients who completed 52 weeks of vedolizumab treatment in GEMINI 2 and continued through to 104 weeks. Sixty-one percent were in remission at 104 weeks, compared with 57% who were in remission at week 52.

In the subgroup of patients with prior anti-TNF exposure and failure, 52% were in remission at week 52 and 51% were in remission at week 104.

Subjects with low serum albumin levels were more likely to have stricturing or penetrating disease, and they also lost response and remission sooner than those with higher levels. Serum Albumin as a Predictor Measuring serum albumin levels at baseline might of Long-Term Response and predict the need for more aggressive therapy with cerRemission With Certolizumab Pegol for Crohn’s tolizumab pegol Disease: Results From 7-Year (400 mg every Patients with low serum albumin levels Data From the PRECiSE 3 Study two weeks (Sandborn WJ, et al) lose response to certolizumab pegol after instead of every Although anti-TNF agents have draan average 1.71 years, compared with four weeks), or matically influenced how we manage suggest that alter3.18 years when levels are normal (P478). refractory IBD, some patients will lose native treatments, response over time or become intolerant such as surgery or to these drugs. Immunogenicity and rapid clearance of the vedolizumab, might be necessary. These data provide an drug have been implicated as causes of these outcomes. impetus for conducting prospective trials examining the This study looked at whether serum albumin lev- effect of increased doses of certolizumab (Cimzia, UCB) els predict loss of response, and indeed found that low in patients with low baseline serum albumin. levels reflected more severe disease and poor response. —Compiled by David Wild

P478.

Bariatric Surgery May Improve Kidney Function

esides helping patients shed pounds, bariatric surgery may improve their kidney function, researchers have found. Patients who are morbidly obese are at increased risk for renal failure. Although bariatric surgery is highly effective for inducing rapid weight loss, the effect of the surgery on kidney function and endstage renal disease has been unclear, said Alex R. Chang, MD, a nephrologist at Geisinger Medical Center, in Danville, Pa., who led the new study. “Our findings suggest a beneficial impact on kidney function in patients with and without baseline kidney disease,” Dr. Chang said. The researchers examined the kidney health of 3,134 patients who underwent bariatric surgery, following them for a median of 2.4 years. The mean age of

the patients was 47 years. More than 36% had diabetes and more than 6% had reduced renal function. One year after bariatric surgery, the patients’ mean weight decreased from 130.1 to 90.9 kg; mean body mass index fell from 46.8 to 32.6 kg/m2; and mean kidney function, estimated from the glomerular filtration rate (eGFR), increased from 94.8 to 99.1 mL/min/1.73 m2 (P≤ P 0.001). For every 5 kg of weight lost, there was an increase in eGFR of 0.50 mL/ min/1.73 m2 in patients with chronic kidney disease who had undergone bariatric surgery over those who did not. In addition, of the 108 patients with albuminuria—a marker of kidney dysfunction—weight loss was associated with resolution of the protein excretion in the urine (P=0.03). P

The study suggests that surgery and the resulting weight loss were beneficial to the kidneys. However, more research is needed, Dr. Chang said, who noted that the current clinical standard to measure kidney function was creatinine, which can be influenced by muscle mass. Rapid weight loss might reduce muscle mass and therefore creatinine levels, but other markers indicate that shedding

pounds does benefit the kidneys. “More emphasis should be placed on promoting healthy lifestyles to avoid morbid obesity and prevent chronic kidney disease,” he said. Dr. Chang’s group presented their findings at the American Society of Nephrology’s 2014 Kidney Week meeting (abstract FR-OR024). —Marie Rosenthal

Obesity in Adolescence Linked to Increased Risk for Colorectal Cancer wedish men who were obese in their youth were 2.37 times more likely to develop colorectal cancer later in life compared with those who were normal weight, according to a new study. The study, which was presented at the 2014 American Association for Cancer Research (AACR) International Conference on Frontiers in Cancer Prevention Research, also found that adolescents who had high levels of inflammation experienced a 63%

higher risk for the disease compared with those who had low levels. Researchers from Harvard School of Public Health, in Boston, analyzed data (erythrocyte sedimentation rate for inflammation and height and weight for obesity) that had been collected from 239,464 Swedish men who were enlisted in the military between 1969 and 1976, when they were aged 16 to 20 years. They compared the military registry with the Swedish national cancer registry an average of 35 years

later, identifying 885 cases of colorectal cancer among the men. “Our results suggest that early-life body mass index and inflammation may independently play a role in the development of cancer later in life,” said Elizabeth Kantor, PhD, a postdoctoral research fellow in the Department of Epidemiology at Harvard School of Public Health, in a statement from AACR about the study. “These results are important because understanding how life-course exposure to high body

mass index and inflammation related to colorectal cancer risk may improve our understanding of this disease and may help guide prevention strategies.” Dr. Kantor noted, however, that further research is needed to better understand these relationships. She also pointed out that the registries the researchers used to obtain the data do not contain information on all variables, such as diet, which may have affected the associations. —Paul Bufano

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Bleed continued from page 1

The quality indicators most significantly associated with a reduced length of stay (LOS) were performance of orthostatics in patients with normal vitals, placement of large-bore IV lines, and appropriate deployment or non-deployment of hemostasis, said Carl Nordstrom, MD, chief GI fellow in the University of California, Los Angeles’ integrated gastroenterology training program. The work was led by Brennan M. Spiegel, MD, director of the Center for Outcomes Research and Education at Cedars-Sinai Medical Center, in Los Angeles.

center. The average age was 63 years, and the average hospital LOS was 7.5 days. The average number of serious comorbidities was 3.3 as calculated with the Charlson Comorbidity Index. In the index hospitalization, to which this analysis was confined, nearly 10% of the patients rebled, and 6.6% died. In general, the greater the number of quality indicators met, the shorter the hospital stay, the researchers found. This included a significant difference in the average stay between those in whom a single quality indicator was met and those without any documented quality indicators (6.5 vs. 10 days; P=0.003). Although the difference for those in whom four to six quality

‘Is it that quality indicators matter or do better doctors do better with quality indicators?’ —James Scheiman, MD

Of 26 quality indicators that were considered, adherence to eight was evaluated, according to Dr. Nordstrom, who presented the findings at Digestive Disease Week 2014 (abstract 330). In addition to the four indicators most closely associated with LOS, these included appropriate documentation of nasogastric lavage findings, admission of hypovolemic patients to an ICU, endoscopy within 24 hours and use of a largebore therapeutic endoscope. The patients in the study were treated over a 10-year period (1996-2007) at a single Veterans Affairs medical

indicators were achieved was only marginally better than for those with one to three, the average stay for those in whom all eight quality indicators were met was only four days. The researchers found no association between quality indicators and a patient’s risk for death, but incremental increases in the number of quality indicators performed were linked to a substantial reduction in the need for a second endoscopy in addition to the reduction in LOS. “There is a large variation in the process of care

Pathology Common in Tissue From Gastric Sleeve Resection

hree-fourths of the gastric tissue samples retrieved during gastric sleeve resection had potentially significant cellular abnormalities, new research indicated. The review of patient charts and histology at a large Midwest hospital found that among tissue samples from 343 gastric sleeve surgery cases, 237 (69%) showed evidence of gastritis, six (1.7%) had ulcers, two (0.58%) had gastrointestinal stromal tumors and one (0.3%) each had adenocarcinoma, polyp, gastric diverticulum and pyloric stenosis. Rachel Gordezky, MD, a pathology resident at the University of Illinois Hospital and Health Sciences System, in Chicago, who led the study, noted that at most institutions these tissues currently are routinely examined by pathologists.

“But there’s been talk in different medical communities that tissues from procedures like sleeve gastrectomy, because of budget cuts, don’t need to be routinely examined,” Dr. Gordezky told Gastroenterology & Endoscopy News. “So we did this project to show that even with routine surgeries it’s still important to do pathology on them.” Dr. Gordezky presented the findings at the College of American Pathologists’ 2014 annual meeting (poster 84). She and her colleagues found that 75.2% of patients who underwent bariatric surgery at the University of Illinois between January 2009 and August 2013 had incidental findings in their gastric sleeve surgical specimens that were not documented in their charts preoperatively. Dana Telem, MD, associate director

among institutions for acute gastrointestinal bleeds,” Dr. Nordstrom said. He suggested that these data provide evidence that the quality indicators could at least reduce hospital stays, if not improve overall outcomes in gastrointestinal (GI) bleeds, but cautioned that these findings “should be confirmed in a prospective study.” Using quality indicators to guide improved care is a growing phenomenon. In colonoscopy, for example, some third-party payors are considering documentation of quality indicators, such as an endoscope withdrawal time of at least six minutes, for reimbursement. In managing GI bleeds, however, Dr. Nordstrom said prospective evidence is needed to show that adhering to such indicators affects outcomes. James Scheiman, MD, professor of gastroenterology at the University of Michigan, in Ann Arbor, said it is critical to demonstrate that establishing these kinds of processes of care actually changes physician behavior. “Is it that quality indicators matter or do better doctors do better with quality indicators?” he asked. He expressed concern about “pop up” reminders in electronic medical record systems calling for physicians to perform quality measures not yet proven to affect outcomes. Improving processes of care must be aligned with incentives in an integrated health care system that both encourages and facilitates physicians to adhere, Dr. Scheiman said. Goals must be realistic. He noted that endoscopy within 24 hours was one of the quality indicators in the latest study, but it was only achieved about half the time, even in a center with a protocol for handling acute gastrointestinal bleeding. Quality indicators are useful and have the potential to improve outcomes while reducing cost, Dr. Scheiman added, but their real value emerges “if we can get people who are not very good at this to do it better.” —Ted Bosworth Dr. Nordstrom reported no relevant financial conflicts of interest. Dr. Spiegel has relationships with Amgen, Ironwood Pharmaceuticals, Prometheus Laboratories, Shire Pharmaceuticals and Theravance. Dr. Scheiman has financial relationships with AstraZeneca, Pfizer, Pozen and Stryker.

of the Bariatric and Metabolic Weight Loss Center at Stony Brook University, in Stony Brook, N.Y., said, “The way you could look at this is, with the high rate of findings, many of which are significant, should all patients undergo preoperative endoscopy? “My practice right now is to perform selective endoscopy—for example, if there’s clinical indication or family history that would put out a red flag” for possible underlying gastric abnormalities, said Dr. Telem, who was not involved in the latest study. “But I’ve been considering switching to routine endoscopy performance preoperatively.” Dr. Telem noted that although some insurance companies mandate routine preoperative endoscopy, others do not, and that practices vary significantly in which patients receive the test before surgery. —Rosemary Frei, MSc Drs. Gordezky and Telem reported no relevant financial conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Many Providers Stray From Guidelines For Diagnosis and Management of Celiac Disease

espite clear guidelines outlining the diagnosis and management of celiac disease, many clinicians still offer suboptimal care of the condition, results from a survey of 80 health care providers suggest. The survey found that only one-fifth of respondents said they would diagnose celiac disease using endoscopic examination, which is the diagnostic gold standard. The findings, which were presented at the 2014 annual meeting of the American College of Gastroenterology (abstract P180), also revealed that nearly 10% of clinicians would not recommend the mainstay therapy for celiac disease, a gluten-free diet, as the first line of treatment for newly diagnosed patients. Benjamin Lebwohl, MD, MS, the Herbert Irving Assistant Professor of Medicine and Epidemiology at the Celiac Disease Center at Columbia University, in New York City, called the results concerning. “There are details of celiac disease management that are subject to debate, but certain aspects of care, such as the need for a strict gluten-free diet, are beyond debate,” said Dr. Lebwohl, who was not involved in the research. Awareness of celiac disease has grown with increased media attention, patient advocacy and professional education, said Aline Charabaty, MD, director of the IBD Center at Georgetown University Hospital, in Washington, D.C., who helped conduct the survey. For the study, Dr. Charabaty and several of her colleagues asked 450 U.S. health care providers to complete an online questionnaire inquiring about disease understanding, diagnosis and management. Eighty of the invited providers responded to the questionnaire, including 16 gastroenterologists; 26 primary care physicians; and 29 osteopaths, nurse practitioners and obstetricians (nine others did not indicate their specialty or academic degree). Approximately half of the respondents had been in practice for less than five years. Roughly two-thirds (65%) of respondents said they learned about celiac disease in medical school; 72% said the topic had been covered in residency or postgraduate training; and 29% received continuing medical education on the disease. Dr. Charabaty’s team found that 70% of respondents said their awareness of celiac disease increased after they entered clinical practice. Slightly less than half of the respondents said they treated more than 10 patients per year with celiac disease, and nearly all

respondents said they had made the diagnosis in these patients themselves. Of concern, 63% of respondents reported using serologic testing alone to confirm suspected celiac disease. Only 19% said they would combine serologic testing with endoscopic evaluation to make a diagnosis, whereas 15% said they would refer patients with suspected celiac

1978

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disease to a gastroenterologist. “We have seen a move toward serologic diagnosis without confirmatory duodenal biopsy, in contrast to what is suggested in all the guidelines and espoused by nearly all experts,” said Daniel A. Leffler, MD, MS, director of research at The Celiac Center at Beth Israel Deaconess Medical Center (BIDMC) and director of quality

assurance in the Division of Gastroenterology at BIDMC, in Boston. “I think there is insufficient awareness of the potential for false-positive results with the tTG [tissue transglutaminase antibody],” added Dr. Leffler, who was not involved in the research. More encouraging findings showed that a diagnosis of celiac disease would

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prompt 63% and 68% of respondents to refer patients directly to a gastroenterologist and a dietitian, respectively. However, 91% said they would recommend that newly diagnosed patients initiate a gluten-free diet. Dr. Charabaty added that surveyed providers mainly recognized the typical gastrointestinal manifestations of celiac disease. “Few physicians recognized the atypical manifestations of the disease,” she

said, pointing to additional findings indicating inadequate screening for possible nutritional deficiencies, complications such as low bone mineral density and associated complications such as thyroid disease. Atypical symptoms include osteoporosis at a young age, neurologic symptoms, reproductive health issues, dermatitis herpetiformis and blood work abnormalities, such as iron deficiency anemia and abnormal liver enzymes.

Dr. Charabaty also said only a few respondents looked for the disease in high-risk populations, such as individuals with type 1 diabetes or Down syndrome. “These undiagnosed patients not only suffer for longer periods from symptoms of celiac disease, but they are also at higher risk for developing complications from untreated celiac disease,” she said. “Clearly, there is a need for awareness efforts toward all providers, including gastroenterologists, primary care

providers and other medical subspecialists,” Dr. Charabaty concluded. The American College of Gastroenterology’s clinical guidelines on diagnosis and management of celiac disease appeared in the May 2013 issue of the American Journal of Gastroenterology (108:656-676). —David Wild Drs. Charabaty, Leffler and Lebwohl reported no relevant financial conflicts of interest.

