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The Independent Monthly Newspaper for Gastroenterologists

Volume 63, Number 12 • December 2012 40th ANNIVERSARY 1972–2012

ACG 2012

Vedolizumab Safe, Promising for UC

Colonoscopy Surveillance Guideline Solidifies Established tablished ablished Evidence By Rosemary Frei, MSc

By Monica J. Smith Las Vegas—Vedolizumab appears to be safe and effective in maintaining clinical remission in patients with moderate to severe ulcerative colitis (UC) who have see Vedolizumab for UC, page 16

Prolonged Intubation Compromises Adenoma Detection By Monica J. Smith Las Vegas—The minimum withdrawal time of seven minutes suggested by the U.S. Multisociety Task Force on Colorectal Cancer as a quality measure for colonoscopy does not appear to result in improved adenoma detection rates (ADRs), possibly because it does not see Intubation Time, page 24

The U.S. Multisociety Task Force on n Colorectal Cancer recently released a new guideline for colonoscopy surveillance that bolsters the evidence foor many common practices in the field. Published in September 2012, the guideline supports previously published recommendations that endorse surveillance intervals of 10 years foor a negative colonoscopy or when onlyy one or two small tubular adenomaas are found, and an interval of five to 100 years when three to 10 tubular adenomas are found (Lieberman DA et al. Gastroenterologyy 2012;143:844-857). The task force included repreeseentatives from the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy and the American College of Gastroenterology. “The principles of the guidelines have not really changed, but the evidence for some of the

recommendations is much stronger now,” said David Lieberman, MD, professor of medicine and chief, Division of Gastroenterology and Hepatology, Oregon Health & Science University, in Portland, and lead see Colonoscopy Guideline, page 24

SPECIAL COVERAGE

I N S I D E

Hurricane Sandy Hits Hard Doctors, Staff Improvise To Keep Medical Centers Afloat

EXPERTS’ PICKS Best of the American College of Gastroenterology: Part 1 Experts share their favorite abstracts from the 2012 ACG Annual Scientific Meeting .............................page 17

By Monica J. Smith

Photo: Cynthia Gordon

Decimated boardwalk in Rockaway Beach, Queens

New York City—By y the time Hurricane Sandy, the largest Atlantic hurricane ever recorded, was over, the storm had claimed an estimated 200 lives in seven countries, cost tens of billions of dollars through direct damages and business

Brian Bosworth, MD

Filippo Cremonini, MD, PhD, MSc

see Hurricane Sandy, page 40

Advances in Stent Technology for Esophageal Cancer see page 19

Timothy Gardner, MD


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Doctor’s Eyes Only: Exclusive Financial Strategies for Today’s Doctors and Dentists

Thomas Martin; Paul Larson; Jeffrey Larson March 13, 2012 This book is the missing financial guide that physicians need as a supplement to their ongoing professional training. These pages include basic financial wisdom that could end up saving them millions of dollars throughout their medical careers.

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ERCP: Expert Consult—Online and Print

Todd H. Baron, MD; Richard Kozarek, MD; David Leslie Carr-Locke, MD, FACG, FRCP Elsevier/Saunders, October 25, 2007 This comprehensive and user-friendly book combines an in-depth review of ERCP with easily accessible, detailed and authoritative instructions on how to safely gain access to the biliary and pancreatic ducts and deliver effective therapy. The intricacies of the procedures are shown using beautifully drawn step-by-step illustrations.

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Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition

John DiBaise April 20, 2012 The book features about 3,500 questions with only the correct answer provided, reinforcing the answer students need to remember on exam day. Emphasis is placed on distilling key facts and clinical pearls essent a for tial o exam e a success. success

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Hepatology: Diagnosis and Clinical Management

E. Jenny Heathcote November 13, 2012 This is a highly practical handbook on hepatology, aimed at residents// trainees in gastroenterology, GI nurses and recently qualified consultants for use as a quick reference when managing patients presenting with possible or overt liver disease.

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The Gastrointestinal System at a Glance, Second Edition

Keshav October 30, 2012 This concise introduction to the gastrointestinal system encapsulates the fundamental facts and principles of this rapidly growing and changing specialty.

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Brenda Wren November 16, 2012 Possessing an unparalleled wealth of information, the Medical Direc-toryy database contains details of 117,000 medical doctors, including career data. The 2013 database has been revised and updated, providing a unique resource that allows one to easily find contact details of medical doctors.

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Unaccountable: What Hospitals Won’t Tell You and How Transparency Can Revolutionize Health Care

Marty Makary, MD September 18, 2012 To patients, the health care system is a black box. Doctors and hospitals are unaccountable, and the lack of transparency leaves both bad doctors and systemic flaws unchecked. Accountability in health care would expose dangerous doctors, reward good performance and force positive change nationally, using the power of the free market. Unaccountable is a powerful, no-nonsense, nonpartisan diagnosis for healing our hospita s and tals a d reforming eo g our ou broken b o e health ea t care ca e system. syste GEN1212


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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

From the Literature

HER2 Expression Not Independently Prognostic of Overall Survival in Gastric Cancer By Kevin Enright Human epidermal growth factor receptor 2 (HER2) status is not an independent prognostic factor of patient outcome in metastatic gastric or gastroesophageal (GE) junction adenocarcinoma, according to a study published in the Annals of Oncologyy (Janjigian YY et al. 2012;23:2656-2662). Although some cancers are associated with an increase in cellular expression of HER2, studies assessing HER2 status in patients with gastric and GE junction cancers have been equivocal. In this study, investigators from Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, both in New York City, and Krankenhaus Nordwest University Cancer Center, in Frankfurt, Germany, set out to determine the significance of HER2 status on the prognosis of patients with gastric or GE junction cancers. Researchers examined tumor

samples from 381 patients with metastatic gastric or GE junction adenocarcinomas who were enrolled in six first-line metastatic chemotherapy trials at Krankenhaus Nordwest and

The researchers identified 78 patients (20%) with HER2-positive tumors. Using a multivariate logistic model, they noted significantly higher rates of HER2 positivity in patients

‘Unlike breast cancer, HER2 positivity is not independently prognostic of patient outcome in metastatic gastric or GE [junction cancers].’ —Janjigian YY et al

Memorial Sloan-Kettering Cancer Centers. About half of patients had stage IV adenocarcinomas of the middle to distal stomach; 37% of patients had adenocarcinomas of the GE junction. There were similar numbers of patients with Lauren’s diffuse/ mixed (46%) and intestinal (48%) tumors. None of the patients in the study were treated with anti-HER2 first- or second-line chemotherapy.

with liver metastasis (31% vs. 11% in patients without liver metastasis; P=0.025), as well as higher rates of HER2 positivity in tumors with intestinal histology (33% vs. 8% for diffuse/mixed tumors; P=0.001). Additionally, the authors found that patients with HER2-positive gastric cancer had a longer median overall survival (OS) compared with those with HER2-negative tumors (13.9 vs.

11.4 months, respectively; P=0.047). However, a multivariate analysis revealed that HER2 status was not an independent prognostic indicator of OS (hazard ratio, 0.79; P=0.194). The researchers also did not observe a significant correlation between HER2 status and progression-free survival. “Our study supports the idea of substantial molecular differences between histologic tumor types … by demonstrating that HER2 amplification is extremely rare in diffuse gastric carcinoma … and that HER2 expression is more often found in gastric carcinomas that spread to the liver,” the researchers noted. The authors concluded that HER2 biology in gastric cancer needs further exploration in order to strengthen the success of HER2 targeting in these diseases. “Unlike breast cancer, HER2 positivity is not independently prognostic of patient outcome in metastatic gastric or GE [junction cancers],” they wrote.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

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December 2012

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GASTROENTEROLOGY & ENDOSCOPY NEWS, the independent monthly newspaper for gastroenterologists, has been providing physicians with comprehensive and objective information since 1978. The newspaper is circulated to more than 17,100 gastroenterologists, colorectal surgeons, and hepatologists, and GI-speciďŹ c physician assistants and nurse practitioners (as reported to BPA Worldwide, Publishers Audit, based on circulation data as of July 2012). Gastroenterology & Endoscopy News (ISSN 0883-8348) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing oďŹƒces. POSTMASTER: Please send address changes to Gastroenterology & Endoscopy News, 545 W. 45th Street, 8th Floor, New York, NY 10036.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

Personalized Medicine Inches Closer to Role in IBD Experts Predict Genetic-Based Approach Will Become the Norm in IBD By Christina Frangou Chicago—Physicians consider multiple factors when deciding how to manage illness in a patient with inflammatory bowel disease (IBD). What is the patient’s response to prednisone or immunomodulators? Is the patient suffering from

frequent flare-ups? Are they developing life-threatening complications? And soon, doctors will factor in one more element into their decision making: a patient’s genetic makeup. “How close are we to using genetics in IBD? Close,” said Walter A. Koltun, MD, professor of surgery and Peter and Marshia Carlino Chair in IBD, Penn

State Hershey Medical Center, Hershey, Pa. “Soon, we will be doing surgical decision making using genes, just like we do now for cancer.” In a presentation at the 2012 Clinical Congress of the American College of Surgeons, Dr. Koltun said that scientific understanding of genes has progressed so far that genetic analysis will soon be used

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to subclassify and diagnose patients with IBD, similar to the way genetic testing is used in the diagnosis and management of patients with colorectal cancer. Researchers have identified many of the genes and gene mutations that come into play in IBD, Dr. Koltun said. Now, the focus is on understanding how those genes influence outcomes in the disease. Once those studies are completed, genetic analysis can shift out of the research lab and into physicians’ offices and hospitals. “Genetic analysis in IBD will happen, but when depends on how you define ‘very soon,’ ” said Alessandro Fichera, MD, professor of surgery, University of Washington Medical Center, Seattle. “I think we’ll start applying it in clinical trials and experimental approaches in the next two decades.” But moving personalized medicine out of the laboratories and into clinical practice is still some time away, he said. “As far as genetic-directed approaches to therapy, I think it’s going to take a little longer before it is ready for prime time,” he added.

Putting the Human Genome Project Into Practice Over the past two decades, researchers have come a long way in understanding the interplay of genes and disease. Significant advancements came as the human genome project progressed. When it was


GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

completed in 2003, scientists had mapped out approximately 20,000 to 25,000 genes. That accomplished, research efforts zeroed in on identifying links between specific genes and disease. To figure out gene–disease associations, scientists carry out genome-wide association studies. Researchers compare a group of healthy patients with a group of patients with a particular disease and look at hundreds of thousands of single nucleotide polymorphisms (SNPs) to find correlations with specific disease types. Researchers and surgeons at Penn State Hershey Medical Center have led the way in investigating genetic abnormalities that relate to IBD and surgical outcomes. In 1998, physicians and researchers at Penn State established the area’s first IBDdedicated BioBank, consisting of three components: 1) an IBD patient registry that characterizes the clinical factors that define subcategories of IBD, 2) a DNA bank derived from leukocytes of patients with IBD and 3) an IBD tissue library, harvested from patients at the time of surgery. To date, investigators have entered information collected from nearly 1,400 patients, some with three generations of family members in the registry. The program is unique in that surgeons’ participation is front and center, said Dr. Fichera. “That means they can look at surgical outcomes in addition to medical. Because they started so long ago, they’re way ahead of the curve,” he said. What the research from Penn State, as well as other institutions, has shown is that the role of genes isn’t as simple as “one gene, one disease,” said Dr. Koltun. Instead, it’s a very complex process, whereby numerous genes and predisposing factors interact with numerous environmental factors. The end result is a unique phenotype for patients with IBD.

Genetic Pathways in Crohn’s And Ulcerative Colitis To date, about 300 SNPs and 100 genes have been shown to have an association with IBD. Some genes are affiliated with Crohn’s disease (CD), some with ulcerative colitis (UC) and some with both. To date, the most important genes identified in IBD include the interleukin-23 pathway genes, which contribute to the immune responses that play a role defending against microbial infection and intestinal inflammation; TNFSF15, an immune regulatory gene associated with severe pouchitis and medication-refractory UC; and the NOD2/CARD15 gene. In 2001, two groups independently identified NOD2, also known as CARD15, as the first susceptibility gene for CD (Hugot JP et al. Nature

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What the research from Penn State, as well as other institutions, has shown is that the role of genes isn’t as simple as ‘one gene, one disease.’

2001;411:599-603, Ogura Y et al. Nature 2001;411:603-606). This gene’s role in IBD is still somewhat murky. But there is no question the genetic mutation is strongly associated with ileal disease, stricturing disease and earlier-onset disease. (Interestingly, no role for NOD2 has been demonstrated in UC.) In almost every month of the past year, researchers have published studies looking at NOD2 and IBD, and most research links the gene to poor outcomes. A study this summer reported that NOD2 mutations are an independent risk factor for surgery in patients with CD (Nasir BF et al. J Clin Gastroenterol 2012 Jun 25 [Epub ahead of print]). Another study, a single series of 185 patients, showed that a higher percentage of patients with CD who had the NOD2 mutation were steroid refractory but could be treated well with other immunosuppressants (Niess JH et al. Dig Dis Sci 2012;57:879-886). Researchers hope that these genetic insights will one day help provide IBD patients with a personalized prognosis, especially regarding the natural history of the disease, said Dr. Koltun. A genetic approach to IBD could help direct therapy over a lifetime for patients with CD, who are usually diagnosed in their 20s or 30s. The potential benefits of “knowing genetically what the future of a young IBD patient will be is tremendous,” Dr. Fichera said. “We don’t know what their outcomes will be so, today, we subject them all— and I would add blindly subject them all—to very standard medical approaches and surgical treatment without knowing,

in reality, who will benefit from them. We don’t know who needs a more aggressive approach, who needs surgery right away or, for that matter, who we are overtreating,” he said. “Imagine being able to let a 19-yearold girl who has her entire life ahead of her know if she needs aggressive therapy or an early surgery that could spare her years of treatment with the associated well-known side effects. That benefit is huge.”

To Operate or Not To Operate One recent study clearly demonstrates that genetic analysis is getting closer to shaping surgical decision making for patients with CD (Sehgal R et al. Dis Colon Rectum 2012;55:115-121). Dr. Koltun and his colleagues studied the genetic makeup of 66 patients (30 male) with ileocolonic CD who had undergone ileocolectomy and examined each patient for the 83 SNPs associated with IBD. They found that patients carrying the SNP rs4958847 in the IRGM gene underwent surgery once every 6.87 years (±1.33 years) compared with patients with the wildtype genotype who averaged one operation every 11.43 years (±1.21 years; P=0.001). P “The presence of this IRGM SNP [rs4958847] may be a marker for disease severity and/or early recurrence after ileocolectomy and may assist in surgical and medical decision making,” the investigators concluded. The results of the study also might help identify patients who can be spared expensive biologic therapies after surgery,

said Dr. Koltun. Most patients who undergo ileocolectomy eventually require a second procedure for recurrent disease; however, about one-fourth of patients will go 15 or 20 years before they experience a recurrence, he said. “That subset would be helpful to identify because those patients probably don’t need expensive and dangerous drugs like TNF [tumor necrosis factor]-antagonists or immunosuppressants. Those patients can get a very good response from surgery alone,” Dr. Koltun said. Patients with UC, too, stand to benefit tremendously from a personalized approach to surgical management. A genetic analysis could be used to help predict the likelihood of complications, such as fistuli or severe pouchitis following an ileal pouch; if the probability is high, then “you might decide not to do the operation,” Dr. Koltun said. Additionally, genetic analysis could be used to detect an IBD patient’s risk for cancer. “We could potentially save them from yearly colonoscopies, multiple biopsies or the risk for missing a cancer,” said Dr. Fichera. Experts say they expect that the management of patients with IBD will follow the paradigm of cancer care, where personalized medicine is becoming the standard. “I think this is not that different from colorectal cancer,” Dr. Koltun said. “I believe the use of genetic analysis probably will be a paradigm for care for all our patients in the future, as we approach this personalized medicine concept.” ■


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I N F L A M M AT O R Y B O W E L D I S E A S E

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

UCLA IBD Patients Get iPads To Use as ‘Virtual Hospitals’ Program Aims To Personalize Treatment and Improve Care Using iPad App By David Wild Physicians at the University of California, Los Angeles (UCLA) are arming more of their patients with inflammatory bowel disease (IBD) with iPads, asking them to share information on their symptoms, quality of life and productivity in real time. Daniel Hommes, MD, professor of medicine at UCLA and director of the UCLA Center for Inflammatory Bowel Diseases, believes closer patient contact through handheld technologies will help head off disease flares and reduce the incidence of complications. “The data patients provide through their iPads means we have a 24/7 grip on their disease and can instantly detect even slight changes in disease-related parameters,” Dr. Hommes told Gastroenterology & Endoscopy News. According to Dr. Hommes, the data that patients provide, as well any email correspondences that patients send through the web-based application, are read by nurse specialists who respond as needed, usually within 24 hours. Their responses might include a recommendation for a medication switch or for an office visit. “Essentially, we’re supplementing the direct care provided in the hospital setting with preventive care through a virtual hospital,” said Dr. Hommes. UCLA is providing iPads to patients in the program at no cost. In addition to features of the software that help patients track their symptoms, quality of life and productivity, the app includes three other programs: 1. “My Academy,” an online educational program that offers information about IBD, medications and common diagnostic tests; 2. “My Work,” a job coach that provides in-depth analyses of patients’ work ability and recommends suitable work adjustments in light of particular conditions; and

3. “My Coach,” a “mental reinforcement program” that evaluates common IBD-related problems such as coping, anxiety, depression, stress and pain, and directs patients to supportive resources. The program even provides traffic reports to patients en route to see their physician, so that their time spent on appointments is minimized, Dr. Hommes said.

Some Skepticism Sharon-Dudley Brown, PhD, FNP-BC, assistant professor in the Schools of Medicine and Nursing at Johns Hopkins University in Baltimore, said that she is excited about the potential for greater nurse involvement in IBD patient care, but she is wary of embracing a clinical decision-making model heavily based on remotely shared patient information. “I think technology is great, but it can’t replace clinical judgment and acumen, acumen,” Dr. Dudley-Brown Dudley Brown said, adding

that “we have no data showing this approach is superior to usual care that includes specialist IBD nurses.” Despite the absence of outcomes data demonstrating the UCLA program’s efficacy, Sunanda Kane, MD, professor of medicine in the Division of Gastroenterology and Hepatology at Mayo Clinic College of Medicine in Rochester, Minn., pointed to some benefits of the approach. “Apps like these are the wave of the future in terms of chronic disease management,” said Dr. Kane, who was not involved in the study. Dr. Kane pointed to a Dutch study showing that increased computer-based communication between patients with ulcerative colitis and their health care providers can reduce hospital and clinic visits, and shorten the period between symptom flares and medication changes (Elkjaer M et al. Gut 2010;59:1652-1661). see iPad IBD, page 13

“A simple graph on the iPad shows me exactly how my symptoms, quality of life and productivity have changed over time,” explained Hershel D. Sinay, a patient with ulcerative colitis who was the first to enroll in UCLA’s pilot program to evaluate the iPad application. Photo courtesy of UCLA

Disease Monitoring in IBD—There’s an App for That! By David Wild The following apps can be used to monitor symptoms, diet and medication use among patients with IBD. All of the apps generate graphic or PDF summaries of disease activity that can be shared with a health care provider. Unique features of each program are noted below. • GI BodyGuard from the Canadian Digestive Health Foundation (free for iPhone). Patients using this app can set reminders for medication use and water consumption. • GI Monitor from WellApps (free for Apple and Android devices). This app includes extensive food and drug databases. Patients can set medication alerts to improve drug adherence. The app also includes an IBD news feature. The program correlates symptoms with diet and medication use. • MyGiTrack from GI Track, LLC ($2.99 for Apple devices). This app includes an extensive food and medication database, as well as a list of bowel movement descriptions and disease-specific symptom descriptions. It also identifies possible symptom triggers. • myIBD from the Hospital for Sick Children, Toronto (free for Apple and Android devices). This app contains an educational component, including videos.

