The April 2013 Digital Edition of Gastroenterology and Endoscopy News by McMahon Group

1978 —

35th Anniversary

— 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 4 • April 2013

gastroendonews.com IBS Awareness Month

Food Allergy Explored in IBS By Christina Frangou

Defending Against Malpractice: Steps To Winning a Lawsuit Start Before It Begins By Monica J. Smith

Allergies to foods or food additives may contribute to the pathogenesis of irritable bowel syndrome (IBS)– like symptoms, according to a recent study published in the Journal of the American Academy of Dermatology (Stierstorfer MB et al. 2013;68:377-384). see Allergies, page 14

Binge Drinking Linked to IBS Symptoms By Brigid Duffy Binge drinking may worsen gastrointestinal (GI) symptoms in women with irritable bowel syndrome (IBS), according to a study published in the February issue of the American Journal of Gastroenterology (Reding KW et al. 2013;108:270-276).

A recent study found that, over a 40-year career, doctors spend an average of 11% of their time dealing with unresolved, open malpractice suits (Seabury SA et al. Health Aff 2013;32:111-119). But there are steps that physicians can take to reduce the risk for malpractice suits, to manage the complications that may lead to them and to increase the likelihood of winning a case should they be faced with one. “There are things you can do ahead of time— things you can do during the procedure and after the event—that you need to know about,” said John Baillie, MB, ChB, director of medical gastroenterology, Carteret General Hospital, Morehead City, N.C. Dr. Baillie said that physicians must know the national standards for endoscopic practice that are available on gastroenterology society websites and accessible to non-members. “In the event of a malpractice litigation, the plaintiff ’s intent is to show that the physician has deviated from the standard of care, [defined as] what a reasonable physician would have

see Alcohol, page 14

see Malpractice, page 26

I N S I D E

EXPERT ROUNDTABLE

Therapy for Barrett’s Esophagus What, When and in Which Patients? By Maureen Sullivan Over the past decade, new advancements in ablation therapy have expanded treatment options for patients with Barrett’s esophagus (BE). Introduced to clinical practice in 2005, radiofrequency ablation (RFA) is one of the most recent ablation techniques available for the treatment see Barrett’s Esophagus, page 18

EXPERT REVIEW Fecal Microbial Transplantation: An Increasingly Important Alternative for the Treatment of C. difficile �� page 6

Allen Kamrava, MD, MBA

Gary H. Hoffman, MD

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Best of Five MCQs for the Gastroenterology SCE

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Pancreatic Exocrine Insufficiency Part 1 of 2: Treatment Approaches ViVek kadiyala, Md Shadeah laila SuleiMan darwin l. Conwell, Md, MS Center for Pancreatic Disease Brigham and Women’s Hospital Division of Gastroenterology, Hepatology, and Endoscopy Harvard Medical School Boston, Massachusetts

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G A ST R O E N T E R O LO GY & E N D O S cO P Y N E wS • A P R I L 2 0 1 2

1978

35th Anniversary — 2 0 1 3

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gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

For more than three decades, Gastroenterology & Endoscopy News has been providing gastroenterology health care professionals with specialty-specific news and reviews, offering comprehensive and objective information for the practicing clinician. 1978 —

35th Anniversary — 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 1 • January 2013

gastroendonews.com ACG 2012

IBS No Longer Only Functional Disorder By david Wild

Experienced Physicians Offer Tips To Trainees on Landing a Job It’s Never Too Early To Start the Search By Christina Frangou

las vegas—For the first time, investigators have documented structural abnormalities in the small bowel of patients with irritable bowel syndrome (IBS). These findings “will fundamentally change our thinking on the disease,” researchers told attendees of the 2012 see iBS, page 8

Mesalamine Elicits Response in IBS By MoniCa J. sMith las vegas—Mesalamine, a 5-aminosalicyte acid that is effective for maintenance of remission in patients with ulcerative colitis, also may be effective in relieving and controlling symptoms in irritable bowel syndrome see Mesalamine, page 9

If they haven’t already, fellows and residents should add one more resolution to their New Year’s list: Start the job search. The earlier that trainees begin the search, the better, experts say. Many recommend that residents and fellows start the process 18 months before they are due to finish training. With recruiting season kicking into high gear over the next few months, Gastroenterology & Endoscopy News summarized some practical tips for finding a job in academic medicine or private practice, as outlined by two gastroenterologists with experience in each area. see Job Search, page 25

Experts’ Picks

I N S I D E

Best of the American college Of Gastroenterology: Part 2

Mds and dos Plan uniﬁed Accreditation System For Graduate Medical Education page 5

EXPERT REVIEW:

Sexual Misconduct by Professionals: A New Model of Understanding

CoMPiled and Written By david Wild Gastroenterology & Endoscopy News asked several experts to select their favorite abstracts from the 2012 American College of Gastroenterology (ACG) Annual Scientific Meeting. Inside is a collection of their selections and comments that reflect the varied interests of the experts who we interviewed. (Part 1 of this series appeared in the December 2012 issue of Gastroenterology & Endoscopy News.) see Best of ACG, page 14

BY GREGORY E. SKIPPER, MD, AND STEPhEN SChENThAL, MD page 29

EXPERT REVIEW:

Safeguarding Yourself Against Allegations Of Sexual Abuse or Patient Impropriety BY hARVEY TETTLEBAUM, JD, AND KEVIN MEYERS, JD page 33

PRODUCT ANNOUNCEMENT Clinical Applications of Probiotics in Gastroenterology: Questions and Answers, An Issue of Gastroenterology Clinics see page 37

The Gastric Cancers: Targeted for Personalized Medicine see pages 10-11

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

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Gastroenterology & Endoscopy News • April 2013

Vol. 64, No. 4 Medical Advisory Board Manoop S. Bhutani, MD

Gary R. Lichtenstein, MD

Houston, Texas

Philadelphia, Pennsylvania

Alan F. Cutler, MD

Nirmal S. Mann, MD, BSc, MS, PhD, DSc

Farmington Hills, Michigan

Fredric Daum, md Mineola, New York

Steven M. Faber, MD Elizabeth City, North Carolina

Ronnie Fass, MD Cleveland, Ohio

Barbara B. Frank, MD Philadelphia, Pennsylvania

Frank G. Gress, MD Brooklyn, New York

Christopher Jolley, MD Gainesville, Florida

Sacramento, California

Peter R. McNally, DO Fort Carson, Colorado

Tarun Mullick, MD St. Charles, Illinois

Joel E. Richter, MD Tampa, Florida

David robbins, MD New York, New York

Ellen J. Scherl, MD New York, New York

Prateek Sharma, MD Kansas City, Kansas

Myron Lewis, MD

Jerome H. Siegel, MD

Memphis, Tennessee

New York, New York

April 2013

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Gastroenterology & Endoscopy News • April 2013

Fecal Microbial Transplantation An Increasingly Important Alternative for the Treatment of C. difficile Allen Kamrava, MD, MBA Gary H. Hoffman, MD Los Angeles Colon and Rectal Surgical Associates Los Angeles, California

Dr. Hoffman

Dr. Kamrava

Despite the hard and fast medical school tenet that Clostridium difficile (C. difficile) colitis is not an uncommon aftereffect of clindamycin therapy, numerous other antibiotics also are strongly associated with the development of C. difficile colitis. Beginning in 2000, hypervirulent strains of C. difficile have emerged, which seem to be linked to the increased use of fluoroquinolones and cephalosporins.1 These hypervirulent strains have caused more severe and refractory cases of colitis and have increased the need for ICU treatment, long-term antibiotic therapy and the need for emergent subtotal colectomies. Although current standards set out by the Joint Commission and the

National Surgical Quality Improvement Program have effectively decreased the incidence of surgical site infections, they also may have inadvertently caused the emergence of this hypervirulent C. difficile strain. The mechanism of action of these hypervirulent strains of C. difficile has been shown to be the result of increased production levels of toxins A and B. Recent studies also have isolated the emergence of a new toxin that has been referred to as “binary toxin.”2 These new strains have become epidemic and have been linked to increased use of fluoroquinolones. Populations that previously have been considered to be at low risk for infection are increasingly

becoming afflicted with refractory C. difficile infections.

Traditional Antibiotics: Declining Effectiveness Although the understanding of the bacteriology of the disease has advanced, the rate of improved and more effective antimicrobial therapies has not kept pace. The standard therapy for C. difficile colitis continues to focus on two antibiotics: metronidazole and vancomycin. The specific uses and modalities of therapy remain the only variables, with some practitioners starting treatment with metronidazole therapy and others see FMT, page 8

From the Literature

Fecal Transplantation Beats Vancomycin Alone for Recurrent C. difficile Infection ‘This, By All Standards, Is Proof ’ of Concept, Says One Expert By George Ochoa Fecal transplant proved more effective than vancomycin for the treatment of recurrent Clostridium difficile infection in a randomized controlled trial in the Netherlands. The study was published in the Jan. 31 issue of The New England Journal of Medicine (van Nood E et al. 2013;368:407-415). “This study is critically important,” said Lawrence J. Brandt, MD, professor of medicine and surgery, Albert Einstein College of Medicine, and emeritus chief, Division of Gastroenterology, Montefiore Medical Center, New York City, in an interview with Gastroenterology & Endoscopy News. Dr. Brandt was not involved with the study. “I would call it a landmark study—the first randomized controlled trial of fecal transplant in the treatment of recurrent C. difficile infection. Prior to this publication, although the world’s experience with fecal transplant had been outstanding, with an average cure rate of 92% for more than 375 cases, there were still people who needed evidence-based data to support their beliefs. They still wanted ‘proof,’ and this, by all standards, is ‘proof,’” said Dr. Brandt. The researchers randomly assigned patients with recurrent C. difficile infection to one of three treatment groups. One group received an initial vancomycin regimen (500 mg orally four times per day for four days), followed by bowel lavage and an infusion of a donor feces suspension through a nasoduodenal tube. The second group was treated with a standard vancomycin regimen (500 mg orally four times per day for 14 days). The third group received the standard vancomycin regimen with bowel lavage. The study was stopped after an interim analysis showed an “overwhelming difference between treatment groups,” according to senior author Josbert J. Keller, MD, PhD, a gastroenterologist at Haga Teaching

Hospital, The Hague, Netherlands. Of 16 patients in the fecal transplant group, 13 (81%) had resolution of C. difficile-associated diarrhea after the first infusion of donor feces. The three other patients received a second infusion of feces from a different donor; of these, two were cured, for an overall cure rate of 15 of 16 patients (94%). In contrast, the group receiving vancomycin alone achieved resolution of C. difficile infection in four of 13 patients (31%), and the group receiving vancomycin with bowel lavage achieved resolution in three of 13 patients (23%) (P<0.001 for both comparisons with the fecal transplant group). Adverse events did not differ significantly among the three groups except for mild diarrhea and abdominal cramping in the infusion group on the day of infusion. Fecal transplant increased fecal bacterial diversity, making it similar to that of healthy donors. The authors suggested that the mechanism underlying the fecal transplant’s effectiveness is “probably the reestablishment of the normal microbiota as a host defense against C. difficile.” Although Dr. Keller acknowledged it as a limitation, the small study size was a result of having the study terminated; initially, 120 patients were planned for inclusion. “Fecal transplantation was so effective that the study was prematurely terminated,” explained Dr. Brandt. “It would have been ethically improper to continue it. The small size of the study is testimony to the effectiveness of the treatment.” Dr. Keller cited two reasons for the study’s importance: first, “that it’s the first randomized study of this treatment for patients with C. difficile infection,” and second, “it shows that this treatment strategy of using donor feces infusion [fecal transplant], which is a kind of a super probiotic, to influence the microflora, can cure people.” He noted the open-label nature of the study as a limitation.

Dr. Brandt said, “The study has no major limitations.” “I’m doing a randomized controlled trial with Colleen Kelly, MD, of the Miriam Hospital in Providence, R.I.,” Dr. Brandt noted. “Under a National Institutes of Health grant, we’re studying patients with at least three recurrences of C. difficile infection. The patients get back their own stool or get donor stool in a blinded fashion. We hope our controlled trial will prove that the technique of fecal microbiota transplantation is rapidly effective and safe.” Asked how his study could change treatment, Dr. Keller suggested, “The first and second episodes of C. difficile infection would be treated with antibiotics. The third episode, or the second recurrence, could be treated with antibiotics or you could consider donor feces infusion in certain patients. At the fourth episode, or the third recurrence, consider donor feces infusion as a serious possibility.” “This will definitely help change the treatment of recurrent C. difficile colitis,” said Dr. Brandt. “My opinion is that for a third recurrence, fecal transplant is the treatment of choice. I personally believe that it should be used more frequently and widely than is currently practiced. I would use it as first-line [therapy] in severely ill patients who may not be able to wait for vancomycin to take effect. I would prefer fecal transplant to antibiotics for the first episode of C. difficile because antibiotics perturb the intestinal microbiome and may lead to antibiotic resistance.” In future studies, Dr. Keller said, “we need to show that enemas are effective, and whether we can use stored feces and frozen feces. We need to determine which bacteria are responsible for the clinical effect and develop a mixture of bacteria to replace donor feces.” Dr. Brandt reported receiving a grant for research support from Optimer Pharmaceuticals, Inc. Dr. Keller reported no relevant financial conflicts of interest.

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Gastroenterology & Endoscopy News • April 2013

FMT continued from page 6

with vancomycin therapy. In general, it is advocated that metronidazole be used for milder forms of the disease and vancomycin be reserved for more severe cases. In advanced cases, the two medications may be combined and also can be administered transrectally in the hope of increasing bacteriologic penetration. The emergent hypervirulent strains have demonstrated resistance to these standard medications. Kelly and LaMont reported that 25% of patients adequately treated with either of these medications experienced a disease recurrence.3 Patients followed one of two clinical pathways. In the first group, despite aggressive therapy, the disease progressed to fulminant colitis, necessitating an emergent subtotal colectomy. In the second group, the disease remained quiescent during the course of antibiotic administration, yet quickly relapsed once therapy was completed. Relapses most often occurred within the first several days after the completion of antimicrobial therapy. Recently, a new bacteriocidal antibiotic, fidaxomicin, was introduced to treat C. difficile colitis. Fidaxomicin is a narrow-spectrum macrolide that inhibits RNA transcription. Its major metabolite, OP-1118, is also therapeutically active. Fidaxomicin is active against virulent forms of C. difficile.4 In an industrysponsored trial of 629 patients, a cure was achieved in 88.2% of those treated with fidaxomicin, and 85.8% in those treated with vancomycin. Recurrence rates were 15% and 25.3%, respectively.5 Non–industry-sponsored investigations have demonstrated similar responses.

Despite the treatment improvements with fidaxomicin, there remains much more to be done in the effort to cure C. difficile colitis.

The New Kid on the Block: Stool The increasing incidence and refractoriness of C. difficile infections have prompted the search for alternative therapies. Fecal microbial transplantation (FMT) is one such alternative therapy. FMT is performed by placing a fecal suspension of fresh stool harvested from a healthy individual into the gastrointestinal tract of an individual with a C. difficile infection. Placement is performed through a standard colonoscope side channel or through a previously placed enteral tube. Enema suspensions also have shown promise. This is not so much a new therapy as it is an alternative form of therapy. The first reported use of FMT was in the 17th century in veterinary medicine. The first reported use of this novel approach in humans was in 1958, in a four-patient case series by Eiseman.6 In a multicenter study, primary cure rates for FMT have been reported to be 91% after the first course of treatment, and 98% if a second treatment was necessary.7 The study reproduced the results from the only other multicenter study with 317 patients in eight countries that demonstrated a primary cure rate of 92%.8 The investigators used stool from a healthy, screened donor and infused it via a colonoscope into the recepient’s colon. Several other studies confirmed these results. The investigators noted that the response to FMT was rapid,

FMT: Risks and Contraindications • Colonoscopic perforation rates are approximately one in 3,000 colonoscopies. • There is a theoretical risk for transmitting infections when potentially infected stool is transferred from a donor with a transmissible disease to an otherwise uninfected recipient with a C. difficile infection. To mitigate this risk, choosing well-known family members as donors is the best option. • Absolute contraindications to donor FMT include: – Recent, illlicit drug use; history of incarceration; high-risk sexual activity; known HIV; and tattoos/piercings within the previous six months. – Antibiotic use within the previous three months; risk factors for Creutzfeldt-Jakob disease; known past history of inflammatory bowel disease, irritable bowel syndrome, idiopathic constipation or chronic diarrhea. – Donor blood testing may include screening for hepatitis A, B and C; Helicobacter pylori; human T-lymphotropic virus; and Giardia antigen.

with improvement of symptoms within three days of treatment in the majority of patients. Although all of the study participants underwent FMT via colonoscopy, other investigators have reported success using enema instillation, nasogastric tube instillation or esophagogastroduodenoscopy instillation.

number drops to two of 100 patients. The risks associated with colonoscopic FMT in the outpatient setting are considered to be no greater than the risks

Current indications for FMT include patients who are found to be refractory to antimicrobial therapy or who have had at least two documented disease recurrences after completing adequate antimicrobial treatment. In a study of nasogastric FMT published this year in The New England Journal of Medicine, cure rates were found to be 81% after the first FMT and 94% overall when a second FMT was performed (see “Fecal Transplantation Beats Vancomycin Alone for Recurrent C. difficile Infection,” page 6).9 This study, however, was performed on a highly selected group of patients and further investigation must be done with a broader range of patients. Additionally, unsedated outpatients might be wary of having a nasogastric tube removed after fresh feces had been inserted through the tube. It is in this realm where genetically engineered bacteria might be of use. The reported cure rates using FMT are higher than those achieved by using vancomycin or the newer agent, fidaxomicin. FMT is clearly a viable treatment option for patients with C. difficile infections. Current indications for FMT include patients who are found to be refractory to antimicrobial therapy or who have had at least two documented disease recurrences after completing adequate antimicrobial treatment. FMT therapy should be considered for patients with moderate disease who have not improved symptomatically after one week of therapy. Case reports of the successful use of FMT in ICU patients with advanced disease have prompted calls for further investigation of the use of FMT in the ICU setting.