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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 see HCV Screening, page 18

NAFLD Threatening Public Health 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

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FOCUS

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Nausea, Vomiting Reduced With IV Acetaminophen But overall opioid use unchanged in lap chole study MONTREAL—Preliminary data indicate reduced postoperative/post-discharge nausea and vomiting (PONV/PDNV) and improved patient satisfaction after a single dose of IV acetaminophen in patients undergoing laparoscopic cholecystectomy, compared with traditional opioid-based anesthetics. Despite this, the overall amount of opioid administered

intraoperatively and in the postanesthesia care unit (PACU) was not reduced. “There have been a lot of reports, both anecdotally and in the literature, about ways to help minimize PONV and pain,” commented Daniel Bosshart, MD, assistant professor of anesthesiology at Hofstra North Shore–LIJ School of Medicine, in Hempstead, N.Y. “So, we wanted to

determine the effect of a single dose of IV acetaminophen on PONV, PDNV, pain and overall patient satisfaction.” Dr. Bosshart and his colleagues enrolled 65 outpatients, American Society of Anesthesiologists (ASA) physical status 1 to 3, scheduled for laparoscopic cholecystectomy, into the trial. Each patient received a regimen of an opioid and an

inhalational anesthetic, with preemptive antiemetics based on preoperative PONV risk according to ASA guidelines. The intervention group of 32 patients received 1,000 mg of IV acetaminophen (Ofirmev, Cadence Pharmaceuticals) after removal of the gallbladder but before emergence. The control group of 33 patients received opioids and other analgesics, including

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

ketorolac, as per usual practice. Pain scores were recorded with an 11-point rating scale before surgery and at 10-minute intervals in the PACU. Both PDNV and patient satisfaction were assessed within seven days of surgery. “We wanted to measure the effect of giving an intraoperative dose of Ofirmev versus just giving standard, opioid-based analgesics that clinicians would typically give for these cases,” Dr. Bosshart explained. “We picked this particular procedure because it’s one of the most

’The problem with looking at postdischarge results is that they will be somewhat affected by what the surgeon prescribes after the surgery.’ —Raafat Hannallah, MD commonly performed surgeries in the outpatient setting.” As Dr. Bosshart reported at the 2014 annual meeting of the International Anesthesia Research Society (abstract S-29), PACU pain scores did not differ

significantly between the IV acetaminophen patients and the controls at 10 minutes (1.4±3.1 vs. 2.3±3.0, respectively; P=0.12) or one hour after surgery (2.6±2.5 P vs. 2.1±2.3, respectively; P P=0.77). Total opioid use (intraoperative plus PACU) as

measured by morphine equivalents also was comparable between groups (72±36 vs. 69±36 mg, respectively; P=0.9). P Trends toward less PONV were observed in the PACU, with 36% of controls experiencing the side effect compared with 21% of the treatment group (P=0.3). P Similar results were found for PDNV, which affected 38% of controls and 14% of patients receiving IV acetaminophen (P=0.08). P “We also found that PDNV was see Lap Chole, page 32

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Lap Chole continued from page 31

actually more prolonged in the control group,” Dr. Bosshart said. Indeed, 24% of controls reported PDNV on the day of surgery, with 7% and 7% reporting the adverse event on postoperative days 2 and 3, respectively. “In the IV acetaminophen group,” he said, “it was only noted on the actual day of surgery [P<0.05].” Patient satisfaction with pain control, PONV management and overall

experience also trended in favor of IV acetaminophen, although this did not reach significance: 67%, 71% and 84%, respectively, for controls versus 84%, 93% and 96% for the treatment group (P=0.5, 0.1 and 0.4). “We found the effect of the IV acetaminophen on nausea particularly interesting, not only initially, but also after discharge,” he said. “It was equally interesting that overall patient satisfaction was higher in the treatment group, despite the actual perception of the pain

being similar in both groups. We expect these differences to reach statistical significance once we finish enrollment. “These preliminary results seem to demonstrate that there’s another factor involved here with regard to PONV than just opioid sparing,” Dr. Bosshart added. “It seems there is a central effect that may have something to do with a metabolite of acetaminophen and how it affects cannabinoid receptors in the brain.” The study is ongoing. Session moderator Raafat Hannallah,

MD, professor of anesthesiology and pediatrics at Children’s National Health System, in Washington, D.C., proposed a possible confounding factor that may have influenced the results. “The problem, of course, with looking at postdischarge results is that they will be somewhat affected by what the surgeon prescribes after the surgery. These agents will be responsible for at least some of the observed response.” —Michael Vlessides

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

PPIs Plus Diuretics Ups Risk for Hospitalization From Low Magnesium

atients taking a combination of proton pump inhibitors (PPIs) and diuretics are at increased risk for low magnesium levels severe enough to warrant hospitalization, researchers have found. Canadian investigators calculated that patients taking the drug combination were 73% more likely to require hospitalization for hypomagnesemia than those

not on the medications. The risk for all outpatients taking PPIs was 43% greater than for those not on the reflux agents. This translates into one excess hospitalization with hypomagnesemia among 76,591 outpatients treated with PPIs for 90 days. David Juurlink, MD, a scientist at the Institute for Clinical and Evaluative

Sciences, in Toronto, Ontario, and his colleagues analyzed data from patients in Ontario from April 2002 to March 2012. They focused on 366 patients aged 66 years and older hospitalized with hypomagnesemia and 1,464 matched controls. Current use of PPIs was associated with an adjusted odds ratio (OR) for hypomagnesemia of 1.43 (95% confidence interval

[CI], 1.06-1.93). The risk was highest among patients who also were taking diuretics (OR, 1.73; 95% CI, 1.11-2.70). “We would like to replicate the study using serum magnesium levels,” Dr. Juurlinck told Gastroenterology & Endoscopy News. “We don’t yet have those data, but when we do, we’ll replicate it.” The researchers reported their findings in PLoS Medicinee (September 30). —Rosemary Frei, MSc Dr. Juurlink reported no relevant financial conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Overdose continued from page 1

susceptible to adverse events from anesthesia, such as hypotension, given the cardiovascular, pharmacokinetic and pharmacodynamics changes associated with aging,” said Vicki Bing, BS, a medical student at Yale who helped conduct the study. “So it is recommended that anesthetic dose be adjusted for age. It’s been unclear, however, whether current practices adequately correct dosing for increasing age.” Ms. Bing’s group reported their

finding at the 2014 annual meeting of the American Society of Anesthesiologists (ASA; abstract 3164). Ms. Bing and her colleagues sought to determine whether induction anesthetics are dose-adjusted for age and, if they are, if this results in increased hypotension. They examined the anesthesia records of 799 adults who underwent non-emergent, ambulatory gastrointestinal procedures at Yale over a six-week period in 2013. They recorded induction doses of propofol and fentanyl, and looked

for changes in mean arterial pressure (MAP) within 10 minutes of induction. Anesthetic doses and changes in MAP were compared across age groups (the oldest group aged ≥80 years) and across ASA classes 1 to 4, which indicate severity of illness.

No Adjustment for Age in Fentanyl The researchers found that fentanyl dosing was not different between the age groups, indicating that this anesthetic’s dose is not being reduced appropriately for elderly patients. Interestingly, mean

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fentanyl dose increased with increasing ASA class (P=0.03). P Propofol dosage, in contrast, was significantly different across age groups (P<0.01), with older patients (≥65 years) receiving less drug than younger (<65) patients. An exception was patients in ASA classes 1 and 2, in which propofol dosage did not differ between young and old patients. Notably, despite the fact that older patients received lower propofol doses, patients aged 65 and older experienced significantly greater drops in MAP (Table). “Our take-home point is that propofol

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

dosing is not appropriately adjusted for age and for ASA classes 1 and 2, and with propofol dose adjustments, MAP changes are still significant in older patients,” Ms. Bing said. Shamsuddin Akhtar, MD, associate professor of anesthesia at Yale School of Medicine and senior author of the study, said the findings show that anesthesia providers are more likely to adjust dosing by ASA class than by age. “Sicker patients get a little less anesthetic,” Dr. Akhtar said. The researchers’ next step, he said, is

Table. Mean Anesthetic Doses and MAP Changes by Age Patient Group

Fentanyl, mcg/kg

Propofol, mg/kg

Change in MAP, mm Hg

All: Young vs. old

0.10 vs. 0.09

2.02 vs. 1.71

–8.39 vs. –13.73

ASA class 1 and 2: Young vs. old

0.08 vs. 0.06

2.08 vs. 2.00

–7.54 vs. –12.97

ASA class 3 and 4: Young vs. old

0.12 vs. 0.10

1.96 vs. 1.55

–9.35 vs. –14.15

to delve into the pharmacodynamics data for the oldest age group, which is an area not well understood. He believes they

will find that MAP reductions are even greater in that subset. As for recommendations, Dr. Akhtar

said, “We think there are opportunities to decrease the dose, and [clinicians] should not only be looking at ASA class but also age. There’s more room for reducing the dose in the elderly, especially patients above age 80.” “We know the elderly lack the cardiac, respiratory and renal reserves that younger patients have,” he explained. “Significant drops in MAP can result in end-organ damage, but they also trigger therapeutic interventions with vasopressors, fluids and so forth that can have negative consequences in patients with minimal reserves. Prevention of these scenarios is better than cure.” Basavana Goudra, MD, assistant professor of anesthesiology and critical care medicine at the Hospital of the University of Pennsylvania, in Philadelphia, said, “Almost 80% of my work is for gastrointestinal procedures, so I do these sedations frequently. I have found that optimal dosing goes far beyond just age and ASA classification. It’s more an art than a science,” Dr. Goudra told Gastroenterology & Endoscopy News. Anesthetic pharmacokinetics and pharmacodynamics are extremely variable among patients, he pointed out. “With older patients, we typically start with low doses, but having said that, I once sedated a 104-year-old patient for colonoscopy,” Dr. Akhtar said. “I ended up dosing her almost as much as a 50-year-old. If I administer propofol to maintain a plasma concentration of 2 mcg per cc in 100 patients, the response could range from awake to deep general anesthesia, depending on the brain response of the given patient. “You need a very observant clinician,” he added. “No matter what you do, you will have some patients slipping too low and some being awake.” Dr. Goudra added that he would like to see brain function monitoring be part of training clinicians to measure the depth of sedation. “It’s very difficult to learn dosing. It’s very provider-dependent,” he said. —Caroline Helwick Ms. Bing, and Drs. Akhtar and Goudra reported no relevant financial conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY Y NE NEW NEWS • DECEMBER 2014 GASTROENTEROLOGY & ENDOSCOPY NEWS WS W S • DECEMBER 2014

ND CO Y U SU I TE E E N D OES COOSP YPS IT

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Algorithm continued from page 1

The improvement is meaningful for quality assurance, because recent case reports have suggested that transmission of pathogens from one patient to another, although uncommon, does occur. The risk for transmission was reinforced by the substantial contamination rate documented before the new cleaning algorithm was implemented, according to data presented at Digestive Disease Week 2014 (DDW; abstract 218). Using a bioburden detection system, 37% of endoscopes had unacceptably high biomass after cleaning but before high-level disinfection. Now that the cleaning protocol has been improved, the pass rate exceeds 90%, said Brett B. Bernstein, MD, director of endoscopy at Mount Sinai Beth Israel Medical Center, in New York City, who led the study. Concern about cleanliness arose when endoscopes were monitored with a commercial bioburden detection system. Of several available systems, the one that

Beth Israel uses is the 3M Clean-Trace Hygiene Management System, which detects adenosine triphosphate (ATP), an energy transporter found in all living cells. When the surface of the endoscope is brushed with a swab containing an enzyme that reacts with ATP, it generates light. The intensity of the light, expressed in relative light units (RLU), is a measure of the level of bioburden. “A RLU of 200 or less is considered to represent minimal biomass,” explained Carrie Wong, MD, a fellow in gastroenterology at Beth Israel, who presented the results at DDW. An RLU of 201 or above is considered an unacceptable level of organic matter, indicating a need for additional cleaning. When the failure rate over a threemonth period was found to be 37%, a new protocol for cleaning was implemented and the staff was retrained. The new protocol consists of 11 well-defined steps of what parts to wipe, detach,

100

Percentage

80 60 40 20 0 Dec 2012

Jan 2013

Feb 2013

Scope Pass/Failure Rates

Mar 2013 ■ Fail

Apri 2013

May 2013

■ Caution

Figure. Implementation of the cleaning algorithm resulted in a 95% pass rate.

June 2013 ■ Pass

immerse, brush, flush, submerge, and dry, and for how w long. After the staff was retrained, routine monitoring was implemented (Figure). Pass rates rapidly increased to 90% and remained at that level forr a follow-up period of siix months. In the new protoccol, which is implemented beforee the instruments are submitted ffor final disinfection, the first failure sends the scope back for a full reprocessing. After a second failure, the scope is retturned to the manufacturer. Adequate reduction of biomass is essential because excessive debris defeats the final disinfection step, creating a risk for transmission, which may deserve more attention, according to Dr. Wong. She speculated that there may be a greater risk for transmission than previously thought because of under-reporting of such cases. “Pathogen transmission between patients has been previously thought to be quite low, but recently we have become aware of outbreaks such as one involving CRE [carbapenem-resistant Enterobacteriaceae],” Dr. Wong reported at DDW. “That is why studies like ours have some potential value in considering how to improve processing of scopes.” Estimates of pathogen transmission from contaminated endoscopes vary widely. In one review of published estimates, rates ranged from 0.0001% to 6% (Kovaleva, et al. Clin Microbiol Rev 2013;26:231-254). Essentially all transmissions are believed to result from failure of adequate cleaning and disinfection. Dr. Wong suggested that the data from the new study indicate that rigorous protocols are needed to reach the highest

standards t d d off transmission t i i prevention. ti Lawrence Hookey, MD, of the gastrointestinal diseases research unit at Queen’s University, in Kingston, Ontario, Canada, said it is difficult to prove that one method is superior to another when transmission rates are so low. When infections do occur, they are generally attributed to a breakdown in the cleaning protocol, rather than a signal that the existing protocol is inadequate. “It is intuitive that a reduction in biomass will reduce risk of infection, but intuitive assumptions are not always correct,” said Dr. Hookey, who is vice president of clinical affairs for the Canadian Association of Gastroenterology. With any new approach, efficacy is generally demonstrated by post-disinfection culture because infection rates would be expected to be too low to measure. “The study presented at the DDW is intriguing,” Dr. Hookey said. “But I think it is a first step in the absence of evidence that biomass is a meaningful surrogate of infection risk.” —Ted Bosworth Drs. Bernstein, Hookey and Wong reported no relevant financial conflicts of interest.

Random Biopsies in Endoscopically Normal Esophagus Find Recurrences After Ablation CHICAGO—In patients who have undergone ablative removal of esophageal lesions, random biopsies detect more recurrent metaplasia than targeted surveillance based on endoscopic signs, new research shows. Suspicious mucosal changes leading to a targeted biopsy also were an important predictor of recurrence in the study—increasing the odds ratio by 17.7-fold (P<0.001) relative to the absence of a suspicious lesion— but random biopsies led to identification of a greater number of recurrences even if most were of lower grade, the researchers found.