UCLA is currently developing “Value-based Insurance Designs,” a new software application for IBD patients that will offer rebates for their participation in their care. The health plans will take into account the severity of a patient’s illness and will include prespecified schedules of laboratory and clinic visits that patients will be expected to follow. Photo courtesy of UCLA


For the treatment of exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF) or other conditions

ULTRESA™ helps treat malabsorption* and stool symptoms 1-2 of EPI

Important Safety Information ™ Fibrosing colonopathy is associated with high-dose use of pancreatic enzyme replacement. Exercise caution when doses of ULTRESA exceed 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) ™ To avoid irritation of oral mucosa, do not chew ULTRESA or retain in mouth ™ Exercise caution when prescribing ULTRESA to patients with gout, renal impairment, or hyperuricemia ™ There is theoretical risk of viral transmission with all pancreatic enzyme products, including ULTRESA ™ In rare cases, patients taking pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase) have experienced severe allergic reactions including anaphylaxis, asthma, hives, and pruritus

 ™ The most common adverse reactions (*7% of patients treated with ULTRESA) were headache, pharyngolaryngeal pain, and epistaxis  ™ Use of ULTRESA in pediatric patients is limited by the available capsule dosage strengths and their ability to provide the recommended dose based on age and weight  ™ ULTRESA is not interchangeable with any other pancrelipase product *Reduction in malabsorption is shown by improvement in coefficient of fat absorption (CFA), primary endpoint, and coefficient of nitrogen absorption (CNA), secondary endpoint.1-2 References: 1. Konstan MW, Liou TG, Strausbaugh SD, et al. Efficacy fi and safety of a new formulation of pancrelipase (Ultrase MT20) in the treatment of malabsorption in exocrine pancreatic insufficiency fi in cystic fibrosis. Gastroenterol Res Pract. 2010. 2. Data on file (UMT20CF05-01), Aptalis Pharma US, Inc., Bridgewater, NJ.

 ™ Exercise caution when administering pancrelipase to a patient with a known allergy to proteins of porcine origin Please read brief summary of full US Prescribing Information on following pages.


ULTRESA (pancrelipase) delayed-release capsules, for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR ULTRESA (pancrelipase) delayed-release capsules: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE ULTRESA™ (pancrelipase) is a combination of porcine-derived lipases, proteases, and amylases indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions. 2 DOSAGE AND ADMINISTRATION ULTRESA is not interchangeable with other pancrelipase products. ULTRESA is orally administered. Therapy should be initiated at the lowest recommended dose and gradually increased. The dosage of ULTRESA should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet as described in the Limitations on Dosing below [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)]. 2.1 Administration Children and Adults ULTRESA should be taken during meals or snacks, with sufficient fluid. ULTRESA capsules should be swallowed whole. ULTRESA capsules p and capsule p contents should not be crushed or chewed. For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents sprinkled on a small amount of applesauce, yogurt and other acidic soft food with a pH of 4.5 or less at room temperature. The ULTRESA-soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion. Care should be taken to ensure that no drug is retained in the mouth to avoid mucosal irritation. Any unused portion of capsule contents should be discarded, and not used for subsequent dosing. The remaining exposed contents may lose potency and become less effective. 2.2 Dosage Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences. ULTRESA should be administered in a manner consistent with the recommendations of the Conferences provided in the following paragraphs. Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme. Children Older than 12 Months and Younger g than 4 Years and Weight g 14 kgg or Greater Children older than 12 months and younger than 4 years, weighing under 14 kg should not be dosed with this product because capsule dosage strengths cannot adequately provide dosing for these children. Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day. Children 4 Years and Older and Weight g 28 kgg or Greater and Adults Children 4 years and older, weighing under 28 kg should not be dosed with this product because capsule dosage strengths cannot adequately provide dosing for these children. Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day. Usually, half of the prescribed ULTRESA dose for an individualized full meal should be given with each snack. The total daily dosage should reflect approximately three meals plus two or three snacks per day. Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh more but tend to ingest less fat per kilogram of body weight. Limitations on Dosing: g Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines. If symptoms and signs of steatorrhea persist, the dosage may be increased by a healthcare professional. Patients should be instructed not to increase the dosage on their own. There is great inter-individual variation in response to enzymes; thus, a range of doses is recommended. Changes in dosage may require an adjustment period of several days. If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Doses greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of fibrosing colonopathy, in children less than 12 years of age [see Warnings and Precautions (5.1)]. Patients currently receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range. Use of ULTRESA in children is limited by the available capsule dosage strengths and their ability to provide the recommended dose based on age and weight. Attempting to divide the capsule contents in small fractions to deliver small doses of lipase is not recommended. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Fibrosing Colonopathy Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually with use over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in children less than 12 years of age. Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs. It is generally

recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day [see Dosage and Administration (2.2)]. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range. 5.2 Potential for Irritation to Oral Mucosa Care should be taken to ensure that no drug is retained in the mouth. ULTRESA should not be crushed or chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective enteric coating resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity [see Dosage and Administration (2.1) and Patient Counseling Information (17.1) in the full prescribing information] For patients who are unable to swallow intact capsules, the contents may be sprinkled on applesauce, yogurt and other acidic soft food with pH 4.5 or less. The ULTRESA-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion. 5.3 Potential for Risk of Hyperuricemia Caution should be exercised when prescribing ULTRESA to patients with gout, renal impairment, or hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels. 5.4 Potential for Viral Exposure from the Product Source ULTRESA is sourced from pancreatic tissue from pigs used for food consumption. Although the risk that ULTRESA will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported. 5.5 Allergic Reactions Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase). The risks and benefits of continued ULTRESA treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient. 6 ADVERSE REACTIONS The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and allergic reactions [see Warnings and Precautions (5.1, 5.3 and 5.5)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The short-term safety of ULTRESA was assessed in two clinical trials conducted in 40 patients with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF). Study 1 was conducted in 31 patients, ages 8 years to 37 years; Study 2 was conducted in 9 patients, ages 7 years to 11 years. Study 1 was a randomized, double-blind, placebo-controlled, crossover study of 31 patients, ages 8 to 37 years, with EPI due to CF. In this study, patients were randomized to receive ULTRESA at doses not to exceed 2,500 lipase units per kilogram per meal or matching placebo for 6 to 7 days of treatment, followed by crossover to the alternate treatment for an additional 6 to 7 days. The mean daily dose of ULTRESA was 6,270 lipase units per kilogram body weight per day. The mean exposure to ULTRESA during this study was 5.4 days. The most common adverse reactions (≥7%) were headache, pharyngolaryngeal pain, and epistaxis. Table 1 enumerates adverse reactions that occurred in at least 2 patients (greater than or equal to 7%) treated with ULTRESA at a higher rate than with placebo in Study 1. TABLE 1 Adverse Reactions Occurring in at Least 2 Patients (≥ 7%) in Cystic Fibrosis (Study 1) ULTRESA n=30 n (%)

PLACEBO n=31 n (%)

Headache

2 (7%)

1 (3%)

Pharyngolaryngeal Pain

2 (7%)

1 (3%)

Epistaxis

2 (7%)

0

Adverse Reaction

Study 2 was an open-label study of 9 patients, ages 7 years to 11 years, with EPI due to CF. After a screening period of up to 15 days on individually-titrated doses of ULTRESA not to exceed 2,500 lipase units per kilogram per meal, patients entered a washout phase (no treatment) of up to 7 days before returning to a treatment phase of up to 12 days on the same individually-titrated dose of ULTRESA. Two patients discontinued during the washout phase leaving 7 patients in the treatment phase. The mean daily dose of ULTRESA was 6,361 lipase units per kilogram body weight per day during the last 4 days of the screening phase, and was 6,846 lipase units per kilogram body weight per day during the treatment phase. The mean duration of the treatment phase was 5.7 days. Adverse reactions that occurred during treatment with ULTRESA were nasal congestion (14%), neck pain (14%), beta-hemolytic streptococcal infection (11%), ear pain (11%), and lymphadenopathy (11%). 6.2 Postmarketing Experience Postmarketing data for ULTRESA has been available since 2003. The safety data is similar to that described below. Because these reactions are reported voluntarily from a population of uncertain size,


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iPad IBD continued from page 10

However, she noted, a quantitative increase in communication is not without some downsides. “Certainly, tighter control of active symptoms and potential avoidance of steroids are big pluses to this program,” she said. “But the obvious downside with 24/7 access that patients may have to their health care providers is that some may abuse the system and overwhelm their providers with data that become meaningless.”

Improved Care, at a Cost? Increased communication may indeed come with some disadvantages, but Dr. Hommes believes that the bulk of information that patients share through their iPads will ultimately improve care. He explained that standardized information is fed into data warehouses, where it is processed and analyzed. Warehoused patient information is correlated with the most up-to-date epidemiologic data and clinical research findings from institutional, national and international levels, and the whole data set is used to direct clinical decision-making algorithms.

The decision-making support helps create “a truly personal care approach,” Dr. Hommes said. “We have already seen a tremendous drop in administrative burden, which allows us to spend more quality time with our patients.” In March, Hershel D. Sinay, aged 74 years, became the first patient to enroll in the iPad pilot program. (The pilot is now completed and the program is being offered to all patients at UCLA’s Center for Inflammatory Bowel Diseases.) For Mr. Sinay, using the iPad “keeps patients and doctors working together as a team. “Providing my medical team with input gives me a sense of empowerment over what I’m doing. This has been very important to me,” said Mr. Sinay, a magazine publisher diagnosed with ulcerative colitis in early 2012. “A simple graph on the iPad shows me exactly how my symptoms, quality of life and productivity have changed over time,” he said, adding that “it was easy to learn how to use the program.” Other patients have been equally receptive to the program, as evidenced by a 95% patient satisfaction score and

it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Pancreatic enzyme products (delayed and immediate-release) with different formulations of the same active ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has been described in the medical literature. The most serious adverse events included fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS), recurrence of preexisting carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus. The most commonly reported adverse events were gastrointestinal disorders, including abdominal pain, diarrhea, flatulence, constipation and nausea, and skin disorders including pruritus, urticaria and rash. 7 DRUG INTERACTIONS No drug interactions have been identified. No formal interaction studies have been conducted. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic g effects Pregnancy Category C. Animal reproduction studies have not been conducted with pancrelipase. It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ULTRESA should be given to a pregnant woman only if clearly needed. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency. Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth. Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ULTRESA is administered to a nursing woman. The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency. 8.4 Pediatric Use The short-term safety and efficacy of ULTRESA were assessed in two clinical studies in pediatric patients with exocrine pancreatic insufficiency due to cystic fibrosis; one study included patients aged 8 years to 17 years, and the other included patients aged 7 years to 11 years. Study 1 was a randomized, double-blind, placebo-controlled crossover study of 31 patients with exocrine pancreatic insufficiency due to cystic fibrosis including 2 children aged 8 to 11 years, and 12 adolescents aged 12 to 17 years. The safety and efficacy in pediatric patients in this study were similar to that in adult patients [see Adverse Reactions (6.1) and Clinical Studies (14) in the full prescribing information]. Study 2 was an open-label study of 9 pediatric patients, ages 7 years to 11 years, with exocrine pancreatic insufficiency due to cystic fibrosis. Patients showed similar control of fat malabsorption as in the treatment arm of Study 1 [see Adverse Reactions (6.1) and Clinical Studies (14) in the full prescribing information].

a dropout rate of only 2%, Dr. Hommes said. Handheld technologies will play an increasingly integral role at UCLA, as the institution is planning to offer a new IBD patient care approach beginning in 2013. “We are currently designing ‘Valuebased Insurance Designs’ for IBD patients that will offer rebates for their participation in their care,” Dr. Hommes said. The health plans will take into account the severity of a patient’s illness and will include prespecified schedules of laboratory and clinic visits that patients will be expected to follow. Between these visits, they will be asked to track their disease, quality of life and productivity using their iPads or other mobile devices for which UCLA is developing similar software. If, through close adherence to the plan and close monitoring of their disease, the costs of care at the end of one year are lower than the initially projected cost of a patient’s particular care plan, the savings will be redistributed and patients will receive a rebate on their premium or copay.

Time will tell if UCLA’s approach leads to the program’s desired outcomes, but IBD expert Alan Buchman, MD, MSPH, struck a cautionary note about relying too heavily on an algorithmic approach to treatment. “A program such as UCLA’s, which uses prognoses that are based on laboratory values and remotely reported disease signs and symptoms, does not take into account individual patient variations and threatens to ‘depersonalize’ the very patient for whom ‘personalized’ care is being offered,” Dr. Buchman said in an interview with Gastroenterology & Endoscopy News. “This is an important point in light of an increasing body of research suggesting that IBD is actually a group of many different diseases, rather than the limited number of illnesses that we’ve tended to treat all the same until now,” he said. “Nothing replaces doctor– patient interactions.” ■ None of the contributors reported any relevant conflicts of interest.

The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience. Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis Foundation Consensus Conferences. However, use of ULTRESA in children is limited by the available capsule dosage strengths and their ability to provide the recommended dose based on age and weight. Attempting to divide the capsule contents in small fractions to deliver small doses of lipase is not recommended [see Dosage and Administration (2)]. Doses of other pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy and colonic strictures in children less than 12 years of age [see Warnings and Precautions (5.1)]. 8.5 Geriatric Use Clinical studies of ULTRESA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 10 OVERDOSAGE There have been no reports of overdose in clinical trials or postmarketing surveillance with ULTRESA. Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures [see Dosage and Administration (2) and Warnings and Precautions (5.1)]. High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment [see Warnings and Precautions (5.3)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase.

Marketed by: Aptalis Pharma US, Inc. 22 Inverness Center Parkway Birmingham, AL 35242 USA Manufactured by: Aptalis Pharma S.r.L. Pessano, Italy 20060 ULTRESA and APTALIS are trademarks. © 2012 APTALIS PHARMA US, INC.


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New Assay More Sensitive in Measuring Infliximab Antibody Levels in IBD Patients But Clinical Implications Unclear By David Wild A novel assay is more sensitive than previous widely used assays in detecting serum antibodies to infliximab (IFX) and may capture more patients with low drug levels, researchers said at the 2012 American College of Gastroenterology annual meeting.

‘There is currently no gold standard technique for measuring IFX antibodies, and it is yet unknown if detected antibodies against IFX are in fact functionally active.’ —Casper Steenholdt, MD

Casper Steenholdt, MD, a physician in the Department of Gastroenterology at Herlev Hospital in Copenhagen, and his colleagues compared IFX levels and IFX antibody measurements in 67 patients with Crohn’s disease who recently had lost response to IFX using three assays: Anser IFX from Prometheus Labs, iLite from Biomonitor A/S (Copenhagen, Denmark) and solid-phase enzyme-linked immunosorbent assay (ELISA). These assays are used to determine whether a loss of response to IFX has occurred because of inadequate drug levels, IFX antibody formation or a combination

of the two. The Anser IFX assay uses a previously studied serum IFX cutoff of 3 mcg/mL to distinguish between IFX levels associated with loss of response and those associated with remission (Feagan B et al. Gastroenterologyy 2012;142[5 suppl 1]:S-114. Abstract 565). The assay has a

lower limit of detection (LLOD) of 3.13 laboratory units (U)/mL for measuring antibodies against IFX. In comparison, iLite and ELISA use IFX cutoffs of 0.5 and 1.4 mcg/mL, respectively, and have antibody LLODs of 10 U/mL and 0.56 U/mL, respectively.

The investigators found that iLite and ELISA classified 78% of patients the same, whereas Anser IFX and iLite were concordant in 71% of cases and Anser IFX and ELISA were concordant in 57% of cases. Anser IFX detected antibodies in 23 patients, whereas iLite did so in 18


GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

patients; ELISA detected drug antibodies in only six patients. Although Anser IFX was more sensitive in detecting antibodies to IFX, Dr. Steenholdt noted, “there is currently no gold standard technique for measuring IFX antibodies, and it is yet unknown if detected antibodies against IFX are in fact functionally active.” Dr. Steenholdt’s team also found that Anser IFX classified 44.8% of patients as having low drug levels compared with 38.8% with ELISA and 25.3% with iLite. Although the disagreement in serum

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IFX classifications is partly a reflection of the different cutoffs of the three assays, absolute IFX measurements differed significantly between the assays: The median IFX value with Anser IFX was 3.3 mcg/mL compared with 2.2 and 3.9 mcg/mL with iLite and ELISA, respectively (P<0.0001 for all). “The therapeutic implications of using different assays are substantial for those individuals who are classified differently,” Dr. Steenholdt said. However, Alan Moss, MD, of the Division of Gastroenterology at Beth Israel

Deaconess Medical Center and assistant professor of medicine at Harvard Medical School, both in Boston, argued that “from a clinical practice perspective, once a patient’s trough IFX level is below a certain threshold, additional information about exactly how low it is may not be clinically meaningful.” Furthermore, “the cutoff level of serum IFX below which patients should have their dose adjusted for optimal clinical efficacy has not been prospectively validated,” said Dr. Moss, who was not involved in the study.

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Nevertheless, he said, “the ability to measure IFX drug levels has become increasingly important in inflammatory bowel disease, as more studies report the association between low drug levels and loss of clinical response, and the results of this study primarily suggest that the new device is better than the old assays for detecting low levels of serum IFX.” ■ Dr. Steenholdt has served as a speaker for Abbott Laboratories, and as a speaker and consultant for Merck & Co. Dr. Moss has served as a consultant for Janssen Pharmaceuticals.

I Will Follow… Thank you, readers, for your enormous interest in our November 2012 cover story, “Twitter for Gastros: Twitter Deconstructed, in More Than 140 Characters,” by Christina Frangou. If you missed the article, it can be found on page 1 of our November issue, or online at gastroendonews.com. Furthermore, follow us on Twitter—@gastroendonews— to keep up with what we’re tweeting and who we’re following. We’re always updating our list of “Who To Follow.” At the 2012 American College of Gastroenterology (ACG) annual meeting in October, we started following, David T. Rubin, MD, who happened to be the ACG meeting’s “most frequently retweeted person!” You can follow Dr. Rubin at @IBDMD.