Risks Associated With FMT There are few risks associated with FMT. The most common is treatment failure, which is estimated to occur in approximately eight of 100 treated patients after a single stool transfer. With a second stool transfer, that

of standard colonoscopy. Colonoscopic perforation rates are estimated to be approximately one in 3,000 colonoscopies. The risk for endoscopic perforation increases when FMT is performed in patients with more advanced disease, especially in the ICU setting. Although not prohibitive, this risk should be clearly discussed with patients because a perforation in an acutely inflamed bowel with pseudomembranous colitis will necessitate an emergency total abdominal colectomy. Absolute contraindications to donor FMT are recent illicit drug use, highrisk sexual activity, known HIV, history of incarceration, tattoo or body piercing within the previous six months, current or known exposure to communicable disease or antibiotic use within the prior three months, travel to an area with known diarrheal disease within the prior six months or risk factors for Creutzfeldt-Jakob disease. Other contraindications for the donor are a known past history of inflammatory bowel disease, irritable bowel syndrome, idiopathic constipation or chronic diarrhea. Donors should not have been on systemic antineoplastic agents within the prior year, or should not be on major immunosuppressive agents and should not have had a history of a GI malignancy. Donors should notify the physician if there are any symptoms of an infection between the screening time and the time of donation. Donor blood testing may include screening for hepatitis A, B and C, Helicobacter pylori, syphilis, HIV, human T-lymphotropic virus, Cryptosporidium antigen and Giardia antigen. see FMT, page 12

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infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. t *ODSFBTFE TZTUFNJD HMVDPDPSUJDPJE TVTDFQUJCJMJUZ 3FEVDFE MJWFS DOSAGE AND ADMINISTRATION function affects the elimination of glucocorticosteroids. The recommended dosage for UCERIS is one 9-mg tablet to be taken t 0UIFS HMVDPDPSUJDPJE FGGFDUT $BVUJPO TIPVME CF UBLFO JO QBUJFOUT once daily in the morning with or without food for up to 8 weeks. with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or IMPORTANT SAFETY INFORMATION glaucoma, or with any other condition where glucocorticosteroids CONTRAINDICATIONS may have unwanted effects. UCERIS is contraindicated in patients with known hypersensitivity ADVERSE REACTIONS to budesonide or any of the ingredients of UCERIS. Most common adverse reactions (incidence â&#x2030;Ľ2%) are headache, WARNINGS AND PRECAUTIONS nausea, decreased blood cortisol, upper abdominal pain, fatigue, t )ZQFSDPSUJDJTN BOE BESFOBM TVQQSFTTJPO 4JODF 6$&3*4 JT B flatulence, abdominal distension, acne, urinary tract infection, glucocorticosteroid, general warnings concerning glucocorticoids arthralgia, and constipation. should be followed. DRUG INTERACTIONS t 5SBOTGFSSJOH QBUJFOUT GSPN TZTUFNJD DPSUJDPTUFSPJET Avoid Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit Risk of impaired adrenal function when transferring from oral steroids with high systemic effects. Taper patients slowly from juice). May cause increased systemic corticosteroid effects. systemic corticosteroids if transferring to UCERIS. USE IN SPECIFIC POPULATIONS t *NNVOPTVQQSFTTJPO 1PUFOUJBM XPSTFOJOH PG JOGFDUJPOT FH )FQBUJD JNQBJSNFOU .POJUPS QBUJFOUT GPS TJHOT BOE PS TZNQUPNT existing tuberculosis, fungal, bacterial, viral, or parasitic of hypercorticism. CORE STUDY DESIGNS: Two randomized, double-blind, placebo-controlled studies were conducted in a total of 899 adult patients with active, mild to moderate UC (Ulcerative Colitis Disease Activity Index [UCDAI]: â&#x2030;Ľ4 and â&#x2030;¤10 at entry). The primary endpoint was induction of combined clinical remission and mucosal healing (defined as a UCDAI score of â&#x2030;¤1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a â&#x2030;Ľ1-point reduction in the endoscopic index score) after 8 weeks of treatment.1

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A SAFETY PROFILE THAT OFFERS CONFIDENCE1 t The rates of overall expected glucocorticoid-related side effects were similar for UCERIS and placebo at 8 weeks— 10.2% vs 10.5%, respectively1*

www.UCERIS.com The Important Safety Information does not include all of the information needed to use UCERIS safely and effectively. Please see Brief Summary of Prescribing Information on the following page and Full Prescribing Information at www.UCERIS.com. *In a pooled analysis of 2 Phase III clinical trials.1,3 References: 1. UCERIS Prescribing Information. Santarus, Inc. January 2013. 2. Brunner M, Ziegler S, Di Stefano AF, et al. Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol. 2005;61:31-38. 3. Data on file. Santarus, Inc. UCERIS is a trademark of Santarus, Inc. MMX is a registered trademark of Cosmo Technologies, Ltd.

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FMT continued from page 8

There is a theoretical risk for transmitting infections when potentially infected stool is transferred from a donor with a transmissible disease to an otherwise uninfected recepient with a C. difficile infection. To mitigate this theoretical risk, patients are advised to solicit donors from well-known family members. The donor stool may be screened and tested for transmissible diseases. These include salmonella, BRIEF SUMMARY Please see package insert for Full Prescribing Information available at www.uceris.com UCERIS (budesonide) extended release tablets, for oral use Rx Only INDICATIONS AND USAGE UCERIS (budesonide) extended release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. CONTRAINDICATIONS UCERIS is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of UCERIS. Anaphylactic reactions have occurred with other budesonide formulations. WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamuspituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed. Transferring Patients from Systemic Glucocorticosteroid Therapy Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously. Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG.) If chicken pox develops, treatment with antiviral agents may be considered. Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections. Replacement of systemic glucocorticosteroids with UCERIS tablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Systemic Glucocorticoid Susceptibility Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis. Other Glucocorticosteroid Effects Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. ADVERSE REACTIONS Systemic glucocorticosteroid use may result in the following: t )ZQFSDPSUJDJTN BOE "ESFOBM 4VQQSFTTJPO t 4ZNQUPNT PG TUFSPJE XJUIESBXBM JO UIPTF QBUJFOUT USBOTGFSSJOH from Systemic Glucocorticosteroid Therapy t *NNVOPTVQQSFTTJPO t *ODSFBTFE 4ZTUFNJD (MVDPDPSUJDPTUFSPJE 4VTDFQUJCJMJUZ t 0UIFS (MVDPDPSUJDPTUFSPJE &GGFDUT 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 practice. The safety of UCERIS has been evaluated in controlled and open-label clinical trials which enrolled a combined total of 1105 patients with ulcerative colitis. In two 8-week, placebo-controlled studies in patients with active disease (Study 1 and Study 2), a total of 255 patients received UCERIS 9 mg, 254 patients received UCERIS 6 mg, and 258 patients received placebo. They ranged in age from 18-77 years (mean 43), 56% were male, and 75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. The adverse reactions occurring in 2% or more of patients on therapy with UCERIS 9 mg are summarized in Table 1. Table 1. Summary of Adverse Reactions in Two Placebo Controlled Trials Experienced by at Least 2% of the UCERIS 9 mg Group (Studies 1 and 2)

Headache Nausea Decreased Blood Cortisol Upper Abdominal Pain Fatigue Flatulence Abdominal Distension Acne Urinary Tract Infection Arthralgia Constipation

UCERIS 9 mg (N = 255) n (%) 29 (11.4) 13 (5.1)

UCERIS 6 mg (N = 254) n (%) 37 (14.6) 12 (4.7)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3)

11 (4.3)

6 (2.4)

1 (0.4)

10 (3.9)

8 (3.1)

5 (1.9)

8 (3.1) 6 (2.4) 6 (2.4) 6 (2.4) 5 (2.0) 5 (2.0) 5 (2.0)

5 (2.0) 8 (3.1) 4 (1.6) 2 (0.8) 1 (0.4) 5 (2.0) 1 (0.4)

5 (1.9) 5 (1.9) 2 (0.8) 5 (1.9) 1 (0.4) 4 (1.6) 2 (0.8)

Gastroenterology & Endoscopy News â&#x20AC;˘ April 2013

shigella, pathogenic E. coli, 0157:H7, Campylobacter, Entamoeba histolytica, Yersinia enterocolitica, C. difficile, ova and parasites such as Cryptosporidium, Giardia and others. To date, there have been no reported cases of disease transmission from donor to recipient. In the study performed by Brandt et al,10 stool transfers from individuals within the same household demonstrated a significantly higher cure rate than otherwise. Thus, our predilection for using family members as stool donors serves a dual purpose: higher cure rates coupled with 0G 6$&3*4 NH QBUJFOUT B UPUBM PG EJTDPOUJOVFE USFBUNFOU EVF to any adverse event (including adverse reactions) compared with 17% in the placebo group. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebocontrolled studies. Table 2. Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)

0WFSBMM Mood changes Sleep changes Insomnia Acne Moon face Fluid retention Hirsutism Striae rubrae Flushing

UCERIS 9 mg (N = 255) n (%) 26 (10.2) 9 (3.5) 7 (2.7) 6 (2.4) 6 (2.4) 3 (1.2) 2 (0.8) 1 (0.4) 0 0

UCERIS 6 mg (N = 254) n (%) 19 (7.5) 10 (3.9) 10 (3.9) 6 (2.4) 2 (0.8) 3 (1.2) 3 (1.2) 0 0 1 (0.4)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3) 12 (4.7) 8 (3.1) 5 (1.9) 4 (1.6) 3 (1.2) 0 2 (0.8) 3 (1.2)

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS and placebo after 8 weeks of induction therapy. Study 3 was an open-label study evaluating UCERIS 9 mg once daily for 8 weeks in 60 patients who had previously completed an 8-week induction study (Study 1), but had not achieved remission. Among patients who took UCERIS 9 mg up to 16 weeks cumulatively across Study 1 and Study 3 combined, similar rates of adverse reactions and glucocorticoid-related effects were seen compared to those who took UCERIS 9 mg for 8 weeks in Study 1. In Study 4, the safety of long-term treatment with UCERIS 6 mg was evaluated in a placebo-controlled 12-month maintenance study of 123 patients. Patients who had previously completed 8 weeks of therapy in any induction study (Study 1, 2, or 3) and were in remission were randomized to UCERIS 6 mg or placebo once daily for 12 months. In patients who took UCERIS 6 mg for up to 12 months, similar rates of adverse reactions were seen between placebo and UCERIS 6 mg. After up to 12 months of study treatment, 77% (27/35) of the patients in the UCERIS 6 mg and 74% (29/39) of the patients in the placebo treatment groups had normal bone density scans. In Study 4, the glucocorticoid related effects were similar in patients with up to 12 months of therapy with UCERIS 6 mg and placebo. (Table 3) Table 3. Summary of Glucocorticoid Related Effects Over 12-month Treatment (Study 4)

0WFSBMM Insomnia Mood changes Moon face Sleep changes Acne Hirsutism Flushing Fluid retention

UCERIS 6 mg (N = 62) n (%) 9 (14.5) 4 (6.5) 4 (6.5) 3 (4.8) 3 (4.8) 3 (4.8) 3 (4.8) 1 (1.6) 1 (1.6)

Placebo (N = 61) n (%) 7 (11.5) 4 (6.6) 2 (3.3) 3 (4.9) 3 (4.9) 0 0 1 (1.6) 1 (1.6)

Postmarketing Experience The following adverse reactions have been identified during postapproval use of oral budesonide. 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. Immune System Disorders: anaphylactic reactions Nervous System Disorders: benign intracranial hypertension Psychiatric Disorders: mood swings DRUG INTERACTIONS Interaction with CYP3A4 inhibitors Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eightfold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of UCERIS should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with UCERIS administration. Inhibitors of Gastric Acid Secretion Since the dissolution of the coating of UCERIS is pH dependent, the release properties and uptake of the compound may be altered when UCERIS is used after treatment with gastric acid reducing agents (e.g., PPIs, H2 blockers and antacids). USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). There are no adequate and wellcontrolled studies in pregnant women. Budesonide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving glucocorticosteroids during pregnancy. Such infants should be carefully observed. Nursing Mothers The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable

the theoretical potential for lower risk for disease transmission.

The Protocol: Patient and Physician Education Is a Must In our practice, a clear protocol has been designed to help patients through the entire FMT process. Information packets have been created that address the numerous and most common questions patients may have. We work closely with referring physicians who understand the protocol and who also have their own standard protocol for screening donors. to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant). The recommended daily dose of UCERIS extended release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 Îźg daily) given to mothers in the above study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/L which is up to 10 times higher than the 1-2 nmol/L for an 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Since there are no data from controlled trials on the use of UCERIS by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from UCERIS, a decision should be made whether to discontinue nursing or to discontinue UCERIS, taking into account the clinical importance of UCERIS to the mother. Budesonide, is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric Use Safety and effectiveness of UCERIS in pediatric patients have not been established. Glucocorticosteroids, such as UCERIS may cause a reduction of growth velocity in pediatric patients. Geriatric Use Clinical studies of UCERIS did not include sufficient numbers of subjects aged 65 and over to determine whether they SFTQPOE EJGGFSFOUMZ GSPN ZPVOHFS TVCKFDUT 0UIFS SFQPSUFE DMJOJDBM experience has not identified differences in responses between the elderly and younger patients. In general, UCERIS should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS tablets should be considered in these patients. OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in SpragueDawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Mutagenesis Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/â&#x20AC;&#x201C;) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocycte UDS test and the mouse micronucleus test. Impairment of Fertility In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

UCERISâ&#x201E;˘ is a trademark of Santarus, Inc. U.S. Patent Nos: 7,410,651; 7,431,943; RE43799; 8,293,273. ÂŠ 2013 Santarus, Inc.

1-UCE13033 V1

We have attempted to educate the medical community regarding the diagnosis and treatment of resistant or recurrent C. difficile infections. The FMT is performed in an outpatient surgical center and patients return home the same day. In most patients, we are able to determine success or failure within several days after the fecal transfer. We are receiving an increasing number of patient requests for FMT as patient awareness has increased and physician education has evolved. Although an individualâ&#x20AC;&#x2122;s first reaction to a stool transfer is usually some form of anxiety, most patients who consider this option have reached a frustration point in their failed treatment that they welcome this therapy. With our results and international results as promising as they seem to be, with risks no higher than that of a standard colonoscopy, and with a rapid cure rate after infusion, we have embraced this therapy and will continue to offer its use for the treatment of resistant or refractory C. difficile infections.

References 1. Gould CV, McDonald LC. Bench-tobedside review: Clostridium difficile colitis. Crit Care. 2008;12(1):203. 2. Blossom DB, McDonald LC. The challenges posed by reemerging Clostridium difficile infection. Clin Infect Dis. 2007;45(2):222-227. 3. Kelly CP, LaMont JT. Clostridium difficileâ&#x20AC;&#x201D;more difficult than ever. N Engl J Med. 2008;359(18):1932-1940. 4. Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431. 5. Dificid [package insert]. San Diego, CA: Optimer; 2011. 6. Eiseman B, Silen W, Bascom GS, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44(5):854-859. 7. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107(7):1079-1087. 8. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis. 2011;53(10):994-1002. 9. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415. 10. Brandt LJ, Reddy SS. Fecal microbiota transplantation for recurrent Clostridium difficile infection. J Clin Gastroenterol. 2011;45(suppl):S159â&#x20AC;&#x201C;S167.

Gastroenterology & Endoscopy News • April 2013

Poor Results Achieved With Fecal Transplantation for Ulcerative Colitis By David Wild Only one of five patients with moderate to severe ulcerative colitis (UC) who were treated with fecal transplantation (FT) experienced clinical and endoscopic improvements following the procedure, according to an abstract presented at the 2012 United European Gastroenterology Week (abstract P374). Lead investigator Walter Reinisch, MD, associate professor in the Division of Gastroenterology and Hepatology at the Medical University of Vienna, Austria, conducted the procedure in two women and three men with moderate to severe UC who were resistant to previous other treatments. All participants were undergoing immunosuppressant therapy before FT and discontinued treatment before transplantation. All patients received antibiotics and probiotics for five to 10 days before the procedure and underwent a single bowel lavage immediately before transplantation. Healthy adult fecal donors were screened for enteric pathogens and viral diseases.

UC Activity showed a decrease in median scores from 11 at baseline to 9 among the three patients who did not experience clinical disease flares and who completed the protocol. One patient experienced a Mayo endoscopic subscore change from 3 to 2. “Although plenty of donor-derived bacteria were established in all of the patients, successful colonization by beneficial bacteria, such as Faecalibacterium prausnitzii, was achieved only in the one patient who had a good clinical response,”

Dr. Reinisch noted. His group is investigating whether patients with milder UC experience a more favorable response to FT, citing positive findings from a case series that included six patients with a less aggressive form of UC (Borody TJ et al. J Clin Gastroenterol 2003;37:42-47). Lawrence Brandt, MD, professor of medicine and surgery at Albert Einstein College of Medicine, and emeritus chief of the Division of Gastroenterology at Montefiore Medical Center, both in New York

City, did not see similar outcomes in 22 patients with UC that he treated with FT. “I haven’t analyzed data from my patients but my impression is that some respond very well to FT,” he said. “Now the challenge is to discover who and why. There is so much variability in how FT is done, and so much detail was left out of this abstract, that it is difficult to say why the results were poor.” n Drs. Brandt and Reinisch reported no relevant conflicts of interest.

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‘There is so much variability in how fecal transplantation is done, and so much detail was left out of this abstract, that it is difficult to say why the results were poor.’

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—Lawrence Brandt, MD Dr. Reinisch simultaneously administered a saline-diluted fecal solution via a nasojejunal tube (median 23.8 g) and an enema (median 20 g). All of the patients experienced fever, increased C-reactive protein (CRP) levels and exacerbated UC symptoms during the first procedure, and one recipient also experienced emesis. The procedure was repeated over three consecutive days in all but one patient, whose fever and increases in CRP levels were more severe and required discontinuation of treatment until five weeks after initial administration. During the follow-up period, adverse events included upper respiratory tract viral infection, pruritus, erythema, paresthesia of the hip, fainting and tongue blistering. There was no evidence of bacterial pathogens in blood cultures, Dr. Reinisch reported, and hydrogen-glucose breath tests showed that none of the patients had small bowel bacterial overgrowth. Twelve weeks after FT, clinical disease activity had worsened in two patients. The Mayo Scoring System for Assessment of

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IBS Awareness Month

Allergies continued from page 1

Investigators concluded that skin patch testing might help identify causative allergens that, through dietary avoidance, may alleviate symptoms. Researchers performed skin patch tests for food allergies in 51 patients with known or suspected IBS. Of these, 30 individuals (58.8%) had at least one doubtful or positive test result for a food allergy. Patients then completed a one-week avoidance diet of the foods/food additive to which they reacted. Nearly half—47.7%—reported a moderate to great improvement in symptoms, 13% reported a slight improvement and 39% reported no improvement.