“In addition to taking biopsies of suspicious lesions, these data support the value of random biopsies to increase detection of recurrent metaplasia,” said Sarina Pasricha, MD, a fellow in the Division of Gastroenterology and Hepatology at the University of North Carolina (UNC), at Chapel Hill. Dr. Pasricha presented the data on behalf of an investigative team led by Nicholas J. Shaheen, MD, director of the UNC Center for Esophageal Diseases and Swallowing. The relative value of random biopsies was not trivial. According to data presented at Digestive Disease

Week 2014 (abstract 106), 74% of the recurrences were detected during random biopsies, leaving only 26% detected when endoscopic signs, such as nodules or suspicious changes in surface appearance, prompted a targeted biopsy. For the single-center study, the researchers reviewed the medical records of all patients who underwent radiofrequency ablation for Barrett’s esophagus (BE) at the institution’s hospitals between 2006 and 2013. The analysis was restricted to the 168 patients who achieved see Random, page 38

ScopeGuide Real-time, 3D visualization of the scope configuration

Physicians: Identify and mitigate loops.

Nurses: Document precise locations for biopsies.

Assistants: Apply abdominal pressure to the correct location.

Patients: Experience a more comfortable colonoscopy.

Watch Video or visit www.medical.olympusamerica.com/scopeguide/gen Contact a sales representative at 800-848-9024 ÂŠ2014 Olympus America Inc. Registered Trademark of Olympus or its afďŹ liates. I www.medical.olympusamerica.com/scopeguide/gen I OAIGI0813AD11548

33 88

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

ENDOSCOPY SUITE

Under Pressure: Is Insufflated Gas During Endoscopy a Patient Hazard?

as used for insufflation during endoscopic procedures is emitted at extremely high pressure, needlessly increasing the risk for potentially lethal emboli, researchers have found. The study, by a group from the University of Florida, showed that the overinflation could rise to nearly three times normal systolic blood pressure—more than enough to trigger a gas embolism. “In traditional endoscopy, an endoscope is inserted within the lumen of a hollow organ and a gas is pumped through the end of the endoscope in order to expand the space undergoing examination and improve viewing conditions,” said Jeffrey White, MD, assistant clinical professor of anesthesiology at the University of Florida, in Gainesville, who led the study. “We wanted to know much pressure is typically exerted by that gas during a normal exam.” Dr. White and his colleagues tested three commonly used Olympus endoscopes: GIF-Q180 used for esophagogastroduodenoscopy, CF-Q180 for colonoscopy and TJF-Q180 for endoscopic retrograde cholangiopancreatography (ERCP). To measure flow rate, they set up the Olympus Evis Exera III CV-190 endoscopy processor for regular endoscopy, connected the hospital wall source of carbon dioxide (plumbed at 52 psi) and set the flow meter to the usual flow rate of 2

L per minute. They then placed the distal end of each endoscope into a water-filled, 1-L bottle inverted in a basin of water, fully depressed the endoscope gas flush button and measured the displacement rate of the water.

said. “If you think about that high gas pressure in a situation where there is sufficient proximity to transmit that gas into the bloodstream, it’s a setup for the rapid development of a fatal gas embolism.”

The CT image courtesy of WikiFoundry (www.wikiradiography.net).

Gas was emitted from the tip at close to the set rate, between 1.75 and 1.82 L per minute. But when they then measured the pressure exerted at this flow rate, they found that it exceeded 300 mm Hg for all three endoscopes. “That’s almost three times normal systolic blood pressure,” Dr. White

Diddi Fors, MD, PhD, a senior consultant in the Department of Anesthesia and Intensive Care at Uppsala University Hospital, in Sweden, noted that the rarity of such events—estimated to be from tenths or hundredths of a percent to 1% to 2%, depending on the procedure— might mean the risk is more theoretical

than practical. But endoscopic procedures now being developed use the endoscope to tunnel from a starting point within a natural orifice into and across tissue layers to gain access to other parts of the body, posing a greater potential risk. “We are looking at a whole new horizon of surgical procedures that will be accomplished endoscopically,” Dr. White said. “Along with the benefits of these new procedures, we have to consider the potential risks.” “If there is a wounded and open vein or artery and air is injected directly in the vessel, there is a high risk for gas embolism,” Dr. Fors said. Dr. White suggested that a move toward using carbon dioxide for insufflation, which is more soluble in blood than air, could ameliorate the risk for emboli related to the high pressure. “We really think everyone should consider switching to carbon dioxide as the insufflating gas they use for endoscopy if they are in a practice that still uses air,” Dr. White said. “Carbon dioxide is much more soluble in blood than air, and using it will give you a higher margin of safety over air.” Dr. White’s group presented their findings at the 2014 annual meeting of the American Society of Anesthesiologists (abstract 2058). —Keely Savoie

Random continued from page 36

complete eradication of BE and had undergone at least two surveillance endoscopies. In addition to targeted biopsies during routine endoscopic surveillance, random biopsies were performed every 1 cm in a standard fourquadrant protocol. The researchers identified 19 (11%) histologic recurrences of intestinal metaplasia in the tubular esophagus. Patients who experienced a recurrence underwent a mean of 3.8 surveillance endoscopies. The 14 patients with a randomly detected recurrence were somewhat older and had fewer endoscopies than the five patients with a recurrence found on a targeted biopsy. But the major difference was the type of recurrence. “In those [recurrences] detected with a random biopsy, 70% of the recurrences involved intestinal metaplasia or low-grade dysplasia,” Dr. Pasricha said. “In those detected with a targeted biopsy, 80% had highgrade dysplasia or adenocarcinoma [P=0.016].” P The researchers pointed out that 80% of the recurrences were identified within 1 cm from the top of the

gastric folds (Z line). This included all of the targeted biopsies. Of recurrences found with random biopsies, two were seen in areas of esophagitis, which may have concealed irregularities in the tissue, but the majority of the others were located in normal-appearing tissue. One of the random biopsies did identify adenocarcinoma, according to the researchers. No subsquamous recurrences were found. In a discussion that followed presentation of the data, several gastroenterologists in the audience commented about the high rate of recurrences located close to the Z line. This pattern of recurrence led to speculation that ablation did not extend far enough toward the gastroesophageal junction. Although this did not challenge the basic study conclusion regarding the value of random biopsies, which did identify recurrences more than 1 cm away from the distal fold, it did raise questions about how far to extend radiofrequency ablation in standard ablative procedures. Prateek Sharma, MD, professor of medicine at the

University of Kansas School of Medicine, in Kansas City, noted that the standard method for screening BE patients after ablation is the same as it is in surveillance of BE patients who have not yet developed dysplasia. This approach involves targeted biopsies of suspicious areas followed by what was described by the UNC investigators as “random” biopsies in the four quadrants. The key variable is the rigor of the evaluation, he said. “With the use of high-definition endoscopes and careful inspection, suspicious areas of recurrences can be identified. Use of electronic chromoendoscopy techniques can also be of value,” Dr. Sharma observed. Surveillance has emerged as an important issue because long-term follow-up data have been able to confirm that recurrences after ablation are not uncommon, he said. —Ted Bosworth Dr. Pasricha reported no relevant financial conflicts of interest. Dr. Sharma has financial relationships with Barrx Medical, Cook Medical and Olympus.

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44 00

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

ENDOSCOPY SUITE

In Community Setting, New Biopsy Technique Increases Barrett’s Detection CHICAGO— —When used as an adjunct to conventional biopsy, wide area transepithelial sampling (WATS3D , CDx Diagnostics ) is effective in the hands of community gastroenterologists for detecting Barrett’s esophagus (BE), recent data show. Compared with forceps biopsy alone, WATS3D increased the detection of dysplasia and neoplasia by nearly 70%, a gain that is particularly impressive when considering that these lesions pose a risk for malignant transformation. Unlike brush cytology techniques designed to collect exfoliated squamous cells, WATS3D uses an abrasive brush that passes through the operating channel of the endoscope to obtain a deeper and wider sample of glandular epithelium, described as three-dimensional microbiopsies. By increasing the sample size, the new technology addresses the key weakness of forceps biopsy, which typically is performed at 2-cm intervals, leaving large areas unsampled. The new technique, which is intended to supplement—not replace—forceps biopsy, is relatively rapid and requires minimal training. Several previous studies have suggested that the WATS3D method raised yield compared with that achieved with forceps biopsy alone, but the new work is the largest comparison study conducted so far, according to the researchers. It was also designed to evaluate whether

improved yields persisted in real-world practice outside of an academic setting. The study involved 28 communitybased gastroenterologists with samples from 2,559 patients, said Seth A. Gross, MD, director of endoscopy at Tisch Hospital of New York University School of Medicine, in New York City, who presented the data at Digestive Disease Week 2014 (abstract 371). Participating gastroenterologists performed both forceps biopsy using standard techniques and the WATS3D brush biopsy during the same endoscopic evaluation. Both forceps and brush biopsy samples were sent together to a central pathology laboratory. For the tissue samples obtained by brush biopsy, analysis was computer-aided. With forceps biopsy, 377 cases of BE were detected among the samples, producing a yield of 15.1%. The tissue samples were taken primarily from patients with gastroesophageal reflux disease. Dysplasia was identified in 17 of these cases, or 4.6% of those with BE and 0.7% of the total sample. WATS3D identified an additional 258 cases of BE, raising the overall yield to 25.4%—an absolute increase of more than 10% and a relative increase of more than 65%. The additional yield included 10 cases of dysplasia and one case of cancer missed by forceps biopsy. The increased yield with WATS3D for dysplasia and cancer was 64.7%. Dr. Gross indicated that WATS3D see Biopsy Technique, page 45

Dysplasia detected by the WATS3D biopsy. Images courtesy of CDx Diagnostics.

New York Society for Gastrointestinal Endoscopy Celebrates 40 Years

New Guinea native mask, a Naomi Sarna jewThe NYSGE was created to provide educational gastrointestinal endoscopy. Over the years, the scope of eled frog belt buckle and a private concert by the opportunities for the gastroenterology community to the society has grown far beyond its initial aspirations. Attacca Quartet were only a few of the many learn about what was then a newly emerging science of “For many of its members, NYSGE has provided an whimsical prizes auctioned off at the opportunity for professional collaboration that defined the past of their indiNew York Society for Gastrointestinal Endoscopy’s (NYSGE) 40th anniversary vidual careers,” said NYSGE President gala last spring. For one evening, guests Brian P. Bosworth, MD. “The core traded their white coats for black ties and strength of the society is derived from evening gowns as they celebrated under the strong personal relationships forged the soaring granite arches and catalan among its leaders and their enduring vaulted tile ceilings at Guastavino’s, a commitment to promoting excellence New York City historic landmark. in endoscopy.” The gala provided an opportunity Earlier in the year, the NYSGE for the society’s more than 300 attendexecutive council established an honors ing members to raise funds to support program to recognize significant profesNYSGE’s programs and supplement sional achievement, service to NYSGE, the research fund endowment, and to contributions to education and research honor the society’s past presidents and in endoscopy, and excellence in patient leaders. The evening’s program provided care. The honor, known as Fellowa retrospective, juxtaposing the society’s Past-presidents of the New York Society for Gastrointestinal Endoscopy pose at ship in the NYSGE, was conferred for accomplishments and milestones with the society’s 40th anniversary gala. From left to right: Victor W. Groisser, MD (1980), the first time on all society presidents the social and cultural phenomena of the Jerome H. Siegel, MD (1983); seated, Richard S. McCray, MD (1974, 1975), Jerome D. from the past four decades. Of the 37 Waye, MD (1977), Charles J. Lightdale (1982), Sidney J. Winawer, MD (1978). past four decades. see NYSGE, page 45

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44 22

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

ENDOSCOPY SUITE

Endoluminal Devices Seek Place in Weight Loss Armamentarium MONTREAL—Somewhere between medical therapy and established bariatric surgical options, patients are looking for alternative interventions for weight loss, and endoluminal or endoscopic approaches appear to represent those choices. At the 2014 meeting of the International Federation of Surgery for Obesity and Metabolic Disorders (IFSO), Erik Wilson, MD, medical director of bariatric surgery at Memorial Hermann Texas Medical Center and chief of elective general surgery at the University of Texas Health Science Center at Houston, discussed the design of and preliminary findings from the Primary Obesity Multicenter Incisionless Suturing Evaluation, or PROMISE trial. The trial involves endoscopic sleeve plication and the OverStitch Endoscopic Suturing System (Apollo Endosurgery Inc.), a device approved for endoscopic placement of sutures and stitching together of soft tissue, said Dr. Wilson, one of the study investigators. Performed through the patient’s mouth, the gastric restriction procedure requires no surgical incisions. The trial included 20 patients at each of four U.S. centers, including Massachusetts, Florida, Texas and New Jersey. Patients recruited for the study had a body mass index (BMI) between 30 and 35 kg/m2, and were followed in regular clinical visits every three months up to one year after the procedure, with an endoscopic evaluation at 12 months. “The primary end point is to see if it is safe and if it’s doable, to determine the efficacy, and to see the potential durability as well,” Dr. Wilson said. “There is some space between medical therapy and some of the surgical therapies as far as invasiveness and risk profile,” Dr. Wilson said at a symposium sponsored by Apollo Endosurgery Inc., about options for weight loss treatments in patients with lower BMIs. “Some of the endoscopic procedures fit in this area. Our goal is to try to plicate the stomach with an endoluminal approach.” Patients may be challenged to lose weight through medical therapy—dietary restrictions and lifestyle modifications—and they may want to avoid more invasive approaches, such as a gastric bypass, laparoscopic adjustable gastric banding or sleeve gastrectomy, Dr. Wilson said. The durability, however, of the endoluminal procedure remains to be seen. “We can’t say that it will last for years and years,” Dr. Wilson said. “If you can do something endoluminally that will last one to two years, be revisable, keep options open for other therapies, and you select your patients appropriately, it is probably something worth considering.” To date, the PROMISE trial investigators have not observed any major morbidity or mortality and no major bleeding events that required a transfusion, and there has been no need for operations after the procedure, Dr. Wilson said. Two patients were excluded during the trial because of pregnancy. “We are seeing about a 43% excess weight loss,” he said. Although Dr. Wilson did not say the procedure is contraindicated in patients who have a BMI of 40 kg/ m2 or greater, he said the outcomes would likely be “disappointing” in patients with higher BMIs when comparing outcomes in weight loss with established

The OverStitch Endoscopic Suture System for gastric sleeve plication was studied in the PROMISE trial.

The EndoBarrier is a duodenal–jejunal bypass liner designed to imitate the duodenal–jejunal exclusion of the Roux-en-Y gastric bypass.

surgical options. “We should keep it for lower BMI ranges,” he said. The American Society for Gastrointestinal Endoscopy and the American Society for Metabolic and Bariatric Surgery created a task force to examine endoscopic treatments for obesity and released a white paper on the topic, entitled “A Pathway to Endoscopic Bariatric Therapies,” in 2011.