*Hepatic encephalopathy (HE) recurrence can come crashing in at any time—with catastrophic consequences HE recurrence is a constant, unpredictable threat for most patients. Yet, many go without maintenance therapy for their condition. Prescription claims data from 2011 reveal that 64% of outpatients are not taking any HE medication.1 Even for the minority who are on lactulose, 75% still develop recurrences of HE.2 With each recurrence threatening to leave them disoriented, confused, and less alert at any time, the damage can be devastating.

It’s time to do more to prevent HE recurrences and the damage they cause. Visit HEsBack.com to learn how to do even more to help your patients.

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 12/59-2

References: 1. Data on file. Salix Pharmaceuticals, Inc, Raleigh, NC. 2. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):1012-1017.

David T. Rubin, MD @IBDMD

Co-Director, University of Chicago Inflammatory Bowel Disease Center and Co-Founder, Cornerstones Health, Inc. a non-profit medical education organization


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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

Vedolizumab Beneficial as Maintenance Therapy for Crohn’s about half of the patients completed the study, which is typical of maintenance trials. Las Vegas—Vedolizumab, an anti-in ntegAt 52 weeks, clinical remission was seen rin therapy that targets α4β7 integrin n and in 39% of o patients who received the selectively blocks lymphocyte traaffickdrug every eight weeks, 36.4% ing to the gut, appears to be an eff ffective of tthose who received the drug induction and maintenance theraapy for evvery four weeks, and 21% of treatment of moderate to severe Crohn’s th hose in the placebo group. disease (CD), offering Enhanced clinical response— E another alternative for defined as a reduction from d patients who fail steroids, ba aseline in CDAI score of at ‘W With the opportunity to immunosuppressive agents leasst 100 points—was seen in substantially decrease the or other anti-tumor necro43.5% 5%, 45.5% and 30.1% of patients, sis factor (TNF) therapies. resp pectively, and corticosteroid-free risk for PML in a [gut-selective] “Current therapies for rem mission was seen in 31.7%, 28.8% anti-integrin ti integrin agent, ag this opens CD have important limiand d 15.9% of patients, respectively. tations you’re all aware of,” Among patients with prior antithe door to another avenue nue of treatment.’ tr William Sandborn, MD, TNF TN failure, clinical remission —Sunanda Kane, MD professor of medicine, was seen in 12.8% of patients, and University of California enhanced clinical response was seen San Diego, La Jolla, told in 20.5%. The same end points were attendees of the 2012 American Col- additional 748 patients received open- seen in 26.8% and 38% of anti-TNF– lege of Gastroenterology annual meeting. label induction therapy with vedolizumab. naive patients, respectively. “The aim of this integrated, clinical trial About half of the trial patients were men; “So unlike during the induction study program was to evaluate the efficacy and the average age was 35 years and the mean with vedolizumab where subgroup analysafety of vedolizumab for induction or sus- disease duration was eight to nine years. sis did not show a statistical benefit among tained therapy in CD.” The 461 patients who received vedoli- the patients who had previously failed The study (paper 42) demonstrated zumab induction therapy and whose anti-TNF therapy, as you get into the that vedolizumab is an effective induc- CDAI scores showed a reduction of at maintenance phase, you can see benefits tion therapy and is more effective than least 70 points at week 6 were randomized with vedolizumab, even in the patients placebo in maintaining clinical remission, to receive vedolizumab 300 mg every eight who had previously failed anti-TNF therclinical response and corticosteroid-free weeks, vedolizumab every four weeks or apy,” Dr. Sandborn said. remission. placebo. About half of these patients had “The magnitude of effect relative to plaIn the placebo-controlled induction experienced prior anti-TNF failure. Also, cebo was greater during the maintenance By Monica J. Smith

phase of the trial, 368 patients with Crohn’s Disease Ac Activity Index (CDAI) scores of 220 to 450 who had active inflammation despite treatment with one or a combinambination of corticosteroids, azathioprine, 6-mercaptopurine or anti-TNF agents—received two 300-mg induction doses of vedolizumab. An

Vedolizumab for UC continued from page 1

failed at least one previous therapy, according to new research presented at the 2012 American College of Gastroenterology annual meeting (abstract 5). “The reason the drug was developed specifically was to obtain gut-specific immune suppression,” said Brian Feagan, MD, director of clinical trials, Robarts Research Institute, in London, Ontario, Canada. “So far, based on what we’ve observed, it seems that that promise has come true.” In this double-blind, randomized, Phase III trial, patients who demonstrated a clinical response to vedolizumab induction therapy—defined as a 3-point reduction on the Mayo Scoring System for Assessment of Ulcerative Colitis Activity and a 30% decrease from baseline at week 6—were randomized to receive vedolizumab 300 mg every four weeks, vedolizumab 300 mg every eight weeks or placebo for 52 weeks. The primary end point was clinical remission, defined as a Mayo score of 2 or lower, and a subscore of less than 1 at 52 weeks. Researchers also looked at the secondary end points of durable clinical response, mucosal healing and corticosteroid-free remission at 52 weeks. Of the 895 patients who were enrolled in the induction phase of the trial, 373 were eligible to continue on to the maintenance phase. Of these, 125 were randomized to receive vedolizumab 300 mg every four weeks, 122 received vedolizumab 300 mg every eight weeks

and 126 received placebo. The mean patient age was approximately 40 years, and 60% of patients had received corticosteroids. “Importantly, approximately 40% of those patients had been exposed to anti-TNFs [tumor necrosis factor], and the majority had failed these agents,” Dr. Feagan said. Clinical remission at 52 weeks was significantly higher in both treatment arms—41.8% and 44.8% for those treated every four and every eight weeks, respectively— than in the placebo group, where 15.9% achieved the primary end point. Additionally, both treatment groups experienced significantly higher rates of durable clinical response (56.6% and 52% for the four-week and eightweek dosing groups, respectively) compared with the placebo group (23.8%). More patients in both treatment groups also experienced mucosal healing (51.6% and 56% for the four- and eight-week dosing groups, respectively) compared with the placebo group (19.8%). Corticosteroid-free remission occurred in 45.2% of patients who received vedolizumab at four-week intervals compared with 31.4% of those who received the drug at eight-week intervals, suggesting a better effect with shorter intervals of infusion, Dr. Feagan noted. “But we didn’t see an overall substantial difference in the treatment regimens,” he said. Furthermore, in a subgroup analysis of prior anti-TNF exposure, the placebo response was lower in patients with prior exposure, but the magnitude of clinical effect for both response and remission was similar whether patients had

phase of the study than during the induction phase,” he noted, adding that the same phenomenon has been observed with natalizumab, another anti-integrin monoclonal antibody, in patients with CD. Overall, the rates of adverse events (AEs), as well as AEs resulting in discontinuation, were relatively similar, with a slightly higher rate of drug-related AEs observed in patients who received vedolizumab. Commenting on the study, Sunanda Kane, MD, professor of medicine at Mayo Clinic, Rochester, Minn., said, “Although a good number of patients respond to antiTNF agents, there is the issue of declining response and immunogenicity. We need another mechanism of action to offer these patients. “With the opportunity to substantially decrease the risk for progressive multifocal leukoencephalopathy in a [gut-selective] anti-integrin agent, this opens the door to another avenue of treatment,” she continued. “The data are convincing for both [ulcerative colitis] and Crohn’s and the hard end point of remission was met. The safety profile is also favorable.” ■ This study was supported by Millennium Pharmaceuticals, Inc., which is developing vedolizumab. Dr. Sandborn has served as a consultant and has received grant/research support from Millennium and Takeda Pharmaceuticals.

prior anti-TNF exposure or were naive to those agents. Discontinuation due to adverse events, serious adverse events or serious infections was about the same in all groups, and the treatment groups did not exhibit increased opportunistic or enteric infections. One 66-year-old patient died from acute coronary syndrome 14 days after receiving the initial induction dose. “Our conclusion is that vedolizumab maintenance therapy at four or eight weeks is significantly more effective than placebo to achieve response and remission in anti-TNF–naive patients, or in those who had prior antiTNF failure,” Dr. Feagan said. David T. Rubin, MD, professor of medicine and codirector of the Inflammatory Bowel Disease Center at the University of Chicago, acknowledged the merits of the study. “One of the features that should not be overlooked is the remarkable safety outcome of having a drug look like a placebo,” he said. “That’s really important, due to the gut-specific mechanism of action of this therapy, and holds promise for this therapy as a safe option for our patients.” ■ This study was supported by Millennium Pharmaceuticals, Inc., which is developing vedolizumab. Dr. Feagan receives grant and research support from Merck & Co. Inc., Millennium Pharmaceuticals, Otsuka and other companies. Dr. Rubin did not report any conflicts of interest.


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Experts’ Picks

Best of the American College of Gastroenterology 2012: Part 1 COMPILED AND WRITTEN BY DAVID WILD

Gastroenterology & Endoscopy News asked several experts to select their favvorite abstracts from the 2012 American College of Gastroenterology (ACG) Annual Scientific Meetin ng. Following is a collection of their selections and comments that reflect the varied interests of the expeerts who we interviewed. Part 2 of this series will appear in the January 2013 issue of Gastroenteroloogy & Endoscopy News.

Brian Bosworth, MD Associate Professor of Medicine Division of Gastroenterology and Hepatology Jill Roberts Center for Inflammatory Bowel Disease Weill Cornell Medical College New York, New York

7.

Mesalamine Granules 1,500 mg Once Daily for 12 Weeks Provides Adequate Relief of IBS Symptoms in Irritable Bowel Syndrome with Diarrhea: Results from a Phase 2 Trial (Aron J et al) Uncontrolled, publicly available data suggesting that aminosalicylates may be used to treat patients with diarrhea-predominant irritable bowel syndrome (IBS-D) led these researchers to conduct a randomized, double-blind trial examining the efficacy of mesalamine granules in nearly 150 patients with Rome III–defined IBS-D. The researchers randomized 47 patients to receive mesalamine granules 750 mg, 51 to receive mesalamine granules 1,500 mg and 50 to receive placebo, all once daily for 12 weeks. The investigators documented improvements in abdominal pain, measured on a 10-point Likert scale, as well as stool consistency, which was measured using the Bristol Stool Form Scale. They compared the number of “monthly responders,” which they defined as patients who experienced an average weekly relief of abdominal pain of at least 30% relative to baseline for at least two of four weeks per month, as well as a 50% or greater reduction in the number of days in one week with poor stool consistency, also for at least two weeks per month. The researchers found that 47.1% of patients who received the 1,500-mg dose of mesalamine met the monthly response criteria compared with 28% of placebo recipients (P=0.04). P However, when they separated patients into those with C-reactive protein (CRP) levels higher or lower than 2.24 mg/L, only the former group experienced significant improvements compared with placebo. The number of monthly responders in the 750mg mesalamine group was not significantly higher than in the placebo group. The incidence of adverse events was similar across all three groups, the researchers reported.

Dr. Bosworth: Most prevvious studies examining the efficacy of mesalamine for IBS have been negative, with recent investigations speciifically focusing on postinfectious IBS. The contrasting findings from this study may be due to the different form mulation of the drug that was used, or they may reflect the use of a higher dose. Therefore, the generalizabilityy of the findings is specifically limited to the efficacy of the 1,500-mg dose of mesalamine granules. The use of a well-validated sttool consistency measure, the Bristol Stool Form Scale, means the investigators were able to quantify improvem ments in stool consistency in a very rigorous manner, lending strength to the findings. Although the study populaation was fairly small, the statistical significance of the difference in response is very promising. Future studies are warranted to validate and replicate these results. The findings have potentiaal implications for our understanding of IBS—specificcally, that the efficacy of an anti-inflammatory agent len nds credibility to the idea that there is an inflammatory coomponent to IBS. However, it is also possible that the subjects in this study had underlying microscopic colitis,, as mean CRP levels in both groups were elevated. Th herefore, the conclusions of the study also may be that mesalamine is effective for microscopic colitis.

250 mcg/g of stool, and endoscopic evidence of active CD within four months prior to screening. An incomplete or partial response to prior treatments for CD also was a requirement for study inclusion, with 48% of patients having either primary or secondary failure with anti-tumor necrosis factor (TNF) agents. At baseline, the mean Crohn’s Disease Activity Index (CDAI) score among patients was 326.2. In an intentVedolizumab Induction and Maintenance Therapy to-treat analysis, 14.5% of vedolizumab recipients and for Crohn’s Disease: Results of GEMINI II, a 6.8% of placebo recipients experienced clinical remisRandomized, Placebosion, defined as a CDAI Controlled, Double-Blind, score of 150 or lower by Multicenter Phase 3 Trial week 6 (P=0.02). P Clinical response, defined as ‘The findings are significant since Vedolizumab, a gut-selective a decrease of 100 points they include a large subset of monoclonal antibody that binds or more in CDAI score to α4β7 integrin, is a new class of relative to baseline, patients refractory to prior anti-TNF biologic agent being investigated was not significantly treatment.’ for the treatment of patients with different between the —Brian Bosworth, MD moderate to severe Crohn’s distwo groups (31.4% vs. ease (CD). 25.7%, respectively; In the induction phase of the P=0.23). Among those P GEMINI II trial (abstract P395), 368 patients with with prior anti-TNF failure, 10.5% and 4.3% of vedolimoderate to severe CD were randomized to receive IV zumab and placebo recipients, respectively, experienced vedolizumab 300 mg at days 1 and 15 or placebo, admin- clinical remission by week 6 (P P not available). Sixistered in a double-blind fashion. Patients included in the week remission rates in anti-TNF–naive patients were study had CRP levels higher than 2.87 mg/L, colonos- 17.4% and 9.2% in the two groups, respectively (P P not copy-confirmed active disease within four months prior available). to randomization or fecal calprotectin levels greater than see Best of ACG, page 18

42 & P395.


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Best of ACG continued from page 17

The 52-week double-blind maintenance phase of the GEMINI II trial (abstract 42) included 461 vedolizumab clinical responders from the induction arm as well as clinical responders from a separate open-label induction arm. Patients were randomized to receive vedolizumab every eight weeks (n=154), every four weeks (n=154) or placebo (n=153).

Data included a cumulative 212,917 patient-years, with a median follow-up of six years after UC diagnosis. Thirteen percent of patients had received thiopurines, and 15% of these were continuous users. Among these, the researchers identified 184 cases of non-Hodgkin’s lymphoma and five cases of Hodgkin’s lymphoma. Adjusting for age, gender and race, the investigators determined a lymphoma incidence of 3.2 cases per 1,000 patient-years in the group of ‘The finding that discontinuous thiopurine users did continuous thiopurine users not have a higher risk for lymphoma suggests that brief (range, 1.6-6). The incidence of immunosuppressive “drug holidays” should be explored lymphoma among discontinuous and non-users of thiopurines as a strategy to reduce the risk for lymphoma.’ was 0.7 and 0.8, respectively, per —Brian Bosworth, MD 1,000 patient-years.

Clinical remission rates at week 52 were 39% and 36.4% in the eight- and four-week vedolizumab groups, respectively, compared with 21.6% in the placebo group (P≤0.0042 P for both treatment groups vs. placebo). Clinical response was achieved in 43.5%, 45.5% and 30.1% of the groups, respectively (P≤0.01 P for both treatment groups vs. placebo). Subanalyses revealed that 31.7%, 28.8% and 15.9% of patients, respectively, achieved steroid-free remission at week 52 (P≤0.045 P for both treatment groups vs. placebo). Among the 51% of patients with prior anti-TNF failure, 28%, 27.3% and 12.8% of the three groups, respectively, achieved clinical remission at week 52 (P P not available); clinical response rates were 29.3%, 37.7% and 20.5%, respectively. Among those without prior anti-TNF exposure, 51.5%, 46.5% and 26.8% of patients, respectively, experienced clinical remission, and 60.6%, 53.5% and 38%, respectively, exhibited a clinical response at week 52. Dr. Bosworth: Vedolizumab is an exciting new compound for the treatment of CD. Its unique mechanism of action prevents the trafficking of white blood cells out of the gut vasculature and into the gastrointestinal (GI) tract, thus reducing inflammation. The findings are significant because they include a large subset of patients refractory to prior anti-TNF treatment. Currently, these patients have little in the way of treatment options, and many end up requiring surgery.

64.

Lymphoproliferative Disorders in Patients Receiving Thiopurines for Ulcerative Colitis: A Nationwide 10-Year Retrospective Cohort from the Veterans Affairs Healthcare System (Abbas A et al) Investigators set out to document the rate of thiopurine-associated lymphoma, a topic that has been studied previously with conflicting findings. The researchers prospectively examined medical records of 36,826 individuals with ulcerative colitis (UC) registered in the Veterans Affairs’ (VA) nationwide database between 2001 and 2011. They linked these data with thiopurine medication dispensing records from the VA pharmacy, specifically looking at the “percentage of days covered” (PDC) with thiopurines, a proxy measure of thiopurine use. PDC of at least 90% was considered “continuous” thiopurine use, whereas PDC between 0% and 90% was defined as “discontinuous” use.

Dr. Bosworth: Many studies have looked at the risk for lymphoproliferative disease in the setting of thiopurine treatment. Most recently, a European study of 1,400 patients with inflammatory bowel disease (IBD) found no increase in the risk for lymphoma with thiopurine use (Lakatos PL et al. J Crohns Colitis 2012 Jul 3 [Epub ahead of print]). The strengths of the current study are its use of a large database and the stratification of patients according to continuity of thiopurine use. Continuous thiopurine use in particular was associated with a threefold increase in the incidence of lymphoma, which is higher than previously reported. The study provides us with a good idea of the real-world hazard ratio of lymphoproliferative cancers in UC patients receiving thiopurines. Interestingly, the finding that discontinuous thiopurine users did not have a higher risk for lymphoma suggests that brief immunosuppressive “drug holidays” should be explored as a strategy to reduce the risk for lymphoma. Dr. Bosworth has consulted for Abbott Laboratories, Salix Pharmaceuticals and Shire, and has received grant/research support from Janssen Pharmaceuticals Inc., Pfizer Inc. and Salix Pharmaceuticals.

Filippo Cremonini, MD, PhD, MSc Director, Translational Research/ Motility Center Division of Gastroenterology Beth Israel Deaconess Medical Center/Harvard Medical School Boston, Massachusetts

P445.