Gastroenterology & Endoscopy News • April 2013

Investigators Michael B. Stierstorfer, MD, a dermatologist at East Penn Dermatology PC, North Wales, Pa., and his colleagues said the results suggest a role for allergic contact enteritis, known as type-4 hypersensitivity, in the pathogenesis of IBS. “We hypothesize the same type-4 reaction being demonstrated on the skin [during patch testing] is occurring in the gut … resulting in chronic inflammation.” Inflammation leads to altered gut motility and gastrointestinal symptoms that may mimic IBS, the authors said. They argued that skin patch testing might be useful in identifying causative foods. Dr. Stierstorfer has submitted a skin patch test for IBS. But some gastroenterology experts say the study lacks scientific rigor. “The concept is really interesting and novel, but there are many problems with the study design,” said William D. Chey, MD, professor of medicine and director of the GI Physiology Laboratory, University of Michigan, Ann Arbor. Larger studies with double-blind design (neither patients or testers were blinded in this study), inclusion of patients with

only active IBS, more balanced gender distribution, testing of more foods and food additives, the use of validated assessment tools and more precise quantification of response to dietary avoidance are needed. Only two of the 30 patients who completed the exclusion diet were male, and only 60% of the cohort had physiciandiagnosed IBS. Moreover, only 13% of patients who completed exclusion diets reported great improvement. Most patients classified their improvements as moderate or mild (34.7% and 13%, respectively). “That could be simply placebo effect,” Dr. Chey noted. “I think there is certainly something to this concept— I believe strongly that food hypersensitivity is very prevalent—but this paper, unfortunately, doesn’t do very much to help us to answer the question,” said Dr. Chey. The patch test used in the study included items like garlic, onion, artichoke, cucumber, carrots and lettuce, and food additives like vanilla, propylene glycol and sorbic acid. Garlic was the most common allergen, with one-third of patients showing some reaction. The 2010 guidelines for the diagnosis and management of food allergy issued by the National Institute of Allergy and Infectious Diseases advised against the use of food patch testing to diagnose food allergy with the exception of contact dermatitis because of insufficient evidence to support its use (J Allergy Clin Immunol 2010;126[6 suppl]:S1-S8). n

Alcohol continued from page 1

Noting that women are disproportionately affected by IBS and that previous studies indicate that 12% to 17% of adults with IBS reported perceived intolerances to alcohol, Kerryn Reding, PhD, of the Department of Biobehavioral Nursing and Health Systems at the University of Washington, Seattle, led a study that examined whether specific patterns of alcohol intake among women were associated with the next day’s symptoms. Researchers evaluated data from 166 women with IBS aged 18 to 48 years, along with 48 healthy controls. Over the course of one month, each woman kept a daily log of alcohol and tobacco use, caffeine intake and feelings of stress, while also rating GI symptoms (e.g., abdominal and intestinal pain, gas, nausea, stomach pain and indigestion) on a scale of 0 to 4. Participants also completed a Bowel Disease Questionnaire to establish IBS subtype: IBS-diarrhea (IBS-D), IBS-constipation (IBS-C) or IBS-mixed. The data were analyzed using generalized estimating equations models to assess the relationship of daily intake of alcohol, caffeine and cigarettes to the presence of next day’s GI symptoms. Researchers found that drinking habits were not significantly different between patients with IBS and healthy controls, with a mean of 0.51 drinks

consumed per day among those with IBS compared with 0.53 among controls. Women with IBS who reported binge drinking—defined by the researchers as four or more alcoholic drinks in one day—had more severe diarrhea, stomach pain and indigestion than those who did not, even after adjustment for the prior day’s cigarette smoking and stress. For moderate and light drinking among women with IBS, there was either no observed association or a weak association with next day’s GI problems. Alcohol consumption among healthy controls showed no association. Further analysis found that associations between alcohol intake and GI symptoms were strongest among women in the IBS-D group, and that there was no evidence of an association between alcohol intake and GI symptoms among women with IBS-C. Perhaps most notably, the study provides an indication that “women with IBS-D who binge drink may experience an increase in GI symptoms that is not limited to their episodes of binge drinking.” William D. Chey, MD, professor of medicine and director of the GI Physiology Laboratory, University of Michigan, Ann Arbor, concurred that the study’s results raise concerns about the lasting effects of alcohol on the GI tract. “The fact that it was binge drinking

‘Women with IBS-D who binge drink may experience an increase in GI symptoms that is not limited to their episodes of binge drinking.’ —Reding KW et al. Am J Gastroenterol 2013;108:270-276

‘This is a unique set of data. It makes one wonder about whether or not binge drinking could be associated with changes in the microbiome.’ —William D. Chey, MD

that led to an increase in GI symptoms begs the question, is it related to consumption, or is alcohol simply a marker for other physiologic problems? It could be that binge drinking is associated with lasting changes in the microenvironment of the GI tract.” Although carbohydrate-rich alcohol kills bacteria, it might affect motor patterns and gut permeability, and lead to

hypersensitivity of the GI tract. The researchers conceded that their findings must be replicated before conclusions can be drawn; nevertheless, the study poses an interesting question. “This is a unique set of data,” Dr. Chey noted. “It makes one wonder about whether or not binge drinking could be associated with changes in the n microbiome.”

IBS Awareness Month

Gastroenterology & Endoscopy News • April 2013

Role of Gut Microbiome in Pediatric GI Disease: Evidence Suggestive, But Not Conclusive By Caroline Helwick

‘The question is whether we are seeing

New Orleans—Intestinal dysbiosis may play a role in gastrointestinal (GI) disorders such as necrotizing enterocolitis (NEC) and irritable bowel syndrome (IBS) in children, and prebiotics and probiotics may be efficacious for treating these conditions, according to Philip M. Sherman, MD, professor of pediatrics, microbiology and dentistry at the Hospital for Sick Children, Toronto, and the University of Toronto, and Canada Research Chair in Gastrointestinal Disease. Dr. Sherman delivered a plenary address at the 2012 American Academy of Pediatrics annual meeting entitled, “The Gut Microbiome in Health and Disease: You Are Who You Live With!” He noted that the development of the gut microbiota is complex, evolving from a relatively sterile environment in newborns to the heavily colonized adult scenario. Influences on the microbiome include the mode of childbirth (vaginal vs. cesarean delivery), infant diet (breast-feeding vs. formula feeding), hygiene (exposure to pathogens) and medications (e.g., antibiotics). For example, babies born vaginally have a much more complex microbiotic flora due to acquisition of bacteria through the birth canal. Those born via cesarean delivery, however, have a less diverse microbiome, and

cause and effect (i.e., an active role in

Don’t Disregard Diet in IBS Re: “IBS Remains Mysterious Disorder, With Few Effective Remedies,” by Monica J. Smith. Gastroenterology & Endoscopy News April 2012;63:1,14-15. One reason that IBS remedies are often not effective is that the underlying culprit—the patient’s DIET—is not properly addressed. Research from Australia is plentiful in demonstrating benefits of the FODMAP’s elimination diet. Likewise, I have found that identifying patient-specific non-IgE food allergies can also be extremely beneficial, and even life changing, for some IBS sufferers. Jennifer J. Masters, MS, RD, LDN Via website on Jan. 8, 2013

Editor’s Reply: Thank you for your insight—and impeccable timing—regarding this topic. A diet low in FODMAPs (fermentable oligo-, di- and monosaccharides and polyols) carbohydrates is discussed in an article that was published in our January issue: “Expert Calls Diet ‘Next Big Thing’ in IBS” (by Ted Bosworth Gastroenterology & Endoscopy News January 2013;64:13). Gastroenterology & Endoscopy News Jan. 28, 2013

disease) or an association.’ —Philip M. Sherman, MD

it takes longer for them to acquire the 500 to 1,000 types of microbes that colonize the adult intestine, Dr. Sherman said. Breast-fed infants have a predominance of lactic acid– producing bacteria and bifidobacteria, whereas formulafed babies and breast-fed infants who are weaned have a different composition that results in firmer, darker and thicker stools, with the type of anaerobic bacteria that typically characterize the adult microbiome. Exposure to pathogens and to antibiotics—even a single dose—in the first year of life also can substantially affect, at least in the short term, the composition of the gut bacteria. The growing recognition that bacterial diversity in the gut is important has led to efforts to define its composition, especially for promoting beneficial bacterial growth. Various international Human Microbiome Projects are now under way, which aim to decipher the microbiota of the mouth, skin, vagina and GI tract.

‘The data are not in dispute, but what is in dispute is the interpretation of the data and what it means in clinical practice. … Most studies were conducted outside of North America, and the question is whether the results are transferable to our population.’ —Philip M. Sherman, MD

Necrotizing Enterocolitis and IBS Reduced bacterial diversity, or dysbiosis, is an emerging theme across many GI disease states, including NEC and IBS. “The question is whether we are seeing cause and effect (i.e., an active role in disease) or an association,” Dr. Sherman noted. Restoration of the gut homeostasis may affect these conditions, he said, and management with probiotics and prebiotics is supported by a growing body of evidence, including several meta-analyses that have shown a reduction in NEC and associated infant mortality in children receiving probiotics (Deshpande G et al. Pediatrics 2010;125:921-930). “In the composite, these data show that probiotics are beneficial in reducing NEC,” Dr. Sherman said. “We are not sure of the mechanism of action, but they do transiently colonize the gut and transiently increase the numbers of lactic acid–producing bacteria or bifidobacteria. “The data are not in dispute,” he continued, “but what is in dispute is the interpretation of the data and what it means in clinical practice. … Most studies were conducted outside of North America, and the question is whether the results are transferable to our population.” Although some groups have suggested that probiotics are, in fact, “ready for prime time” for the prevention of NEC (Tarnow-Mordi WO et al. Pediatrics 2010;125:1068-1070), others have maintained that although the data are encouraging, it is too soon to act on the information (Soll RF. Pediatrics 2010;125:10711072). The European Society for Pediatric Gastroenterology, Hepatology and Nutrition has stated that there is “not enough available evidence to indicate that the use of probiotics or prebiotics in preterm infants is safe” (Agostoni C et al. J Pediatr Gastroenterol Nutr 2010;50:85-91). The same magnitude of evidence supports the use

of probiotics for IBS, which is estimated to affect some 10% of children (i.e., those with abdominal pain of unexplained etiology associated with changes in stool form). Compared with healthy controls, children with IBS have less diverse microbiota (Rajilic-Stojanovic M et al. Gastroenterology 2011;141:1792-1801; Saulnier DM et al. Gastroenterology 2011;141:1782-1791). Although this does not equate to a causal association, Dr. Sherman said the findings do raise the question of whether symptoms would be ameliorated if diversity were enhanced. In adults with IBS, a meta-analysis from researchers at McMaster University showed improvement with probiotics (Moayyedi P et al. Gut 2010;59:325-332), with a number needed to treat of four. “That is as good as we see with any other therapy for IBS,” Dr. Sherman noted. Less data exist for the use of probiotics in children with IBS, but studies have suggested a benefit. Interestingly, at least in experimental colitis induced in mice, studies from Dr. Sherman’s lab suggest that “timing matters.” Injury was reduced to baseline when probiotics were given early in the course of an infection but not when given later, in this case six days post-injury (Rodrigues D et al. J Infect Dis 2012;206:99-109).

Challenges Related to Probiotic Use “Probiotics may not be the be-all and end-all,” Dr. Sherman acknowledged. Challenges related to probiotic use include stability, palatability, dosage, timing, relative efficacy of single strains versus combinations, compliance and, especially, safety. “This is especially important in vulnerable populations, like premature babies,” he said. see Microbiome, page 49

Gastroenterology & Endoscopy News • April 2013

SAGES Issues Recommendations On Endoluminal Therapies To Treat GERD By Maureen Sullivan Two endoluminal treatments for gastroesophageal reflux disease (GERD) were the subject of a recent assessment by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Published in February, the clinical spotlight

review recommended Stretta (Mederi Therapeutics), a radiofrequency therapy, as an appropriate option for patients who meet certain indications for GERD. However, the review committee found insufficient evidence to recommend EsophyX (EndoGastric Solutions), a device used for transoral incisionless fundoplication (TIF), as a treatment option.

The process entailed a comprehensive review and analysis of the available literature on the topic. The clinical evidence to support Stretta achieved the highest possible grade (++++) of SAGES’ fourtier grading system and was conferred a “strong” recommendation. “It is extremely gratifying to have a scientific analysis of the overwhelming body

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of clinical evidence supporting Stretta issued by an esteemed organization such as SAGES,” said Will Rutan, CEO of Mederi Therapeutics, in a statement. “The grade of ‘strong’ indicates that no further studies are necessary to validate Stretta as a safe and effective treatment for GERD.” The Stretta system treats GERD using radiofrequency ablation to remodel the musculature of the lower esophageal sphincter (LES) and gastric cardia (Figure). According to the review, clinical studies show that the treatment results in “significant reductions in tissue compliance and transient LES relaxations. These mechanisms act to restore the natural barrier function of the LES as well as to significantly reduce spontaneous regurgitation caused by transient inappropriate relaxations to the sphincter.”

‘Stretta can be done successfully by practicing gastroenterologists because it is not as complicated as EsophyX. Still, the patient population that undergoes Stretta should be carefully selected and [should be made aware] that it is nonreversible.’ —Ronnie Fass, MD

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In its literature review, SAGES cited four randomized controlled studies, a meta-analysis, multiple prospective trials and more than 30 peer-reviewed studies that supported the efficacy and safety of Stretta. They found that treatment outcomes lasted at least 48 months and led to a significant reduction or elimination of the medications required to treat GERD and improvements in quality of life, as measured by the GERD Health-Related Quality of Life scale and Quality of Life in Reflux and Dyspepsia questionnaire. Stretta was recommended as a treatment option for patients over the age of 18 years who have experienced symptoms of regurgitation or heartburn (or both) for more than six months and who have been “partially or completely responsive to antisecretory pharmacologic therapy.” As the SAGES review made clear, making recommendations on a particular therapy does not exclude other options that may be better suited to a particular patient’s needs:

Gastroenterology & Endoscopy News • April 2013

Figure. Stretta delivers low-power, low-temperature radiofrequency energy to remodel the lower esophageal sphincter at the junction of the esophagus and the stomach.

approved by the FDA in 2007. Once the device is placed endoscopically, it is deployed in the stomach and “used to create a full-thickness plication secured by H-shaped fasteners made from polypropylene.” The device underwent a number of revisions: The first technique used the TIF1 device that created a gastrogastric wrap at the gastroesophageal junction; according to the review, “critics likened it to a slipped fundoplication.” The TIF2 device was subsequently

developed to more closely replicate laparoscopic fundoplication. The SAGES review observed that “in short-term follow-up, from six months to two years, EsophyX may be effective in patients with a hiatal hernia of 2 cm with typical or atypical GERD,” but long-term studies are needed to “further evaluate device and technique safety.” “This type of technique should not filter down too quickly to practicing gastroenterologists or surgeons,” Dr. Fass

said. “It is better that it stays in expert hands, for example, esophageal centers, which will ensure that those who receive these types of procedures are going to be properly evaluated, that they are the right candidates. [The health care professionals] who should be involved are those who have expertise and do enough of these procedures on a regular basis to keep their skills at a level that will ensure long-term efficacy and prevent future n complications.”

Photo: PRNewsFoto/Mederi Therapeutics Inc.

“[The recommendations] indicate the preferable, but not necessarily the only acceptable approaches due to the complexity of the health care environment.” This point was reiterated in a press release by Mederi Therapeutics, which stated that “Stretta therapy does not preclude further steps with more invasive procedures, if indicated.” Furthermore, Stretta is not approved for use in pediatric patients, either by its manufacturer or the FDA, and SAGES did not recommend it for treating patients with severe esophagitis, hiatal hernias greater than 2 cm in length, longsegment Barrett’s esophagus, dysphagia or for those with a history of autoimmune disease, collagen vascular disease and/or coagulation disorders. Asked to comment, Ronnie Fass, MD, director of gastroenterology and hepatology and head of the Esophageal and Swallowing Center at MetroHealth Medical Center in Cleveland, said, “From the data we currently have … this technique seems to work, as long as the correct patient population is selected for treatment. Stretta can be done successfully by practicing gastroenterologists because it is not as complicated as EsophyX. Still, the patient population that undergoes Stretta should be carefully selected and [should be made aware] that it is nonreversible.” In its review of EsophyX, SAGES assigned a low (++) quality-of-evidence rating and a “weak” recommendation, as it concluded that not enough long-term data were available to support its use and several studies reported mixed results including “disappointing outcomes” and “significant untoward events.” “I agree with the recommendation,” Dr. Fass noted. “They were cautious because of a lack of long-term trials. One problem with previous endoscopic treatments for GERD that aren’t on the market anymore is that they didn’t demonstrate long-term efficacy.” EsophyX uses TIF, which was first

*Hepatic encephalopathy (HE) recurrence is always lurking, leaving him just one step away from disaster 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 suffer HE recurrences.2 With each episode debilitating patients, undermining their motor skills, and causing mounting cognitive impairment, the damage can be devastating.3 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 12/59-1 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. 3. Bajaj JS, Schubert CM, Heuman DM, et al. Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. Gastroenterology. 2010;138(7):2332-2340.

E x p e r t R O u nd t a b l e

Gastroenterology & Endoscopy News • April 2013

Barrett’s Esophagus continued from page 1

of this disease and is widely used in the medical community. Although studies are emerging that provide evidence of the medium-term effectiveness of RFA, controversy exists among medical specialists about the most appropriate time to administer RFA in the progression of BE. “The gastroenterologists really don’t feel like BE is a big problem—that it’s kind of an anatomic peculiarity and not something to be frightened about,” said Lee Swanstrom, MD, clinical professor of surgery, Oregon Health & Science University, Portland.