Endoluminal bariatric options are attractive for patients because they can be performed in the outpatient setting. One option is an intragastric balloon, such as the ReShape Duo, a dual intragastric balloon intervention, or the Orbera intragastric balloon (Apollo Endosurgery Inc.). Both systems are currently under review with the FDA. Although the balloon avoids possible complications linked to established surgical techniques, it has not been demonstrated to have long-term benefit after removal of the device, Dr. de la Cruz-Munoz said. “Because it is an endoscopic procedure, it’s lower risk,” Dr. de la Cruz-Munoz said. “That makes it an advantage, but it has to be removed after several months, so there is a concern about what is the longterm efficacy.” The EndoBarrier (GI Dynamics), a duodenal–jejunal bypass liner (DJBL), is approved for one-year treatments, is designed to imitate the duodenal–jejunal exclusion of the RYGB, and has been used in many countries such as the United Kingdom, France, Italy, Denmark and Chile. One of the key benefits associated with the procedure is a significant decline in HbA1c (glycosylated hemoglobin) measures and glycemic control, according to Jan Willem Greve, MD, of the Department of Surgery at the University Hospital Maastricht, in the Netherlands. “It’s placed and removed endoscopically quite easily,” Dr. Greve said, but added that perforation of the esophagus has occurred with the device in two cases. “The most significant complication reported has been bleeding, in 1.6% of cases, followed by migration of the device, in 1.3% of cases.” The device can be re-implanted, so that if patients gain weight after explantation, they can be offered the therapy again and return to their initial post-treatment weight, Dr. Greve said. In terms of the pool of patients, Dr. Greve described good candidates for the DJBL device as those with a BMI of 30 to 40 kg/m2 who also have diabetes.

‘If you can do something endoluminally that will last one to two years, be revisable, keep options open for other therapies, and you select your patients appropriately, it is probably something worth considering.’ —Erik Wilson, MD

The National Institutes of Health had originally set out guidelines for bariatric surgery that excluded patients with BMIs below 35 kg/m2, with the exception of patients with severe diabetes or hemoglobin A1c higher than 9%. Patients with lower BMIs are suitable candidates for endoluminal bariatric therapies, with more established surgical options like the Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy being reserved for patients with low BMIs who present with a comorbidity, according to Nestor de la Cruz-Munoz, MD, associate professor of clinical surgery at the University of Miami Miller School of Medicine, in Florida. “If [patients] have low BMIs, but they are sicker patients, then it is worth it to perform stapling procedures in them because it produces better results,” Dr. de la Cruz-Munoz said. “They [RYGB and sleeve gastrectomy] are more effective in the resolution of comorbidities and weight loss” than gastric banding or endoluminal approaches.

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44 44

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

ENDOSCOPY SUITE

Study Finds No Benefit of IV Antibiotics for ERCP PHILADELPHIA—Some studies have suggested prophylactic IV antibiotics may reduce the risk for pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP), but this approach has never been widely adopted. That’s likely a good thing, according to new research indicating the practice has no advantages. “A study published in 2001 showed that the risk of post-ERCP pancreatitis can be reduced using antibiotic prophylaxis, with the theory that the antibiotics can kill bacteria that secrete cytokines that increase the risk of pancreatitis. But since this study was published, no further studies were published to confirm the results,” said Mohamed Abdelfatah, MD, an internal medicine resident at Northeast Ohio University, in Akron ((J Gastrointest Surgg 2001;5:339-345). “We tried to investigate if antibiotic prophylaxis has a role.” In a retrospective, case–control study, Dr. Abdelfatah and colleagues reviewed data on all 281 patients who underwent ERCP at their center between 2007 and 2014, looking for the incidence of postERCP pancreatitis (PEP) in 88 patients on IV antibiotics compared with 192 who were not given antibiotics. A diagnosis of PEP was based on new-onset abdominal

pain requiring at least two nights’ hospitalization, and an increase in serum lipase and/or amylase of at least three times the upper limit of normal level within 24 hours of the procedure. PEP occurred in 15 patients overall: seven of the 88 (8%) in the antibiotic group and eight of the 192 (4%) in the control group, a statistically insignificant difference. Factors that did appear to be significantly associated with PEP included a history of PEP, female sex and difficult or failed ERCP. The study was presented at the 2014 annual meeting of the American College of Gastroenterology (poster P737). “I believe that gastroenterologists sometimes use IV antibiotics if there is evidence of infection, but most do not do it as a prophylaxis. This study answered the question for me. I believe that antibiotics are important to prevent cholangitis in high-risk patients. However, I don’t think there is enough evidence to support use of antibiotics against PEP,” Dr. Abdelfatah said. European guidelines note that ceftazidime reduced the incidence of PEP in one study, but the recommendations acknowledge that the study had methodological flaws, Dr. Abdelfatah added, referring to a paragraph published in the

guidelines with a line calling for more data (Endoscopyy 2010;42:503-515). Girish Mishra, MD, MSc, professor and executive director of the Digestive Health Service Line at Wake Forest School of Medicine, in Winston-Salem, N.C., said the new study may not have been designed to pick up on all cases of PEP, and the study population was fairly small. “I don’t know that they controlled for confounders, and if there were patients with a one-night hospitalization for PEP, they might have underestimated the results. Maybe there would have been a difference,” Dr. Mishra said. “Also, the total number of 281 suggests they’re doing about 40 ERCPs a year, a small cohort. Perhaps there might be some benefit to antibiotic prophylaxis, but nobody administers antibiotics unless

the patient has cholangitis. We don’t know how many patients in this study had cholangitis versus biliary obstruction from cancer, so it’s hard to know. Maybe in a subgroup analysis there might have been a benefit from IV antibiotics.” The concern about post-ERCP complications has prompted a great deal of investigation into ways to mitigate those risks, Dr. Abdelfatah said. “For the last 10 years, we’ve had lots of studies trying to identify prophylactic tools that would prevent PEP—maybe 30 drugs,” he said. In that category is the use of rectally administered nonsteroidal anti-inflammatory drugs. “That has become the major landmark intervention that’s been increasingly accepted over the last five years,” Dr. Mishra said. —Monica J. Smith

Defining Acceptable Failure in ERCP PHILADELPHIA— —When endoscopic retrograde cholangiopancreatography (ERCP) fails in a community practice, those patients are referred to tertiary care centers. But what happens when ERCP fails in these patients? That topic ought to interest gastroenterologists, who are likely going to find their performance in this area evaluated, according to one expert. New data should help. Sami Samiullah, MD, a gastroenterology fellow at Rutgers University, in Newark, N.J., and his colleagues conducted a retrospective chart review of ERCPs performed between 2007 and 2012 at their facility to identify the risk factors and outcomes of failed ERCP. In this study, ERCP was defined as a failure if the endoscopist was unable to cannulate the intended duct or if the intended therapy could not be carried out. During that five-year period, endoscopists at Rutgers performed 1,037 ERCPs. Dr. Sushil Ahlawat, associate professor of medicine in the Division of Gastroenterology & Hepatology, who helped conduct the study, performed most of the procedures. The mean age of the patients was 59 years, and a little more than half were men. Forty-eight cases (5%) were considered unsuccessful. Of these, nine patients (19%) had a successful repeat ERCP with no mortality. Of the remaining 39, 21 (54%) had percutaneous drainage with percutaneous transheptic cholangiography (PTC) and 10 (26%) were managed conservatively. Four patients underwent surgery and four were lost to follow-up.

Of the 25 patients who had a secondary intervention (PTC or surgery), six (24%) developed cholangitis/sepsis, and two (8%) had a bile leak. Six patients required admission to the ICU, and five of these patients died.

‘I think this is a metric we’re going to be held accountable for going forward. Whether a community center or a tertiary referral unit, what is your failure rate?’ —Girish Mishra, MD, MSc The main reason for failed ERCP was inability to cannulate the intended duct, according to the researchers; this problem occurred in 27 patients (56.2%). The second reason was surgically altered gastrointestinal anatomy, which resulted in failed ERCP in seven patients (14.6%). Other reasons included deformity of ampulla, inability to traverse a stricture, visual occlusion of ampulla due to edema and periampullary diverticulum, the Rutgers group reported. “I do not think there is much surprise here,” Dr. Samiullah told Gastroenterology & Endoscopy News. “But I do think the interesting thing we found is that patients who have percutaneous drainage with PTC after failed ERCP often have complications, and then their

outcomes are not so good. Would endoscopic ultrasound [EUS]-guided ERCP be better? It would be interesting to do a head-to-head, randomized comparison of PTC and EUS-guided ERCP after a failed ERCP. We need more data, and a multicenter study would be more appropriate.” Dr. Samiullah presented the findings at the 2014 annual meeting of the American College of Gastroenterology (poster P1511). Girish Mishra, MD, MSc, professor and executive director of the Digestive Health Service Line at Wake Forest School of Medicine, in Winston-Salem, N.C., found the study interesting because it focused on failed ERCP in a tertiary care center instead of a community practice, and the center’s failure rate was laudable. “Their actual proportion of failed ERCPs—less than 5%—is quite low, and I think this is a metric we’re going to be held accountable for going forward. Whether a community center or a tertiary referral unit, what is your failure rate?” Dr. Mishra said. At about 200 ERCPs per year, Rutgers would be considered a fairly low-volume tertiary care center, he added. “They were also able to glean what variables contribute to a failed ERCP. But again, their failure-to-cannulate rate was very low and certainly respectable,” Dr. Mishra said. “The fact that they had some lack of success in postsurgical anatomy is expected, and that number would be present wherever ERCPs are performed.” —Monica J. Smith

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

ENDOSCOPY SUITE

44 55

Biopsy Technique continued from page 40

brush biopsy is not technically demanding. The increased yield from WATS3D is attributed to the ability of brush biopsy to obtain a larger tissue specimen and to the computer-assisted analysis. Screening for BE in patients with reflux disease and additional risk factors is considered reasonable in guidelines published online by the American Gastroenterological Association (AGA) earlier this year. The new data suggest that WATS3D can substantially increase the diagnostic yield when used adjunctively with forceps biopsy. Joel H. Rubenstein, MD, assistant professor in the Division of Gastroenterology at the University of Michigan Medical School, in Ann Arbor, identified sampling errors for dysplasia as a critical

concern in the effectiveness of surveillance endoscopy for BE. He indicated that data from this study support the WATS3D technique for improving detection rates over forceps biopsy alone, but he had some reservations, including those involving the study design. “We need to carefully consider the potential biases in the study design,” Dr. Rubenstein said. “For instance, it is not clear if the study pathologist was blinded

to the results of the WATS3D system. In addition, all patients underwent brush sampling followed by forceps biopsy. It is not clear how much effect this aggressive brushing may have on diminishing the amount of dysplastic epithelium available for forceps sampling. A study that randomized the order of brush and forceps would be more convincing.” Dr. Rubenstein also noted that this proprietary system would raise costs,

suggesting that some type of analysis would be appropriate to determine whether that extra expense is justified. Such considerations require resolution “before rushing to use this technique in clinical practice,” he said. —Ted Bosworth Dr. Gross reported financial relationships with Cook Medical, CSA, EndoCdx, Given Imaging and Olympus America. Dr. Rubenstein reported no relevant financial conflicts of interest.

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NYSGE continued from page 40

past-presidents still living, 23, including founding members Richard S. McCray, MD, Jerome D. Waye, MD, and Sidney J. Winawer, MD, attended the gala. Despite the recent loss of the society’s matriarch, Florence Lefcourt, who served as the organization’s first executive director—a position she held until her death in October 2013—the gala was nonetheless infused with celebration and a general sense of pride at the society’s numerous accomplishments. Attracting an international audience to its education program, the annual New York Course included a live endoscopy presentation and hands-on learning opportunities. In July, the society continued a long-standing tradition by hosting the annual GI Fellows Summer Course. In addition, the NYSGE recently sponsored its second Best of Digestive Disease Week Spring Course, which featured a 35% increase in attendance and doubling of exhibitor support over the last year. “It is a sense of kinship that enables NYSGE to promote endoscopy education at multiple levels, foster collaborative research, and produce clinical and technologic breakthroughs for the advancement of the profession,” Dr. Bosworth said in an interview. “Polypectomy, sphincterotomy, colorectal cancer screening, ablation therapy for Barrett’s esophagus and the use of simulators in teaching endoscopy are some of the landmark achievements championed by NYSGE members.” In celebration of the society’s achievements and unique collegiality, guests clinked glasses as the May sun sank below the line of New York City’s East River. Then it was back to work the next day. —Brigid Duffy

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Adherence Poor for Topical Mesalamine in Ulcerative Colitis Failure to use as directed raises risk for disease relapse

ew research suggests that as many as 70% of patients with ulcerative colitis who are taking topical mesalamine do not use the therapy as prescribed. Experts say the findings point to a need for better education regarding the benefits of using the drug, and the potential harms of failing to take it as directed. “Patients often stop chronic medications because they feel well,” said Alan Moss, MD, associate professor of medicine at Harvard Medical School, and a gastroenterologist at Beth Israel Deaconess Medical Center, both in Boston, who led the study. “In the case of topical mesalamine users, they may not realize

that once they stop, they are at a two- to with ulcerative colitis who had been pre- Dr. Moss’s team also examined pharmacy threefold higher risk of experiencing dis- scribed mesalamine as an enema or a refills during a one-year period after the ease relapse. As a way of improvinterview as a surrogate meaing the likelihood that patients sure of adherence. will continue using topical mesa- ‘For induction therapy for acute symptoms, Patients in the study were lamine, clinicians need to outline a mean of 44 years of age, and it is possible to educate patients regarding the benefits of regular use.” most were male. The average Dr. Moss’s group presented the high value and superior efficacy of duration of disease before the their findings at the 2014 annual study was eight years, and rectal therapy over oral therapy, and thereby meeting of the American College all participants met Mayo of Gastroenterology (abstract improve their adherence.’ Clinic criteria for endoscopic P457). —William J. Sandborn, MD and clinical remission at the Dr. Moss said he and his colbeginning of the study. leagues assumed at the start of Dr. Moss’s team found their study that adherence would be low suppository, and interviewed them about that only 29% of subjects followed their because of the inconvenience of rectal their adherence and factors that affected see Topical, page 51 administration. They enrolled 70 patients their adherence to prescribed regimens.