Fecal Incontinence in U.S. Adults from 2005 to 2010: Epidemiology and Risk Factors (Ditah I et al)

This population-based analysis included data from 52,195 American adults who completed the National Health and Nutrition Examination Survey (NHANES) between 2005—when the Fecal Incontinence Severity

Index was added to the survey—and 2010. The researchers defined fecal incontinence as accidental leakage of solid or liquid stool or mucus at least once during the month preceding survey completion. Participants were aged 20 years or older, and the gender distribution in the study population was approximately equal. The investigators found an overall fecal incontinence prevalence of 8.27% over the five-year study period (95% confidence interval [CI], 7.83%-8.72%). Prevalence increased significantly from 6.96% in 2005-2006 to 8.58% in 2007-2008, and further to 9.01% in 20092010 (P<0.05 for 2007-2008 and 2009-2010 compared with 2005-2006). Leakage of liquid stool accounted for 4.85% of the prevalence of fecal incontinence, with solid stool and leakage of mucus accounting for 1.41% and 2.01% of incontinence rates, respectively. The distribution of leakage types did not fluctuate during the study period, the researchers reported. Fecal incontinence was numerically more common in women than in men (9.1% vs. 7.36%, respectively), but the difference was not statistically significant. The prevalence of fecal incontinence increased with older age, peaking at 17.46% among those aged 70 years and older. Multivariate analyses also revealed that education level and a diagnosis of diabetes were independent predictors of fecal incontinence. Dr. Cremonini: This large, cross-sectional study from Ditah et al provides insight into the epidemiologic features of fecal incontinence and demonstrates an overall increasing temporal trend in fecal incontinence prevalence.

‘As more treatments become available for fecal incontinence, a better understanding of its true disease burden is a key issue.’ —Filippo Cremonini, MD, PhD, MSc

The strength of the findings derives from its use of the well-established NHANES cohort and the inclusion of a validated Fecal Incontinence Severity Index. Moreover, the epidemiologic association of incontinence with the factors of age and diabetes—which is known to affect sphincter function—provides further support to the validity of these conclusions. As more treatments become available for fecal incontinence, a better understanding of its true disease burden is a key issue. Additional data on the degree of incontinence severity and overlap with other GI complaints from the same survey sample may become available in the future.

P1266.

Does Probiotic Use Increase the Risk for Developing Small Intestinal Bacterial Overgrowth? (Samuel M et al)

The prevalence of small intestinal bacterial overgrowth (SIBO)—a phenomenon associated with diarrhea, bloating and malabsorption—has been estimated to be see Best of ACG, page 20


Supported by

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Advances in Stent Technology for Esophageal Cancer Rafael S. Andrade, MD Associate Professor Section of Thoracic and Foregut Surgery University of Minnesota Medical Center, Fairview Minneapolis, Minnesota

Introduction Esophageal stricture and tracheoesophageal fistula in the setting of advanced esophageal cancer can have a devastating effect on quality of life due to severe dysphagia, aspiration pneumonia, and the inability to sustain nutrition or enjoy meals.1 Management of dysphagia is indicated for palliative purposes in patients with unresectable esophageal cancer1 and in order to optimize nutrition prior to surgery in the neoadjuvant setting.2,3 Historically, management of malignant dysphagia consisted of radiation therapy with or without systemic chemotherapy, endoscopic tumor ablation, stricture dilation or enteral feeding.4,5 Although radiation therapy provides excellent palliation, its effect is delayed by weeks.6,7

Esophageal Stenting Endoscopically placed stents are being used for immediate palliation of dysphagia as well as tracheoesophageal fistulae.1,3 The SIREC (Stent or Intraluminal Radiotherapy for Inoperable Esophageal Cancer) study found that newer stents produced more immediate relief of dysphagia than radiation therapy,8 although the latter offers a more durable result for patients with more than 3 months’ life expectancy.8 Thus, the paradigm of esophageal stenting for immediate relief followed by radiation therapy may be the most effective way to palliate dysphagia in patients with malignant dysphagia and a life expectancy of at least 3 months. The WallFlex® (Boston Scientific) fully or partially covered esophageal stent, constructed of multiple braided radiopaque nitinol wires, is indicated for the maintenance of esophageal luminal patency in malignant esophageal strictures or for the occlusion of concurrent esophageal fistulae.9

A prospective study10 assessed the clinical efficacy and safety of the esophageal WallFlex® stent for dysphagia palliation in 37 patients with esophageal cancer.10 Stent placement was successful in 36 of 37 patients, who experienced significant palliation.10 Major complications occurred in 3 patients (pneumonia in 1, severe pain in 2); 8 patients developed recurrent dysphagia because of stent migration, food impaction, or tissue ingrowth or overgrowth.10

Our Experience Multidisciplinary tumor board conferences present the perfect time to discuss our patients and select the most appropriate form of dysphagia palliation in esophageal cancer patients. The typical WallFlex® stent candidate at our institution presents with a T3 tumor and dysphagia; the stent is placed either for palliative purposes or to maintain nutrition and quality of life before neoadjuvant therapy and surgical management (Figure). Radiation therapists at our institution have no difficulty simulating and delivering treatment in the presence of an esophageal stent.11 For those patients who require nutritional support, I favor stenting in lieu of the placement of a jejunostomy feeding tube (J-tube). Placing a J-tube may require a 5-day hospital stay because bolus feeding needs to be gradually instituted. The stent is easier to place and quicker to re-establish enteral nutrition. Stent placement at our hospital is done under general anesthesia and fluoroscopic guidance, and is frequently performed at the time of endoscopic ultrasound staging. We do not predilate except when the

stricture is so tight that we cannot pass the deployment system. We usually select the 18-mm diameter stent to relieve solid-food dysphagia. In instances when the stricture is not as tight, we will place a 23-mm diameter stent. We tend to put in longer stents if we have to stent across the gastroesophageal junction due to tumor involvement since we believe they help address higher migration rates in these instances. We admit the patient for overnight observation and obtain a chest x-ray the following morning to confirm proper stent position. Patients receiving the esophageal stent are initiated on a clear liquid diet with a stepwise progression to a soft solid diet. The patient’s ultimate diet can be determined by trial and error. Patients who are stented across the gastroesophageal junction are instructed to follow aspiration precautions and prescribed twice-daily proton pump inhibitors. Patients are seen in the outpatient clinic 1 week after stent placement for symptom assessment and repeat chest x-ray to evaluate stent position and to assess clinical response. The majority of patients experience immediate dysphagia palliation, but patients often have variable amounts of retrosternal pain, which tends to resolve within 3 to 5 days with the use of oral narcotic pain medication. Reflux symptoms and stent migration remain concerns during follow-up of patients receiving esophageal stents. Stent migration very rarely requires emergent intervention or hospitalization. We usually perform endoscopy within 2 to 4 days. My advice for learning how to place the WallFlex® stent is to approach someone with significant experience and observe the procedure. Ask them how they select patients

Figure. Esophageal tumor before and after placement of the WallFlex® stent.

for this procedure, under which conditions they use general anesthesia and fluoroscopy, and how they ensure proper positioning, and make note of technical pearls.

References 1.

Sharma P, Kozarek R; Practice Parameters Committee of American College of Gastroenterology. Role of esophageal stents in benign and malignant diseases. Am J Gastroenterol. 2010;105(2):258-273.

2.

Pellen MG, Sabri S, Razack A, Gilani SQ, Jain PK. Safety and efficacy of self-expanding removable metal esophageal stents during neoadjuvant chemotherapy for resectable esophageal cancer. Dis Esophagus. 2012;25(1):48-53.

3.

D’Cunha J, Rueth NM, Groth SS, Maddaus MA, Andrade RS. Esophageal stents for anastomotic leaks and perforations. J Thorac Cardiovasc Surg. 2011;142(1):39-46.

4.

Gasper WJ, Jamshidi R, Theodore PR. Palliation of thoracic malignancies. Surg Oncol. 2007;16(4):259-265.

5.

Arends J, Bodoky G, Bozzetti F, et al. ESPEN guidelines on enteral nutrition: non-surgical oncology. Clin Nutr. 2006;25(2):245-259.

6.

Bown SG. Palliation of malignant dysphagia: Surgery, radiotherapy, laser, intubation alone or in combination? Gut. 1991;32(8):841-844.

7.

Siersema PD, Dees J, Van Blankenstein M. Palliation of malignant dysphagia from oesophageal cancer. Rotterdam Oesophageal Tumour Study Group. Scand J Gastroenterol Suppl. 1998;225:75-84.

8.

Homs MY, Steyerberg EW, Eijkenboom WM, et al. Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: multicentre randomised trial. Lancet. 2004;364(9444):1497-1504.

9.

van Boeckel PG, Siersema PD, Sturgess R, et al. A new partially covered metal stent for palliation of malignant dysphagia: a prospective follow-up study. Gastrointest Endosc. 2010;72(6):1269-1273.

10.

Boston Scientific, Inc. WallFlex® Fully and Partially Covered Esophageal Stents. http://www.bostonscientific.com/Device. bsci?page=HCP_Overview&navRelId=100 0.1003&method=DevDetailHCP&id=10115 032&pageDisclaimer=Disclaimer. Accessed October 31, 2012.

11.

Rueth N, Shaw D, D’Cunha J, Cho C, Maddaus M, Andrade R. Esophageal stenting and radiation therapy: a multimodality approach for the palliation of symptomatic malignant dysphagia. Ann Surg Oncol. 2012;10.1245/s10434-012-2459-3.

BB1168

Faculty

www.bostonscientific.com/endo-resources ENDO-114415-AA Nov2012

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between 8% and 40% in the general population (Ford AC et al. Clin Gastroenterol Hepatol 2009;7:1279-1286). Researchers in this study set out to test the hypothesis that probiotics that are not designed specifically to release in the colon may cause SIBO. To this end, investigators conducted a retrospective chart review of a random sample of 221 patients who had undergone duodenal aspirate culture at their institutions. They defined a positive culture as one with greater than 105 colony-forming units (CFU)/mL. Samples with between 0 and 105 CFU/mL were considered to be intermediate. The researchers conducted statistical analyses to determine correlations between culture findings and patient characteristics, as well as medication and probiotic use.

‘The information on the lack of an association between probiotic use and SIBO is useful for clinicians interpreting tests for SIBO.’ —Filippo Cremonini, MD, PhD, MSc

Forty-two percent of cultures were positive for SIBO, 33% were intermediate and 25% were negative. The researchers did not identify a link between probiotic use and SIBO but their analyses did reveal other risk factors: Older age increased the odds for SIBO by 37% for each 10-year increment, and the use of proton pump inhibitors (PPIs) or narcotics led to a fivefold increase in risk; IBS, IBD, pancreatitis, small bowel diverticula, history of GI surgery and intestinal pseudo-obstruction were not associated with SIBO. Dr. Cremonini: This provocative study explores the epidemiologic features, treatment factors and comorbidities of a population with a prior diagnosis of SIBO. The researchers used duodenal aspirate culture as a diagnostic tool for SIBO. Although this tool is costly and not widely available, it remains the reference standard. The high proportion of patients in this study with positive cultures likely reflects the selection bias of a population with multiple underlying GI diagnoses. The information on the lack of an association between probiotic use and SIBO is useful for clinicians interpreting tests for SIBO. The findings are strengthened by the population size, and the quality and accuracy of the information available for retrospective chart review. The conclusions also are supported by the clinical soundness of the associations between age, narcotic or PPI use, and diagnosis of SIBO.

P1559.

Effects of Linaclotide on Abdominal and Bowel Symptoms Over the First Seven Days of Treatment in Patients with Irritable Bowel Syndrome with Constipation (Chang L et al) This study was a pooled analysis of data from two multicenter, randomized, placebo-controlled Phase III

trials examining linaclotide—an orally administered, minimally absorbed guanylate cyclase C agonist—for the treatment of IBS with constipation (IBS-C). The researchers used an intent-to-treat analysis to examine results within the first week of treatment for 805 patients with IBS-C who received linaclotide 280 mcg and 797 patients who received placebo, both once daily. The researchers evaluated several measures of IBS-C symptoms, which patients rated on an 11-point Likert scale. They also examined changes in daily stool consistency using the Bristol Stool Form Scale, and compared rates of spontaneous and complete spontaneous bowel movements (SBMs and CSBMs, respectively) during the first seven days of treatment. The investigators found that linaclotide recipients experienced significantly greater improvements in measures of bloating, fullness, stool consistency and straining than did placebo recipients by the first day, with significant reductions in pain and discomfort by the second day of treatment. Linaclotide also was associated with statistically significant improvements in stool consistency and relief of straining by the first day compared with placebo. Cramping initially worsened among patients in the linaclotide group, but improved significantly by the fourth day compared with baseline and placebo recipients. Additionally, 48.6% of linaclotide recipients reported one or more SBM on day 1 compared with 23.7% of placebo recipients (P<0.0001). The percentage of patients in the linaclotide and placebo groups reporting a SBM increased to 56.8% and 39.9%, respectively, on the second day (P<0.0001). Additionally, approximately 20% of linaclotide recipients experienced a CSBM on the first day of treatment compared with 5.5% of placebo recipients (P<0.0001); this number remained stable in the linaclotide group throughout the seven days but increased to 13% in the placebo group by the last day. Median time to first CSBM was five days in the linaclotide group and 20 days in the placebo group (P<0.0001). Ten percent of linaclotide patients reported diarrhea at least once during the study period compared with 0.4% of placebo recipients.

‘Overall, these findings provide a roadmap for the prescriber to understand the initial foreseeable effects of linaclotide in patients with IBS.’ —Filippo Cremonini, MD, PhD, MSc

Dr. Cremonini: There has been a wealth of data presented from linaclotide studies, including analyses and subanalyses in patients with IBS-C and chronic constipation. The uniqueness of this particular post-hoc analysis of two large linaclotide trials resides in providing a set of useful information for clinicians on the mode and timing of onset of the drug’s clinical effect in patients with IBS-C. These data support an early mechanism of action of linaclotide regarding almost all cardinal symptoms of IBS-C, and the effects appear to be of a clinically relevant magnitude. Notably, there was an initial, paradoxical worsening of abdominal cramping in patients on linaclotide, while measures of abdominal pain and bowel

function improved. This effect is likely a result of the induction of the initial bowel movement. Overall, these findings provide a roadmap for the prescriber to understand the initial foreseeable effects of linaclotide in patients with IBS. Dr. Cremonini serves on the advisory board for Forest Laboratories and Ironwood Pharmaceuticals, and is on the Data Safety Monitoring Board of Alkermes plc.

Timothy Gardner, MD Assistant Professor of Medicine Geisel School of Medicine at Dartmouth Director of Pancreatic Disorders Section of Gastroenterology Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

53.

Alterations in Cross-sectional Imaging and Cyst Fluid Genetics Following Endoscopic Ultrasound Guided Pancreatic Cyst Ablation with Ethanol and Paclitaxel (DeWitt JM et al) Researchers prospectively examined pancreatic cyst fluid for DNA changes, as well as the rate of cyst resolution and procedure-related complications, following endoscopic ultrasound-guided pancreatic cyst ablation (EUS-PCA) using ethanol and paclitaxel. Twenty-two patients underwent EUS-PCA using a 22-gauge needle and EUS-guided lavage for three to five minutes with 100% ethanol, followed by re-aspiration and injection of paclitaxel 2 mg/mL, which was left in place. Follow-up EUS was conducted three months later, and cyst remnants 10 mm or larger were ablated. Researchers identified 12 patients with intraductal papillary mucinous neoplasms, six with mucinous cystic neoplasms and four with serous cystic neoplasms. The median cyst carcinoembryonic antigen (CEA) level at baseline was 315 ng/mL. Median maximum cyst diameter at baseline was 25 mm (range, 14-43 mm), with eight patients having septations and six with mural nodules. At the time of aspiration, no patients had active pancreatitis, necrosis, varices, ascites, coagulopathy or dilated pancreatic ducts. Fluid DNA mutations were present in half of the patients at baseline, including five patients with mutations in the Krass gene alone, one patient with a Kras gene mutation and one allelic loss, two patients with two allelic losses and no Krass mutations, and three patients with one allelic loss and no Krass mutations. Among 19 patients who underwent a second EUS procedure, median cyst volume decreased by 77% (range, 72.8%-99.7%), the researchers found. Eight patients experienced complete elimination of all baseline mutations; however, new allelic losses appeared in three patients. No new allelic losses occurred in the eight subjects without baseline mutations. see Best of ACG, page 22


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ACG 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

Best of ACG continued from page 20

At follow-up EUS, 50% of patients met complete response criteria (defined as cyst volume <5% of baseline), 25% experienced a partial response (cyst volume 5%-25% of baseline) and 25% experienced persistent disease (cyst volume >25% of baseline). Procedure-related complications included abdominal pain (23%), pancreatitis (10%), peritonitis (3%) and formation of gastric wall cysts (3%).

Dr. Gardner: This pilot study evaluated the mutation response of pancreatic cysts to a novel treatment option—EUSPCA with injection of ethanol and paclitaxel using fine-needle aspiration. Most patients had a decrease in cyst volume, but more importantly, eight patients had elimination of baseline mutations, and there were no changes in cyst mutations in eight patients without a baseline mutation, suggesting that

‘Eight patients had elimination of baseline mutations, and there were no changes in cyst mutations in eight patients without a baseline mutation, suggesting that ablation can result in loss of baseline mutations and prevent new mutations from forming.’ —Timothy Gardner, MD

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ablation can result in loss of baseline mutations and prevent new mutations from forming. However, because three patients developed allelic losses despite undergoing ablation, it is clear that not every mutation can be eradicated using this technique, leaving some patients at risk for developing malignancies. A shortcoming of this procedure is its unacceptably high complication rate, with pancreatitis occurring in 10% of patients and peritonitis in 3% of patients in this study. A limitation of this study is its lack of long-term follow-up. The study did not evaluate the long-term, natural history of pancreatic cyst formation because all of the patients underwent treatment. Therefore, it is unknown whether these cysts would have eventually resolved, or grown and progressed into malignancies. Furthermore, the characteristics of the cysts that did not respond to ablation are unclear from the abstract.

P663.

Lessons From Clinical Trials on Early Aggressive Intravenous Hydration in Acute Pancreatitis: A Meta-analysis (Rahmani R et al) Although recent clinical studies evaluating the efficacy of early aggressive intravenous hydration (EAIH) for acute pancreatitis have yielded conflicting results, clinical guidelines have stated uniformly that this is an important element in the treatment of patients with this condition, according to the authors of this abstract. In light of this controversy, the authors conducted a systematic meta-analysis of nine consecutive (prospective and retrospective) studies on the topic. The studies included 668 patients who underwent EAIH and 511 controls, with both groups having similar baseline disease and demographic characteristics. Patients in the EAIH group received an average of 4.325 L rehydration solution during the first 24 hours of treatment compared with an average of 2.643 L for the control group. The authors analyzed


GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

the data based on gender, etiology off pancreatitis and volume of pancreatic fluid present, as well as rates of organ failure, necrosis, mortality and volume of hydration administered within 24 to 72 hours. The data revealed no significant differences in rates of organ failure, pancreatic necrosis, morbidity or mortalityy between the EAIH and control groups. However, patients who received more aggressive hydration during the first six to 12 hours of treatment had lower rates of morbidity and mortality compared with those who did not (P=0.02). Additionally, when the analysis excluded studies that included only patients with severe acute pancreatitis, there was a significant reduction in rates of organ failure and pancreatic necrosis in patients who received EAIH during the first 24 hours (P=0.03).