HALO360+ Ablation Catheter for radiofrequency ablation Image courtesy of Covidien/BÂRRX Medical

‘For my patients with LGD, we do tend to recommend

Romero, MD, esophagologist and assistant professor of medicine, Mayo Clinic College of Medicine, Rochester, Minn. “You would need to ablate about 400 people with nondysplastic BE to help one from developing cancer,” she said. Individuals at most risk for developing BE are white men aged 50 years and older, who are overweight and have a history of gastroesophageal reflux disease. Although the progression from BE to adenocarcinoma is uncommon, when it does develop, it has a very low survival rate. Only 15% to 20% of patients will survive at least five years after diagnosis. The American Cancer Society estimated that more than 17,000 new cases were diagnosed last year, and more than 15,000 patients will die from adenocarcinoma, which is the most rapidly increasing cancer in the Western world.

that they have an ablation. We [first] treat them intensively,

‘With the majority

medically, and repeat their

of LGD, we find

biopsies, but if it comes back a

that it disappears

second time as LGD, then we will recommend those patients undergo ablation.’ —Lee Swanstrom, MD

“I think surgeons tend to be a little more aggressive about it, considering it premalignant along the same lines as colon polyps,” he said. “For my patients with low-grade dysplasia [LGD], we do tend to recommend that they have an ablation. We [first] treat them intensively, medically, and repeat their biopsies, but if it comes back a second time as LGD, then we will recommend those patients undergo ablation.” This philosophical difference in approach becomes one of great significance as gastroenterologists, who were previously focused more on diagnostics,

have entered the realm of treating BE through RFA, which as an endoscopic procedure falls neatly into their sphere of practice. Prateek Sharma, MD, professor of medicine, Division of Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, doesn’t tend to use RFA on all patients with LGD. “With the majority of LGD, we find that it disappears after the first endoscopy is done, so we pretty much wait on those patients because the majority of the LGD disappears in the follow-up endoscopy. It is a difficult disease to define because even expert pathologists cannot agree on the diagnosis,” said Dr. Sharma.

Radiofrequency Ablation During an RFA procedure to treat BE, a sizing balloon is inserted into the esophagus, followed by a catheter that

Procedural steps for endoscopic mucosal resection. Images courtesy of Prasad G. Iyer, MD, Mayo Clinic

inflates to meet the inner esophageal lining. A controlled burst of ablative energy is then administered through the catheter, burning away the abnormal cells of BE and leaving room for new cells to grow in their place. Before ablation became available as an option for treating LGD, the standard of care for patients in this phase was surveillance. Guidelines from the American Gastroenterological Association (AGA) recommend surveillance intervals for LGD patients every six to 12 months (intervals for nondysplastic BE are suggested every three to five years). But the introduction of RFA into the mix has raised the question of whether it is more cost-effective in the long run to replace surveillance with ablation, even though most people with LGD will never progress to cancer. “Some people with LGD will get cancer, but who are they?” asked Yvonne

after the first endoscopy is done, so we pretty much wait on those patients because the majority of the LGD disappears in the follow-up endoscopy.’ —Prateek Sharma, MD

Dr. Swanstrom believes that more attention needs to be given to the management of BE. “I think it’s not totally settled that waiting until a patient has HGD [high-grade dysplasia] and then trying to ablate them is the best therapy,” he said. “There should be a public policy debate on whether all patients with chronic reflux disease should

Gastroenterology & Endoscopy News • April 2013

‘The accuracy rate of determining what is really LGD is pretty low and that’s a problem. That leads some people to recommend treating it aggressively with ablation— better safe than sorry—and other people saying, “well, it’s a 50-50 chance of it really being LGD, so let’s just wait and see… .” ’ —Lee Swanstrom, MD

have an endoscopy and if they have Barrett’s esophagus, be ablated.” Specialists differ not only in their response to the low cancer risk inherent in LGD, but in the diagnosis of BE itself. If a particular phase of the disease is misdiagnosed, then using RFA could end up either undertreating HGD and superficial cancer or overtreating LGD, positioning RFA against a moving target. For example, histologic characteristics of LGD are similar to that of cell inflammation and therefore can lead to difficulty in pathologic interpretation. “One thing that is hard to determine is do cells look funny because of inflammation or funny because of an actual genetic change?” Dr. Romero pointed out. “The accuracy rate of determining what is really LGD is pretty low and that’s a problem,” Dr. Swanstrom said. “That leads some people to recommend treating it aggressively with ablation—better safe than sorry—and other people saying, ‘well, it’s a 50-50 chance of it really being LGD, so let’s just wait and see until we know for sure before you add to the cost of the patient’s treatment.’ ”

Biopsies for Barrett’s Although less ephemeral a diagnosis, determining the phase of HGD also is open to dispute, primarily because the interpretation of pathologic results of biopsies can differ widely. According to AGA guidelines, the “risk for progression from LGD to HGD or adenocarcinoma remains controversial [because of the] difficulty in distinguishing dysplasic from nondysplastic BE and determining with reproducible accuracy the degree of dysplasia.” The standard protocol for performing biopsies in patients with BE is four-quadrant specimens taken every 2 cm and is recommended by the AGA, the American College of Gastroenterology (ACG) and the American Society for Gastrointestinal Endoscopy (ASGE). For patients with known or suspected dysplasia, the societies recommend the Seattle protocol, which requires four-quadrant specimens taken every 1 cm. However, the AGA notes in its medical position statement on the management of BE that “many practicing gastroenterologists do not adhere to those guidelines.” Dr. Romero said that increasing the sampling surface area from 2 cm to 1 cm is still an insufficient sample. “There is error in the system because we only sample a small amount of mucosa. Even if you double from 1% to 2%, it’s not like you capture 50% of the mucosa,” she said.

Endoscopic Mucosal Resection A recent study (Kariv R et al. Clin Gastroenterol Hepatol 2009;7:653-658) supports the view that in patients with HGD, surveillance using the Seattle protocol may not be adequate for cancer detection and recommends that patients be evaluated by endoscopic mucosal resection (EMR). A distinct advantage of EMR is that the abnormal tissue removed can be sent to the lab for analysis, whereas with RFA, biopsies cannot be done at the same time as ablation because of the risk for perforation and strictures. So in effect, ablation burns the evidence.

E x p e r t R O u nd t a b l e

“Ablation is a welcome technology in the right person with the right amount of disease and who is willing to live with risk,” said Dr. Romero. “I’m one of the people who isn’t terribly enthusiastic about ablating. Endoscopic mucosal resection is the key. No one argues against it. EMR is a slam-dunk advance in our field.” Prior to the advent of ablation, the standard of care for HGD was an esophagectomy, a major surgical procedure and a potentially traumatic one for BE patients who tend to be older and have comorbid conditions that make surgery of this magnitude very difficult.

‘Endoscopic mucosal resection is the key. No one argues against it. EMR is a slamdunk advance in our field.’ —Yvonne Romero, MD RFA (combined with EMR) has given patients an alternative to such an invasive procedure, yet it poses its own dilemma: It does not guarantee the complete elimination of precancerous cells in the long term, nor can it address the risk for submucosal abnormalities, therefore committing the patient to a lifetime of follow-up endoscopies. In contrast, esophagectomy, for obvious reasons, can provide this peace of mind.

Which Procedure, Which Patient? Although both gastroenterologists and surgeons perform RFA, an esophagectomy is solely in the domain of surgeons, which leads to the question of who is best positioned to advise on the range of treatment options for BE: One particular study shows that specialists tend to more frequently recommend treatments that

fall within their own field of practice (Dis Esophagus 2008;21:241-250). “Different specialties will likely converge more,” said Steven DeMeester, MD, associate professor, University of Southern California, Los Angeles. “As we’re moving to a point where we’re doing more and more things through the endoscope— both gastroenterologists and surgeons— you can see the natural tendency would be for the blending of those two fields into people who are considered experts in endoscopic surgery.” A thoracic surgeon, Dr. DeMeester performs “the A to Z on the esophagus,” including endoscopic resection, ablation and esophagectomies. “But I’m rare, very rare,” he said. Gary M. Hochheiser, MD, chief, thoracic surgery, Baystate Medical Center and assistant professor of surgery, Tufts University School of Medicine, Boston, said, “Unfortunately, we have specialized in such a way that we specialize to procedure rather than specializing to disease. And so a gastroenterologist is specialized to do endoscopy, a surgeon is specialized to operate, but is there someone who is specialized to treat esophageal disease from top to bottom? I don’t think our training programs are set up that way. If you can develop a program that has a multidisciplinary team and you all treat the patient together, then that is just as good, if not better, because having more minds involved is better than having one person try to do all of this themselves.” Various surgeon and gastroenterologist societies have created guidelines in an effort to streamline procedures like RFA, but differences in their recommendations exist. Guidelines are of no great value, Dr. DeMeester said, as they cannot keep up with the pace of medical research and technology. “Medicine is constantly moving forward. The day [the guidelines] are published, there could be a brand new article that comes out in the literature that completely revolutionizes the way you think about things and it will take years before the guidelines catch up.” see Barrett’s Esophagus, page 20

Gastroenterology & Endoscopy News • April 2013

From the Literature

Revolutionary Endomicroscopy Capsule May Allow Less-Invasive Screening for Barrett’s Esophagus By Maureen Sullivan An alternative to the traditional screening method for Barrett’s esophagus could be on the horizon, as researchers have developed an endomicroscopic capsule that, when swallowed, provides threedimensional, microstructural images of the upper gastrointestinal (GI) tract. The optomechanical, pill-sized capsule uses optical frequency domain-imaging (OFDI) technology to provide “cross-sectional architectural morphologic data that has been previously shown to enable the diagnosis of Barrett’s esophagus and high-grade neoplastic changes in the esophagus,” according to investigators from Boston’s Massachusetts General Hospital and Harvard Medical School in a study they published in the February issue of Nature Medicine (Gora MJ et al. 2013;19:238-240). Once swallowed, the capsule gradually makes its way down the GI tract by the natural force of peristalsis. Researchers were “somewhat surprised” by the degree to which the esophagus remained close in proximity to the outer surface of the capsule, enabling the production of high-quality images. (An average of 94.5% of all frames were considered to be high quality.) The capsule is connected to a “string-like” tether that allows it to be manipulated by the physician, who can pull it back up the esophagus. During its transit up and down the esophagus, detailed OFDI of large segments of luminal tissue are acquired at 30 µm (lateral) × 7 µm (axial) resolution that enable the “comprehensive assessment of subsurface microstructures that are not evident and can be missed by endoscopy,” according to the paper. “This system gives us a convenient way to screen for Barrett’s [esophagus] that doesn’t require patient sedation, a specialized setting and equipment, or a physician who has been trained in endoscopy,” senior

The inch-long endomicroscopy capsule contains a rotating infrared laser and sensors for recording reflected light. By manipulating the plastic ball attached to the flexible tether (right hand) the system operator can control the position of the capsule in a patient’s esophagus.

study author Gary (Guillermo) Tearney, MD, PhD, professor of pathology at Harvard Medical School, affiliated faculty member of the Harvard-MIT Division of Health Sciences and Technology, and associate director of the Wellman Center for Photomedicine at Massachusetts General Hospital, said in a statement. Researchers conducted a study of 13 patients, seven of whom were healthy volunteers and six who had Barrett’s esophagus. The mean transit time for imaging (~15 cm of esophagus) was 58 seconds.

For four imaging passes (two up and two down the esophagus) that produced four complete data sets, the average length of time of the procedure was approximately six minutes from capsule insertion to extraction. No complications were reported, and 12 of the 13 patients preferred capsule endomicroscopy to the conventional method. Once all the images were captured on the imaging console, the capsule was withdrawn through the mouth and disinfected for reuse. Its feasibility of use in many health care settings is supported by the fact that it can be reused, that it takes a short time to complete the procedure and that its ease of use requires minimal training. “An inexpensive, low-risk device could be used to screen larger groups of patients, with the hope that close surveillance of patients found to have Barrett’s could allow us to prevent esophageal cancer or to discover it at an earlier, potentially curable stage,” study co-author Norman Nishioka, MD, associate professor of medicine at Harvard Medical School, said in a statement. “But we need more studies to see if that hope would be fulfilled.” Asked to comment on the report, Prateek Sharma, MD, professor of medicine, Division of Gastroenterology and Hepatology and director of the fellowship training program and clinical research at the University of Kansas School of Medicine and the VA Medical Center, both in Kansas City, said, “This study shows exciting preliminary results using a noninvasive strategy with implications for large-scale screening of the population. The concept of using 3D-OCT [optical coherence tomography] to visualize the layers of the esophagus has been attempted recently with scope devices; however, this is the first attempt at using this technology via a capsule device. Further studies in larger patient populations are required to determine the true diagnostic characteristics of this novel capsule.” n

Barrett’s Esophagus continued from page 19

One of the co-authors of a recent international paper on the management of HGD (Bennett C et al. Gastroenterology 2012;143:336-346), Dr. Romero said, “We accept that guidelines will change with medical advancements, but the question is can we hammer down a process where we are all involved in the conversation?” According to Dr. Romero, research already is under way to find a more definitive way to pinpoint the various stages of BE. Biomarkers such as stool, urine and blood samples are being studied as possible alternatives to biopsies. “My question is how can we get endoscopists and pathologists out of the equation?” New RFA medical devices are being launched by companies like Barrx

‘All these [new devices] open up new doors to treat patients who, a year ago, you would struggle to treat because of the limitations in the technology and the catheter design.’ —Steven DeMeester, MD

Medical (recently acquired by Covidien) that broaden the scope of patients who qualify for ablation therapy, including those with strictures or other esophageal conditions. “All these [new devices] open up new doors to treat patients who, a year ago, you would struggle to treat because of

the limitations in the technology and the catheter design,” Dr. DeMeester said. However, although medium-term results of RFA are encouraging, the long-term effects remain to be seen. “I think [RFA] is a fantastic technology,” said Dr. Swanstrom. “It works amazingly well to get rid of BE. But there are

a lot of questions we don’t know about it. Like, do you need to do something else to make sure it doesn’t just come back in seven or 10 years? In which case, it’s a waste of money.” David Earle, MD, director of Minimally Invasive Surgery, Baystate Medical Center, Springfield, Mass., and assistant professor of surgery, Tufts University School of Medicine, Boston, noted that BE is a complex disease process with multispecialty involvement. “Each specialty has inherent biases toward patient care, leading to wide practice variability,” he said. “As this article brings together thoughts from different specialties … we will hopefully move toward a multidisciplinary approach to clinical care and device development” for patients with BE. n

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26.2

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B. lactis Group

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Before ingestion of B. lactis or control product After ingestion of B. lactis product After ingestion of control product

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Indication and Important Safety Information Prepopikâ&#x201E;¢ for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. r 1SFQPQJL JT DPOUSBJOEJDBUFE JO UIF GPMMPXJOH DPOEJUJPOT QBUJFOUT XJUI TFWFSFMZ SFEVDFE SFOBM GVODUJPO HBTUSPJOUFTUJOBM PCTUSVDUJPO PS JMFVT CPXFM QFSGPSBUJPO UPYJD DPMJUJT PS UPYJD NFHBDPMPO HBTUSJD SFUFOUJPO PS JO QBUJFOUT XJUI B LOPXO BMMFSHZ UP BOZ PG UIF JOHSFEJFOUT JO 1SFQPQJL 1BUJFOUT TIPVME CF BEWJTFE PO UIF JNQPSUBODF PG BEFRVBUF IZESBUJPO BOE QPTU DPMPOPTDPQZ MBC UFTUT TIPVME CF DPOTJEFSFE JG B QBUJFOU EFWFMPQT TJHOJGJDBOU WPNJUJOH PS TJHOT PG EFIZESBUJPO BGUFS UBLJOH 1SFQPQJL r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r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r 1SFQPQJL TIPVME OPU CF VTFE JG HBTUSPJOUFTUJOBM PCTUSVDUJPO PS QFSGPSBUJPO JT TVTQFDUFE 1SFQPQJL JT OPU GPS EJSFDU JOHFTUJPO &BDI QBDLFU NVTU CF EJTTPMWFE JO PVODFT PG DPME XBUFS BOE BENJOJTUFSFE BU TFQBSBUF UJNFT JO BEEJUJPO UP BEEJUJPOBM DMFBS GMVJET BDDPSEJOH UP UIF EPTJOH SFHJNFO *O SBOEPNJ[FE NVMUJDFOUFS DPOUSPMMFE DMJOJDBM USJBMT OBVTFB IFBEBDIF BOE WPNJUJOH XFSF UIF NPTU DPNNPO USFBUNFOU FNFSHFOU BEWFSTF SFBDUJPOT GPMMPXJOH 1SFQPQJL BENJOJTUSBUJPO 1MFBTF TFF CSJFG TVNNBSZ PG 1SFTDSJCJOH *OGPSNBUJPO GPMMPXJOH UIJT BEWFSUJTFNFOU

Prepopik helps patients arrive ready with: t Lowest volume of active prep solution and a ďŹ&#x201A;exible hydration schedule1 t Demonstrated non-inferiority, with both split-dose and day-before regimen1 t Superior cleansing efficacy with ACG-recommended split-dose vs day-before regimen comparator*1 â&#x20AC;&#x201C; 84% vs 74%, respectively, achieving â&#x20AC;&#x153;excellent or goodâ&#x20AC;? visualization, validated per the Aronchick scale* t A dual mechanism that stimulates peristalsis and produces osmotic water retention1 *Evaluated in a randomized trial. The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efďŹ cacy endpoint was the proportion of patients with successful colon cleansing deďŹ ned as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists.1

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Reference: 1. Prepopikâ&#x201E;˘ Prescribing Information, July 2012. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

Gastroenterology & Endoscopy News â&#x20AC;˘ April 2013

Experts Discuss Risk, Benefits of Ablation for Patients With Nondysplastic or LGD Barrettâ&#x20AC;&#x2122;s Esophagus By Ted Bosworth Las Vegasâ&#x20AC;&#x201D;Recent data suggest a reevaluation of when to offer ablation for the prevention of esophageal cancer in patients with Barrettâ&#x20AC;&#x2122;s esophagus (BE). Although there is strong evidence linking aggressive therapy in BE patients

with high-grade dysplasia (HGD) with cancer risk reduction, the evidence for protection in patients with low-grade dysplasia (LGD) is indirect and the justification for ablation in nondysplastic BE is challenged by recently reported lower estimates of risk for progression to cancer. â&#x20AC;&#x153;A rapidly changing landscapeâ&#x20AC;? in the treatment of BE, to prevent cancer, has Aspiration 3DWLHQWV ZLWK LPSDLUHG JDJ UHĂ&#x20AC;H[ DQG SDWLHQWV SURQH WR UHJXUJLWDWLRQ RU DVSLUDWLRQ VKRXOG EH REVHUYHG GXULQJ WKH DGPLQLVWUDWLRQ RI PREPOPIK. Use with caution in these patients.