New Marker for Colon Cancer Identified CHICAGO—EpHA2, a receptor tyrosine kinase (RTK), is an independent marker for poor prognosis in patients with early-stage colorectal cancer (CRC), researchers have found. If validated in further studies, the marker could be used to identify patients who are appropriate for more aggressive treatment, especially in stage II disease where the role of adjuvant chemotherapy treatment remains controversial. Targeting EpHA2 with drugs could provide a new therapeutic avenue for these patients, who have a poor prognosis. Results of the study were presented at the 2014 annual meeting of the American Society of Clinical Oncology (abstract 3581). “This marker has been shown to be highly expressed in other cancers—breast, ovarian, prostate, glioblastoma and others—but this is the first comprehensive work that has been done in colorectal cancer in the context of a specific poor prognostic genotype [KRAS S and BRAF F mutations],” said Sonali Dasgupta, MD, a clinical research fellow at Queen’s University Belfast School of Medicine, in the United Kingdom, who led the study. EpHA2, an erythropoietin-producing hepatocellular RTK, also has been shown to be overexpressed in cancers of the urinary tract, bladder and skin (Expert Opin Ther Targetss 2011;15:31-51). High expression of the molecule in cancer cells is correlated with a poor prognosis, driven by recurrence due to enhanced metastasis. In the new study, Dr. Dasgupta and her colleagues performed a series of experiments in colon cancer cell lines and tissue samples from 509 patients with CRC. They found that EpHA2 is overexpressed in both CRC cell lines and human tissues. High expression of EpHA2 mediated cell migration and invasion in cell lines and was correlated with vascular invasion in clinical samples. In a univariate analysis, high expression of EpHA2 predicted worse overall survival in patients with colon cancer (Table 1). In a multivariate analysis that took into account age, sex, tumor size, ethnic group and vascular invasion, EpHA2 was a strong independent prognostic marker in stage II CRC (Table 2). The researchers also demonstrated that soluble

Table 1. Univariate Analysis of EpHA2 Expression and Overall Survival in Colorectal Cancera Stage

EpHA2

Hazard Ratio

Stage II

Low

High

1.9703

0.00613

Low

0.00376

High

1.597

Stage II/III

P Value

Using Cox proportional hazard ratio.

Table 2. Multivariate Analysis of EpHA2 Expression and Overall Survival in Colorectal Cancera Stage

EpHA2

Hazard Ratio

Stage II

Low

High

1.681

0.0376

Low

0.00755

High

1.549

Stage II/III

P Value

Using Cox proportional hazard ratio. A backward selection method using Akaike’s information criterion was used to determine a refined multivariate model.

EFNA1-Fc ligand or EpHA2 RNA interference can be used to inhibit expression of EpHA2—and possibly control this type of colon cancer. EpHA2 is a “very attractive target” for novel anticancer therapies, Dr. Dasgupta said. “Our study is the first to show that EpHA2 is an independent predictor of poor clinical outcome and a potential target in earlystage CRC,” Dr. Dasgupta said. “If you have a patient who has this marker highly expressed, they are likely to do much worse in terms of survival compared to persons who have low expression. “These patients are potential targets for either intensive surveillance or more treatment,” Dr. Dasgupta added. “This can come in many forms: intense chemotherapy, early chemotherapy, chemotherapy in combination with EpHA2 treatment or even EpHA2-targeted treatment in isolation. However, prospective randomized clinical trials are needed to prove or disprove the individual merit of each option. Right now, we have a soluble ligand to target EpHA2, but we are also looking at monoclonal antibodies that could target EpHA2.” Nilo Azad, MD, a medical oncologist at the Johns Hopkins Kimmel Cancer Center, in Baltimore, said, “The data look interesting, but it is a small group of patients and it will be hard to know where this will end up going.” Dr. Azad pointed out that there have been many markers that have been identified as being prognostic in colon cancer. Large prognostic panels for stage II/ III colon cancer, such as Oncotype DX and ColoPrint, are available commercially. However, these tests are not widely used because it is unclear what to do with patients who are identified as having a poor prognosis. “If you get a result that a patient is at high risk for recurrence, you don’t know what to do with that,” Dr. Azad said. Does that mean if you give that patient chemotherapy that they will do better or do they just have bad biology, so you are not going to be able to change [the prognosis]?” —Kate O’Rourke Drs. Dasgupta and Azad reported no relevant financial conflicts of interest.

INCREASE YOUR ADENOMA DETECTION RATE. Studies show ENDOCUFF™ Endoscopic Overtube assisted colonoscopy significantly increases ADR and assists in complex polyp removal.

Your Best Practice is Our Promise. ENDOSCOPY PROCEDURE • ENDOSCOPY REPROCESSING

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Current Issues in and Approaches to Antimicrobial Resistance Ari Frenkel, MD Infectious Disease Fellow East Carolina University Greenville, North Carolina

Paul Cook, MD Chief, Division of Infectious Diseases East Carolina University Greenville, North Carolina

258 million courses of antibiotics in the outpatient setting; this translates into 833 prescriptions per 1,000 persons, and these numbers do not include the use of these drugs in hospitalized patients.2 It is estimated that up to 50% of all antibiotics prescribed in the United

t is now well known that the use and overuse of antibiotics has resulted in increasing resistance by causing breeding of microorganisms that are no longer susceptible to available antimicrobial agents.1 In 2010, health care providers in the United States prescribed

States in acute care hospitals are improperly prescribed or needless.3 Annually, more than 2 million individuals are infected with antibiotic-resistant organisms.4 These patients are at increased risk for mortality and morbidity as well as extended hospitalization, and increased health care costs.5 The Centers for Disease Control and Prevention (CDC) estimates that in the United States alone, more than 23,000 people die as a result of antibiotic-resistant infections each year.4

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

Expiration Date: February 10, 2015

Chair

Statement of Need

Intended Audience

William D. Chey, MD

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

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

Goal 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.

Learning Objectives 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

The cost of antimicrobial resistance has been estimated to exceed $20 billion.6,7 As a result, the CDC now classifies antimicrobial resistance as one of the most serious health threats worldwide.4 With advancements in areas such as chemotherapy for cancer, transplant medicine, dialysis, and immunomodulating treatments for autoimmune diseases, the need for effective antimicrobial agents has become even more crucial. Health care providers often are left with no choice but to treat with drugs that are frequently more expensive, more toxic, and less effective.4 Therefore, it is essential to have mechanisms in place to reduce the unnecessary use of antibiotics as well as the duration of use in patients who require treatment. At present, the CDC places resistant bacterial organisms into 3 categories: urgent, serious, and concerning (Table 1). Each category assigns a “hazard level” of importance to the threat. An urgent threat refers to a high consequence of antibiotic resistance, which poses a significant threat to patients and has the potential to become a public health concern. A serious threat can also become an urgent threat, but frequently there are antimicrobial therapeutic options available. A concerning threat refers to a low risk for resistance, but it is recommended that bacteria in this category be monitored closely.4

Resistance in Gram-Negative Bacteria Resistance of bacteria to antibiotics occurs in a variety of ways. A common mechanism of resistance is production of β-lactamases, which are enzymes that hydrolyze the β-lactam ring of penicillins, cephalosporins, and carbapenems, thereby rendering the drugs inactive.8 Although antibiotic resistance can occur in both gram-positive and gramnegative bacteria (GNB), the resistance mechanisms are much more complicated in gram-negative organisms. GNB, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii, tend to be highly resistant to antimicrobial agents. In fact, these bacteria can become resistant to nearly all antibiotics. The most concerning gram-negative infections are health care–associated, as these tend to be the most resistant; this is of particular concern in the ICU, where some of the highest rates of multidrug-resistant (MDR) GNB are found.8 Indeed, patients in the ICU often develop colonization with MDR organisms that then make their way to the long-term care facilities and even into the community. This phenomenon can occur when ICU patients circulate through acute and chronic health care facilities. Multidrug resistance is defined as resistance by

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Table 1. Summary of CDC Antimicrobial Resistance Threat Levels Urgent Threats

Serious Threats

Clostridium difficile

Acinetobacter

ESBLs

Non-Typhoidal Salmonella

MRSA

VRSA

CRE

Campylobacter

VRE

Salmonella typhi

Streptococcus pneumoniae

Group A streptococcus

Gonorrhoeae

Candida

Concerning Threats

Pseudomonas aeruginosa

Shigella

Tuberculosis

Group B streptococcus

CDC, Centers for Disease Control and Prevention; CRE, carbapenem-resistant Enterobacteriaceae; ESBLs, extended-spectrum β-lactamases; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistantent erococci; VRSA, vancomycin-resistant Staphylococcus aureus; adapted from reference 4.

the organism to more than 1 agent from 3 or more antimicrobial categories. When an organism is resistant to more than 1 agent in all but 2 categories, it is referred to as extreme drug resistance. Finally, when an organism is resistant to all antibiotics, it is referred to as being pan-drug resistant.8,9 The clinically important β-lactamases in gram-negative organisms include AmpC, extended-spectrum β-lactamases (ESBL), and carbapenemases (Table 2).10 Enterobacterr and Citrobacterr species commonly possess AmpC-type β-lactamases. These organisms are typically resistant to first-, second-, and third-generation cephalosporins. The AmpC gene is chromosomal in Enterobacterr and Citrobacterr and is inducible by β-lactams.

The AmpC gene is poorly expressed or not expressed in Escherichia colii and Klebsiella species, respectively, but the gene can be acquired from a plasmid of another organism, thus giving it the same phenotype as Enterobacter. The carbapenems are the most reliable drugs for these organisms, although cefepime, piperacillin/tazobactam, aminoglycosides, trimethoprim/sulfamethoxazole, and tigecycline may also be effective.10 ESBL-producing bacteria have the ability to hydrolyze penicillins, cephalosporins, and monobactams. Fortunately, these enzymes have no effect on carbapenems, which are the drugs of choice for such infections. These ESBLproducing organisms often carry genes

Table 3. Recommended Treatment of MDR Organisms Type of Resistance

Common Organisms

Recommended Treatment

AmpC β-lactamase

Enterobacter Any carbapenem or cloacae and other cefepime (Maxipime IV, Enterobacteriaceae Hospira)

TMP-SMX, quinolone, tigecycline also may be effective

ESBL

Klebsiella pneumoniae and other Enterobacteriaceae

Any carbapenem

TMP-SMX, quinolone, tigecycline also may be effective

Carbapenemase

K. pneumoniae and other Enterobacteriaceae

Meropenem or tigecycline (Tygacil, Pfizer) + polymyxin E (colistin)

Rifampin plus colistin also may be effective

Alteration of penicillin-

MRSA

Vancomycin

Daptomycin, linezolid, TMP-SMX,

binding protein

Comments

ceftaroline are alternatives

Mutation of DNA gyrase and topoisomerase

Enterococcus faecium (VRE)

Linezolid (Zyvox, Pfizer) or daptomycin (Cubicin, Cubist)

Tigecycline may be an alternative agent

Decreased permeability plus increased refflux plus carbapenemases

P. aeruginosa, Acinetobacter baumannii

Colistin

Tigecycline may be effective against certain strains of A. baumannii

Aminoglycosidemodifying enzymes

Meropenem (Merrem IV, AstraZeneca) or imipenem (Primaxin IV, Merck) or piperacillin/ tazobactam (Zosyn, Pfizer) or cefepime

ESBL, extended-spectrum β-lactamase; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; TMP-SMX, trimethoprim/sulfamethoxazole; VRE, vancomycin-resistant enterococci; adapted from references 17 and 18.

Table 2. Summary of Clinically Relevant β-Lactamases in GramNegative Bacteria Enterobacteriaceae

Pseudomonas aeruginosa

Acinetobacter

AmpC β-lactamases

ESBL

Carbapenemases

DNA gyrase/topoisomerase mutations

Aminoglycoside-modifying enzymes

Multidrug efflux pumps

Porin mutations

Altered penicillin-binding protein

Staphylococcus aureus

Penicillinase ESBL,, extended-spectrum p β-lactamase;; adapted p from references 9-12.

on plasmids that make them resistant to other classes of antibiotics such as aminoglycosides and fluoroquinolones.10 Carbapenemase-producing organisms are increasingly being recognized in Enterobacteriaceae, most commonly K. pneumoniae, and are designated carbapenemase-resistant Enterobacteriaceae (CRE).11 The carbapenemases are a diverse group off β-lactamases; the common types are designated serine carbapenemases (classes A, C, and D) and

metallo-β-lactamases (class B), so-called because of the critical importance of zinc ion to β-lactamase activity. The latter class includes the New Delhi metallo-βlactamase (NDM-1). Because carbapenemase genes are located on plasmids, there is the potential for rapid transfer of the genetic material to other organisms, including other species and P. aeruginosa. Also, cotransfer of other resistance genes from the same plasmid is common, see Resistance, page 50

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Resistance continued from page 49

making these organisms resistant to all β-lactams, aminoglycosides, fluoroquinolones, and tetracyclines.11 Ineffective binding of β-lactams to penicillin-binding protein (PBP) 2a (a mutated form of PBP2) is responsible for the resistance of methicillin-resistant Staphylococcus aureuss (MRSA). Ceftaroline, a fifth-generation cephalosporin, is the only commercially available β-lactam with activity against MRSA.12 DNA

gyrase and topoisomerase mutations lead to decreased susceptibility to fluoroquinolones. Reduced susceptibility to fluoroquinolones also may be due to removal of the drug from the cell via efflux pumps.13,14 Efflux pumps are present in many bacteria and are responsible for removal of a variety of substances, including certain antimicrobial agents from the cell. Upregulation of efflux pumps is a common mechanism of resistance of both P. aeruginosaa and A. baumanniii to carbapenems, particularly meropenem and doripenem, and to fluoroquinolones. Other forms of

resistance seen with P. aeruginosaa include aminoglycoside-modifying enzymes and metallo-β-lactamases.13-15 Finally, porins are outer membrane protein channels that allow certain substances, including some antibiotics, to penetrate the bacterial cell membrane and wall. Downregulation of the outer membrane proteins results in resistance of the organism to the drug (eg, imipenem-resistant P. aeruginosa). It is not uncommon for phenotypic resistance to certain antibiotics to be due to a variety of mechanisms, including carbapenemase activity in

The #1 best-read gastroenterology publication in the USA. Anytime. Anywhere. gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

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HEPATOLOGY

Fecal Transplants for IBD Show Mixed Results in Trials

F O C U S

I N

Probiotics Could Prevent Hepatic Encephalopathy

BY DAVID WILD

BY DAVID WILD Probiotics may be associated with a reduced risk for hepatic encephalopathy, researchers in India have found. But at least one expert questioned the strength of the findings.

see Probiotics, page 11

Studies Challenge Conventional Wisdom In Biliary Stent Cost BY TED BOSWORTH Chicago—Two randomized trials of metal versus plastic stents for drainage of biliary duct obstruction have reached the same conclusion: Self-expanding metal stents, although they carry higher acquisition costs, are no more expensive than plastic stents because they see Stents, page 13

Chicago—Fecal transplant has reached a critical milestone: testing in the first randomized controlled trial of the therapy to treat inflammatory bowel disease. Although this step might be good for science, the news was not quite so encouraging for patients. The treatment did not appear to be better than placebo transplant at alleviating symptoms of ulcerative colitis (UC), according to the researchers. “Although we did not find a statistically significant effect of FMT [fecal microbiota transplantation] in active UC, there is the possibility that FMT may be effective when administered longer than six weeks,” the researchers said, noting that there were no major adverse events. The study, led by Paul Moayyedi, MBChB, PhD, MPH, acting director of the Farncombe Family Digestive Health Research Institute and director

of the Division of Gastroenterology at McMaster University, in Hamilton, Ontario, Canada, was one of several trials of FMT whose results were presented at Digestive Disease Week (DDW) 2014. In the trial, the researchers randomized 27 patients with mild to moderate UC to receive an FMT enema and 26 patients to receive a placebo

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see Fecal, page 19

I N S I D E EXPERTS’ PICKS

Inside Ins ide the Electronic Health Record

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It’ss a common It c complaint: Many physicians who find themselves plugging data into elecctr ctronic health records (EHRs) feel like transcriptionists, not doctors. After all, th heyy say, “I didn’t go to medical school to become a medical journalist” (not, we hasten w h to add, that anything is wrong with that profession). But the world has changed, c and EHRs are here to stay. We asked four individuals who use or aree fam miliar with the software systems in gastroenterology practices how they’ve adapteed d to the new reality—and how those in the specialty who are just making the leap can n lland successfully. see Expert Roundtable, page 22

Experts share their favorite abstracts from DDW 2014 ...................................................................«>}iÊÎÓÊ

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PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

Extending Conventional Endoscopy in Barrett’s Esophagus Using Narrow Band Imaging See page 26

EDUCATIONAL REVIEW Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection?

Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection? MOHAMMAD TITI, MD Division of Gastroenterology and Hepatology Veterans Affairs Medical Center University of Kansas School of Medicine Kansas City, Kansas

NEIL GUPTA, MD

PRATEEK SHARMA, MD

Division of Gastroenterology and Hepatology Loyola University Medical Center Maywood, Illinois

Division of Gastroenterology and Hepatology Veterans Affairs Medical Center University of Kansas School of Medicine Kansas City, Kansas

ÕÌi vÀiiÊ ÊL ÃÌÊÌ Ê Ü " *Ê` iÌÊv ÀÊ - ....page 5

Dr. Sharma has received grant support from CDX Labs, Cook Medical, NinePoint Medical, and Olympus Inc. Drs. Titi and Gupta report no relevant financial conflicts of interest.

olorectal

Bundled payments on the way—how to cope .........«>}iÊÓn

cancer

(CRC) is the second leading cause of

cancer-related in

the

mortality

Western

world.1

Screening colonoscopy and polypectomy have become widely accepted as the mostt effective available methods for for

the presence of decreased expression of porins.15,16

Treatment of MDR Organisms Table 3 illustrates major mechanisms of resistance and the common resistance patterns seen with the more common MDR organisms. Treatment of MDR organisms begins with broad-spectrum antibiotics for the suspected organism.17 Empiric antibiotic therapy should be based on institution-specific antibiograms. Once an organism is identified and susceptibilities are available, antibiotics can be streamlined.17 In certain situations, the only effective antibiotics are highly toxic drugs such as colistin.18 In patients with MDR organisms or with CRE, colistin is frequently used in combination with a carbapenem such as meropenem. The effectiveness of treatment in this scenario depends on the site of infection, control of the source of infection (eg, drainage of an abscess), and type of resistant organism. Host factors, including immunosuppression, diabetes, renal function, and age are major determinants of patient outcomes.17,18 There are investigational agents with activity against β-lactamases, including carbapenemases. One of the more promising drugs is avibactam, which has been used in combination with ceftazidime (Novexel, Forest). Avibactam has good activity against the class A, C, and D carbapenemases, but no activity against the class B metallo-β-lactamases (eg, NDM1).19 Therefore, it is important for microbiology laboratories to be able to identify an organism as one with carbapenemase activity, and also to determine which class of carbapenemase is present.

early detection and prevention of

See page 20

CRC and have shown a reduction iin mortality t lit within the screened population.2 However, colonoscopy remains imperfect and several studies have raised concerns about the miss rate of adenomatous polyps during screening. The overall miss rate is approximately 20%, and ranges from 6% for large (10 mm) adenomas to 26% for diminutive (<5 mm) lesions.3 Missing these adenomas is one of the proposed mechanisms in the development of interval colon cancers that occur within the screened population.4 Improving detection of adenomas during colonoscopy therefore may be the key to more effective screening.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • AU G U ST 2 0 1 4

Rise in colectomy for constipation raises alarm ...... page 37

Preventing Resistance Preventing the development and spread of resistant organisms is a difficult and multidisciplinary task that involves both infection control and antimicrobial stewardship. Effective infection control programs limit the spread of resistant organisms through monitoring and surveillance. Antimicrobial stewardship programs (ASPs) improve the way in which antibiotics are used by shortening the duration of antibiotic treatment, limiting the use of broad-spectrum agents, and monitoring the appropriateness of antibiotic use. The CDC has implemented the Healthcare-Associated Infections Projects. This program involves a network of state health departments and their academic medical centers. The program gathers information on antibiotic resistance and tracks important information such as the number and frequency of infections, and those people at risk for the infection. Current programs include Infection Tracking, Candida Bloodstream Infections, and see Resistance, page 52

CAREER OPPORTUNITIES

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Topical continued from page 46

prescribed regimen during the one-year period. Adherence rates did not differ between periods of patient-reported disease activity or inactivity. The researchers also found that 85% of nonadherent patients said they were intentionally not using their medications as prescribed. Among users of mesalamine enemas, the most commonly cited reasons for intentional nonadherence included finding the mode of administration inconvenient (65%), having a busy lifestyle (40%) and wanting to avoid side effects (15%). Among suppository users, a busy lifestyle (40%), difficulties applying the drug (30%) and side effects (15%) were the most frequently cited reasons for nonadherence. The findings did not surprise William J. Sandborn, MD, chief of gastroenterology at the University of California, San Diego. “I think we in the clinician and research community suspected compliance with rectal therapy would be poor among patients taking it as maintenance therapy,” said Dr. Sandborn,

who was not involved in the study. “I think that for induction therapy for acute symptoms, it is possible to educate patients regarding the high value and superior efficacy of rectal therapy over oral therapy, and thereby improve their adherence,” he said. “Part of that education should emphasize that after the induction period is completed within four to eight weeks, they can stop rectal therapy and continue on oral therapy only.” The effectiveness of that approach would require study, but Dr. Moss said adherence to oral mesalamine—as both induction and maintenance therapy— also is low. “Nonadherence to oral mesalamine is as high as 60% in some studies,” he said. “So, the low adherence with topical mesalamine is not unique to this mode of administration.” The study was funded by Actavis, which markets mesalamine as Delzicol.

As a gastroenterologist, you have options.

As a healthcare leader, we have opportunities. For a wide range of options, talk with a team that can offe ff r a wide range of opportunities. We W are one of the nation’s leading operators of general, acute-care hospitals. Our affiliates operate more than 200 hospitals in 29 stat a es and these locat a ions could provide ideal env n ironments fo f r your profe f ssional success. Comp m ensation packag ages may a include: • Flexible and generous start-up incentives • Medical education debt assistance • Va V rious practice typ y es

For more r info f rmat a ion vi v sit i : www. w ch c smedcare r ers r .com Email: docj c obs@chs.net or Call: 800-367-6813

—David Wild Dr. Sandborn has served as a consultant to Actavis and Salix Pharmaceuticals.

Finger Lakes, NY

PRESBYTERIAN

Hospital-Employed Gastroenterologist

PRESBYTERIAN HEALTHCARE SERVICES Albuquerque, NM

Cortland Regional Medical Center is seeking a dynamic Gastroenterologist to join their rapidly growing medical staff led by our new CEO and VPMA. Competitive compensation package with productivity incentive, signing bonus, relocation allowance, full benefits. Cortland is an affordable, family-friendly community with access to nine universities, a strong local school system with advanced level programs and strong special education programs. Ithaca, Syracuse, The Finger Lakes, Ski Resorts are within a 30 minute radius. Two physician couples welcomed. Contact: Corinne Owens, Owensmds@hotmail.com, or call (630) 707-7080.

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Presbyterian Healthcare Services is seeking Board Certiﬁed Gastroenterology trained physicians to join our established practice of 11 physicians, 2 Gastroenterology Hospitalists and 7 advanced practitioners. Our medical group employs more than 600 primary care and specialty providers and is the fastest growing employed physician group in New Mexico. Presbyterian Healthcare Services is a locally owned, not-for-proﬁt organization based in Albuquerque. Our integrated healthcare system includes eight hospitals in seven New Mexico cities, a medical group, multispecialty clinics and a health plan (over 400,000 members). We have been proudly providing care to New Mexicans for 105 years. In addition to a guaranteed base salary we also offer a sign on bonus, incentive bonus, malpractice, relocation, house hunting trip, health, dental, vision, 403(b) w/ contribution from PHS 457(b), short & long term disability, CME allowance, etc. Albuquerque thrives as New Mexico’s largest metropolitan center with a population of 700,000. Albuquerque has been listed as one of the best places to live in the United States by Newsweek, U.S. News & World Report, Money and Entrepreneur Magazines! Albuquerque is considered a destination city for most types of outdoor activities with 310 days of sunshine. A truly diverse and multicultural city, Albuquerque offers you and your family a great variety of activities and entertainment including national theater productions, sporting events, golf courses ranked among the best in the country, the largest hot air balloon festival in the US, American Indian Cultural activities and much more.

For more information, e-mail Kelly Herrera at kherrera@phs.org or call 505-923-5662. Visit our website at www.phs.org EOE

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Resistance continued from page 50

Antibiotic Use Prevalence Survey. Other programs include Active Bacterial Core Surveillance and Healthcare-Associated Infections–Community Interface. Additionally, the CDC’s national Healthcare Safety network is an electronic reporting system that enables hospitals to report infections, antibiotic use, and resistance.4 The information obtained by these programs provides insight and useful information on preventing the spread of

resistant infections. It also allows facilities to aim at particular areas of interest and make needed improvements. ASPs, meanwhile, were designed to improve antibiotic use. These programs focus on prescribing the correct antibiotics at the correct dose and reducing the duration of antibiotics when longer durations are no longer beneficial. These programs also reduce the rates of infections with resistant organisms and with C. difficile infection.20,21 These programs also have proven to reduce treatment failures and improve patient safety.22,23 Currently, the

CDC recommends that all acute care hospitals set up an ASP.24 For an ASP to function properly, it needs to have financial support, drug expertise via dedicated pharmacists, the ability to implement recommendations, a system to monitor the use of antibiotics and resistant organisms, and the ability to educate others on optimal antibiotic use. Effective ASPs demand close working relationships with infectious diseases, pharmacy, the microbiology laboratory, quality improvement, information technology, clinicians, and nurses.

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ASPs often institute policies that instruct prescribers on the recommended and appropriate dose, duration, and indication for antibiotics. Ideally, this information is made available to all prescribers and is based on national guidelines. Prior authorization often is required for antimicrobial agents that have a broad spectrum of activity, and when there is a particular toxicity or side effect associated with the antibiotic. ASPs often audit charts to assure compliance with the regulations that have been implemented.22,24 Although the primary focus of antimicrobial stewardship is to assure appropriate use of antibiotics, ASPs also save money. In a study at the University of Maryland, an ASP saved $17 million over an 8-year period.25 Another means of preventing overuse of antibiotics and, as a result, the development of antibiotic-resistant organisms is by appropriate vaccination. Pneumococcal vaccine has been proven effective as a way to reduce antibiotic-resistant Streptococcus pneumoniae.26 There are 2 vaccines: the 23-valent polysaccharide vaccine (Pneumovax, Merck) and the 13-valent conjugate vaccine (Prevnar 13, Pfizer). It is clear that these vaccines are underused at present. Vaccination of at-risk populations should help reduce antibiotic use.

Summary The effect of antibiotics on the course of medicine has been enormous. Ironically, antibiotic overuse has led to increased resistance, and increased morbidity, mortality, hospital length of stay, and cost. Discovery of new drugs will be important in the fight against antibiotic resistance. Programs such as infection control and ASPs are critical to prevent or reduce the growing problem of antibiotic resistance.

References

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1. Huttner A, Harbarth S, Carlet J, et al. Antimicrobial resistance: a global view from the 2013 World Healthcare-Associated Infections Forum. 2013;2(1):31. 2. Hicks LA, Taylor TH Jr, Hunkler RJ. US outpatient antibiotic prescribing, 2010. 2013;368(15):1461-1462. 3. Camins BC, King MD, Wells JB, et al. Impact of an antimicrobial utilization program on antimicrobial use at a large teaching hospital: a randomized controlled trial. 2009;30(10):931-938. 4. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/ drugresistance/threat-report-2013/pdf/ ar-threats-2013-508.pdf. Accessed June 30, 2014. 5. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. 2006;42(suppl 2):S82-S89. 6. Alliance for the Prudent Use of

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2014

Antibiotics. The cost of antibiotic resistance to US families and the health care system. http:// www.tufts.edu/med/apua/consumers/personal_ home_5_1451036133.pdf. Accessed July 1, 2014. 7. Roberts RR, Hota B, Ahmad I, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. 2009;49(8):1175-1184. 8. Brusselaers N, Vogelaers D, Blot S. The rising problem of antimicrobial resistance in the intensive care unit. 2011;1:47. 9. Nicasio AM, Kuti JL, Nicolau DP. The current state of multidrug-resistant gram-negative bacilli in North America. 2008;28(2):235-249. 10.Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-spectrum betalactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. 2011;86(3):250-259. 11.Perez F, Van Duin D. Carbapenemresistant Enterobacteriaceae: a menace to our most vulnerable patients. 2013;80(4):225-233. 12.Llarrull LI, Fisher JF, Mobashery S. Molecular basis and phenotype of methicillin resistance in Staphylococcus aureus and insights into new beta-lactams that meet the challenge. 2009;53(10):4051-4063. 13.Jacoby GA. Mechanisms of resistance to quinolones. 2005;41(suppl 2):S120-S126. 14.Hooper DC. Mechanisms of action and resistance of older and newer fluoroquinolones. 2000;31(suppl 2):S24-S28. 15.Bonomo RA, Szabo D. Mechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa. 2006;43(suppl 2):S49-S56. 16.Lister PD, Wolter DJ, Hanson ND. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. 2009;22(4):582-610. 17.Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gram-negative bacteria. 2012;25(3):450-470. 18.Dhariwal AK, Tullu MS. Colistin: reemergence of the “forgotten” antimicrobial agent. 013;59(3):208-215. 19.Zhanel GG, Lawson CD, Adam H, et al. Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. 2013;73(2):159-177. 20.Diaz-Granados CA. Prospective audit for antimicrobial stewardship in intensive care: impact on resistance and clinical outcomes. 2012;40(6):526-529. 21.Elligsen M, Walker SA, Pinto R, et al. Audit and feedback to reduce broad-spectrum antibiotic use among intensive care unit patients: a controlled interrupted time series analysis. 2012;33(4):354-361. 22.Nowak MA, Nelson RE, Breidenbach JL, et al. Clinical and economic outcomes of a prospective antimicrobial stewardship program. 2012;69(17):1500-1508. 23.Kaki R, Elligsen M, Walker S, et al. Impact of antimicrobial stewardship in critical care: a systematic review. 2011;66(6):1223-1230.