ACG 2012

23

The best-read publication in gastroenterology offers Th aan n e-newsletter that alerts you to highlights from the most recently published issue. m Register to receive the FREE e-newsletter at R www.gastroendonews.com.

New

‘The authors’ conclusion that aggressive fluid resuscitation early in the course of disease appears to be beneficial supports what we know from clinical experience.’ —Timothy Gardner, MD

Dr. Gardner: This study is the first meta-analysis performed on the issue of fluid resuscitation in patients with acute pancreatitis. As such, it is an important work in the pancreatology community. The authors’ conclusion that aggressive fluid resuscitation early in the course of disease appears to be beneficial supports what we know from clinical experience. And although the nine published trials are likely heterogeneous, the message about early resuscitation remains clear. The study is limited by the fact that there is a dearth of randomized, controlled trials in this area, and the fact that a summary statistic of the studies was not reported, at least in abstract form. Hopefully, this work will stimulate further exploration of this important topic and lead to more randomized controlled trials. The gastroenterology community needs to understand more about the perceived benefits and possible harms of aggressive fluid resuscitation. Dr. Gardner reported no conflicts of interest.

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ACG 2012

Colonoscopy Guideline continued from page 1

author of the new guidelines. Forty-five new papers on surveillance outcomes after baseline colonoscopy were published in the interval between the preparation of the previous guidelines (Winawer SJ et al. Gastroenterologyy 2006;130:1872-1885) and the latest review of the literature by the current authors. The new document points out that important lesions can be missed at baseline colonoscopy: Adenomas may be incompletely removed at baseline colonoscopy and higher-quality baseline colonoscopy is associated with a lower risk for interval colorectal cancer. Moderate-level evidence now exists to support the following recommendations following baseline colonoscopy: • A 10-year surveillance interval for negative results or small hyperplastic polyps found in the rectum or sigmoid colon. • A five- to 10-year surveillance interval for findings of one to two small (<10 mm) tubular adenomas. • A three-year interval for findings of three to 10 tubular adenomas, one or more tubular adenomas of at least 10 mm in diameter, one or more villous adenomas, or adenoma with highgrade dysplasia. • A less than three-year interval in cases where 10 or more adenomas are found. • A one-year interval for cases of serrated polyposis syndrome.

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

The guideline also contains the first set of recommendations for serrated polyps, but these are based on low-level evidence, as this is a relatively new and evolving field. The authors call for a five-year screening interval—the same as that for low-grade dysplasia—when sessile serrated polyps less than 10 mm in diameter, with no dysplasia, are found on baseline colonoscopy. The guidelines ess also a so call for a shorter interval of three years, which is the same as that for high--grade dysplasia, following a baseline findiing of sessile serrated polyps that are 100 mm or larger in diameter, polypss with dysplasia, or traditional ser-rated adenoma. “The other significant changee in the new guidelines, and I thinkk this is a very important one, is that we addressed what to do after the first surveillance colonoscopy,” Dr. Lieberman said. “Should [patients] keep coming back again and again for surveillance? We found three fairly large new studies that address this, and while the evidence is weak because there was incomplete follow-up of the patients in the study cohorts, it was consistent across the three studies and so we felt it warranted recommendations.” The authors also call for a three-year interval for a second surveillancce colonoscopy for a baseline low- or high-risk adenoma followed by a highrisk adenoma on first surveillance colonoscopy, and a five-year interval ffor or a

Intubation Time continued from page 1

take into account intubation time, according to research presented at the 2012 American College of Gastroenterology annual meeting (paper 12). “Little is known about the relationship between intubation time and withdrawal time and the association with ADRs,” said Erika Boroff, MD, instructor in medicine at Mayo Clinic, Scottsdale, Ariz. “The aims of our study were to assess whether the relationship between intubation time and withdrawal time influences ADRs, and to identify markers of a technically difficult colonoscopy.” Dr. Boroff and her colleagues reviewed endoscopy and pathology reports from 1,797 screening colonoscopies performed by 20 experienced gastroenterologists during a one-year period. The researchers collected data on patient demographics, bowel preparation quality, time required to intubate to cecum and the time used to withdraw the scope. They also collected data on endoscopist measures, such as ADR and polyp detection rate (PDR), the means of which were 29.7% and 47.6%, respectively. The investigators defined a difficult colonoscopy as one in which the intubation time was longer than the mean of 11.6 minutes, or if the endoscopist required assistance for endoscope advancement. Patient

low-risk adenoma on first surveillance colonoscopy. They recommend a full 10-year interval for a baseline low-risk adenoma, followed by no adenoma at first surveillance. They also recommend a five-year interval for a high-risk adenoma followed by no adenoma. The guidelines also address how to proceed if there is a poor bowel preparattion o in tthee base baselinee colonoscopy co o oscopy or o if a patient has a positive fecal occult blood test before the next scheduled surveillance colonoscopy. “The guidelines are very

intolerance was characterized by the need for additional opioids or when nurses reported patient tolerance as “fair” or “poor.” Mean intubation and withdrawal times for the procedures were 11.6 and 12.3 minutes, respectively. When intubation required more time, withdrawal times were shorter; conversely, endoscopists spent more time withdrawing the scope when intubation was speedier than average. The investigators found that procedure time remained about the same regardless of which portion of the exam took more time; however, ADRs were lower in procedures in which intubation time exceeded withdrawal time. Longer intubation times were associated with markers of a difficult colonoscopy, such as needing assistance to advance the endoscope by repositioning the patient or applying external abdominal pressure. Longer withdrawal times were associated with polypectomy. “This suggests that most endoscopists are removing polyps upon withdrawal,” Dr. Boroff said. Controlling for the number of polyps removed and for other factors that may affect ADRs—such as quality of bowel preparation, patient age and gender—the investigators found that when withdrawal exceeded intubation time, the odds for detecting an adenoma were 2.1. Furthermore, for each minute that withdrawal time exceeded intubation, ADRs climbed by 8%. “In conclusion, when intubation times are prolonged,

reasonable and I do follow them routinely,” said Daniel Chung, MD, who was not involved in the creation of the new guidelines. “It is important to note, though, that these recommendations serve as guidelines, and there may be cases where individualization is necessary.” ■ Drs. s. Lieberman Liebe man and Chung reported epo ted no conflicts of interest.

endoscopists may be compromising withdrawal time, negatively affecting ADRs,” Dr. Boroff suggested. “Prolonged intubation may be a marker of difficult colonoscopy,” she added. Difficult colonoscopy may require additional withdrawal time for the endoscopist to inspect folds carefully and maintain adenoma detection, she said. “Maneuvers to assist scope advancement are associated with a reduction in adenoma detection, but additional opioid dosing and nursing report of patient intolerance were not associated with a reduction in ADRs,” Dr. Boroff noted. Douglas K. Rex, MD, Distinguished Professor of Medicine at Indiana University Medical Center, in Indianapolis, said that the study provides an interesting glimpse into how human factors affect colonoscopy outcomes. “This suggests we may be scheduling colonoscopies too closely together for average insertion times to be followed by consistently adequate examination times during withdrawal,” he said. “This is a very useful observation that may lead to a practical recommendation for endoscopists with regard to insisting on adequate withdrawal technique and time in every examination, including in those patients with difficult and prolonged insertions.” ■ The sources did not report any relevant conflicts of interest.


ACG 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

25

ADRs in Surveillance Higher Than in Screening Colonoscopy Should Benchmarks Be Changed? By Monica J. Smith Las Vegas—Adenoma detection rates (ADRs) may be higher for surveillance colonoscopy than for screening colonoscopy, according to research presented at the 2012 American College of Gastroenterology (ACG) annual meeting (paper 11), suggesting that separate benchmarks should be considered for the different types of exams. “There is very little data examining the ADR for surveillance versus screening exams,” said Joseph C. Anderson, MD, associate professor of medicine, Dartmouth College, Lebanon, N.H., who presented research at the ACG meeting on behalf of Lynn F. Butterfly, MD, director of the New Hampshire Colonoscopy Registry. “The aim of our study was

to determine whether or not the ADR is similar for surveillance and screening exams using the New Hampshire colonoscopy registry.”

Dr. Anderson and his colleagues conducted an analysis of 8,300 screening and surveillance examinations conducted at 16 centers between April 2009 and

‘[The data] support continued surveillance for subcentimeter advanced adenomas at intervals similar to those for advanced adenomas equal to or greater than 10 mm.’ —Andrew B. Cummins, MD Suggested ADR benchmarks for screening colonoscopy are 25% in men, 15% in women and 20% overall. Dr. Anderson’s group sought to determine if ADRs in surveillance exams would be higher in high-risk patients with known detected adenomas and lower in patients whose colons were previously clear of adenomas, or the same.

March 2011. The researchers included patients who had first-degree relatives with colorectal cancer or colon polyps, and excluded patients with familial syndromes or inflammatory bowel disease and those younger than 50 years of age. Cases where bowel preparation was documented as anything less than good or excellent, and cases with an indication

Advanced Adenomas Smaller Than 5 mm Predict Same Long-Term Risk As Larger Lesions, Study Says BY TED BOSWORTH SAN DIEGO—A retrospective comparison of five-year outcomes in patients with advanced adenomas revealed little, if any, association between adenoma size and the risk for having a polyp, adenoma or advanced adenoma over the course of follow-up. “There was no significant difference in the rates of advanced adenomas on follow-up exam for patients with subcentimeter advanced adenomas on initial colonoscopy compared with those with centimeter or greater advanced adenomas,” said Andrew B. Cummins, MD, of the Division of Gastroenterology and Hepatology, Scripps Health, La Jolla, Calif. Presenting the data at the 2012 Digestive Disease Week meeting, Dr. Cummins concluded that the results of the study “support continued surveillance for subcentimeter advanced adenomas at intervals similar to those for advanced adenomas equal to or greater than 10 mm.” The retrospective study was based on 248 patients with advanced adenomas who were identified in a database of 4,967 consecutive patients referred for colonoscopy. Dr. Cummins’ team stratified patients into three groups: those with advanced adenomas less than 5 mm in size, those with advanced adenomas 6 to 9 mm in size and those with advanced adenomas of at least 10 mm. Patients were followed for up to five years. Approximately half of the cohort had a repeat colonoscopy at an average of 35 months after baseline examination. In the group with the smallest advanced adenomas at initial examination, 59% had a polyp on repeat examination, of which 77% were adenomas and 21% were advanced adenomas. Of the patients with 6- to 9-mm adenomas at initial examination, 68% had a polyp on repeat examination, of which 76% were adenomas and 18% were advanced adenomas. And in the

group with the largest adenomas, 50% had a polyp on repeat examination, of which 68% were adenomas and 18% were advanced adenomas. Although those with the largest baseline advanced adenomas were twice as likely to have an advanced adenoma at follow-up defined by size rather than histology (12% vs. 6%) than either those with 6- to 9-mm lesions (4.5% vs. 13.5%) or the smallest lesions (5% vs. 16%), the overall rate of advanced adenomas did not differ significantly among the three groups. Although an adenoma of at least 10 mm is considered an advanced lesion by definition, this study suggests that the likelihood of developing a new advanced lesion during follow-up is similar for patients with smaller advanced adenomas defined by histology. The results of the study support the “null hypothesis that there is no difference in outcomes of patients with centimeter or greater advanced adenomas compared to subcentimeter advanced adenomas at five years of follow-up,” Dr. Cummins said. Linda Cummings, MD, MS, assistant professor of medicine at Case Western Reserve University School of Medicine, in Cleveland, called the data “intriguing.” However, she suggested that the results “should be interpreted with caution due to the study’s retrospective design.” Dr. Cummings questioned whether the researchers sufficiently controlled for other factors that could have affected the rate of advanced adenomas in the three groups, such as the total number of adenomas at index colonoscopy, surveillance interval, family history, quality of bowel preparation and colonoscope withdrawal time. Additionally, “the 5% rate of advanced adenomas overall was somewhat lower than the 6% to 10% rate reported from other large endoscopic databases, suggesting that the population in this study might have had a lower colorectal cancer risk,” Dr. Cummings noted.

that the procedure was incomplete, also were excluded. For screening colonoscopy, the researchers found an overall ADR of 22% compared with 32% for surveillance colonoscopy. ADRs in both types of exams were higher in men than in women, but were much higher for surveillance colonoscopy: In men, the ADR was 38% for surveillance compared with 27% for screening, and the ADR was 25% and 18% in women for surveillance and screening, respectively. This trend was observed in patients aged 50 to 65 years, but not in those older than 65 years of age. Dr. Anderson noted that the study does have some limitations, including the homogeneous nature of the population of New Hampshire, but nevertheless has many implications. “It suggests that ADRs are higher in surveillance than in screening exams, thus a higher benchmark should be used for surveillance exams than is currently used for screening,” he said. “Providers of surveillance and screening exams need to be cognizant of these findings when they calculate their ADRs for quality purposes,” he added. “Adding the surveillance examinations to the screening colonoscopies may distort the screening ADR by falsely elevating the rate. Finally, we may need separate ADRs for age and gender,” he said. Douglas K. Rex, MD, Distinguished Professor of Medicine, Indiana University Medical Center, Indianapolis, noted that although quite a few studies during the past three decades have described the yield of post-polypectomy surveillance procedures, few of those descriptions have included a control group of patients undergoing screening colonoscopy. “The study by Anderson et al indicates that for now we should stay with the 2006 American Society for Gastrointestinal Endoscopy/ACG Taskforce recommendations [Rex DK et al. Am J Gastroenterol 2006;101:873-885] to measure ADR in screening patients,” he said. “The targets for ADR … were derived from screening studies.” Additional studies of this type, Dr. Rex added, will be needed to understand optimal target ADRs for surveillance exams, diagnostic exams or for all indications combined. “In the meantime, we should measure ADRs in screening exams as is already recommended in guidelines,” he said. ■ The sources did not report any relevant conflicts of interest.


26

SAGES 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

Surgeons Explore Options for Medically Refractory Gastroparesis Laparoscopic Subtotal Gastrectomy Promising; Temporary GES Tested as Predictor of Response By Monica J. Smith

‘It would be important San Diego—Gastric electrical stimulation (GES) can improve symptoms in patients with gastroparesis, but after retrospectively reviewing patient outcomes, researchers at the University of Southern California are now offering laparoscopic subtotal gastrectomy to these patients as a primary treatment option. “Our initial algorithm for patients with medically refractory gastroparesis who needed surgery was placement of a stimulator as a first line of treatment, and if that fails, a laparoscopic subtotal gastrectomy,” said Joerg Zehetner, MD, assistant professor of surgery in the Department of Surgery, Keck School of Medicine, University of California, Los Angeles, who presented the research at the 2012 annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). “But now, after our study, we think we should tell patients right away that laparoscopic subtotal gastrectomy also can be seen as a primary therapy because it has a significantly higher rate of symptom improvement, acceptable morbidity and comparable mortality to GES.” The study was published ahead of print in Surgical Endoscopy (Zehetner J et al. 2012 Jun 30 [Epub ahead of print]). The researchers, led by John C. Lipham, MD, evaluated outcomes in 103 patients who received treatment at their center for medically refractory gastroparesis between January 2003 and January 2012; 72 patients received GES by either laparoscopy (n=20) or mini-incision (n=52), and 31 patients received a laparoscopic subtotal (n=27), total (n=1) or completion gastrectomy (n=3). Thirty-day morbidity was significantly greater in the gastrectomy groups than in those who received GES (23% vs. 8%) but this difference leveled out over time. Inhospital mortality was about 3% for both groups. About two-thirds (63%) of the patients in the GES group achieved symptom improvement as assessed by the Gastroparesis Cardinal Symptom Index, whereas 87% of those in the gastrectomy group reported significant relief of nausea, vomiting, epigastric pain and other symptoms that plague gastroparesis patients. In the GES group, 19 patients (26%) had to have the device removed due to device malfunction, infection or failure to respond; these patients received laparoscopic subtotal gastrectomies, and 100% reported symptom relief. Notably, of the patients who failed GES,

to know the factors ahead of time that might predict which patients would be more likely to improve following gastric

‘We think we should

electrical stimulation,

tell patients … that

resection or other

laparoscopic subtotal

procedures.’

gastrectomy also can

—Daniel J. Deziel, MD

be seen as a primary therapy because it has a significantly higher rate of symptom improvement, acceptable morbidity and comparable mortality to GES.’ —Joerg Zehetner, MD

80% had diabetes-related gastroparesis. “This was a little unusual because you would expect those with diabetes gastroparesis to respond better” than patients with idiopathic or postsurgical gastroparesis, Dr. Zehetner said. In conclusion, the researchers recommended laparoscopic subtotal gastrectomy as a primary treatment, and to reserve GES for patients who don’t want a gastrectomy or a more invasive procedure. “The good thing about the stimulator is that we can see it as a breaching treatment; it does not prevent us from doing a gastrectomy,” Dr. Zehetner said. Daniel J. Deziel, MD, Helen Shedd Keith Professor and chair of the Department of General Surgery, Rush University, Chicago, found it interesting that there was no statistically significant difference in morbidity and mortality between the two groups. “One might intuitively think GES a safer approach. Perhaps the number of patients in each group was too small to detect a difference, or perhaps this simply reflects the fact that this is a seriously compromised patient population to start with,” he said. “It would be important to know the factors ahead of time that might predict

which patients would be more likely to improve following GES, resection or other procedures that have been used,” he added. “Is success related to the etiology of the disease? If we knew this, we might be more effective in terms of our initial therapeutic recommendations, and could perhaps identify patients who would not benefit from any major operative intervention other than jejunostomy placement.”

Which Patients Benefit From Gastric Electrical Stimulation? Researchers from the United Kingdom attempted to answer some of these questions by seeing if placement of temporary GES (tGES) could predict which patients would benefit from a permanent GES. “We know now that GES works, and that it works better in some subgroups,” said N.V. Jayanthi, MD, who also presented the research at the SAGES meeting. “But we don’t know who fails to improve with GES. So that brings us to tGES.” The idea of using tGES to predict who will benefit from permanent GES is not new. “Dr. Thomas Abell proposed this several years ago,” noted Abeezar I. Sarela, MD, from the Department of Upper

Gastrointestinal, Metabolic and Bariatric Surgery at St. James’s University Hospital in Leeds, United Kingdom. “But the uptake on tGES has been quite low.” Dr. Abell and his colleagues initially reported a 97% response rate in patients selected by tGES (Digestion 2002;66:204212). Subsequent research showed a strong correlation between symptom relief in tGES and permanent GES (Ayinala S et al. Gastrointest Endosc 2005;61:455-461). Also, tGES has been used as a treatment for nausea and vomiting in patients who do not have gastroparesis (Ducrotté P, Gourcerol G. Digestion 2011;83:1-2). Dr. Sarela has long been interested in GES for gastroparesis, a condition he thinks is far too often under- or misdiagnosed. “The vast majority of patients with gastroparesis are lost among the diagnosis of functional dyspepsia,” he said. “I think this is due to lack of awareness. But even if we do make a diagnosis of gastroparesis, there are very few definitive treatments for that condition.” The most problematic patients are those who do not improve with dietary changes and prokinetics, and whose condition is so severe that they cannot tolerate oral intake see Gastroparesis, page 31


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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

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ACT NOW!