Not for Direct Ingestion (DFK SDFNHW PXVW EH GLVVROYHG LQ RXQFHV RI FROG ZDWHU DQG administered at separate times according to the dosing regimen. The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information. LQJHVWLRQ RI WKH XQGLVVROYHG SRZGHU PD\ LQFUHDVH WKH ULVN RI QDXVHD YRPLWLQJ GHK\GUDWLRQ DQG HOHFWURO\WH GLVWXUEDQFHV INDICATIONS AND USAGE PREPOPIKâ&#x201E;˘ (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. Clinical Trials Experience %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV CONTRAINDICATIONS DGYHUVH UHDFWLRQ UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW PREPOPIK is contraindicated in the following conditions: EH GLUHFWO\ FRPSDUHG WR UDWHV LQ FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ Â&#x2021; 3DWLHQWV ZLWK VHYHUHO\ UHGXFHG UHQDO IXQFWLRQ FUHDWLQLQH FOHDUDQFH QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG LQ SUDFWLFH less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium DQG YRPLWLQJ ZHUH WKH PRVW FRPPRQ DGYHUVH UHDFWLRQV ! Â&#x2021; *DVWURLQWHVWLQDO REVWUXFWLRQ RU LOHXV IROORZLQJ 35(323,. DGPLQLVWUDWLRQ 7KH SDWLHQWV ZHUH QRW EOLQGHG WR Â&#x2021; %RZHO SHUIRUDWLRQ WKH VWXG\ GUXJ 6LQFH DEGRPLQDO EORDWLQJ GLVWHQVLRQ SDLQ FUDPSLQJ Â&#x2021; 7R[LF FROLWLV RU WR[LF PHJDFRORQ and watery diarrhea are known to occur in response to colon cleansing Â&#x2021; *DVWULF UHWHQWLRQ SUHSDUDWLRQV WKHVH HIIHFWV ZHUH GRFXPHQWHG DV DGYHUVH HYHQWV LQ Â&#x2021; $Q DOOHUJ\ WR DQ\ RI WKH LQJUHGLHQWV LQ 35(323,. WKH FOLQLFDO WULDOV RQO\ LI WKH\ UHTXLUHG PHGLFDO LQWHUYHQWLRQ VXFK DV a change in study drug or led to study discontinuation, therapeutic or WARNINGS AND PRECAUTIONS GLDJQRVWLF SURFHGXUHV PHW WKH FULWHULD IRU D VHULRXV DGYHUVH HYHQW Serious Fluid and Serum Chemistry Abnormalities RU VKRZHG FOLQLFDOO\ VLJQLÂżFDQW ZRUVHQLQJ GXULQJ WKH VWXG\ WKDW ZDV $GYLVH SDWLHQWV WR K\GUDWH DGHTXDWHO\ EHIRUH GXULQJ DQG DIWHU WKH QRW LQ WKH IUDPH RI WKH XVXDO FOLQLFDO FRXUVH DV GHWHUPLQHG E\ WKH XVH RI 35(323,. 8VH FDXWLRQ LQ SDWLHQWV ZLWK FRQJHVWLYH KHDUW LQYHVWLJDWRU IDLOXUH ZKHQ UHSODFLQJ Ă&#x20AC;XLGV ,I D SDWLHQW GHYHORSV VLJQLÂżFDQW YRPLWLQJ 35(323,. ZDV FRPSDUHG IRU FRORQ FOHDQVLQJ HIIHFWLYHQHVV ZLWK or signs of dehydration including signs of orthostatic hypotension D SUHSDUDWLRQ FRQWDLQLQJ WZR OLWHUV / RI SRO\HWK\OHQH JO\FRO SOXV after taking PREPOPIK, consider performing post-colonoscopy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compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were GRFXPHQWHG RXW WR VHYHQ GD\V SRVW FRORQRVFRS\ Table 1: Treatment-Emergent Adverse Reactions observed in at )OXLG DQG HOHFWURO\WH GLVWXUEDQFHV FDQ OHDG WR VHULRXV DGYHUVH HYHQWV Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** DQG HOHFWURO\WH DEQRUPDOLWLHV VKRXOG EH FRUUHFWHG EHIRUH WUHDWPHQW ZLWK 35(323,. ,Q DGGLWLRQ XVH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen IRU SDWLHQWV ZKR KDYH FRQGLWLRQV RU ZKR DUH XVLQJ PHGLFDWLRQV WKDW Reaction LQFUHDVH WKH ULVN IRU Ă&#x20AC;XLG DQG HOHFWURO\WH GLVWXUEDQFHV RU WKDW PD\ PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* LQFUHDVH WKH ULVN RI DGYHUVH HYHQWV RI VHL]XUH DUUK\WKPLD DQG UHQDO (N=305) with 2 x 5-mg (N=296) with 2 x impairment. n (% = n/N) bisacodyl n (% = n/N) 5-mg bisacodyl tablets (N=302) n (% = n/N) 1DXVHD 8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3) Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7) Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0) / 3(* ( WZR OLWHUV SRO\HWK\OHQH JO\FRO SOXV HOHFWURO\WHV VROXWLRQ DEGRPLQDO EORDWLQJ GLVWHQVLRQ SDLQ FUDPSLQJ DQG ZDWHU\ GLDUUKHD QRW UHTXLULQJ DQ LQWHUYHQWLRQ ZHUH QRW FROOHFWHG

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of these data because way we think of Barrettâ&#x20AC;&#x2122;s esophagus.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Nicholas J. Shaheen, MD

Among recent studies, data from a nationwide population-based registry in Denmark found that the incidence rate of cancer in BE patients without dysplasia was one case per 1,000 patient-years (Hvid-Jensen F et al. N Engl J Med 2011;365:1375-1383). The same rate was derived based on data from a registry in Northern Ireland (Bhat S et al. J Natl Caner Inst 2011;103:1049-1057). In a more recently published pooled analysis of 57 studies, the rate of cancer was about 3.3 cases per 1,000 patient-years (Desai TK et al. Gut 2012:61:970-976). All of these reports were below previous estimates, which hovered around five cases per 1,000 patient-years. â&#x20AC;&#x153;If the risk is lower, then this changes the estimates of costâ&#x20AC;&#x201C;benefit, as well as the estimates of riskâ&#x20AC;&#x201C;benefit,â&#x20AC;? Dr. Shaheen said. Currently, there is increasing enthusiasm for radiofrequency ablation (RFA) for eradication of BE epithelial cells because of its low relative morbidity compared with photodynamic therapy; however, Dr. Shaheen noted that complication rates, although lower than other procedures, are not zero. Perforations and bleeding events do occur, and stricture rates exceed 5% in many series.

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(ACG) annual meeting, Dr. Shaheen indicated that new data are forcing physicians to reconsider riskâ&#x20AC;&#x201C;benefit ratios. â&#x20AC;&#x153;It is important that clinicians be aware of these data because they are changing the way we think of Barrettâ&#x20AC;&#x2122;s esophagus,â&#x20AC;? Dr. Shaheen said. Although there are numerous potential confounders in estimating the risk for esophageal adenocarcinoma based on histology (e.g., sampling errors or disagreement among pathologists about the presence or severity of dysplasia), the consistency of recent evidence suggests that the accepted rate of risk is changing.

Seizures 7KHUH KDYH EHHQ UHSRUWV RI JHQHUDOL]HG WRQLF FORQLF VHL]XUHV ZLWK WKH XVH RI ERZHO SUHSDUDWLRQ SURGXFWV LQ SDWLHQWV ZLWK QR SULRU KLVWRU\ RI VHL]XUHV 7KH VHL]XUH FDVHV ZHUH DVVRFLDWHG ZLWK HOHFWURO\WH DEQRUPDOLWLHV H J K\SRQDWUHPLD K\SRNDOHPLD K\SRFDOFHPLD DQG K\SRPDJQHVHPLD DQG ORZ VHUXP RVPRODOLW\ 7KH QHXURORJLF DEQRUPDOLWLHV UHVROYHG ZLWK FRUUHFWLRQ RI Ă&#x20AC;XLG DQG HOHFWURO\WH DEQRUPDOLWLHV 8VH FDXWLRQ ZKHQ SUHVFULELQJ 35(323,. IRU SDWLHQWV ZLWK D history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or EHQ]RGLD]HSLQHV SDWLHQWV ZLWK NQRZQ RU VXVSHFWHG K\SRQDWUHPLD

been driven by a series of recent studies that show risk for those with nondysplastic disease to be no more than half of the previous estimates, said Nicholas J. Shaheen, MD, director of the Center for Esophageal Diseases and Swallowing at the University of North Carolina at Chapel Hill. Speaking at a symposium during the 2012 American College of Gastroenterology

Gastroenterology & Endoscopy News • April 2013

In patients with HGD, there are data, including a study of RFA conducted by Dr. Shaheen, that link eradication of BE to a significant reduction in risk for subsequent cancer (Shaheen NJ et al. N Engl J Med 2009;360:2277-2288). In patients with LGD, a reduction in risk for cancer has not been shown directly, but is a “reasonable” expectation based on the natural history of BE. Again, however,

‘It is not unreasonable to consider ablation in a patient

treatment of patients with BE should be driven by a clear understanding of the current evidence regarding cancer risk. Asked for a comment on the changing estimates of cancer risk in BE patients with LGD or no dysplasia, Vani Konda, MD, a gastroenterologist at the Center for Endoscopic Research and Therapeutics, University of Chicago, also emphasized the importance of providing patients with accurate information about both the risks for cancer and the risks associated with treatment. Many patients are already aware of the association

between BE and esophageal cancer, so their expectations must be managed. “The diagnosis of BE may introduce panic in some patients,” Dr. Konda said. “We should be prepared to meet this fear with education, incorporating our evolving understanding about cancer risk in BE.” Although current evidence indicates that surveillance is the most appropriate strategy in patients with nondysplastic BE, Dr. Konda agreed that there is considerable “uncertainty” regarding the benefit–risk ratio of ablation for LGD. She

noted that patients with LGD are almost certainly a heterogeneous group for which there is no one right answer. While waiting for further data to “clarify which patients are at highest risk for progression to cancer and would benefit most from treatment,” Dr. Konda said that appropriate counseling of patients based on current information regarding the risk for cancer versus the risk associn ated with ablation is “essential.” Drs. Shaheen and Konda reported no onflicts of interest.

with LGD, but I think patients must be told that there is

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no direct evidence that this will prevent cancer, and they should also be informed of the risks of the procedure.’

AUGUST 9-11, 2013 FAIRMONT CHICAGO MILLENNIUM PARK CHICAGO, IL

—Nicholas J. Shaheen, MD

several studies, including the Danish registry, suggest the risk for progression to cancer in patients with LGD is lower than previously estimated, and Dr. Shaheen indicated that these data should be taken into consideration. “It is not unreasonable to consider ablation in a patient with LGD, but I think patients must be told that there is no direct evidence that this will prevent cancer, and they should also be informed of the risks of the procedure,” Dr. Shaheen said. He noted that ablation is often attractive to patients, who “are typically more comfortable with a proactive approach” when they are told they have a precancerous condition, but the costs of the procedure and the risk for complications must be factored into a discussion of treatment options. Although recent estimates of cancer risk suggest a need for greater caution in considering aggressive modes of therapy in BE patients without dysplasia, Dr. Shaheen noted that there may be exceptions, such as those with a genetic predisposition to BE and esophageal cancer, and very young patients who have already developed long-segment BE. However, he believes that clinical decisions for

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Gastroenterology & Endoscopy News • April 2013

Malpractice continued from page 1

done under the same circumstances,” said Dr. Baillie, noting that these standards are based more on the actions of local experts than on those of renowned leaders in the field. “So it’s important to know what your local and regional experts do.” Physicians should be adequately experienced in the procedures they perform, stay abreast of changing patterns of care and keep current with the literature. “Nothing looks worse in a deposition

than a doctor who, when asked what journals or textbooks he reads, replies, ‘I don’t,’ ” Dr. Baillie said. Always document informed consent and ideally, have it witnessed. “Many states in the U.S. do not actually require informed consent in writing, but from a legal perspective, if it’s not in writing, it never happened,” Dr. Baillie said. If an adverse event (AE) does occur, be honest with the patient and family about

what has happened. In many states, an apology cannot be used as an admission of liability or guilt. “But don’t flagellate yourself in the aftermath; it’s not helpful and is damaging to your defense,” Dr. Baillie noted. In that vein, physicians should maintain their composure in front of their colleagues and avoid emotional discussions with them as they may be called to testify in court. Documenting the course of events

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following an AE is as important as documenting the informed consent. “A record that has no way of tracking the thought process and people involved is damning in a lawsuit,” Dr. Baillie said. Make sure the patient is managed properly, even if it means cancelling personal plans. If you must be absent, leave a note in the chart describing the management plan for the patient, make it clear that you are available around the clock for consultation and provide your cell number. “And call in daily to see what’s happening. That tells the jury that you’re interested in the patient.”

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they can be an immense help: minimize damage.’ —John Baillie, MB, ChB Don’t be afraid to coordinate with your hospital’s risk management office. “Many physicians fear [engaging with] risk management because they worry they’ll be labeled as a bad doctor,” Dr. Baillie said. “But if you have a good risk management office, they can be an immense help: They actually have ways to minimize damage.” And never, ever alter any piece of paper in the record, especially the informed consent document. “This is a no-brainer, but it keeps happening,” Dr. Baillie said. “It’s fraud, and it destroys any chance you have of winning a case.”

Colonoscopy-Related Mishaps There are several issues specific to colonoscopy that stand out as potentially problematic, including perforation, undiagnosed cancer, splenic injury that requires splenectomy, acute colonic pseudo-obstruction and postpolypectomy hemorrhage, said Douglas Rex, MD, Distinguished Professor of Medicine, Indiana University Medical Center, Indianapolis. He noted, however, that postpolypectomy hemorrhage rarely results in a suit because outcomes are usually favorable. Successful perforation suits are usually based on events that occurred after the colonoscopy, Dr. Rex said. see Malpractice, page 29

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Gastroenterology & Endoscopy News • April 2013

Malpractice continued from page 26

“If you suspect that a perforation occurred, evaluate your patient aggressively and document your thinking; if you manage it nonoperatively, [you should] still get a surgeon involved and keep a close eye on the patient.” The resolution of cases involving splenic injury usually comes down to whether the injury could have occurred within the normal forces of colonoscopy or if the injury was the result of excessive force. In cases of acute colonic pseudo-obstruction, the strength or weakness of a case often depends on the duration of distension before decompression. “This is a source [of lawsuits], even in the neostigmine era. If you give the patient neostigmine and it doesn’t work, or if you can’t prescribe neostigmine, the most important predictor for perforation is delay,” Dr. Rex said. “If it keeps going on, you need to think about trying to decompress. Use CO2, put a tube in, get a surgeon involved early and document your thinking.” In cases of missed cancer, the procedure itself is key. “Allegations are going to be about what happened during the procedure and how you instructed the patient after the procedure, particularly if there is rectal bleeding,” Dr. Rex said. The first thing the plaintiff has to prove in these cases is whether there was a violation in the standard of care, resulting in negligence. “That’s referred to as ‘causation,’ and what the plaintiff has to prove could differ from state to state,” Dr. Rex said. For example, the plaintiff may only have to present the argument that more likely than not, if the procedure had been done correctly, the patient would be alive. In other states, it’s simply a reduction in the chance of a patient’s survival that can be grounds for causation. The paradox in these situations is that the smaller and earlier the cancer, the harder it is to detect, and the more reasonable it is that the physician may overlook it. Thus, it behooves the gastroenterologist to know the miss-rate literature. “I’ve heard experts for the plaintiff say that it’s malpractice to miss lesions that are less than 1 cm in size, even down to 5 mm,” Dr. Rex said. “They’ll also say the standard of care requires a six-minute withdrawal time. The jury may well believe that because it’s in our guidelines, but the guidelines also say that that applies to average withdrawal times and should not be applied to specific individual cases.” Dr. Rex repeatedly pointed out that colonoscopies in general are poorly documented. “The truth is, nobody really knows whether you were careful or not,” he said. “So people look at the record and extrapolate from the quality of the documentation whether you are a careful person.” He suggested several ways gastroenterologists can maintain accurate records: • Get informed consent for missed lesions. • Perform a rectal exam and document the results. • Record the quality of the preparation: “excellent,” “good,” “fair” or “poor.” “If you say it’s ‘fair’ or ‘poor,’ then you should be repeating the exam at an earlier interval,” Dr. Rex noted. • Show that you reached the cecum by photographing the appendiceal orifice and the ileocecal valve from just distal to it. “If you go to the terminal ileum, photograph that, and if you retroflex in the right colon, take a photograph there too,” Dr. Rex

said. This establishes the quality of the preparation and shows that you did a thorough examination of the right colon. • Describe the landmarks you viewed, and record the withdrawal time. “It’s OK to use standard language, such as ‘during withdrawal, the mucosa was examined slowly with careful circumferential rotation of the instrument tip,’ ” Dr. Rex said. • Know your adenoma detection rate (ADR) and be willing to provide that information. “This has become very powerful. It establishes that you’re really interested in quality, and that you know what the recommendations are,” Dr. Rex said. • If there is rectal bleeding, identify the source and either treat it yourself or make it clear to your patients that they need to follow up with their primary care providers; document these discussions.

‘The truth is, nobody really knows whether you were careful or not. So people look at the record and extrapolate from the quality of the documentation whether you are a careful person.’ —Douglas Rex, MD

‘The general basis of the “The general basis of the defense is this: Colonoscopy is not perfect. The patient was aware of this through the informed consent process. The quality of this examination is well documented. The doctor photographed the cecum, described the preparation, documented the withdrawal time, described and photographed retroflexion. Everything that was documented suggests a highquality examination,” Dr. Rex said. “If we can further say that the doctor participates in a colonoscopy quality program and knows his or her ADR, then we have even more evidence that this is the kind of doctor who does a high-quality examination,” he added.