24. Fridkin S, Baggs J, Fagan R, et al; Centers for Disease Control and Prevention (CDC). Vital signs: improving antibiotic use among hospitalized patients. 2014;63(9):194-200. 25. Centers for Disease Control and Prevention. Antibiotic stewardship—the ultimate return on investment. http://www.cdc.gov/getsmart/healthcare/learn-from-others/factsheets/antibiotic-use. html. Accessed July 1, 2014. 26. Alicino C, Barberis I, Orsi A, et al. Pneumococcal vaccination strategies in adult population: perspectives with the pneumococcal 13-valent polysaccharide conjugate vaccine. 2014;105(1):89-97.

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December 2014

The Role of Technology in Optimizing Colonoscopy Quality and Efficiency Faculty Seth A. Gross, MD, FACG Chair

Steven A. Gorcey, MD

Steven Lichtenstein, DO

Amit Rastogi, MD, FASGE

Andreas M. Stefan, MD

Assistant Professor of Medicine Director of Endoscopy Tisch Hospital Division of Gastroenterology NYU Langone Medical Center New York, New York

Associate Professor of Medicine University of Kansas Medical Center Kansas City VA Medical Center Kansas City, Kansas

Chief, Division of Gastroenterology Maine Medical Center Associate Director The Pancreaticobiliary Center Portland, Maine

Introduction With ongoing efforts to reform health care and contain related costs, steps have been taken to implement quality measures that optimize outcomes while ensuring efficiency. As part of the health reform initiative, preventative and procedural measures, such as colonoscopy, are considered a gateway to managing patient care more effectively. Considered the most effective screening and surveillance test for colorectal cancer (CRC), colonoscopy has been associated with a reduced mortality rate.1-4 Colonoscopy, however, is a highly technical procedure with significant risks and complications (eg, loop formation) that can cause patient discomfort and increase expenses.5,6 A successful colonoscopy depends on a number of variables, including patient- and disease-related factors, but particularly the clinicianâ&#x20AC;&#x2122;s expertise and the technology being used.6-8 In an effort to reduce variability, improve colonoscopy outcomes, and maximize efficiency, quality measures, including cecal intubation rate and adenoma detection rate (ADR), have been implemented.1,3,7 In the future, these measures will be used to determine a clinicianâ&#x20AC;&#x2122;s level of reimbursement; success in achieving these quality measures will result in higher reimbursement, whereas failure to achieve these marks will subject clinicians to penalties.1,9 An assessment of the available technology for colonoscopy demonstrates the benefits of using devices that enhance visualization and control to improve outcomes. The Olympus EVIS EXERA III system offers clinicians advanced technology that optimizes visualization and maneuverability, while reducing patient discomfort using a new generation of innovative colonoscopes, along with ScopeGuide and the UCR Endoscopic CO2 Regulation Unit.

Essential Quality Measures In 2006, the American College of Gastroenterology (ACG) and the American Society of Gastrointestinal Endoscopy (ASGE) formed a task force to develop quality indicators for endoscopy,7,10 which were then incorporated into a voluntary reporting program known as the GI Quality Improvement Consortium, Ltd (GIQuIC).11 This program is a quality metrics registry approved by the Centers for Medicare & Medicaid Services (CMS) and qualified by the Physician Quality Reporting System (PQRS). GIQuIC provides endoscopists with a mechanism to meet quality documentation standards to avoid future reimbursement penalties and adjustments.1,9,12 The quality measures, including cecal intubation rate and ADR, for colonoscopy screening and surveillance are listed in Table 1.11

Cecal Intubation Rate As the initiating point of a colonoscopy, cecal intubation refers to the complete passage of the colonoscope tip in the cecal caput with visualization of the medial wall between the appendiceal orifice and the ileocecal valve.1,7 Cecal intubation improves overall sensitivity, eliminating the need for radiographic procedures or repeat colonoscopy, thus reducing associated costs.7 According to the ACG/ ASGE recommendations, clinicians should be able to achieve cecal intubation in at least 90% of all colonoscopies and 95% of screening colonoscopies.9

Adenoma Detection Rate

Improving Visualization and Control in Colonoscopy

ADR is considered the benchmark quality indicator in colonoscopy and represents a gauge of an endoscopist’s skill and care in visualizing the entire mucosa during a procedure.3 Current guidelines indicate an expected ADR of at least 25% for men and at least 15% for women over the age of 50 years.7 In a recent study of 314,872 colonoscopies, Corley and colleagues evaluated the relationship between ADR and risk for CRC.13 Results showed that a 1% increase in ADR was associated with a 3% decrease in risk for CRC.13 Implementation of these standards increases the likelihood of detecting neoplastic lesions in the colon, and further advances the benefit of universal considerations in screening and surveillance.

Innovations in technology have improved visualization and control capabilities during colonoscopy. The Olympus EVIS EXERA III system provides a foundation on which to add other devices to further enhance the clinical experience to achieve the quality measures while minimizing patient discomfort.

The Difficult Colonoscopy The success of a colonoscopy ultimately depends on the anatomy and physiology of the colon.6,7 To reach the cecum and achieve complete visualization of the entire colon, the scope must be extended through the colon, which is too flaccid to resist or redirect the force of insertion.14 Even the most skilled clinicians experience difficulty preventing the scope from looping into unwanted positions. Stretching the colon may lessen control over the colonoscope, increasing the risk for looping and perforations.6,15 The current standard of applying abdominal pressure and changing patient position is only minimally effective in resolving loops in a difficult colonoscopy.6 Perforation is rarely caused by the tip of the scope, but instead occurs when pushing the scope to traverse a curvature that expands due to pressure from the scope to then split from the expanding colonoscope loop.15 Because these types of tears are not located near the tip of the scope, they often are unnoticed until scope withdrawal.15 Because looping and perforation can cause pain and discomfort during the procedure, enhanced visualization through the scope lens will enable clinicians to direct the scope with greater control and maneuverability.

Table 1. GIQuIC Quality Measures for Colonoscopy 1.

History and physical documentation

Informed consent documentation

Adequacy of bowel preparation

Written discharge instructions for outpatients

ASA category documentation

Indication documentation

Cecal intubation rate with photo documentation A. All colonoscopies—screening, surveillance, and diagnostic B. Screening

Adenoma detection rate—screening A. Female B. Male

Withdrawal time

EVIS EXERA III The Olympus EVIS EXERA III platform implements a set of standards that advances visualization, scope control, and workflow during colonoscopy. The EVIS EXERA III platform features Dual Focus, an innovative optical system consisting of adjustable optics that enhance resolving power and sharpness down to 2 mm—an advantage when examining tissue.16 With its proprietary Responsive Insertion Technology (RIT), the Olympus EVIS EXERA III system provides optimal scope control and maneuverability using 3 modalities—Passive Bending (PB), High Force Transmission (HFT), and Variable Stiffness.16 Located between the tip and the first segment of the scope, the PB segment senses the change in pressure when the scope tip contacts the colon wall and bends automatically in the direction of the lumen, creating a gentle curve that allows the scope to pass flexures.16 HFT enables a 1:1 transfer of pushing and rotating forces to the distal end of the scope, which improves the ergonomics and responsiveness of the scope.16 Variable Stiffness allows the operator to modify the stiffness of the scope along its length, adjusting to the anatomy of each patient, and is helpful in reducing looping of the scope.16

A New Generation of Scopes The availability of the Olympus 190-series colonoscopes further enhances the visualization and control capabilities that make colonoscopy more efficient. The depth of field is 5 to 100 mm in normal view and 2 to 6 mm in near view.17 As part of the EVIS EXERA III system, the 190-series colonoscopes possess the 3 RIT modalities—PB, HFT, and Variable Stiffness—giving the clinician more control to maneuver while adjusting the rigidity of the scope as needed.17

10. Immediate adverse events ASA, American Society of Anesthesiologists; GIQuIC, GI Quality Improvement Consortium, Ltd Based o on reference e e e ce 11..

Figure 1. A ScopeGuide image. Photo courtesy of Steven Lichtenstein, DO

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ScopeGuide The inclusion of ScopeGuide allows clinicians to observe the shape and position of the colonoscope inside the body in real time.18 The 3-dimensional representation of the colonoscope is made possible by magnetic coils in the colonoscope that generate a pulsed, lowfrequency magnetic field (Figure 1).18 These magnetic pulses are transmitted to an external receiver and processor that create a representation of the colonoscope on a screen alongside the endoscopic image. The capability to visualize the scope allows the clinician to identify and mitigate loops as they form, and aids in identifying where to apply abdominal pressure, if necessary.19 Additionally, clinicians can use ScopeGuide images for documentation and training.

Technology Improving Quality Measures In addition to its visualization and scope control capabilities, the Olympus EVIS EXERA III system is able to streamline workflow, further maximizing efficiency and containing costs.

Cecal Intubation Rate Recent research demonstrated faster intubation times using the Olympus EVIS EXERA III system 190-series colonoscope (CFHQ190L) as compared to the 180-series instrument (CF-H180AL).20 A post hoc analysis of 1,080 patients who participated in 2 clinical trials evaluated cecal intubation times using the 2 colonoscopes operated by 11 endoscopists with varying levels of experience.20 The median and mean cecal intubation times for the 190-series scope were consistently shorter than the times using the 180-series instrument, regardless of the experiential level of the endoscopist (Table 2).20 Results showed that 8 endoscopists had shorter cecal intubation times using the 190-series colonoscope with up to a 20%

Table 2. Cecal Intubation Time Versus Clinician Experience Cecal Intubation Time, min

180 Series

190 Series

P Valuea

Overall Mean±SD Median

6.0±4.0 5.0

5.3±3.5 4.0

0.0053 0.0067

<5,000 colonoscopies Mean Median

6.7±4.4 6.0

6.2±4.2 5.0

0.3832 0.2863

5,000-9,999 colonoscopies Mean Median

5.2±3.7 4.0

4.6±3.1 4.0

0.0591 0.0878

>10,000 colonoscopies Mean 6.2±3.7 Median 5.0

5.6±3.1 5.0

0.0753 0.1184

SD, standard deviation a The 2-sample t test was used to calculate P value for mean, and the nonparametric Wilcoxon-Mann-Whitney test was used to calculate the P value for the median. Based o on reference e e e ce 20. 0.

reduction in cecal intubation time.20 As a primary quality indicator for colonoscopy, a high cecal intubation rate may indicate a more efficient procedure with less time spent repositioning the patient.1 With the addition of ScopeGuide, clinicians are able to improve cecal intubation time, as well as minimize the duration of looping. In a study of 44 patients with features or history indicating a difficult colonoscopy, results showed that using ScopeGuide reduced the cecal intubation time from 9.1 to 6.6 minutes, while the duration of looping was shorter (2.2 vs 4.3 minutes, respectively).21 Although these results were not statistically significant with this sample size, the study demonstrated an improvement in patient comfort during a difficult colonoscopy.

Adenoma Detection Rate Instrument capability has been demonstrated to contribute significantly to ADR,6 and several features of the Olympus EVIS EXERA III colonovideoscope (Olympus CF-HQ190L/I) improve visualization of the mucosal surface. As previously noted, Dual Focus, a unique innovation of the Olympus instrument, allows the observer to toggle between 2 focus settings (Figure 2).17 This feature enables the endoscopist to quickly zoom in on any feature and back out to continue the examination. Additionally, the EVIS EXERA III platform has a new optical system that provides enhanced image quality, including a brighter image, increased contrast, and reduced noise and halation.17 Finally, EVIS EXERA III has a photo documentation capability that enables the endoscopist to capture consistently sharp still images at near and normal foci. A recent study demonstrated the visualization accuracy of the Olympus EVIS EXERA III colonovideoscope (Olympus CF-HQ190L/I) in detecting adenomas in patients with average risk.22 In all, 600 patients participated in the study in which 927 polyps were examined by 6 endoscopists each with a different level of experience and number of procedures.22 The ADR was 50% with the 190-series colonoscope.22

Reducing Patient Discomfort Methods of reducing patient discomfort are important because preconceptions about pain may limit patient receptiveness for screening colonoscopies. Patients’ negative perceptions can be changed, however, and several actions can be taken to make screening more comfortable.23

Figure 2. Photographs of a polyp: normal view (left) and near-focus view (right), using an Olympus EVIS EXERA III System colonoscope and Dual Focus.

CO2 Efficacy

During CO2 insufflation

1 minute after CO2 insufflation

1 minute 10 seconds after CO2 insufflation

2 minutes after CO2 insufflation

Absorption Rates CO2 30-60 minutes

Air 24-72 hours

Figure 3. Colon distention during CO2 insufflation.

Table 3. Mean Pain Scores During and After Colonoscopy Using Air or CO2 Period During Colonoscopy

Air

CO2

CO2 Withdrawal

P Value

During procedure

4.55±1.98

4.69±2.34

4.56±2.32

0.957

At end of procedure

3.59±2.49

2.43±1.83

2.26±2.07

0.026

Postprocedure, 1 h

2.68±2.47

0.62±1.07

1.02±1.78

<0.001

Based on reference 30.

Colonoscopies that are more comfortable were found to promote patient compliance, and low discomfort scores were significantly associated with patient willingness to have a repeat procedure.24 Using ScopeGuide as part of the EVIS EXERA III system, endoscopists are able to identify and mitigate loops more effectively, apply abdominal pressure more accurately, and visualize the anatomy better, thus reducing potential patient discomfort while making the procedure more efficient in terms of time to completion.18

UCR Endoscopic CO2 Regulation Unit Insufflation is required during colonoscopy to enable adequate visualization of the bowel.23,25 Minimal insufflation can be used during 4

insertion and withdrawal of the colonoscope to permit safe introduction, and to ensure optimal inspection of the colonic mucosa.6 Thus, the ideal agent for colon expansion should be effective in facilitating cecal intubation and optimal examination of the mucosal surface, be safe and readily available, and minimize intra- and postprocedural pain.25 Because carbon dioxide (CO2) is absorbed faster than air, insufflation with CO2 is a method that has been shown to reduce patient discomfort and pain without causing safety issues or significant costs (Figure 3).23,25 Using the Olympus UCR Endoscopic CO2 Regulation Unit, clinicians are able to apply intraluminal insufflation using CO2 during colonoscopy to minimize bowel distention while reducing patient discomfort during and after colonoscopy.

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Randomized controlled trials have consistently shown the benefit of CO2 insufflation using the UCR Endoscopic CO2 Regulation Unit.26-28 Use of CO2 instead of air for insufflation has been associated with reduced intra- and postprocedural pain and decreased postprocedural flatus.26 The benefit of CO2 insufflation also was observed in difficult colonoscopies.29 In potentially difficult colonoscopies, patient-rated pain scores were significantly better in patients who received insufflation with CO2 than air, predominantly in the 2-hour period immediately after the procedure.29 Other research suggests that CO2 insufflation could be restricted to the withdrawal phase only, with comparable results.30 A prospective, single-blind, randomized controlled study of 100 patients with symptoms indicating the need for colonoscopy compared insufflation with air, CO2, or CO2 during the withdrawal phase only.30 Patient discomfort was similar for CO2 and air during the procedure, regardless of whether CO2 was used for the whole procedure or only during withdrawal; however, it improved with CO2 at the end of the procedure and 1 hour postprocedure (Table 3).30 Whether used routinely or for potentially difficult cases, CO2 insufflation benefited patients by reducing pain and discomfort. The CO2 insufflation capability of the UCR Endoscopic

CO2 Regulation Unit provides minimal luminal distention, and has a selectable flow rate and compact design.