Gastroparesis continued from page 26

and require jejunostomy tubes. “That is a miserable existence for these patients,” Dr. Sarela said. “For patients with gastroparesis of this sort, the treatment options are very limited.” As far as the mechanism by which GES works in gastroparesis, “we do not know; it is not as simplistic as it improves gastric emptying, and there have been conflicting studies,” Dr. Sarela explained. “We had positive experiences with GES, but one dilemma is that not everyone benefits. It is a fairly straightforward procedure, but still invasive and carries some risk for side effects and complications. It also is very expensive so it’s important to select the patients most likely to have a good response.” Dr. Sarela and his colleagues set out to see if they could establish a role for tGES in patient selection. Of 71 patients with medically refractory gastroparesis referred to their center, 51 received tGES. “We endoscopically placed an electrode into the stomach lining. The electrode runs through the patient’s nose and connects to the stimulator on the outside. That is kept in place for about two weeks, during which time the patient maintains

a symptom diary and we assess how well they do,” Dr. Sarela said. Improvement was seen in 39 patients (74%), and 31 received a permanent GES. At 10 months follow-up, 22 patients (71%) showed significant sustained improvement compared with a 50% improvement associated with GES in the longest series to date (McCallum RW et al. Clinical Gastroenterol Hepatol 2011;9:314-319). It is not yet clear whether transmucosal stimulation is equivalent to GES. Also, not all patients tolerate the stimulation, and leads can dislodge inside the stomach without patients or physicians realizing it. “But lacking other tools, tGES is less invasive and shows that in selected patients, it can improve GES success rate,” Dr. Jayanthi said. Interpreting the presentation, Dr. Deziel noted that although the results were promising, the follow-up was fairly short. “We have to keep in mind how durable and significant is the clinical response,” he said. Also, the improvement was based on patient self-report. “We didn’t really have any objective

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today at GastroEndoNews.com/Renew physiologic measures of improvement—it would be interesting to know if they had any objective data to quantify the effect of the pacing on gastric emptying, and whether it is gastric emptying of solids or liquids and how that correlated with symptom improvement,” Dr. Deziel said. He added, “One question I have is why some patients responded to tGES and not GES.” The answer to that may have to do with the differences between tGES and permanent GES in terms of how the electrodes are placed, and perhaps in other differences between the two modalities that are not well understood at this time. Regardless, Dr. Sarela said, “There

seems to be a good increase in success that we see with tGES. Once we are to the stage of treating someone with GES, we should consider a tGES as a selection parameter.” Most important, however, is management of patient expectations. “When they come to our service, they are very desperate and will try anything you want,” Dr. Jayanthi said. “This needs to be carefully managed because if it fails, they have no other option than a gastric resection.” ■ Drs. Jayanthi, Sarela and Zehetner reported no conflicts of interest. Dr. Lipham is a consultant for Medtronic.

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32

DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

Benefits Shown for Gastric Electrical Stimulation In Children With Functional Dyspepsia

San Diego—Gastric electrical stimulation (GES) was associated with objective benefits in children with gastroparesis or functional dyspepsia, according to one of

the first efforts to systematically evaluate this intervention in a pediatric population. The benefits of GES were seen not only in favorable changes in quality of life (QoL) but also in a reduction in school absences and dependence on tube feeding or parenteral nutrition.

series to date of children receiving gastric electrical stimulation.’

Small Study, Yet Largest Series to Date By Ted Bosworth

‘This is the largest

—Peter L. Lu, MD “This is the largest series to date of children receiving GES,” said Peter L. Lu, MD, who was a co-investigator in this study while training at Nationwide Children’s Hospital, in Columbus, Ohio. The principal investigator on the study was Hayat Moussa, MD, medical director

‘GES, long used successfully in adults, may be beneficial in children.’ —Thomas L. Abell, MD

of the Center for Advanced Research in Neuromuscular Gastrointestinal Disorders at Nationwide. The study, which was presented at the 2012 Digestive Disease Week (DDW) meeting, included only 24 patients and was not randomized or controlled; however, it is the largest study conducted in this population so far and suggests that GES is at least as effective in children as in adults, for whom the technique has been licensed for more than a decade. The patients in this study ranged in age from 4 to 19 years and had experienced symptoms for a median duration of 24 months, the longest being 14 years. GES was attempted in most of these patients after several other interventions had failed. At the time of treatment, 60% of the patients had a documented delay in gastric emptying, 46% required tube feeding and 25% required parenteral feeding. All of the patients were followed prospectively with the Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms Module, a validated QoL tool for measuring changes in gastrointestinal (GI) symptoms in pediatric patients. Patients also were monitored for global health and for other relevant


DDW 2012

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

emerged in the discussion that followed the presentation of the data. Despite the significant up-front cost of GES, the investigators predicted that a reduction in health care use by patients who respond favorably to the treatment is likely to make this approach attractive. Prospective studies would be needed to determine the cost-effectiveness of the procedure. Asked to comment, Thomas L. Abell, MD, director of the Division of Digestive Diseases at the University of Mississippi, in Jackson, called the data “important.”

changes, such as school absenteeism and food consumption. At a median of six months after GES placement, the proportion of patients requiring tube feeding (13%) or parenteral feeding (13%) had decreased. School absenteeism also fell from 57% to 31%. Additionally, scores on the PedsQL instrument improved significantly for a range of symptoms, including upset stomach, stomach pain, early satiety, bloating, nausea and epigastric pain (P<0.01 for all symptoms). However, some symptoms, such as diarrhea, were generally unchanged. In a discussion that followed the DDW presentation, Henry Parkman, MD, director of the GI Motility Laboratory at Temple University, in Philadelphia, pointed out that because of the absence of some form of sham procedure, a placebo response could not be completely ruled out. Dr. Lu noted that another study is being considered in which some of the devices would be randomly switched off. In the current study, he said, because early response generally correlated with longterm symptom relief, the results support a physiologic response to GES. Questions about the cost of GES

Dr. Abell, who was part of the team that implanted the first GES device more than 20 years ago, said that the data are consistent with other recently presented work that “shows GES, long used successfully in adults, may be beneficial in children.” Dr. Abell referred to a study presented at the 2012 meeting of the American Pediatric Surgical Association, which was held in San Antonio around the time of the DDW meeting. In that study, presented by Saleem Islam, MD, associate professor in the Division of Pediatric

Surgery at the University of Florida, Gainesville, favorable outcomes of GES were observed in 78 patients, 45 of whom underwent long-term follow-up. As in the DDW study, this study was uncontrolled, but the data suggest that GES response, benefits and safety in children are on par with those reported in adults. ■ Drs. Lu, Moussa and Islam reported no relevant conflicts of interest. Dr. Abell has served as a consultant and has received research grants from Medtronic, Inc., which manufactures several GES devices.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

Renewed Interest in Esophageal Dilation for Some Patients With Eosinophilic Esophagitis Procedure Found Safe and Effective in Selected Patients By Ted Bosworth San Diego—Discriminating between two major subtypes of eosinophilic esophagitis (EoE) is an important and useful step toward selecting the most

appropriate intervention for adult patients, according to a state-of-theart lecture delivered at the 2012 Digestive Disease Week (DDW) meeting. Although diet and anti-inflammatory medications are appropriate first-line therapies when disease is largely limited

to inflammation, dilation was identified as a first-line approach for adult patients with fibrosis who also had dysphagia and stricture. “The inflammatory form of this disease is where the money is for using antiinflammatory medications and dietary

‘The inflammatory form of this disease is where the money is for using antiinflammatory medications and dietary modifications; but dilation is needed in the stricturing form.’ —Joel E. Richter, MD

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Be the first to get the latest news delivered directly to your computer. The new interactive format has embedded Web site links that give you instant access to gastroendonews.com, where you will find additional information as well as unique search features and article printing capabilities. Each installment contains top-line summaries of the most important articles from the current month’s issue and breaking news ahead of the print edition.

modifications; but dilation is needed in the stricturing form,” said Joel E. Richter, MD, who delivered the DDW lecture. “This is not to say I do not use anti-inflammatory agents in those with strictures, but I would estimate that I add these agents in about one-third of the EoE patients with strictures versus all of those with a dominant inflammatory component,” said Dr. Richter, who is chair of esophagology and gastroenterology at the University of South Florida, in Tampa.

Dilation Safe for Some According to Dr. Richter, dilation for EoE previously had fallen out of favor because of reports of significant rates of perforation and hospitalization for chest pain; however, a series of studies at centers experienced in this technique is reversing that trend. Citing his own study, conducted while he was at Temple University School of Medicine, in Philadelphia, Dr. Richter said there is a growing acceptance that dilation can be safe and effective, and offer long-term relief (Bohm M et al. Dis Esophagus 2010;23:377-385). At the University of South Florida, allergy testing is an important part of the workup for EoE, in both children and adults without stricture, but there is no longer hesitation to offer dilation, often accompanied by proton pump inhibitors, when stricture and dysphagia are an important part of the clinical presentation. Delaying dilation in EoE patients with strictures is likely to prolong symptoms in these patients, he suggested. After an initial esophageal dilation of 15 to 17 mm diameter in order to permit a regular diet, subsequent dilations are offered on an as-needed basis, Dr.


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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

contrary, there does not appear to be an inordinate frequency of esophageal perforation from dilation in patients with eosinophilic esophagitis,” Dr. Spechler said. Like Dr. Richter, “I also caution patients that they might experience bad chest pain and odynophagia for a number of days after dilation,” he said. He added that although esophageal dilation is a procedure that must be performed with caution in all patients, it probably is no more hazardous for patients with EoE than for patients with other

‘Esophageal dilation is an effective, and perhaps underutilized, therapy for patients with EoE who have dysphagia caused by esophageal rings and strictures.’ —Stuart J. Spechler, MD Richter said. Either the through-thescope or bougie methods are effective; in cases of multiple areas of narrowing, Dr. Richter prefers bougies. He cautions patients prior to the procedure that chest pain is a common side effect of treatment; with this in mind, most patients tolerate the procedure well, with analgesics used to minimize discomfort. Minor mucosal tears may occur after dilation, but Dr. Richter does not routinely take a second look during the procedure. Data show that perforations are an uncommon complication (<0.1%) when experienced clinicians perform the dilation, he noted. Anti-inflammatory agents are employed after dilation in patients who also have an inflammatory component of EoE, but Dr. Richter warned that elimination of eosinophilia is difficult. In general, the goal is a reduction in eosinophil counts in order to prevent or delay recurrence. Repeat dilations in patients who experience recurrence are typically effective and usually are required no more than every two to three years. Although dilation is a relatively reliable intervention in patients with strictures, Dr. Richter said, controlling the inflammation in some patients is far more challenging. “The most difficult patients in my experience are the adult EoE patients with multiple food allergies,” he said. Stuart J. Spechler, MD, chair of gastroenterology at the University of Texas Southwestern Medical School, in Dallas, agreed with Dr. Richter’s approach to managing EoE. “Esophageal dilation is an effective, and perhaps underutilized, therapy for patients with EoE who have dysphagia caused by esophageal rings and strictures. Despite some early reports to the

causes of esophageal stricture. However, Dr. Spechler said, he does not begin with dilation in these patients but first attempts medical therapy. He conceded that there is no clear consensus regarding how long medical therapy should be administered before resorting to esophageal dilation. “Nor is it clear what diet, medications or combinations of treatments should be tried before a patient is deemed a medical treatment failure,” he said. But he suggested that esophageal

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biopsy might be one tool for guiding the timing of dilation. “If a patient has dysphagia and esophageal biopsies show little or no infiltration of eosinophils, then the patient is unlikely to respond to medical therapy aimed at reducing eosinophils. It should be noted, however, that there are few published data that support this approach,” Dr. Spechler said. ■ None of the sources in this article reported any relevant conflicts of interest.


BRIEF SUMMARY: Consult the Full Prescribing Information for complete product information.

LIALDAÂŽ (mesalamine) Delayed-Release Tablets

Rx only

INDICATIONS AND USAGE LIALDA is indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis and for the maintenance of remission of ulcerative colitis. CONTRAINDICATIONS LIALDA is contraindicated in patients with known hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of LIALDA. [See Warnings and Precautions, Description and Adverse Reactions in the Prescribing Information] WARNINGS AND PRECAUTIONS Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as LIALDA that contain mesalamine or are converted to mesalamine. It is recommended that patients have an evaluation of renal function prior to initiation of LIALDA therapy and periodically while on therapy. Exercise caution when using LIALDA in patients with known renal dysfunction or a history of renal disease. In animal studies, the kidney was the principal organ for toxicity. [See Drug Interactions and Nonclinical Toxicology in the Prescribing Information] Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difďŹ cult to distinguish from an exacerbation of ulcerative colitis. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, and sometimes fever, headache, and rash. Observe patients closely for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with LIALDA. Hypersensitivity Reactions Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to LIALDA tablets or to other compounds that contain or are converted to mesalamine. Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported with LIALDA and other mesalamine medications. Caution should be taken in prescribing this medicine to patients with conditions predisposing them to the development of myocarditis or pericarditis. Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering LIALDA to patients with liver disease. Upper GI Tract Obstruction Pyloric stenosis or other organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastric retention of LIALDA which would delay mesalamine release in the colon. ADVERSE REACTIONS The most serious adverse reactions seen in Lialda clinical trials or with other products that contain or are metabolized to mesalamine are: s2ENALIMPAIRMENT INCLUDINGRENALFAILURE [See Warnings and Precautions (5.1)] s-ESALAMINE INDUCEDACUTEINTOLERANCESYNDROME [See Warnings and Precautions (5.2)] s(YPERSENSITIVITYREACTIONS [See Warnings and Precautions (5.3)] s(EPATICIMPAIRMENT INCLUDINGHEPATICFAILURE [See Warnings and Precautions (5.4)] Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reďŹ&#x201A;ect the rates observed in practice. LIALDA has been evaluated in 1368 ulcerative colitis patients in controlled and open-label trials. Induction of Remission In two 8-week placebo-controlled clinical trials involving 535 ulcerative colitis patients, 356 received 2.4 g/day or 4.8 g/day LIALDA tablets and 179 received placebo. The most frequent adverse reaction leading to discontinuation from LIALDA therapy was exacerbation of ulcerative colitis (0.8%). Pancreatitis occurred in less than 1% of patients during clinical trials and resulted in discontinuation of therapy with LIALDA in patients experiencing this event. Adverse reactions occurring in LIALDA or placebo groups at a frequency of at least 1% in two 8-week, double blind, placebo-controlled trials are listed in Table 1. The most common adverse reactions with LIALDA 2.4 g/day and 4.8 g/day were headache (5.6%and 3.4%, respectively) and ďŹ&#x201A;atulence (4% and 2.8%, respectively). Table 1: Adverse Events in Two Eight-Week Placebo-Controlled Trials Experienced by at Least 1% of the LIALDA Group and at a Rate Greater than Placeboa,b

The following adverse reactions, presented by body system, were reported infrequently (less than 1%) by LIALDA-treated ulcerative colitis patients in the two controlled trials. Cardiac Disorder:: tachycardia Vascular Disorders:: hypertension, hypotension Skin and Subcutaneous Tissue Disorders: acne, prurigo, rash, urticaria Gastrointestinal Disorders:: abdominal distention, colitis, diarrhea, pancreatitis, rectal polyp, vomiting Investigations:: decreased platelet count Musculoskeletal and Connective Tissue Disorders:: arthralgia, back pain Nervous System Disorders:: somnolence, tremor Respiratory, Thoracic and Mediastinal Disorders:: pharyngolaryngeal pain General Disorders and Administrative Site Disorders:: asthenia, face edema, fatigue, pyrexia Ear and Labyrinth Disorders:: ear pain Maintenance of Remission of Ulcerative Colitis The dose evaluated in three studies of LIALDA given for the maintenance of remission in patients with ulcerative colitis was 1.2 g twice daily or 2.4 g/once daily. One of these studies was a 6-month double-blind comparator study while two were 12- to 14-month open-label studies. The most common adverse reactions with LIALDA in the maintenance arms of long-term trials were colitis ulcerative (5.8%), headache (2.9%), liver function test abnormal (2.3%), and abdominal pain (2.2%). Of the 1082 subjects in the all maintenance studies pooled, 1.9% had severe adverse reactions. The most common severe adverse reactions were gastrointestinal disorders; these were mainly symptoms associated with ulcerative colitis.

Table 2: Adverse Reactions in Three Maintenance Trials Experienced by at Least 1% of the LIALDA Group (maintenance phases of trials)

The following adverse reactions, presented by body system, were reported infrequently (less than 1%) by LIALDA-treated ulcerative colitis patients in the three long-term maintenance trials (maintenance phases of these trials): Cardiac Disorder:: tachycardia Skin and Subcutaneous Tissue Disorders:: acne, alopecia, pruritis, urticaria Gastrointestinal Disorders:: colitis, ďŹ&#x201A;atulence, nausea, pancreatitis, rectal polyp, vomiting Nervous System Disorders:: dizziness Respiratory, Thoracic and Mediastinal Disorders:: pharyngolaryngeal pain General Disorders and Administrative Site Disorders:: asthenia, pyrexia Ear and Labyrinth Disorders:: ear pain Postmarketing Experience In addition to the adverse reactions reported above in clinical trials involving LIALDA, the adverse reactions listed below have been identiďŹ ed during post-approval use of LIALDA and other mesalamine-containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole:: lupus-like syndrome, drug fever Cardiac Disorders:: pericarditis, pericardial effusion, myocarditis Gastrointestinal: pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer Hepatic:: jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, Kawasaki-like syndrome including changes in liver enzymes Hematologic:: agranulocytosis, aplastic anemia Neurological/Psychiatric:: peripheral neuropathy, Guillain-Barre syndrome, transverse myelitis Renal Disorders:: interstitial nephritis Respiratory, Thoracic and Mediastinal Disorders:: hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis) Skin:: psoriasis, pyoderma gangrenosum, erythema nodosum Urogenital:: reversible oligospermia DRUG INTERACTIONS .OINVESTIGATIONSOFINTERACTIONBETWEEN,)!,$!ANDOTHERDRUGSHAVEBEENPERFORMED(OWEVER the following interactions between mesalamine medications and other drugs have been reported. Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal antiinďŹ&#x201A;ammatory drugs (NSAIDs) may increase the risk of renal reactions. Azathioprine or 6-mercaptopurine The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood disorders. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats at doses up to 1000 mg/kg/day (1.8 times the maximum recommended human dose based on a body surface area comparison) and rabbits at doses up to 800 mg/kg/day (2.9 times the maximum recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Mesalamine is known to cross the placental barrier. Nursing Mothers Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. The clinical signiďŹ cance of this has not been determined and there is limited experience of nursing women using mesalamine. Caution should be exercised if LIALDA is administered to a nursing woman. Pediatric Use Safety and effectiveness of LIALDA in pediatric patients have not been established. Geriatric Use Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia and pancytopenia in patients who were 65 years or older who were taking mesalamine-containing products such as LIALDA. Caution should be taken to closely monitor blood cell counts during mesalamine therapy. Clinical trials of LIALDA did not include sufďŹ cient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients. Systemic exposures are increased in elderly subjects. [see Clinical Pharmacology in the Prescribing Information]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reďŹ&#x201A;ecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients. OVERDOSAGE LIALDA is an aminosalicylate, and symptoms of salicylate toxicity may include tinnitus, vertigo, headache, confusion, drowsiness, sweating, seizures, hyperventilation, dyspnea, vomiting, AND DIARRHEA 3EVERE INTOXICATION MAY LEAD TO DISRUPTION OF ELECTROLYTE BALANCE AND BLOOD P(

hyperthermia, dehydration, and end organ damage. There is no speciďŹ c known antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may be beneďŹ cial in the event of acute overdosage. Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy. Adequate renal function should be maintained. Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087, USA by Cosmo S.p.A., Milan, Italy. By license of Giuliani S.p.A., Milan, Italy. U.S. Patent No. 6,773,720 Š 2011 Shire US Inc. Rev. 08/11 LIA-02667


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GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

37

Understanding Unexplained ained Nausea and Vomiting By Caroline Helwick San Diego—Innovative approaches are needed when working up and treating patients with unexplained nausea and vomiting, said Nicholas J. Talley, MD, PhD, professor of epidemiology and medicine at Mayo Clinic, Rochester, Minn., who spoke on the topic at 2012 Digestive Disease Week meeting.