Complications of IBD The potential for lawsuits pertaining to the management of patients with inflammatory bowel disease (IBD) frequently arises in the misdiagnosis of IBD, mismanagement of perioperative complications, missing IBD-related cancer and AEs related to IBD drug treatments, especially steroids. Asher Kornbluth, MD, clinical professor of medicine, Mount Sinai School of Medicine, New York City, provided an example of a misdiagnosis of IBD where the patient’s previous medical records were not

defense is this: Colonoscopy is not perfect. The patient was aware of this through the informed consent process. The quality of this examination is well documented. … Everything that was documented suggests a high-quality examination.’ —Douglas Rex, MD obtained. The option of a flexible sigmoidoscopy for the patient was deferred due to suspicion of severe active colitis disease. The patient was treated with a prolonged course of steroids for IBD—which he did not have—and his progressive decline led to complicated, life-altering surgery for what was found to be diverticulitis with multiple postoperative complications. “We always need current, objective confirmation of IBD. In the absence of an obvious megacolon, there is rarely a reason to avoid a flexible sigmoidoscopy,” Dr. Kornbluth explained. see Malpractice, page 30

Gastroenterology & Endoscopy News • April 2013

Malpractice continued from page 29

With serological testing yet standardized guidelines have alone, or minimal, nonspecific been in place for many years. endoscopic or video “After eight to 10 ‘Even with meticulous capsule, there is an years of extensive coliincreased likelihood tis, I take biopsies every efforts to taper steroids, this of false-positives. 10 cm for each colonic malpractice suit is often found “You treat the segment,” Dr. Kornin favor of the plaintiff since he patient, he doesn’t bluth said. “We are not get better, you escalate yet at the stage where, or she will report that they were the therapy and he still after several negative never warned about this very doesn’t get better— exams, we can repeat it might very well be the exam at three to five serious complication. The case because he doesn’t have years. Different guideis lost based on the absence of IBD. It’s very important lines vary in their recomto avoid that trap.” mendations, but it seems documented, informed consent As an example of a reasonable to screen at regarding this particular AE.’ patient in whom IBD was least every other year, in —Asher Kornbluth, MD not recognized, Dr. Kornthe absence of any dysplasbluth described a 23-yeartic lesions.” old man diagnosed with and Failure to adequately survey treated empirically for infecfor CD also is a mistake. tious colitis after the acute onset “Patients with extensive of bloody diarrhea. After treatment colitis in CD are at similar risk with ciprofloxacin and metronidazole, for colorectal dysplasia or colorecthe patient’s condition declined; flexible tal cancer as for UC, so whatever you sigmoidoscopy revealed extensive colitis, do in UC for surveillance, do with CD,” and biopsies were consisted with ulcerative Dr. Kornbluth said. colitis (UC). The patient was treated too late with Although there is substantial debate over what to do steroids and required an emergency subtotal colectomy. when low-grade dysplasia is found, high-grade dysplasia “The take-home message here is that it is important is cancer until proven otherwise. to remember that some people don’t fit the typical pro“Let patients know prior to surgery that if no cancer file; you cannot make the assumption that it is some- is found, that’s the preferred scenario. These operations thing other than UC without looking for it specifically,” should be cancer prevention operations, not cancer Dr. Kornbluth said. treatment operations,” Dr. Kornbluth said. Postoperative complications in patients with Crohn’s The list of potential drug-related concerns is extendisease (CD) sometimes occur in the setting of the cre- sive, but steroids alone are probably the most frequent ation of a primary anastomosis in a patient undergoing cause of drug-related malpractice cases in IBD. surgery for severe penetrating disease or intraabdominal “Usually the problems are inappropriate indication, abscess. The patient may quickly develop an anastomotic treating with steroids when it is not active IBD, with leak that looks like an “early recurrence.” too high a dose and too long a duration,” Dr. Korn“If an anastomotic leak is suspected, it may be the case bluth said. in which to insist on re-exploration. A temporary divertSome of the major issues to watch out for include: ing ostomy will probably be necessary,” Dr. Kornbluth • Drastic changes in mental/emotional status. Mood said. “Inform the patient in advance and document that changes are common, but patients should be warned this is what they need.” that if they develop serious depression or other Lawsuits arising from missed cancer in IBD patients imbalances, they need to inform you. stem from a failure to perform adequate surveillance, • Infection. Steroids actually pose a far larger risk for

infection and mortality than anti-tumor necrosis factor therapies. • Osteoporosis. Gastroenterologists are not trained to treat this but should know when to screen and refer for treatment. “Patients who have had a lifetime exposure total of three months cumulatively, especially if they are postmenopausal, must be screened,” Dr. Kornbluth said. • Osteonecrosis. This is possibly the most significant complication and the court case gastroenterologists are most likely to lose. “It’s almost always related to a high cumulative steroid dose,” Dr. Kornbluth said. “The goal is to minimize steroid use at every patient encounter. Even with meticulous efforts to taper steroids, this malpractice suit is often found in favor of the plaintiff since he or she will report that they were never warned about this very serious complication. The case is lost based on the absence of documented, informed consent regarding this particular AE.”

Summation Going through a malpractice lawsuit can be a difficult experience and it may be hard for doctors not to take it personally when a patient, particularly a longstanding one, decides to take legal action. “Most cases are successfully defended, but it’s a long process to go through,” Dr. Rex said. “During that time, you have to enjoy life and put [the lawsuit] in its proper perspective.” Dr. Kornbluth pointed out that Ty Cobb, the great baseball batter, hit successfully less than 40% of the time and that Mark Price, a great free-throw shooter, missed 10% of his free throws. In contrast, Dr. Kornbluth said, “We make hundreds of decisions a day. Our decision rate is probably ‘correct’ more than 99.99% of the time.” Still, practice the standards; don’t hesitate to get a second opinion; and in the event of a lawsuit, insist on getting the best expert witness you can find. “It’s our job to have a formidable, nationally recognized expert,” Dr. Kornbluth said. “And remember, part of what you’re buying with malpractice insurance should be peace of mind.” n Drs. Baillie, Rex and Kornbluth reported no relevant conflicts of interest.

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Gastroenterology & Endoscopy News • April 2013

From the Literature

Actively Engaged Patients Have Lower Health Care Costs, Better Outcomes By George Ochoa Patients with the knowledge, skills and confidence to be actively engaged in their health care are likely to incur lower health care costs than patients without those characteristics, according to a February report in Health Affairs (Hibbard JH et al. 2013;32:216-222). Furthermore, an accompanying literature review by two of the same authors

found a growing body of evidence that more actively engaged patients—or, “activated” patients—also have better health outcomes and health care experiences (Hibbard JH, Greene J. Health Aff 2013;32:207-214). In the cost study, researchers examined data from 33,163 primary care patients enrolled with Fairview Health Services, a hospital system based in Minneapolis. Patient activation was measured with a scoring

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system consisting of 13 items such as “I know how to prevent problems with my health” and “I am confident that I can tell a doctor my concerns, even when he or she does not ask.” The researchers found that patient activation scores from 2010 were a significant predictor of cost of care in the first half of 2011: Patients with the lowest activation level had costs 21% higher than patients with the highest activation level (P<0.05). The findings held

true even after controlling for sociodemographic factors and the severity of health conditions. “The study highlights the important role that patients play in determining outcomes,” lead author Judith H. Hibbard, PhD, MPH, professor emerita in the Department of Planning, Public Policy, and Management at the University of Oregon, Eugene, said in a statement. “We found that patients who were more knowledgeable, skilled and confident about managing their dayto-day [treatment] … had health care costs that were substantially lower than patients who lacked this type of confidence and skill.”

‘We found that patients who were more knowledgeable, gastroendonews.com

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skilled and confident about managing their day-to-day [treatment] … had health care costs that were substantially lower than patients who lacked this type of confidence and skill.’ —Judith H. Hibbard, PhD, MPH

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The literature review, by Dr. Hibbard and Jessica Greene, PhD, MPH, director of research at the George Washington University School of Nursing, in Washington, D.C., identified several interventions that have been shown to increase patient activation, such as tailored coaching—a strategy that helps customize support to the individual’s activation level. Efforts to expand patient activation are, the authors concluded, “a pathway toward improving outcomes.” n

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Gastroenterology & Endoscopy News • April 2013

Parallel Drop in UGI Hemorrhage–Related Mortality, Increased Use of Endoscopy No Causal Link, But Wider Use of Diagnostic, Therapeutic Endoscopy Thought To Play a Role Table. Trends in UGIH-Related Mortality, Endoscopy Use

By David Wild Las Vegas—The past two decades have seen a 50% drop in the number of deaths due to upper gastrointestinal hemorrhage (UGIH), with a coinciding increase in inpatient endoscopies in those individuals, according to epidemiologic findings presented at the 2012 American College of Gastroenterology annual scientific meeting (abstract 2). Although the researchers could not establish a causal link between the two variables, they believe that wider use of diagnostic and therapeutic inpatient endoscopies, along with improved UGIH-specific medical treatment, has played a substantial role in lowering rates of UGIH-related mortality.

1989

1994

1999

2004

2009

Mortality among inpatients with UGI hemorrhage

4.69%

3.34%

2.93%

2.43%

2.13%

Total inpatient endoscopy rate

69%

80%

85%

86%

85%

Therapeutic endoscopies as a percentage of total inpatient endoscopies

18%

22%

23%

27%

UGIH, upper gastrointestinal hemorrhage

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‘This is a very strong study and the findings are reliable, especially because the data were drawn from a nationally representative and validated database.’ —Sravanthi Parasa, MBBS

Sravanthi Parasa, MBBS, an expert in UGI bleeding, of the Department of Internal Medicine at the University of Kansas Medical Center, Kansas City, believes that gastroenterologists and endoscopists should pride themselves on heading off inpatient deaths among individuals with UGIH. “This is a very strong study and the findings are reliable, especially because the data were drawn from a nationally representative and validated database,” said Dr. Parasa, who was not involved in the research. Marwan Abougergi, MD, and John Saltzman, MD, researchers in the Division of Gastroenterology at Brigham and Women’s Hospital, Harvard Medical School, in Boston, analyzed information from the Nationwide Inpatient Sample (NIS) collected between 1989 and 2009, dividing the data into five-year intervals. They used International Classification of Diseases (ICD)-9 codes to identify primary diagnoses of UGIH. Their analysis revealed the incidence see UGIH, page 38

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Gastroenterology & Endoscopy News • April 2013

From the Literature

Number of Antireflux Surgeries at Low-Volume Centers Grows, Despite Worse Outcomes By Ted Bosworth The number of antireflux surgeries performed at high-volume centers has fallen over the past decade while antireflux surgery at low-volume centers has been associated with worse outcomes, including longer hospital stays and fewer routine discharges,

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according to a retrospective study of U.S. hospitals (Colavita PD et al. J Gastrointest Surg 2013;17:6-13). “Despite better outcomes at highvolume centers, low-volume centers have increased their percentage of antireflux operations over time,” said lead author of the study, Paul D. Colavita, MD, Carolinas Medical Center, in Charlotte, N.C. “The urban

non-teaching hospitals have experienced the largest gains in caseload.” Dr. Colavita said that there was no difference in mortality between lowand high-volume centers, but just about every other outcome, including cost of the procedure, favored centers that do these procedures more frequently. The study was conducted using data

35th Anniversary — 2013

from the Nationwide Inpatient Sample (NIS), which captures about 20% of all hospitalized patients in the United States, and is considered to be representative of hospital practice. To evaluate trends, data collected in 1998-1999 were compared with data collected in 2008-2009, and hospitals were stratified by annual volume into terciles. “Low volume” was defined as 14 or fewer procedures per year, whereas “high volume” was defined as 38 or more procedures per year. The investigators included procedures for control of conditions associated with acid reflux in the analysis; procedures for other indications, such as achalasia, were excluded.

‘Despite better outcomes at high-volume centers, lowvolume centers have increased their percentage of antireflux operations over time.’ —Paul D. Colavita, MD

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Although the investigators presumed there would be increased regionalization of antireflux surgery due to consistent evidence that outcomes are better for complex surgeries at centers where they are performed most frequently, the opposite was found. While about one-third of antireflux surgeries were

35th Anniversary — 2013

UGIH continued from page 37

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of UGIH began decreasing in 1994, from 83 cases per 100,000 Americans in that year to 78 cases per 100,000 Americans in 2009. Rates of inpatient mortality among UGIH patients also dropped, from 4.69% in 1989 to 2.13% in 2009 (Table, page 37). The combined use of diagnostic and therapeutic endoscopy increased from 69% to 85% over the study period. As a proportion of all inpatient endoscopies, the percentage of therapeutic endoscopies rose dramatically, from 2% of all UGIH-related inpatient endoscopies in 1989 to 27% in 2009, they found. Dr. Abougergi also reported the proportion of endoscopies performed within 24 hours of admission increased from 23% in 1989 to 54% in 2009. This might partially account for the drop in hospital lengths of stay from 4.52 days in 1989 to 2.85 days in 2009, he said. One finding that surprised the

Gastroenterology & Endoscopy News • April 2013

performed at low-volume centers in the first time period, the proportion was slightly greater than 40% in the second period. High-volume centers, which accounted for 33.4% of the procedures in the first time period, accounted for only 25% of the procedures in the second. Unlike procedures such as complex oncologic resections, the investigators observed that antireflux procedures have not undergone regionalization: One likely factor is that thousands of surgical residents have been trained to perform laparoscopy, and they perform antireflux procedures as part of their education. Many consider these procedures to be part of the general surgeon’s armamentarium, and they are now performing these procedures in a wide variety of centers. A patient’s preference to have surgery close to home also may play a role. The fact that all outcomes, except for mortality, were worse in the second period may be partially attributed to the fact that patients undergoing surgery in the second period were, on average, seven years older and had more comorbidities compared with patients in the first period. However, the fact that outcomes were worse in low-volume centers for both periods was considered the most important factor. For example, after controlling for an array of independent variables, the risk for complications was almost twice as high in low-volume centers (P<0.0001) in both the first and the second periods. In addition, average hospital charges per procedure were about $3,000 higher

researchers was that, despite the shorter hospital stays, the average inflationadjusted cost of treating a patient with UGIH has risen sharply, from $9,249 in 1989 to $20,370 in 2009. “Although we are not sure why this is, we think it reflects the general increase in per-day hospitalization charges,” Dr. Abougergi said. “Those can be driven by charges for room and board, or charges for the increasingly more costly medications used during treatment, among others.” Dr. Parasa observed that Charlson comorbidity index scores in the analysis increased, from 0.68 in 1989 to 0.93 in 2009. “The results are particularly impressive given that rates of UGIH-related deaths have dropped, despite an increased number of comorbidities,” she said. n Drs. Abougergi and Parasa reported no conflicts of interest.

(P=0.0032) in low-volume centers. Researchers could not analyze the readmission or re-fundoplication rates because the NIS does not include such information in the database. This information could have an impact on relative differences between low- and high-volume centers, but Dr. Colavita indicated that the increased complication rate at low-volume centers is consistent with other data that surgical outcomes tend to be better at centers where the surgeries are performed most frequently. He concluded that

support of regionalization of antireflux surgery “may improve outcomes.” Joel Richter, MD, chair of esophagology and gastroenterology, University of South Florida, Tampa, co-authored a similar study on the relationship between volume and outcomes of antireflux surgery (Wang YR et al. Dis Esophagus 2011;24:215-223). There is a need, he said, to set standards for competency in the performance of fundoplication and for experienced gastroenterologists in the community setting to perform the necessary

workup, such as pH testing and motility testing, to confirm that patients are good candidates for surgery. “Why not establish standards for individual surgeons and hospitals regarding the volume of antireflux surgery that should be performed on a yearly basis to maintain competency?” Dr. Richter asked. “Frankly, this is an issue that the surgical societies like SAGES [Society of American Gastrointestinal and Endoscopic Surgeons] should address,” he said. n

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Study Shows Owners of Ambulatory Surgery Centers Perform More Surgeries By George Ochoa Orthopedic surgeons who On the issue of the were owners and on the profitability of patients, board of directors of an Dr. Hopson comambulatory surgery cenmented, “I don’t think ter (ASC) in Florida did every ASC is the same. 76 more surgeries per year We have to do a certhan nonowners. For every tain amount of unpaid surgery a nonowner percharity [procedures]. formed, an owner comI do free hernias. We pleted 1.8. This finding serve the commuraises the question of why? nity just as much as a This issue was addressed nonprofit.” in a webinar, “Why OwnPolicy implications ers of Ambulatory Surgical of her research, Dr. Centers (ASCs) Do More Yee said in the webiSurgery,” presented on nar, might include Oct. 30. medical costs, access Study author and webito care, financial stabilnar presenter, Christine A. ity of hospitals, current Yee, PhD, an economist regulation on physician at Workers Compensaownership and reimtion Research Institute bursement rates. For (WCRI) in Cambridge, Mass., studied these issues, more data are needed—for Florida orthopedic surgeons from 1997 to example, on whether all the additional Recruitment of higher-volume surgeons to become owners 2004, specifically those who performed outsurgeries at ASCs are necessary. turned out to be one of the top reasons why ASC owners did patient knee, shoulder, and wrist arthrosco“We can’t tell if the surgeries were pies and carpal tunnel surgeries. Surgeons necessary or unnecessary,” said Dr. Yee more surgery, as well as the presence of entrepreneurial were tracked longitudinally, from when they in an interview. surgeons who might be more likely to start an ASC. were not owners to when they were. OwnThe study’s main limitation, said Dr. ers were identified in three ways: board ownYee, was its length. ers (surgeons who serve on an ASC’s board of directors), His ASC, he noted, is a joint venture with Bon Secours “It may be a little long, but it’s hard to tell all sides of threshold owners (surgeons who referred or performed Mary Immaculate Hospital. the story without such comprehensiveness.” 30% of procedures at a single ASC) and frequent userDr. Hopson, who was not affiliated with the webinar, As new directions for research, she suggested, “to find owners (surgeons who collectively accounted for 50% of did not agree that owners of ASCs perform more surger- out if the additional surgeries, due to financial incentives, an ASC’s procedures). ies than nonowners. were necessary or unnecessary and increase the scope of Recruitment of higher-volume surgeons to become “Nonowners have the same reason as owners to go to the study beyond orthopedic surgeons in Florida.” owners turned out to be one of the top reasons why an ASC. They’re there to get the cases done and get out She added, “New research methods were developed to ASC owners did more surgery, as well as the presence of there.” He added, “The incentive is that doing more approach this topic of physician ownership and there are n of entrepreneurial surgeons who might be more likely to cases in a shorter amount of time gives general surgeons a many other directions to go.” start an ASC. better lifestyle. They can be home in time to have dinner “The data would not support teasing out the recruit- with the family.” ment effect separately from the entrepreneurial effect and The efficiency effect, as well as other effects, was not so they were estimated as one effect,” Dr. Yee explained. as prominent in Dr. Yee’s research as the entrepreneurial/ “Entrepreneurial/recruitment was the largest factor, fol- recruitment effect and financial incentives. lowed by financial incentives.” “The efficiency effect, capacity effect (such as when a There also was an ASC efficiency effect: When a surgeon adds on an ASC or hospital), and technology/ surgeon shifted from a hospital to an ASC, the surgeon market trends (such as an overall increase in the numcould perform more surgery in a given time. ber of arthroscopies being performed over time) affected “We can’t tell if a given arthroscopic surgery at an ASC both owners and nonowners and as such did not explain took less time than at a hospital,” said Dr. Yee, “or if more as much of the difference,” said Dr. Yee. invasive, time-consuming surgeries were taking place at The ASC efficiency effect was moderate in its contrihospitals, leaving less room to schedule arthroscopic sur- bution size; in capacity effect, small; and in technology geries. Surgeons can schedule more surgery at ASCs, but and market trends, smallest. In contrast, the contribution we don’t have the data to isolate the reason why.” size of the financial incentives effect was large and that of Steven Hopson, MD, board member and hernia sur- the entrepreneurial/recruitment effect, largest. geon at Mary Immaculate Ambulatory Surgery Center Ownership in ASCs changed surgeons’ practices. today at in Newport News, Va., emphasized the importance of The volume of surgeries increased by 15% to 22%; ownefficiency. ers shifted 28% to 54% of their surgeries to their owned GastroEndoNews.com/ “You increase your surgeries because you’re more effi- ASC, and owners treated more patients covered by paycient. At the ASC, processes are in place to turn cases ers who reimbursed at higher rates, such as workers’ Renew around quicker. Your volume will go up.” compensation.