Conclusion In providing safe and effective screening colonoscopies, quality and efficiency are vital issues. In the current health care environment, quality metrics are linked to professional standing and procedure reimbursement, and may soon be included in databases that will be available to patients. Many variables influence quality, and one of the most important is the technology used. Employing the EVIS EXERA III system for colonoscopies has several advantages. The instrumentation is easier to use given its improved flexibility and maneuverability. The unique advantage of being able to visualize the position and shape of the scope during the procedure provides clinicians with the ability to recognize instrument looping as it forms and correctly apply abdominal pressure as needed. The improved optics of the EVIS EXERA III system enhances polyp detection and documentation. Although not directly related to quality, CO2 insufflation results in decreased patient pain during and after colonoscopy, and may promote increased patient compliance.

Evaluating New Technology in Clinical Practice Olympus invited 5 physicians, Drs. Gross, Gorcey, Lichtenstein, Rastogi, and Stefan, to compare 190-series colonoscopes, ScopeGuide, and CO2 insufflation versus the previous generation 180-series colonoscopes with the goal of understanding the effect of new technology in clinical practice. Each

physician reviewed data from 50 cases conducted with a CF-HQ190L, ScopeGuide, and CO2 insufflation and 50 cases conducted using a CF-H180AL. The following key data points were noted during the study review: time to cecum, ADR, mean adenomas per patient, required patient position changes

to reach the cecum, the use of abdominal pressure, and length of stay in recovery. The interim results of the cases were combined and analyzed, and the results suggest that a more efficient and effective colonoscopy can be performed using 190-series scopes, ScopeGuide, and CO2 insufflation.

Efficiency Case Study Results

Efficiency Case Study Attribute

190-Series Colonoscope, ScopeGuide, and CO2 Insufflation

180-Series Colonoscope

Time to Cecum, min

4:33

5:03

Patients Requiring Abdominal Pressure, %

20.4

31.3

Patients Requiring Position Changes, %

4.0

8.0

Adenoma Detection Rate, %

45.9

42.5

Mean Adenomas per Patient

0.89

0.88

Patient Time in Recovery, min

38.5

43.7

A Roundtable Discussion The following discussion was moderated by Seth A. Gross, MD, FACG, and provides clinical insights on the role of technology and the use of the Olympus EVIS EXERA III system. Seth A. Gross, MD, FACG: For those of you who have worked with the 180-series colonoscopes and the 190-series colonoscopes, what are some key differences that you’ve appreciated that could potentially help your practice on any given day when you’re doing colon cancer screening and surveillance? Steven Lichtenstein, DO: I’m not through with the 180 patient arm yet, but I’m noticing early on that I’m applying a lot more abdominal pressure with the 180 scopes than I had to with the 190s. I think the Responsive Insertion Technology or just the maneuverability and the bending of the 190, the difference of the 190 responsiveness seems to get me to the cecum with minimal, if any, abdominal pressure. With the 180s, I’ve probably applied pressure in at least one-third of them. Amit Rastogi, MD, FASGE: I think the flexibility and the torque ability of the scopes have improved. We actually performed a post hoc analysis of a prospective, randomized, controlled study that compared the 180-series colonoscopes to the 190-series colonoscopes for real-time actual polyp histology prediction. We looked at what the median time to reach the cecum was in 2 arms. Across 3 centers and more than 1,000 patients (500 in each arm), we found that the median time decreased by 1 minute. Now, it might not be a huge deal, but the median time to reach the cecum was 25% to 30% less with the 190-series colonoscopes. And this was in the hands of experienced endoscopists. So, how it will translate to less-experienced endoscopists or trainees remains to be seen, but it seems to be an advantage. The other improvement that I saw was in the Narrow Band Imaging (NBI). The images are much brighter, and the illumination and the brightness is enhanced as compared with the 180-series. This was a major criticism of the 180 NBI, the image was very dark. The freeze-frame function, which helps us to take good images, is a huge difference. Andreas M. Stefan, MD: We’ve been using the 190s for over a year in our ambulatory surgery center and have been extremely pleased with the performance of these scopes. This is due to multiple factors including the increase in field of view from 140 to 170 degrees and improved tip flexibility without compromising insertion force transmission. The expanded field of view makes retroflexion in the rectum almost redundant since you can see nearly 180 degrees at the tip. The flexibility of the new line is impressive. I have had the experience of not being able to navigate a sigmoid turn in a particularly thin patient with the 180 line, but was able to complete the exam using the 190 series. I think this is due to the Passive Bending section in the 190-series. Having said that, I have also found the new 190-series scope to hold its shape better once straightened. I’m using a scope stiffener far less often with the newer scopes. Steven A. Gorcey, MD: I think that Dual Focus is one of the keys to the scope, not only as a diagnostic tool but also as a therapeutic tool. As we start getting into endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), it’s extremely important to see where the edge is of the lesion. Dual Focus is just an outstanding technology to delineate those edges before you start dissection. Dr. Gross: I think we highlighted all of the key differences between 6

the 180 and 190 and how—from all of the things you all said—they could certainly affect the quality of our exam and also potentially impact the efficiency. Do you think new technologies can aid physicians in meeting or exceeding the new colonoscopy standards like ADR? You’ve all probably heard that in the coming months those benchmarks that we all hold ourselves to (of 25% for men and 15% for women) are likely to increase. Where do you feel new technologies could affect some of these quality metrics like ADR? Dr. Rastogi: For detection, I always talk about technique. Technique remains the mainstay, and if you have poor technique then no matter what technology you use it’s not going to help. So technique pretty much stays the same no matter what scope you’re using a lot. The torque ability probably helps the 190 because if there’s a better transmission of your torque down the colonoscope then you basically can look at the proximal aspects of the fold better compared with when in a looped position the transmission is not that great as with the older versions of the scope. So that is one way this can help. The other way technology has helped, based on some studies and some meta-analyses, is the high-definition feature. Both the 180 and 190 are high definition but if you look at technology, I think improving the definition of the scopes—moving over to the high-definition scopes—has improved the ADRs to a certain extent. There are a host of other technologies that can help to inspect the proximal aspects of the folds, and the one I like is cap-assisted colonoscopy because it’s pretty inexpensive and very efficient. You put a cap at the end of the colonoscope and use the cap to flatten the folds. The proximal aspects of the folds are the blind areas where you usually miss the edges of the polyps, especially flat lesions. Dr. Lichtenstein: More literature is coming out, and more people are talking about the ADRs and the quality measures that we’ll be expecting over the next couple of years. Just that alone, I think, is going to hold most gastroenterologists to a higher level of picking up these polyps that may have once been missed. Having said that, the new technology, such as the 190 scopes with Dual Focus and with the improved NBI, is going to allow us to fulfill the requirements of acheiving higher adenoma detection rates. So the new technologies will be beneficial. I agree with Dr. Rastogi: If your technique is bad it’s going to be bad straight through no matter what scope you’re using. I agree with that about 90%. But I think for the talented endoscopists, we’re going to be increasing our ADRs. I think the less talented endoscopists will need the new technology more so to perhaps improve the ADRs to a greater degree. So, I think just the awareness of what’s coming down the pike with quality measures along with new technology, it’s going to improve everyone’s ADR to some extent, but probably a little bit more for the less talented endoscopists than for the higherlevel endoscopists. Dr. Gross: I think that a lot of these new technologies ultimately need to prove themselves. As many of you have echoed, technique is paramount, and I think just high-definition white light has really improved what we do. And I think we’ll learn a lot more in the next 12 to 24 months about which of these enhancements to colonoscopy has staying power. But the technique will carry through for sure.

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Dr. Gorcey: It’s important to mention that no matter how good your technology is, if you don’t have a good prep then you’re not going to have the ADR. If your prep is not good, then you’re not going to detect small polyps. Dr. Gross: I think that’s an excellent point. I imagine that most of you—if not all of us—are using a split-dose bowel prep of one formulation or another to try to get that high-quality bowel preparation. How has ScopeGuide affected your practice? Additionally, where have you seen the benefits of using CO2 insufflation for a colonoscopy? Dr. Rastogi: I usually don’t use ScopeGuide routinely in my clinical practice, but I’ve used it a few times in the past. Obviously, there is good data supporting its use, especially for trainees and less-experienced endoscopists. It has been shown to help the trainees and lessexperienced endoscopists get to the cecum in a higher proportion of cases and requiring less assistance in the form of pressure or position change. CO2 is something that I use, and I really like it. There is good level 1 evidence showing that it decreases intraprocedural as well as postprocedural pain with the most prominent effect at 1 hour postprocedure, which is the time when patients are waking up and basically are getting ready to be discharged, and you can’t discharge them if they have pain. Anecdotally in my unit, once we started using CO2 on a regular basis, the nurses mentioned that the complaints from patients of abdominal distention and postprocedure pain dramatically decreased. So again, that was anecdotal, but that is something the nurses in the recovery area noted, that once we started using CO2 on a more regular basis very few, if any, patients were complaining of abdominal discomfort at the end of the procedure when they were waking up from sedation. Dr. Gorcey: We had ScopeGuide for about 6 months before anyone even tried it. And I was one of those guys who said I don’t need ScopeGuide. One day I decided to try it on a patient who couldn’t be done by someone else. I’m looking at it, and it’s like having fluoro on the patient with your foot on the pedal the whole time. It was unbelievable. So I started using it, and again everything is hardwired at this point in our lives, and I think none of us really think when we scope. But to actually see what the scope is doing while we’re doing it somehow clicked something in my head, and I started seeing where most of the loops usually occur. I started bringing the concept back to my surgery center where I don’t have ScopeGuide. On the tougher cases I would start thinking “what would it have looked like on ScopeGuide?”. When I think back, it made me a better colonoscopist just by making that visual connection with what was already hardwired in my brain. Not only that but for localization of polyps; now I see a polyp, I take a picture, I switch the screen and I take a picture of the ScopeGuide image. Now I have a perfect marker of where the polyp was—which side of the flexure it was on—and I don’t need to tattoo it. Let’s say you get a surprise polyp, and you didn’t tattoo it. Now at least, you have a marker. Additionally, on the tough cases where you need 2- and 3-point pressures, it speeds the case up from an hour down to 15 minutes to get to the cecum when you know where to put the hands, when you know where the loops are forming. So I think it’s a great tool. I think it could help everyone. I use it to teach the residents; they pick it up much faster because they can see the loops. I think if you’re a poor colonoscopist it’s going to make you better, and if you’re a really good colonoscopist it’s going to give you added information that you never had before and make it that much more fulfilling for you.

Dr. Stefan: I would echo those comments. I initially thought I wouldn’t use it much but what I have found is that loop formation and reduction can be quite subtle. Sometimes you’re surprised that you can reduce a loop earlier rather than waiting. This has obvious implications for patient comfort during the procedure as well as total procedure time if you are continually struggling with a loop. I have also appreciated the ability to more exactly pinpoint where a lesion is using ScopeGuide. This is particularly helpful in describing lesions that are not endoscopically resectable. In regard to using CO2, it is clear that patients are more comfortable in the recovery area and there is less flatus being passed which can be a source of embarrassment for some. Dr. Lichtenstein: I agree. I’m very conscious of removing most of the air that I put in, but there’s always going to be some air pockets that we cannot remove. But most of the time my patients are fairly comfortable in the postanesthesia care unit because I’m conscious of removing the air. But I felt that after using the CO2 it would not change my patient comfort outcomes because they released fairly quickly. But I think it has. I haven’t seen anyone with gas pains after CO2, so there is a benefit there. Dr. Gross: Overall, CO2 has helped colonoscopy and patient satisfaction in the postprocedure. ScopeGuide certainly has its benefits—not just for the physicians but also for the medical assistants and nurses to help better pinpoint the pressure. I think some physicians will benefit from it for every case, and some physicians will benefit from it on demand when they encounter really challenging colonoscopies. But I think it has tremendous added value. How can we deliver a quality colonoscopy in an increasingly efficiency-focused industry? Dr. Rastogi: Basically, good bowel prep; high-definition colonoscopes, which means high-def scopes, high-def processor, and high-def monitor; good technique; and having some accessory tools to visualize the proximal aspects of the 170-degree fold, which is the 190-series scope that has a wider view or something like cap-assisted colonoscopy. But definitely use CO2 for better patient satisfaction and shorter stay in the recovery area. Dr. Gross: Lastly, I think many of us have already invested in the 190-series scopes and platform, but does the added investment of the 190-series scopes, ScopeGuide, and CO2 result in increased efficiency and improved patient satisfaction? Dr. Stefan: I’d have to say yes. I had a patient come in today for followup colonoscopy. On this occasion, we used a 190 pediatric scope with CO2, and she felt so much better during and after the procedure. I think the new platform improves patient satisfaction and procedure quality. Dr. Gorcey: When I keep my colonoscopy records, I mention whether or not it was as a difficult case. So what I’ve been doing is pulling the ones that I’ve said were very difficult over to the hospital to use ScopeGuide. I had 2 that I couldn’t get through; 1 that I couldn’t get through twice. And I got through both of them with ScopeGuide, and I don’t think I would have been able to get through without it. When I add ScopeGuide, the ones identified as being really difficult were no longer difficult. But you could see why they might have been difficult because of the loops that were formed. I knew which rotational torsion to go in on. Anytime you do someone like that it’s a risk. When you’re looping like that in someone, and you know you’re looping, but you’re not sure exactly where, and you can’t get the pressure, that’s a risk. You’re stretching, and it’s amazing you don’t even realize 7

how much you’re stretching until you start seeing that splenic flexure start going up when it starts looping on ScopeGuide. Sometimes it goes right up to the chest, and then you know how you can give somebody a splenic hematoma. You don’t realize these things. Dr. Lichtenstein: We already mentioned patient satisfaction, I believe, and increased efficiency with time to cecum, but what this question doesn’t address is the physician satisfaction. We all talk about patient satisfaction; we know that’s important. But this is our

livelihood and coming in every day and scoping 4 out of 5 days a week and doing 50 to 60 scopes a week you want to be happy with what you do, you want to enjoy what you do. And just by the CO2, the 190, and ScopeGuide, I think it just makes everything so much more enjoyable, and a happy physician then leads to happy patients and it’s passed along to the staff and residents. And I think that’s huge yet rarely discussed, but I think it’s something definitely worth mentioning.

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Disclosures: Drs. Gross, Gorcey, and Stefan reported that they have served as consultants for Olympus. Dr. Lichtenstein reported that he has served on the speakers’ bureaus for Salix Pharmaceuticals, Santarus Inc., and Takeda Pharmaceuticals, and as a consultant for Olympus. Dr. Rastogi reported that he received grant support from and served as a consultant for Olympus. Disclaimer: This article is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Olympus, and the authors neither aﬃrm or deny the accuracy of the information contained herein. No liability will be assumed for the use of the article, 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. 8

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