Cyclic Vomiting Cyclic vomiting in adults is characterized by acute episodes of vomiting, usually lasting from several hours to several days and typically occurring without warning or symptoms between episodes. Patients may have abdominal pain, migraines, motion sickness or atopy; psychiatric symptoms are uncommon. Dr. Talley described a 32-year-old patient with an 11-year history of recurrent nausea, retching, generalized abdominal pain and anorexia, unrelated to food intake. Acute episodes, occurring several times per year, were marked by three to four emeses per hour. The patient obtained some relief from sitting in a hot bath, which became a compulsive habit. He also acknowledged using cannabis. The diagnosis: drug-induced vomiting due to regular use of cannabis. The triad of chronic cannabis use, cyclic vomiting and compulsive bathing has been documented previously, and abstinence from cannabis has been shown to reduce cyclic vomiting, Dr. Talley noted. “Some have disputed this link, but my clinical impression is that it’s real. If patients stop cannabis, they often get better.” It can be difficult to distinguish cyclic vomiting from functional vomiting—unexplained chronic vomiting—but a recent study, led by Dr. Talley, uncovered some hallmarks (Choung RS et al. Neurogastroenterol Motil 2012;24:2026). The study examined 82 patients with cyclic vomiting syndrome and 62 with functional vomiting over a 13-year period. The investigators did not uncover any distinguishing clinical features, but patients with cyclic vomiting syndrome were more likely to be younger (odds ratio [OR], 0.7) and male (OR, 0.4), and to use cannabinoids (OR, 2.9). No significant associations were found between diagnosis (i.e., cyclic vomiting vs. functional vomiting) and age, body mass index, smoking status, alcohol use, gastrointestinal symptoms or gastric emptying. The mainstay of treatment for cyclic vomiting is tricyclic antidepressants, which can be effective in more than half of patients. Anti-migraine drugs also help some individuals. The Cyclic Vomiting Syndrome Association (which can be accessed online at www.cvsaonline.org), is a good resource for patients, Dr. Talley noted.

Chronic Unexplained Nausea and Vomiting A newer syndrome is chronic unexplained nausea and vomiting (CUNV). This diagnosis is uncommon and is associated with significant morbidity. Studies performed decades ago indicated that CUNV—once labeled psychogenic vomiting—was associated with a high prevalence of conversion disorder. Patients with CUNV have symptoms similar to gastroparesis, and whether CUNV is a new syndrome or a part of a spectrum of functional vomiting disorder according to the Rome III criteria is unclear, Dr. Talley said. A study of 425 patients—106 with CUNV and

‘Just what is this condition with symptoms like gastroparesis but is not gastroparesis?’ —Nicholas J. Talley, MD, PhD

‘Cyclic vomiting is increasingly prevalent in young adults. You definitely see it in the ER.’ —Richard McCallum, MD

‘Although you don’t abolish vomiting episodes with antiepileptics, you certainly reduce the frequency and seem to improve quality of life.’ —Nicholas J. Talley, MD, PhD

normal gastric emptying, and 319 with gastroparesis— showed that patients with normal gastric emptying and symptoms of nausea and vomiting had a clinical presentation and disease course indistinguishable from those with delayed gastric emptying (Pasricha PJ et al. Clin Gastroenterol Hepatol 2011;9:567-576). Symptom severity indexes were similar between groups for nausea, retching, vomiting, stomach fullness, inability to complete a meal, feeling excessively full after meals, loss of appetite, bloating and a visibly larger stomach. “They look remarkably similar, which raises the question, ‘Just what is this condition with symptoms like gastroparesis but is not gastroparesis?’” Dr. Talley said. “In the study, the majority of patients did not fulfill the Rome criteria for functional vomiting, although the syndrome otherwise looks a lot like functional vomiting. Is it really different, or are we splitting hairs about terminology and should we pool all these syndromes together?” These patients may not respond to antiemetic or prokinetic agents. Tricyclic antidepressants, again, are the first-line treatment and should be started at a low dose and titrated slowly. Antiepileptic medications, such as zonisamide and levetiracetam, also can be effective: An uncontrolled study documented responses in approximately 75% of patients who had not responded to tricyclic antidepressants and 20% of patients attained symptomatic remission (Clouse RE et al. Clin Gastroenterol Hepatol 2007;5:44-48). “We started using these in patients who are referred to us and have already been on tricyclics; they do not have many options,” Dr. Talley said. “Although you don’t abolish vomiting episodes with antiepileptics, you certainly reduce the frequency and seem to improve quality of life.” Dr. Talley also advocates a trial of dietary modification to help the stomach handle meals more efficiently: frequent small meals, reduced fat, reduced fiber, avoidance of indigestible material, and splitting the intake of liquids and solids. Alternative therapies may help the occasional patient but are not backed by convincing data.

Finally, Dr. Talley encouraged clinicians to always consider other etiologies. For example, vomiting can be an atypical presentation of gastroesophageal reflux disease (GERD) and may respond to appropriate acidsuppressive therapy. “Even in patients without heartburn and a normal endoscopy, I think about [GERD] in my differential,” he said.

‘You Have To Be a Detective’ Richard McCallum, MD, professor and founding chairman of internal medicine and chief of gastroenterology at Texas Tech University Health Sciences Center, in El Paso, said that although Dr. Talley maintained that cyclic vomiting is “rare,” he believes that the average clinician sees cyclic vomiting and associated conditions not infrequently. “Cyclic vomiting is increasingly prevalent in young adults. You definitely see it in the ER [emergency room],” Dr. McCallum said. “Dr. Talley provided excellent information that clinicians can use tomorrow,” he added. Dr. McCallum said that the workup for most patients with nausea and vomiting should include a gastric emptying test. “If the test is normal, I wonder if I am missing something, like cyclic vomiting syndrome or dumping syndrome, which can present with very similar symptoms—unexplained nausea and vomiting, yet gastric emptying that is rapid. You have to be a detective,” he said. ■ Dr. Talley has served as a consultant for ARYx Therapeutics, AstraZeneca, Boehringer Ingelheim GmbH, Falk Pharma, Focus Medical Communications, Forest, Ironwood Pharmaceuticals Inc., Janssen-Cilag, MD Evidence, Meritage Pharma, Procter & Gamble and Zeria Pharmaceutical Co. Dr. McCallum has served on an advisory committee and review panel for SmartPill Corporation, and has received grants or research support from Takeda and Tranzyme Pharma.


References: 1. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syndrome. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:1559-1574. 2. Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Carcinoid tumour. Lancet. 1998;352(9130):799-805.


What’s behind the symptoms? Carcinoid Syndrome Can Be Deceptive Early diagnosis of carcinoid syndrome is essential. The most common symptoms of carcinoid syndrome are severe diarrhea, flushing, abdominal pain, cardiac disease, wheezing, and telangiectasia.1,2 To learn more, visit www.carcinoidfacts.com.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

©2012 Novartis

9/12

CAR-1052009


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SPECIAL COVERAGE

Hurricane Sandy continued from page 1

interruptions, and laid waste to hundreds miles of coastline. In the United States, Sandy swept the east coast from Florida to Maine, traveling inland as far west as Michigan and Wisconsin. New York City was hit particularly hard when the storm made landfall in the early morning of Oct. 29, with surging waters that flooded tunnels, subway lines and streets. A power outage left most of Manhattan, south of about 40th Street, dark for the better part of a week and crippled mass transit services throughout the region. Some low-lying neighborhoods—the Rockaways, in Queens, and Coney Island and Red Hook, in Brooklyn— experienced widespread destruction by flood and fire. Staten Island, where floods initially claimed eight lives within an area of about eight blocks, had the highest density of storm-related mortality in the country. Fuel shortages and lack of power at the majority of service stations in New York City, Long Island and New Jersey resulted in rationing and hours-long lines at the gas stations that were still functional. The New Jersey coastline was badly battered, with mass devastation crippling coastal towns. Even two weeks after the storm, some areas in the outer boroughs, Long Island and New Jersey remained without power. Hospitals and medical centers were not immune to the destruction. In New York City, five major medical centers—New York Downtown Hospital, Coney Island Hospital, Bellevue Hospital Center, Manhattan Veterans Affairs Medical Center and New York University (NYU) Langone Medical Center—moved their most vulnerable patients before the storm hit, and were forced to evacuate remaining patients to nearby centers when flooding and other storm-related damages forced them to close. New York Downtown Hospital quickly reopened and Coney Island offered limited services in the days after the storm, expecting to regain full function by the first week of January. But it is as yet unclear when the other centers will fully recover.

NYU Langone Medical Center Hit Hard NYU Langone was able to get most of its ambulatory care centers and faculty group practices up and running less than a week after Sandy hit, but the medical center’s main campus, including its emergency department, laboratory testing services, blood bank and pharmacy, were not running as of Nov. 10. Engineers were brought in to

NYU Langone Medical Center’s main campus, including its emergency department, laboratory testing services, blood bank and pharmacy, remained closed nearly two weeks after the storm. Photo: Cynthia Gordon, PhD

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

assess the full extent of damages and what caused them. New York City is no stranger to volatile weather and tropical storms, and NYU’s emergency power system was designed to meet all safety codes. “We believed we could withstand a surge of approximately 12 feet, which is above the 100-year flood level for New York City,” wrote Christopher Rucas, director of media relations, in an email, noting that the facility did not experience any major damages during Hurricane Irene in 2011. This time, however, the basement of Langone, one of the city’s top academic medical centers, was flooded by the East River, causing damage that resulted in the failure of its emergency electrical systems, which will require extensive resources to repair and rebuild. “Even though our facility and our faculty and staff were trained and prepared for the storm, this was an unprecedented event,” Mr. Rucas said. “The surge for Hurricane Sandy was recorded at 13.88 feet at Battery Park, which was 2.68 feet higher than the record level in 1821. In our location, we believe the surge from Sandy may have been even higher.”

‘We believed we could withstand a surge of approximately 12 feet, which is above the 100-year flood level for New York City.’ —Christopher Rucas, director, media relations, NYU Langone Medical Center

Jacobi Helps Rescue Shuttered Bellevue With the closing of these large, major medical centers, neighboring facilities rose to the challenge to accommodate redirected patients and, in some cases, staff that needed to continue working and residents who needed to continue learning. In one case, Jacobi Medical Center/North Central Bronx Hospital, a member hospital of New York City Health and Hospitals Corporation (NYCHHC), opened up new wings of its facility and mobilized staff to accommodate patients evacuated from Bellevue, also an NYCHHC facility. “I’ve spoken with some of the patients who were transferred over,” said Peter K. Kim, MD, assistant professor of surgery at Albert Einstein College of Medicine, New York City. “[Bellevue] was without power, and physicians and nurses carried patients down stairs in the dark. Ambulances waiting out front brought them to all the city hospitals that could provide services.” Eric Manheimer, MD, former medical director of Bellevue, gave his account of that hospital’s harrowing evacuation in a New England Journal of Medicinee editorial that was published online on Nov. 14 (www.nejm. org/doi/full/10.1056/NEJMp1213611): “Prisoners, hundreds of psychiatric patients, neonates, new mothers, post-op surgical patients, ICU patients on ventilators—the breadth and depth of an acute care hospital in the flood zone needed to go, stat. The power went, the elevators filled with water, one generator after another failed. Firefighters, EMTs and police officers helped hospital staff walk, carry and slide patients down through darkened stairwells on hard plastic boards to

NYU Langone Medical Center and neighboring Bellevue Hospital Center, situated along the East River in Manhattan, both suffered unprecedented flooding and were forced to close. Photo: Cynthia Gordon, PhD

waiting taxis, car services and ambulances. Staff organized bucket brigades to take water to patient floors and fuel to generators.” Jacobi Medical Center had preemptively cancelled all elective operations prior to the storm and discharged patients who could go home in the event that after the storm they might not be able to get home. Still, physicians, surgeons, residents, nurses and staff all worked overtime to provide care for the influx of new patients, many of whom were very ill, in need of surgery or immediate postoperative care. “It was very busy for the people on call,” Dr. Kim said. “But some people were sort of trapped in the hospital; many live in Manhattan and couldn’t get back, so they slept in the hospital and helped take care of these patients.” Jacobi did lack some services that they would normally have, such as social workers who were unable to make it to work on the day of the storm and for the two days after. But they picked up some of Bellevue’s nurses and residents, for whom the transition went fairly smoothly, partly because the operating systems between Jacobi and Bellevue are quite similar. “So it’s not like you’re working in a different system,” Dr. Kim said. Furthermore, Jacobi is well versed in disaster care. “Last year we were involved with the Bronx bus accident—the worst bus accident in New York City’s history—and we all came together and took care of those patients,” Dr. Kim said. “I think a lot of us who work at Jacobi, a level 1 trauma center, are used to being ready for anything, and being creative.” Until Bellevue recovers, all staff associated with that facility are doing their best to maintain continuity of care for patients, despite lack of a home base. Danielle Ofri, MD, PhD, described the situation in a second New England Journal of Medicine editorial published online on Nov. 14 (www.nejm.org/doi/ full/10.1056/NEJMp1213843): “The 4,000 faculty and staff members, residents and medical students of Bellevue have been dispersed throughout the five boroughs, taking care of our inpatients, struggling to care for our tens of thousands of outpatients. The generosity of spirit from the hosting hospitals, our peripatetic patients, and our coworkers has been boundless. But without our nexus of Bellevue to knit us together, we feel unmoored. When a hospital is forced to halt, it’s not just the patients who are evacuated.” see Hurricane Sandy, page 42


1

WITH LOWER DOSE

EFFICACY YOU EXPECT1

HalfLytely and Bisacodyl Tablet Bowel Prep Kit is a combination of PEG-3350, an osmotic laxative and bisacodyl, a stimulant laxative, indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>3%) are overall discomfort, abdominal fullness, abdominal cramping, nausea, and vomiting. There have been reports of ischemic colitis in patients with use of HalfLytely and 10 mg or 20 mg Bisacodyl Tablets Bowel Prep Kit. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reďŹ&#x201A;ex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Please see brief summary of Prescribing Information on adjacent page.


42

SPECIAL COVERAGE

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

Hurricane Sandy continued from page 40

Staff Shortages Pose a Problem At NewYork-Presbyterian NewYork-Presbyterian Hospital/Weill Cornell Medical Center sits on a platform suspended above FDR Drive, which runs alongside the East River in Manhattan. Water lapped up over the drive and caused extensive flooding on the Upper East Side of Manhattan, but did not cause any major damages to the hospital, which also did not lose power.

NewYork-Presbyterian Hospital/Weill Cornell Medical Center sits on a platform suspended above FDR Drive, which runs alongside the East River in Manhattan. Photo: Julia Sorenson © 2009

EFFFICACY YOU EXPECT1

WITH WIT TH LO OWER R DOSE1

• LLowest volume phosphate-free lavage1,2 •N No oral sodium phosphate

Referennces: 1. HalfLytely® andd Bisacodyl Tablet Boweel Prep Kit [ppackage inseert]. Braintreee, MA: Brainntree Laboraatories, Inc; 2010. 2. See package inserts: GoLYTELYY®(PEG-3350 and Elecctrolytes forr Oral Solutioon), 2001; NuLYTELYY® (PEG-3350, Sodium Chlooride, Sodiuum Bicarbonate and Potaassium Chloride for Oral Solution), 2008. Braintree, MA: Braintree PEG 3350 Sodium Sulfate, Sulfate Sodium m Chloride, Chloride Potassium Chloride, Chloride Soodium Ascorrbate and Ascorbic Acid for Oral Solution), 2006; Morrisville, NC: Laborattories, ories Inc Inc.;; MoviPrep® ( PEG-3350, Salix Phharmaceuticcals, Inc.

Brieff Summ mary: Before prescribing, please see fulll Prescribing Information and Medication Guide for HalfLytely HalfL Lytely aand nd Bisa Bisacodyl acodyl TTablet ablet B Bowel owel P Prep rep Kit. Kitt INDIC INDICATIONS CATION NS AND USAGE: Combination of PEG-3350, an osmotic laxative and bisacodyl, a stimulant laxative, indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus. WARNINGS AND PRECAUTIONS: HalfLytely and Bisacodyl Tablet Bowel Prep Kit is a combination of PEG-3350, an osmotic laxative and bisacodyl, a stimulant laxative, indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>3%) are overall discomfort, abdominal fullness, abdominal cramping, nausea, and vomiting. There have been reports of ischemic colitis in patients with use of HalfLytely and 10 mg or 20 mg Bisacodyl Tablets Bowel Prep Kit. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established. Geriatric Use: Of the 148 patients who took HalfLytely and 5 mg Bisacodyl Tablet Bowel Prep Kit in clinical trials, 42 (28%) were 65 years of age or older, while 10 (7%) were 75 years of age or older. The rates of success appear to be lower in patients 65 years and older. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of HalfLytely may not be absorbed completely. Do not take the bisacodyl delayed-release tablet within one hour of taking an antacid. ADVERSE REACTIONS: Most common adverse reactions (>3%) are overall discomfort, abdominal fullness, abdominal cramping, nausea, and vomiting. Oral Administration: Take one 5 mg bisacodyl tablet with water. Do NOT chew or crush. Dissolve the HalfLytely powder in 2 liters of water. Wait for a bowel movement (or maximum of 6 hours) then drink all the HalfLytely solution at a rate of 8 ounces every 10 minutes. Consume only clear liquids until the colonoscopy. STORAGE: Store at 20-25°C (68-77°F). Excursions permitted between 15-30°C (59-86°F). The reconstituted solution, may be refrigerated, use within 48 hours. Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit us at www.halflytely.com fl ©2011 Braintree Laboratories, Inc.