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From the Literature

Nasal MRSA Infection a Risk Factor for Postoperative Surgical Site Infection By David Wild Preoperative methicillin-resistant Staphylococcus aureus (MRSA) colonization is “strongly predictive of” MRSA-associated surgical site infections (SSIs), according to research published earlier this year in the Journal of Gastrointestinal Surgery (Ramirez MC et al. 2013;17:144-152). “Preoperative nasal swab testing with decolonization of MRSA-positive patients could decrease lengths of stay and reduce the incidence of MRSAassociated SSI after major gastrointestinal surgery,” said the senior author of the paper, Harry Papaconstantinou, MD, chief of colorectal surgery at Scott & White Memorial Hospital, in Temple, Texas. Investigators said the results, which were first presented at last year’s Digestive Disease Week meeting, may justify a policy of universal preoperative nasal swabbing and MRSA decolonization. Dr. Papaconstantinou and his colleagues retrospectively reviewed the charts of all patients who underwent major gastrointestinal (GI) surgery between December 2007 and August

2009. Patients had undergone nasal swab testing within 48 hours of hospital admission for MRSA and methicillin-sensitive S. aureus (MSSA). The investigators identified 1,137 cases; of these, swabs showed that 73 patients (6.4%) were MRSA-positive, 167 (14.7%) were MSSA-positive and 897 (78.9%) were S. aureus-negative on admission. Demographic traits of the three groups were similar (mean age, 59.5 years; 44.5% male; 47.9% of patients underwent colorectal surgery).

(aggregated across MRSA, MSSA and uninfected groups) had a hospital length of stay (LOS) of 15.7 days compared with 6.2 days among those with no SSIs (P<0.001). Including individuals with and without SSIs, MRSA-positive patients had a significantly longer LOS (mean, 12.5 days for MRSA-positive vs. 8.8 and 7.6 days for MSSA-positive and uninfected patients, respectively; P<0.001). However, when the investigators examined only those with SSIs, they found no significant differences

‘Preoperative nasal swab testing with decolonization of MRSApositive patients could decrease lengths of stay and reduce the incidence of MRSA-associated surgical site infection after major gastrointestinal surgery.’ —Harry Papaconstantinou, MD

The researchers found that 13.7% of MRSA-positive patients developed an SSI compared with 4.2% of MSSApositive patients and 9.4% of uninfected patients (P<0.05 for MRSA vs. MSSA and uninfected patients). Patients who developed an SSI

in LOS between patients with wound MRSA colonization and those with MRSA-free SSIs. Mortality rates also did not differ among the three groups, with each approximately 4%. Dr. Papaconstantinou was surprised that 70% of patients who had positive

nasal swabs also had MRSA-positive wound cultures. He said that he expected most post-GI surgery wound pathogens to originate from the gut. In contrast, only 8.5% of patients who had negative nasal swabs had MRSApositive wound cultures (P<0.0001). Philip S. Barie, MD, MBA, professor of surgery and professor of public health at Weill Cornell Medical College, in New York City, who was not involved in the study, said that MRSA colonization has been linked to an increased risk for SSIs in cardiac and orthopedic surgery patients (Harrop JS et al. J Am Acad Orthop Surg 2012;20:94-101). He said that this is the first study to document a link in GI surgery. “These findings get the message out that MRSA-related SSIs can occur after a broader spectrum of operations than was previously believed,” Dr. Barie said. “The question remains as to what is the best course of preventive action. This retrospective study makes an important observation, but does not constitute proof that screening and decolonization will be effective before GI surgery.” n Dr. Papaconstantinou reported no conflicts of interest. Dr. Barie is a consultant for Forest Laboratories, Merck & Co., and Pfizer.

‘Strong for Surgery’ Program Seeks To Optimize Outcomes By Targeting Modifiable Patient Risk Factors Before Surgery By Christina Frangou Surgeons in Washington state are targeting surgical complications by focusing on something often overlooked in quality initiatives: the things that patients can do to improve their outcomes in the weeks and days before they come into the operating room. Surgeons in the state have launched a new program called Strong for Surgery. The first large-scale program to target the preoperative well-being of patients, it is designed to educate health care providers and patients about things patients can do to better prepare themselves for elective surgery. “Most things we’ve done to improve quality are based on the idea that it’s what we do once the patients get into the hospital that makes the difference in outcomes, but that’s not the whole story. We can often identify patients who are going to have a good outcome or a bad outcome when we see them in the office and that’s the time to intervene,” said David Flum,

MD, a general surgeon at the University of Washington who came up with the idea for Strong for Surgery. Dr. Flum, who led the creation of the state’s quality program, the Surgical Care and Outcomes Assessment Program (SCOAP), is partnering in the Strong for Surgery initiative together with the University of Washington’s Comparative Effectiveness Research Translation Network and the American College of Surgeons’ Education Division. Strong for Surgery aims to get patients in peak shape for surgery by targeting the known patient risk factors for poor outcomes, specifically those risk factors that can be addressed in a period of several weeks or months. The initiative is focused on four key areas: preoperative nutritional status and the use of immunonutrition, glycemic control and diabetes management, smoking cessation and medication use. Preoperative counseling and patient engagement are things that most bariatric surgeons have done for years. But outside of bariatric surgery, other surgeons have

not routinely required patients to modify their high-risk factors. Organizers hope that patients can help bring about a “move-the-needle kind of improvement in outcomes that we’ve been looking for, for 20 years,” said Dr. Flum. Other quality initiative programs such as SCOAP and the National Surgical Quality Improvement Program have whittled away at surgical complication rates by targeting the actions of surgeons and hospital staff once a patient is admitted, said Dr. Flum. By doing so, they have missed some of the most critical elements when it comes to patient outcomes. Study after study has shown that the modifiable factors that have the greatest influence on outcomes are not always things like surgeon volume and operative times; rather, they are patient characteristics like smoking, nutritional status, glycemic control and medication use. For instance, malnourished patients undergoing surgery for gastrointestinal (GI) cancer have more than 10-fold increased morbidity. That’s often a problem that can be identified on a

standardized screening and addressed with a nutritionist’s intervention. Another example: Among patients who do not have malnutrition but are planning to have GI surgery, a five-day course of a nutrition formula with arginine and omega-6 fatty acids can decrease the risk for complications dramatically, according to a meta-analysis looking at 3,104 patients across 28 randomized controlled trials. This type of supplementation, often referred to as immunonutrition, is associated with a 41% reduction in risk for infectious complications after elective surgery (Marik PE, Zaloga GP. JPEN J Parenter Enteral Nutr 2010;34:378-386). “That’s the kind of game changer that we have been looking for,” said Dr. Flum. Surgical experts not affiliated with the program said they expect surgeons will offer broad support for the initiative. Strong for Surgery will encourage patients to be more proactive about reducing their surgical risk, which should translate into better outcomes and better informed consent. see Strong for Surgery, page 46

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February 15, 2013 Highly practical, expertly written and packed with useful text tools like case histories, pitfall boxes and management algorithms, this convenient and user-friendly manual provides a complete clinical guide to gastroesophageal reflux disease (GERD), one of the most common conditions that gastroenterologists face every day. GEN0413

Strong for Surgery continued from page 44

“Times have changed and cultures have changed. Now, patients know that they are an integral part of the operation and they, too, can contribute to better things happening to them rather than them just coming to the plate and asking to be taken care of,” said Julie A. Freischlag, MD, William Stewart Halsted professor and surgeon-in-chief, The Johns Hopkins Hospital, Baltimore. “At the same time, we also feel

Gastroenterology & Endoscopy News • April 2013

empowered to tell people that there are things they need to do, too. In the end, if we can get patients to do it, I think this will be a game changer.” After being tested in a pilot project last year, Strong for Surgery is being rolled out to about 55 partner offices throughout Washington state for more testing. SCOAP hospitals will report use of the different measures and organizers will use those results to develop a standardized checklist that can be integrated into every surgeon’s office. “Strong for Surgery takes the idea

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of checklists and moves them to where decisions are mostly being made, before the patient gets to the hospital,” said Dr. Flum. “There would never be an airplane that would start a checklist when it is already moving down the runway, and the same concept applies to surgery. The doctor’s office is the last opportunity to have those important discussions about whether the patient is ready for an operation.”

Tom Varghese Jr, MD, director of Strong for Surgery, a patient-centered approach to improving the health of patients in the presurgical clinic.

In this next phase, the campaign will address the nutritional status of all patients before surgery through implementation of nutritional screening and use of evidencebased nutritional support. Results from SCOAP show that one marker of nutritional level, preoperative albumin level less than 3.0 g/dL, is associated with higher postoperative complication rates: 25% with levels of 2.5 to 2.9 and 50% with levels of 2.0 to 2.4 g/dL. From there, the campaign will move on to the other modifiable factors like smoking, diabetes control, use of herbal preparations that can increase bleeding risk or anesthesia complications, and the use of medications like aspirin and β-blockers that patients may be taking chronically, said Richard P. Billingham, MD, clinical professor of surgery, University of Washington, and medical director for quality and education in colorectal surgery at Swedish Cancer Institute and Medical Center in Seattle. He plans to retire after instituting the Strong for Surgery program in Swedish Hospital. Dr. Billingham noted that important research questions must be answered before the nutrition program expands beyond the test hospitals. Much of the existing research was conducted with industry sponsorship and authorship. “Therefore, the objectivity of the results is a little bit in question.” Investigators also need to assess the effectiveness of nutritional supplements in the real world and their cost-effectiveness. Right now, patients pay about $60 for the immunonutrition supplements. More information about the program is available at the Strong for Surgery website (www.becertain.org/strong_for_surgery). n Strong for Surgery receives support from the ACS Division of Education, the Agency for Healthcare Research and Quality, the Life Sciences Discovery Fund and Nestlé HealthCare Nutrition. The latter does not provide funding to promote a specific product.

Gastroenterology & Endoscopy News • April 2013

F D A UP D AT E & PR O D U C T N E W S

AAAHC Launches New Medical Home On-Site Certification Program The Accreditation Association for Ambulatory Health Care (AAAHC) has launched a new Medical Home On-Site Certification program for organizations interested in evaluating their services against nationally recognized standards for the patient-centered medical home. AAAHC announced the launch of the new program in January, following the successful completion of a pilot study, which included certification of four organizations: a community health center in Colorado, an HIV/AIDS clinic in California, a primary care organization in Pennsylvania and a schoolbased health clinic in Detroit.

In addition to the on-site certification program, AAAHC also offers medical home accreditation as an option of a general accreditation survey. With accreditation and on-site certification, AAAHC offers the most comprehensive patient-centered medical home survey process available, according to the organization. In a statement, Sam Romero, MD, MBA, medical director of AAAHC, said, “The success of the pilot program

demonstrated that the AAAHC certification program offers value to organizations that are looking to become medical homes. Our surveyors work collaboratively with organizations to ensure that patients receive high-quality care, consistent with AAAHC standards.” Founded in 1979, AAAHC is recognized as a symbol of quality by thirdparty payers, medical organizations, insurance companies, state and federal agencies and the public, according to

the organization. Currently, there are more than 5,000 organizations accredited nationwide, including ambulatory surgery centers, medical and dental practices and community health centers. AAAHC is also the official accrediting organization for the U.S. Air Force and the U.S. Coast Guard. For further information, visit www.aaahc.org/en/accreditation/ primary-care-medical-home. —Based on a press release from the AAAHC

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gastroendonews.com Read all the articles from each month’s issue online. According to AAAHC, certification demonstrates an organization’s dedication to the standards of patient-centered medical care. AAAHC’s “Medical Home On-Site Certification Handbook” provides specific guidelines for adhering to these standards, which include a focus on patients’ rights, the patient/ care team relationship, and accessibility, comprehensiveness and quality of care.

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US Endoscopy Launches Oracle EUS Balloon for Endoscopic Ultrasound Procedures

Ethicon Receives FDA 501(k) Clearance For Enseal G2 Articulating Tissue Sealer

The Oracle EUS balloon is made of silicone, unlike traditional latex EUS balloons.

Photo courtesy of US Endoscopy

On Feb. 6, US Endoscopy announced the full market release of the Oracle EUS balloon for endoscopic ultrasound (EUS) procedures. The Oracle EUS balloon is made of durable silicone material and offers superior tear resistance and ease of application. According to US Endoscopy, traditional EUS balloons, which contain latex, can be difficult for medical staff to apply to the endoscope and frequently tear during application and use. “Nurses and technicians experience many frustrations with EUS balloons. The Oracle EUS balloon is a safe, convenient option that minimizes waste, saves money for facilities and helps eliminate exposure to latex,” said Gulam Khan, president of US Endoscopy. The Oracle EUS balloon also eliminates the risk for exposing patients and staff to latex. The elastic band design not only allows for easy application, but also offers a secure grip to ensure that the balloon stays on the endoscope. It is compatible with both radial and curvilinear endoscopes. —Based on a press release from US Endoscopy

Gastroenterology & Endoscopy News • April 2013

On Feb. 4, Ethicon Endo-Surgery Inc., announced the FDA 510(k) clearance of the Enseal G2 Articulating Tissue Sealer. According to Ethicon, the instrument is the first advanced bipolar energy tissue cutter and sealer approved in the United States that can bend back and forth, helping surgeons get strong vessel seals in difficult-to-reach parts of the anatomy. One of the big challenges that surgeons face, especially when performing colorectal procedures, is operating within a challenging anatomy. The Enseal G2 is designed to help surgeons maneuver around corners and behind structures, providing better access to tissue in deep or tight spaces with greater control of the angle of approach to vessels. “The articulation helps give me a perpendicular angle on vessels which gives me a strong seal in one bite,” said Steven A. Elg, MD, a surgeon at Iowa Methodist Hospital in Des Moines, in a press release. The Enseal G2 allows surgeons to take a perpendicular approach to seal vessels up to 7 mm in diameter and lymphatics through a 5-mm port. Vessels sealed perpendicularly are stronger than those sealed at oblique angles, according to

data from Ethicon. Stronger sealing helps to reduce the likelihood of internal bleeding and postsurgical complications, the company stated. The Enseal G2 articulating tissue sealer builds on the unique benefits of the Enseal portfolio, which is designed for superior tissue sealing by providing uniform compression, controlling temperature and minimizing thermal spread. The proprietary I-Blade technology delivers high uniform compression for sealing vessels consistently along the length of the jaw, and the offset electrode configuration device is designed to minimize thermal spread. Other bipolar devices do not have the Positive Temperature Coefficient technology and offset electrode configuration designed for minimizing energy spread into surrounding tissue, according to Ethicon. For more information about the Enseal product portfolio, visit www.ethicon. com/healthcare-professionals/products/ energy-devices#!enseal-portfolio. —Based on a press release from Ethicon Endo-Surgery Inc.

The Enseal G2 from Ethicon Endo-Surgery Inc. Photos courtesy of Ethicon Endo-Surgery Inc.

Muscle Strengthening Device Launched To Treat Symptoms of Dysphagia Swallow Solutions LLC has launched the Madison Oral Strengthening Therapeutic (MOST) device to treat patients with dysphagia. The MOST device is a customized, adjustable mouthpiece that is used with a laptop to provide pressure readings from embedded sensors, indicating performance levels and calculating therapeutic strengthening targets. “By strengthening head and neck muscles integral to swallowing, the device has been shown to improve dysphagia after an eight-week regimen,” said Brent

Embedded sensors in the mouthpiece of the MOST device provide pressure readings to a computer, which indicates performance levels and calculates therapeutic strengthening targets. Photo courtesy of Swallow Solutions LLC

Benson, the newly appointed director of sales and marketing for Swallow Solutions. “A lot of patients who are dysphagic can go back to normal lives and eat regular food after just the initial eight-week study, removing any connection to a feeding tube for sustenance. It can be truly life changing.” MOST is listed with the FDA and is allowed for sale as a class 1 product in the United States. Introduced in August, the first-generation MOST device is being shipped to hospitals, extended care facilities and speech pathologists nationwide. Multisite clinical trials also are under way to provide the data necessary to garner Medicare and private health care reimbursement. The next-generation MOST 2.0 will be launched in the near future, according to a company press release. The American Speech-Language-Hearing Association estimates that approximately 10 million Americans are evaluated with swallowing difficulties each year. Affecting millions of infants, children and adults, dysphagia is increasingly common in older individuals. As people age, muscles weaken, including the muscles of the head and neck. Aspiration of foods can lead to pneumonia, malnutrition and dehydration, especially in older individuals. “The products offered by Swallow Solutions have been developed to address swallowing problems in patients of all ages and medical conditions,” Mr. Benson said. —Based on a press release from Swallow Solutions LLC

Gastroenterology & Endoscopy News • April 2013

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“Regulators have been slow to approve probiotics. The issue is what might one use other than a live organism to get the same beneficial effect?” One possibility is to decipher how the probiotic is working, isolate its active ingredient, and produce a “pharmabiotic,” he suggested. For NEC and IBS, this approach would be antimicrobial, phagebiotic, immunoregulatory, antiinflammatory, cytoprotective and even analgesic, studies suggest. The pharmabiotic approach is being studied now. The other approach is to use a prebiotic, a complex sugar that promotes the growth of beneficial organisms such as lactic acid–producing bacteria and bifidobacteria. Breast milk is actually a rich source of prebiotics: Oligosaccharides are abundant in breast milk; they are a complex mixture of galacto-oligosaccharides, have bifidogenic properties, affect microbiome composition and are normally not present in infant formulas. Prebiotics also are found in foods that contain fructooligosaccharides (e.g., asparagus, leeks, onion, garlic). A systematic review of 11 randomized controlled trials involving nearly 1,500 infants and preschoolers showed

that prebiotics produced softer, more frequent stools, increased the numbers of bifidobacteria and lactobacilli, and reduced stool pH, without affecting body weight (Rao S et al. Arch Pediatr Adolesc Med 2009;163:755-764). But studies have been small and short term, and their clinical impact has not been assessed. “There is initial evidence that prebiotics promote the growth of beneficial microbes, may protect against harmful enteric bacteria and may reduce entericspecific and overall infection rates, but we need more data,” Dr. Sherman said. He summed up the topic by maintaining that intestinal dysbiosis could well play a role in NEC and IBS, along with other disease states. Measures can be taken to adjust the composition of the microbiome with probiotics and prebiotics, but more evidence of efficacy and safety is needed.