HL-12437T

January, 2011

“Fortunately, there was no damage to critical systems,” said Philip S. Barie, MD, MBA, professor of surgery and public health, at Cornell, and chief of acute care surgery at the hospital. “We were affected more from a human resources perspective,” he said. Some could not make it in to work, whereas others were unable to leave. One ICU nurse worked eight days in a row before being able to return to her home in New Jersey, and a clinical pharmacist worked five or six days in a row before she was able to return to her home in Queens. The center set up shower facilities, helped match people with temporary roommates nearby and kept everyone fed. “Everybody pitched in to keep us functional,” Dr. Barie said. In preparation for the storm, the center activated its disaster plan the Friday evening before Sandy hit, cancelling all elective surgeries and closing the urgent care center to preserve resources for emergencies. “Because of staff shortages, we were able to operate only two of our 38 operating rooms on Monday. But by Tuesday, we were able to get 11 operating rooms staffed and functional,” Dr. Barie said. By Wednesday the center had reached about 40% of its capability to perform surgeries, and had returned to performing limited elective procedures, “depending, it seems kind of silly, but in part on which doctors and patients could get here,” Dr. Barie said. “I did one elective procedure on Wednesday because I was around and my patient lived in the neighborhood and was willing to proceed as scheduled.” By Thursday, Weill Cornell Medical Center was functioning normally, but now, and for the foreseeable future, it has to contend with a substantial increase in demand for trauma care until the shuttered New York City hospitals reopen. “We have seen an immediate and sustained doubling of our trauma services provided since the storm,” Dr. Barie said. “We are prepared for Bellevue to be out of service until, what I’ve heard most recently, February or March of next year.” Many of the trauma patients arriving at NewYork-Presbyterian after the storm had the same types of injuries as those seen during the blackout of 2003. “We saw a lot of head injuries from people falling either on the darkened streets or in their darkened apartments. We saw exactly the same phenomenon when we had the blackout,” Dr. Barie said. The trauma volume at Bellevue and NewYork-Presbyterian are about equal, so it stands to reason that the latter would experience a 100% increase in emergency room visits and trauma admissions. At one point during the height of the storm and its immediate aftermath,


SPECIAL COVERAGE

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

NewYork-Presbyterian had patients on gurneys in the lobby, as its disaster plan calls for. The emergency department, operating rooms and ICUs are at full capacity. “The docs are all for it—that’s what we’re here for,” Dr. Barie said. “But I’m starting to hear stories that other people who are integral parts of the team are stretched pretty thin. Trauma patients, in particular, are very needy. It’s putting a lot of stress on our physical therapists and social workers.” As for the rest of the city, two weeks after the storm, the areas that were hit most severely continued to dig out, and some in the outer boroughs were still without power. Most public transportation had been restored, but gasoline rationing was still in effect with many service stations still closed. The use of sanitation vehicles to clear snow from the streets after a nor’easter blew through town a week after the hurricane added to the somewhat alien, postdisaster effect. “In New York City, they put plow blades on the garbage trucks, so when there is a snow emergency, they stop collecting garbage,” Dr. Barie said. “You can walk the streets of Manhattan now and see closed, roped-off gasoline stations, refuse in bags at street level waiting for pick-up, and see that we’re not completely recovered.”

went down because there was no power, so we had to cancel office hours for the week,” Dr. Parker said. “Ultimately, once the phone service was up and running, we were able to rig a number and work around that, so any patient who absolutely had to be seen could reach us through the hospital. The operators would connect the patients to us, and we were usually able to see them in the emergency room.” The hospital cut back to doing only emergency procedures during the first two days of the storm, but Dr. Parker

resumed a nearly full schedule of surgery shortly thereafter. “I was able to do two colon resections a day without a problem—mostly inhouse patients, but some from the elective schedule,” he said. There were some, however, on whom they could not operate due to the storm’s effect on their homes. “They couldn’t go home to a dark place without power or hot water and expect to convalesce; there were a number of cases where we couldn’t operate on patients because their homes were wiped out. They

43

had no place to heal,” Dr. Parker said. For Howard Ross, MD, director of the Colon and Rectal Oncology Program at Meridian Health System, chief of colon and rectal surgery at Riverview Medical Center and clinical associate professor of surgery at University of Medicine and Dentistry, New Jersey, in Red Bank, his hospital literally served as a port in the storm. “It was the only place to get warm,” Dr. Ross said. “The hospital was really extraordinary see Hurricane Sandy, page 44

Two Jersey Shore Hospitals Survive in the Storm Jersey Shore University Medical Center was designed with generators capable of running the entire hospital in the event of power outages, and when Hurricane Sandy hit, the facility was successfully sustained by generator-only power for two days, during which they performed only emergency procedures. “But after that, they were pretty much full court press,” said Glenn Parker, MD, vice chair of the Department of Surgery. The administrators set up a command center in the boardroom and designated different areas of the hospital for preoperative care and a holding area to contain overflow from the emergency department. “They were prepared from the standpoint of administrators, physicians and nurses,” Dr. Parker said. “There was also a tremendous amount of coordination trying to get patients out of the hospital—into a rehabilitative facility or home—before the hurricane hit to allow for accommodation if there were any catastrophic events or multiple injuries.” As efficient as the hospital was, communications were complicated by the enduring loss of power to Ocean Township. “The phone service for our office

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SPECIAL COVERAGE

Hurricane Sandy continued from page 43

through all of this. It went on generator power, so it always functioned. But what was really awe-inspiring to me was how some of the unsung heroes—custodians, patient transport, cafeteria workers, the people who don’t get a lot of glamour—hung on in the hospital through the storm and afterward, even though their families were at home.” The hospital served as a shelter and second home for the people who worked there, most of whom were without power for 12 days. “We had no heat, no light [at home]. It was almost sensory deprivation, except when you were in the hospital, which was functioning. It made me very proud to be associated with the hospital and medicine during this time that was so hard for the shore.”

Monmouth Hospital Prevails, But Residents Devastated At this point, Monmouth and Ocean counties resemble a war zone in their devastation. “It’s an absolute tragedy,” Dr. Ross said. “If you’re not from here, it’s hard to understand how badly it was actually hit. These are beach towns and they got absolutely decimated.” Unable to conduct office hours during the week after the storm, Dr. Ross and other physicians and hospital colleagues set out to help friends and neighbors clean up. “You saw whole lives—pictures, beds, televisions, couches—piled up by the side of the road, all the way down the street. People who didn’t have boats had boats sitting on their lawns that just floated into town. Signs from restaurants and stores crossed the river and drifted into people’s yards. It was absolutely shocking.” Even for residents of the two counties who do not live on the water, the beach towns are a focal point of their lives, and the devastation is emotionally wrenching.

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

“We go to [the towns] not just in summers, but in off seasons. The most special time to be at the beach is in the fall or spring, when it’s only the locals. Now to see the towns where entire storefronts are blown out, no glass, big red X’s meaning they’re uninhabitable. … It’s very sad,” Dr. Ross said. In the week or so after the storm, during which time Michael A. Goldfarb, MD, chairman/program director of surgery at Monmouth Medical Center, was able to rely on a gas-powered generator to light and heat his home, he and his family helped out those less fortunate. “We took them in the house. They slept here; we fed them. Friends walked in and showered. It “You saw whole lives—pictures, beds, televisions, couches— was kind of a revolving door,” he said. piled up by the side of the road, all the way down the street. “Most of the people around here left or are People who didn’t have boats had boats sitting on their lawns staying with friends who have generators at that just floated into town. Signs from restaurants and stores their houses,” he continued. “But that’s small crossed the river and drifted into people’s yards. It was absostuff. A lot of people were killed. The death total lutely shocking,” said Howard Ross, MD, of the devastation in now I don’t think is nearly what it’s going to be.” Monmouth County, N.J. Photo: Trevor Higginson Dr. Goldfarb’s medical center, backed by generators, never lost power and was efficiently managed throughout the crisis. Less than 10 days after the storm, the hospital was running at full know what people who live in low-lying areas are going steam. to do,” Dr. Goldfarb said. “But the lost revenue for a week in a hospital is unbe“This is not a five-mile or one-town problem. This is lievable,” Dr. Goldfarb said. “The residents and nurses a 1,000-mile problem.” and everyone pitched in, but it’s a matter of getting If Hurricanes Irene and Sandy, described as once-inthere, too. The roads are blocked with downed trees and a-lifetime storms yet both occurring within a toddler’s wires.” years, are harbingers of emergent weather patterns and The hospitals will recover from their financial losses, storms to come, our days of enjoying the pleasures vast and the people whose properties were damaged will and simple of proximity to oceans, beaches and rivers repair them. But the bigger question is what will become may indeed be numbered. ■ of those who lost their homes entirely. “Do they rebuild where they were living, raise houses Below: A decimated boardwalk in Rockaway Beach, in the air? Do they knock down their houses and collect Queens, serves as a reminder to residents of the $250,000 in flood insurance, if they were lucky? I don’t devastating potential of the nearby ocean.

Photo: Cynthia Gordon, PhD

44


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46

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • DECEMBER 2012

Class I Recall: FDA Recalls Three Ethicon Endo-Surgery Staplers On Oct. 26, the FDA notified health care professionals of the recall of three stapler products manufactured by Ethicon Endo-Surgery: Proximate HCS Hemorrhoidal Circular Stapler and Accessories 33mm (product code PPH01); Proximate PPH Hemorrhoidal Circular Stapler and Accessories 33mm (product code PPH03); and Transtar Circular Stapler Procedure Set (product code STR10). The devices are used in the surgical treatment of prolapse and hemorrhoids, or in other applications where circular or semicircular stapling of anorectal tissue is needed. The Class I recall was initiated on Aug. 3 due to the difficulty users were having in firing the stapler devices, resulting in an incomplete firing stroke and staple formation. Failure to complete the firing stroke of the stapler can lead to adverse effects such as sphincter dysfunction, rectal wall damage, bleeding, sepsis and occlusion of the rectal canal. Class I recalls are the most serious type and occur when there is a reasonable probability that use of the product in question will cause serious, adverse health consequences

or death. Ethicon Endo-Surgery initiated this voluntary, global recall in August, for all products manufactured from April 16, 2011 to July 24, 2012 and distributed from April 18, 2011 to July 23, 2012. A list of the recalled lot numbers with images is available on Ethicon Endo-Surgery’s website at www.ees.com/sites/default/files/US-only-PPHattachments.pdf. According to the FDA, customers who purchased the faulty devices were notified by letter via overnight delivery. All customers should

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respond using the Business Reply Form included with the letter to indicate whether they have the affected devices, the quantity of affected devices they have and if they have already returned, or intend to return, the product(s). Customers with the device also can contact Ethicon Endo-Surgery’s customer support center at (800) 873-3636 or customersupport@eesus.jnj. com for more information. —Based on a press release from the FDA

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47

FDA Approves Labeling Update for Baraclude New Label Includes Data on Blacks, Liver Transplant Recipieents With HBV The FDA recently approved a labeling update for entecavir (Baraclude, Bristol-Myers Squibb) based on two studies of patients with hepatitis B virus (HBV) infection. The new labeling includes data on black patients with HBV infection as well as liver transplant recipients with the disease. HBV is of particular concern to the black community, with approximately 1.4 to 2 million individuals in the United States infected. Similarly, patients with end-stage liver disease and HBV require special attention, as these patients may undergo liver transplantation as a treatment option but recurrence of HBV can damage the new liver. “Treating patients with chronic hepatitis B who have undergone a liver transplant can be complicated,” said Michael Charlton, MBBS, hepatology director and liver transplant director, Mayo Clinic, Rochester, Minn., in a statement. “These data included in the Baraclude label will help health care providers prescribe the treatment among chronic hepatitis B patients, including liver transplant recipients.” A nucleoside analogue, Baraclude was first approved by the FDA in March 2005. It is indicated for use in adults with chronic HBV infection with evidence of active viral replication and either evidence of persistent elevations in alanine aminotransferase (ALT) or aspartate aminotransferase, or histologically active disease. In the first study on which the new labeling was based, investigators assessed the safety and efficacy of Baraclude (0.5 mg once daily) in hepatitis B e antigen (HBeAg)–positive or -negative, nucleoside-naive black (n=40) and Hispanic patients (n=6) with chronic HBV infection. Thirty-two patients (70%) achieved HBV DNA levels less than 50 IU/mL (approximately 300 copies/mL) at 48 weeks; 31 patients (67%) had normalization of ALT, and 12 of 26 (46%) HBeAgpositive patients experienced HBeAg seroconversion. Because of low enrollment, the safety and efficacy of Baraclude in Hispanic patients was not established. In the second study, investigators assessed the safety and efficacy of Baraclude (1 mg once daily) in 65 patients who had received a liver transplant for complications arising from chronic HBV infection. Of the 53 patients (82%) who completed the trial, all achieved HBV DNA levels less than 50 IU/mL at or after 72

weeks of treatment. Baraclude is not a cure for HBV and patients should be advised that its use has not been shown to reduce the risk for transmission of HBV to others through sexual contact or blood contamination, the manufacturer noted. For more information, visit www. baraclude.com. —Based on a press release from Bristol-Myers Squibb

BRIEF SUMMARY Please consult package insert for full prescribing information. INDICATIONS AND USAGE APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. DOSAGE AND ADMINISTRATION The recommended dose for maintenance of remission of ulcerative colitis in adult patients is 1.5 g (four APRISO capsules) orally once daily in the morning. APRISO may be taken without regard to meals. APRISO should not be co-administered with antacids. An evaluation of renal function is recommended before initiating therapy with APRISO. CONTRAINDICATIONS APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components of APRISO capsules. WARNINGS AND PRECAUTIONS Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as APRISO that contain mesalamine or are converted to mesalamine. It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history of renal disease. In animal studies, the kidney was the principal organ for toxicity. Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO. Hypersensitivity Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to APRISO capsules or to other compounds that contain or are converted to mesalamine. Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering APRISO to patients with liver disease. ADVERSE REACTIONS APRISO was studied in two placebo-controlled trials (n=367 treated with APRISO) and in one open-label, long-term study (n=190 additional patients). The population consisted of patients with ulcerative colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received doses of APRISO administered orally once per day for six months in the placebo-controlled trials and for up to 24 months in the open-label study. In the two placebo-controlled trials, 59% of APRISO-treated patients experienced an adverse reaction compared with 64% of placebo patients. Most adverse reactions with APRISO were mild or moderate in severity. Severe adverse reactions occurred in 6% of APRISO-treated patients and 5% of placebo-treated patients. Discontinuations due to adverse reactions occurred in 11% of APRISO-treated patients and 17% of placebo-treated patients; the most common adverse reaction resulting in study discontinuation was recurrence of ulcerative colitis (APRISO 6%, placebo 14%). The most common treatment-related adverse events occurring in at least 3% of adult patients taking 1.5 g/day of APRISO and at a rate greater than placebo were headache (11% vs 8% for placebo), diarrhea (8% vs 7% for placebo), upper abdominal pain (5% vs 3% for placebo), nausea (4% vs 3% for placebo), nasopharyngitis (4% vs 3% for placebo), influenza and influenza-like illness (4% vs 4% for placebo), and sinusitis (3% vs 3% for placebo).

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human dose based on a body surface area comparison) and rabbits at doses up to 495 mg/ kg/day (about 5.4 times the recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Mesalamine is known to cross the placental barrier. Nursing Mothers Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine. Caution should be exercised when APRISO is administered to a nursing woman. Pediatric Use Safety and effectiveness of APRISO capsules in pediatric patients have not been established. Geriatric Use Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing APRISO. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia, pancytopenia, in patients who were 65 years or older who were taking mesalamine-containing products such as APRISO. Caution should be taken to closely monitor blood cell counts during mesalamine therapy. Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy. (see WARNING AND PRECAUTIONS) Phenylketonuria Patients with phenylketonuria should be aware that APRISO contains aspartame, equivalent to 0.56 mg of phenylalanine. CLINICAL STUDIES Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult patients in remission from ulcerative colitis. Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity Index1 (DAI), which is a sum of four subscores based on stool frequency, rectal bleeding, mucosal appearance on endoscopy, and physician’s rating of disease activity. Patients were randomized 2:1 to receive either APRISO 1.5 g or placebo once daily in the morning for six months. In both studies, the proportion of patients who remained relapse-free at six months was greater for APRISO than for placebo. In study 1 (N=305), 68% of subjects taking APRISO were relapse-free at 6 months EOT vs 51% with placebo (P<0.001). In study 2 (N=257), 71% of subjects in the APRISO group were relapse-free at 6 months EOT vs 59% for placebo (P=0.046). HOW SUPPLIED APRISO is available as light blue opaque hard gelatin capsules containing 0.375 g mesalamine and with the letters “G” and “M” on either side of a black band imprinted on the capsule. NDC 65649-103-02 NDC 65649-103-01

Bottles of 120 capsules Bottles of 4 capsules

STORAGE AND HANDLING Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). See USP Controlled Room Temperature. Reference: 1. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology. 1987;92:1894-1898.

GM 08/22-2

Salix Pharmaceuticals, Inc. Raleigh, NC 27615 MANUFACTURED FOR:


L A S R A E H N: O E I R ISS Y M R R E HE N: V R N O I E E S S I E H SE YOUR MTAIN ISSIO IN REM A M UC

Maintain ulcerative colitis (UC) remission with once-daily APRISO so your adult patients can experience what they love, for longer* Proven to maintain remission in 2 clinical trials for up to 6 months1 INTELLICORº delayed- and extended-release delivery initiates at pH ≥6, providing coverage throughout the colon1,2 1.5-g once-daily dose (4 capsules) can be taken with or without meals1 The most common adverse reactions (incidence ≥3% and >placebo) are headache, diarrhea, upper abdominal pain, nausea, nasopharyngitis, influenza and influenza-like illness, and sinusitis1

APRISO is the fastest-growing once-daily 5-ASA in the United States2 APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. *The use of APRISO for treating ulcerative colitis beyond 6 months has not been evaluated in controlled clinical trials. References: 1. APRISO [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012. 2. Data on file. Salix Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information, including Important Safety Information. Please see full Prescribing Information available at AprisoRx.com. APRISO® and INTELLICOR® are registered trademarks of Salix Pharmaceuticals, Inc. ©2012 Salix Pharmaceuticals, Inc. All rights reserved. GM 11/45-3


The December 2012 Digital Edition of Gastroenterology and Endoscopy News