Germ Warfare or Germ Welfare? “The sea change in how we view the bacteria in us and on us can be measured by popular culture, as on the cover of The New Yorker magazine (“Germ Welfare”) and Michael Specter’s article therein, “Germs are Us” (The New Yorker, Oct. 22, 2012), as well as by the scientific literature,” said Robert Shulman, MD, see Microbiome, page 50

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Microbiome continued from page 49

professor of pediatrics at Baylor College of Medicine, Houston, who conducts research on the gut microbiota in children. “For example, the number of scientific papers relating to probiotics has increased sevenfold in the past 10 years compared with the total number published in all years prior to 2002,” Dr. Shulman noted. “It now seems foolish that for so long we seemingly had no real appreciation for why we evolved to have trillions of

bacteria from mouth to anus, not to mention on and in other anatomical sites.” Dr. Sherman mentioned important issues regarding microbes as “potential allies in health,” he said, acknowledging that much remains to be learned regarding cause and effect. The evidence that probiotics can, in some cases, treat diseases underscores the overall potential importance of bacteria in health. For example, early experience of benefit in treating

recurrent Clostridium difficile infection with fecal transplantation (Rubin TA et al. Anaerobe 2013;19:22-26; van Nood E et al. N Engl J Med 2013;368:407-415) highlights Dr. Sherman’s points about the importance of a diverse, balanced gut microbiome, Dr. Shulman said. “Implicit in his observations is that we look to specific strains of bacteria to examine their effects rather than making blanket statements about ‘probiotics’ being effective

treatments or not,” Dr. Shulman said. “Two strains of the same bacteria—much less two species—may behave very differently. The current application of ‘omics’ (e.g., metagenomics, metabolomics, metatranscriptomics, metaproteomics; Maccaferri S et al. Dig Dis 2011;29:525-530) will help unravel the workings of the gut microbiota and their complex interaction with us, and

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will likely help us move into the era of the ‘pharmabiotic,’ as Dr. Sherman points out.” Dr. Sherman also emphasizes that “we are not created equally,” he added. “Some bacteria used as probiotics may cause disease (e.g., sepsis), in the case of some immune-compromised patients (Mehta A et al. Bone Marrow Transplant 2013;48:461-462) and some with short bowel syndrome (De Groote MA et al. Pediatr Infect Dis J 2005;24:278-280). It’s not always easy to know who your n allies really are.” Dr. Sherman has received research funding from Institut Rosell-Lallemand Inc., and has served on the medical advisory boards for Abbott Laboratories, Mead Johnson and Procter & Gamble. Dr. Shulman has served as a consultant for Gerson Lehrman Group and QOL Medical, LLC.

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Gastroenterology & Endoscopy News • April 2013

Regorafenib Approved for Advanced Gastrointestinal Stromal Tumor On Feb. 25, the FDA expanded the approved use of regorafenib (Stivarga, Bayer HealthCare Pharmaceuticals/ Onyx Pharmaceuticals) to treat patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who no longer respond to other FDA-approved treatments for the disease. The other approved treatments are imatinib (Gleevec, Novartis) and sunitinib (Sutent, Pfizer). Regorafenib was approved in September 2012 to treat colorectal cancer.

with locally advanced, unresectable or metastatic GIST that progressed after treatment with imatinib and sunitinib. In the randomized, double-blind, multicenter trial, patients were randomized in a 2:1 ratio to receive either regorafenib or placebo until either the cancer progressed or toxicity became unacceptable. All patients also received best supportive care. Patients who took regorafenib experienced significantly longer progression-free survival

(PFS): Median PFS was 4.8 months in the regorafenib arm versus 0.9 months in the placebo arm (P<0.0001). The most frequent side effects reported in patients treated with regorafenib were asthenia/fatigue, palmarplantar erythrodysesthesia, diarrhea, decreased appetite, hypertension, mucositis, infection, dysphonia, pain, weight loss, stomach pain, rash, fever and nausea. Serious side effects, occurring in less than 1% of patients,

MoviPrep® (PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid for oral solution) The following is a brief summary only; see full Prescribing Information for complete product information.

Photo courtesy of Bayer HealthCare Pharmaceuticals

INDICATIONS AND USAGE MoviPrep is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older. CONTRAINDICATIONS

“[Regorafenib] provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. A multikinase inhibitor that blocks several enzymes that promote cancer growth, regorafenib was reviewed under the FDA’s priority review program and was granted orphan product designation because it is intended to treat a rare disease. According to the National Cancer Institute, an estimated 3,300 to 6,000 new cases of GIST occur annually in the United States, most often in older adults. “While great progress has been made in the treatment of GIST since the introduction of kinase inhibitors as effective therapies for this orphan disease, we have been looking for additional, effective treatments for GIST patients whose disease worsens despite currently approved therapies,” said George D. Demetri, MD, principal investigator of the Phase III study (GIST—Regorafenib in Progressive Disease [GRID]) that led to the drug’s approval, and director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute, in Boston. “These data show that regorafenib can slow disease progression in patients who are no longer responding to other approved therapies, and may provide another avenue for GIST patients who would otherwise have no FDA-approved treatment option.” The GRID trial included 199 patients

MoviPrep is contraindicated in patients with the following conditions: gastrointestinal (GI) obstruction, bowel perforation, gastric retention, ileus, toxic colitis or toxic megacolon, or hypersensitivity to any components of MoviPrep. WARNINGS AND PRECAUTIONS Use with caution in patients using concomitant medications that increase the risk of electrolyte abnormalities (such as diuretics, angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs), patients with known or suspected hyponatremia), patients at increased risk of cardiac arrhythmias, patients with a history of seizures or at increased risk of seizures such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with impaired renal function or patients taking concomitant medications that affect renal function (such as diuretics, ACE inhibitors, ARBs, or non-steroidal anti-inflammatory drugs), patients with severe ulcerative colitis or inflammatory bowel disease, patients with impaired gag reflex or patients prone to regurgitation or aspiration, patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of stimulant laxatives and MoviPrep may increase the risk and is not recommended. The potential for mucosal ulcerations resulting from the bowel preparation should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. If gastrointestinal obstruction or perforation is suspected, appropriate diagnostic studies should be performed to rule out these conditions before administering MoviPrep. If a patient experiences severe bloating, abdominal distension, or abdominal pain, administration should be slowed or temporarily discontinued until symptoms abate. Patients with electrolyte abnormalities should have them corrected before treatment with MoviPrep. Patients should be advised to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep post-colonoscopy lab tests (electrolytes, creatinine, and BUN) should be considered. Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment. MoviPrep contains phenylalanine (233 mg per treatment). ADVERSE REACTIONS

In clinical trials, the most common adverse reactions for split dosing regimen (incidence 5%) were malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing regimen (incidence 5%) were abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness. Isolated cases of urticaria, rhinorrhea, dermatitis, and anaphylactic reaction have been reported with PEG-based products and may represent allergic reactions. Published literature contains isolated reports of serious adverse events following the administration of PEG-based products in patients over 60 years of age. These adverse events included upper gastrointestinal bleeding from a MalloryWeis tear, esophageal perforation, asystole, and acute pulmonary edema after aspirating PEG-based preparation. In addition to adverse reactions reported from clinical trials, the following adverse events have been identified during post-approval use of MoviPrep: hypersensitivity reactions including anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritis, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness. Fever, chills and dehydration. DRUG INTERACTIONS Use caution when prescribing MoviPrep for patients with conditions, or who are using medications that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and prolonged QT in the setting of fluid and electrolyte abnormalities. Consider additional patient evaluations as appropriate. Oral medication administered within 1 hour of the start of administration of MoviPrep may be flushed from the gastrointestinal tract and the medication may not be absorbed.

were hepatotoxicity, severe bleeding, skin blistering and peeling, very high blood pressure requiring emergency treatment, heart attack, and perforations in the intestines. Regorafenib’s label includes a boxed warning citing the risk for severe and sometimes fatal hepatotoxicity. For more information about regorafenib, visit www.stivarga-us.com. —Based on press releases from the FDA and Bayer HealthCare Pharmaceuticals

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C. Animal reproduction studies have not been performed with MoviPrep. It is also not known if MoviPrep can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MoviPrep should be given to a pregnant woman only if clearly needed. Nursing Mothers: Because many drugs are excreted in human milk, caution should be exercised when MoviPrep is administered to a nursing woman. Pediatric Use: The safety and effectiveness of MoviPrep in pediatric patients has not been established. Geriatric Use: Of the 413 patients in clinical studies receiving MoviPrep, 91 (22%) patients were aged 65 or older, while 25 (6%) patients were over 75 years of age. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in responses between geriatric patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. OVERDOSAGE There have been no reported cases of overdose with MoviPrep. Purposeful or gross accidental ingestion of more than the recommended dose of MoviPrep might be expected to lead to severe electrolyte disturbances, including hyponatremia and/or hypokalemia, as well as dehydration and hypovolemia, with signs and symptoms of these disturbances. The patient who has taken an overdose should be monitored carefully, and treated symptomatically for complications. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Long-term studies in animals to evaluate the carcinogenic potential have not been performed with MoviPrep. Studies to evaluate potential for impairment of fertility or mutagenic potential have not been performed with MoviPrep. STORAGE Store carton/container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). When reconstituted, store upright and keep solution refrigerated. Use within 24 hours. PATIENT COUNSELING INFORMATION s Advise patients to read the Medication Guide included in the full prescribing information. s Advise patients who require a diet low in phenylalanine that MoviPrep contains phenylalanine. s Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration. s Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquid (e.g., water, clear soup, fruit juice without pulp, soft drinks, tea and/or coffee without milk) according to instructions. s Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep. s Tell patients not to take other laxatives while they are taking MoviPrep. s Tell patients that MoviPrep produces a watery stool (diarrhea) which cleanses the colon before colonoscopy. Advise patients receiving MoviPrep to adequately hydrate before, during, and after the use of MoviPrep. Patients may have clear soup and/or plain yogurt for dinner, finishing the evening meal at least one hour prior to the start of MoviPrep treatment. No solid food should be taken from the start of MoviPrep treatment until after the colonoscopy. s Tell patients that the first bowel movement may occur approximately 1 hour after the start of MoviPrep administration. Abdominal bloating and distention may occur before the first bowel movement. If severe abdominal discomfort or distention occurs, stop drinking MoviPrep temporarily or drink each portion at longer intervals until these symptoms diminish. If severe symptoms persist, notify your health provider. Rx only Manufactured by: Norgine B.V. Hogehilweg 7 1101 CA Amsterdam Zuidoost Netherlands For: Salix Pharmaceuticals, Inc. Raleigh, NC 27615 © 2012 Salix Pharmaceuticals Inc. Feb 12

MoviPrep® #1 prescribed branded purgative in the United States1

Seeing is believing MoviPrep has proven 89% excellent or good cleansing when used as a split dose2 ° Low-volume PEG-3350 provides consistent, clear visibility of the entire colon ° FDA approved for PM|AM Split Dosing™ ° Osmotic laxative with electrolytes ° Most common adverse reactions for split dosing (incidence 5%) are malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing (incidence 5%) are abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness.

Please see Brief Summary of complete Prescribing Information for MoviPrep on reverse. References: 1. Medi-Span® Price Rx® [database online]. Indianapolis, IN: Wolters Kluwer Health. http://www.medispan.com/drug-pricing-analysis-pricerx.aspx. Accessed July 13, 2012. 2. MoviPrep [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012. Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel·866.669.SLXP (7597) MoviPrep® is a registered trademark and PM | AM Split Dosing™ is a trademark of Salix Pharmaceuticals, Inc. © 2013 Salix Pharmaceuticals, Inc. All rights reserved. MOV11/41-4

www.MoviPrep.com

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Pancreatic Exocrine Insufficiency Part 1 of 2: Treatment Approaches VIVEK KADIYALA, MD SHADEAH LAILA SULEIMAN DARWIN L. CONWELL, MD, MS Center for Pancreatic Disease Brigham and Women’s Hospital Division of Gastroenterology, Hepatology, and Endoscopy Harvard Medical School Boston, Massachusetts

n Part 1 of this 2-part review, treatment approaches for patients with pancreatic enzyme insufficiency

(PEI) are covered, including the proper use of currently FDA-approved pancrelipase preparations.

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Treatment of diagnosed PEI is vital to maintaining nutritional status, thereby preventing exacerbation of complications related to cystic fibrosis (CF) and chronic pancreatitis (CP).1 Nutrition and lung health are closely linked; for example, PEI exacerbates pulmonary disease and negatively effects quality of life.1,2 Evidence indicates that maldigestion and malabsorption, secondary to CP and other pancreatic diseases, are associated with serious and potentially fatal complications, such as cardiovascular events associated with low plasma concentrations of high-density lipoprotein cholesterol, apolipoprotein A-I, and lipoprotein A.3 A prospective study of 23 patients recovering from acute pancreatitis and experiencing significant weight loss, demonstrated that PEI developed in 86% of patients classified with severe pancreatitis as defined by preset criteria.4 In these patients, pancreatic enzyme replacement therapy (PERT) may hasten recovery of pancreatic function.4 Patients who have been diagnosed with pancreatic cancer will require PERT for the remainder of their lives, regardless of concomitant therapies, to improve their level of nutrition and to potentially reduce pain associated with high cholecystokinin levels.5-8 Clinical pancreatic malabsorption may remain despite the use of PERT and therefore requires individualized therapy and monitoring. In addition to PERT, treatment of PEI also should encompass dietary modifications and fat-soluble vitamin supplementation.

Goals of PERT PERT is the standard therapy for PEI; 93% of patients in the US Cystic Fibrosis Registry are treated with pancreatic enzyme replacements.9 Clinical therapeutic goals of enzyme replacement include optimizing quality of life by correcting macronutrient and micronutrient malabsorption, and reducing or eliminating abdominal symptoms associated with maldigestion.8 In adults, PERT should prevent weight loss and wasting when accompanied by a normal diet.10 The pharmacokinetic objective of PERT is to optimize the nutritional value of each meal by achieving an adequate and timely concentration of active enzymes in the duodenal lumen for proper digestion.5,11-13 Despite the diverse armamentarium of available pancreatic enzyme replacement products (differing in enzyme content, dosage formulation, and coating) individual response to therapy is highly variable and limited, restoring fat absorption to only 80% to 85% of normal function.5,11-14

Pancreatic Enzyme Replacement Products Pancreatic enzyme replacement products were first marketed as powders, tablets, and capsules. All were

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comprised of porcine pancreatic extracts of lipase, amylase, and protease because of their similar composition to human pancreatic enzymes.15 The United States Pharmacopeia (USP) previously defined standards for 2 pancreatic enzyme preparationsâ&#x20AC;&#x201D;pancreatin and pancrelipaseâ&#x20AC;&#x201D;which are measured in units of lipase activity, as lipase is the lead enzyme.5 Pancreatin, a conventional preparation obtained from ox or swine pancreas, contained no less than 2 USP units of lipase activity and no less than 25 USP units of amylase and protease activity in each milligram.5 Pancrelipase, the newer preparation obtained from swine pancreas, contains no less than 24 USP units of lipase activity and no less than 100 USP units of amylase and protease activity per milligram.5 Because of the greater number of tablets required to achieve appropriate enzymatic concentration in the duodenum with pancreatin, the newer pancrelipase formulation has replaced the older preparation as the standard for PERT.5 The Table displays the commercially available, FDAapproved pancrelipase enzyme replacement products. Previously, a wide array of unapproved products were available in 2 formulations: uncoated, conventional immediate-release and enteric-coated microencapsulated enzymes.5 As of April 2010, only FDA-approved pancreatic enzyme replacement products are commercially available in the United States; at press time, 6 products meet those requirements.16 There are no approved powdered formulations, nor are there any approved generic enzyme preparations. Creon is an appropriate first-line agent as it is approved for use in CP, pancreatectomy, and CF.16 Because of the acidic environment of the stomach, Viokace, the lone uncoated immediate-release preparation, is susceptible to inactivation before reaching the duodenum17,18; its efficacy has been established only when coadministered with proton pump inhibitors (PPIs). Enteric coating with acid-resistant film only allows the pancreatic enzyme replacements to be released from the microencapsulation when the pH exceeds 5.5, targeting release into the small intestine only.5 First introduced in the 1970s, one of the initial challenges with enteric-coated tablets was their inability to dissolve.15 The development of variably sized, enteric-coated microspheres with small diameters (<2 mm) was an attempt to circumvent this issue by facilitating more even distribution within chime throughout gastric emptying.5 However, this theoretical advantage has never been evaluated.5 Taken correctly with food, enzymes last for approximately 1 hour following ingestion.19 When protected from acid degradation either by microencapsulation or by concomitant administration of acid-suppressive

Table. FDA-Approved Pancreatic Enzyme (Pancrelipase) Preparations Product

Enzyme Content/Unit Dose, United States Pharmacopeia units Lipase

Amylase

Protease

Viokace 10,440

10,440

39,1550

39,150

Viokace 20,880

20,880

78,300

Immediate-release capsule Non–enteric-coated

Delayed-release capsules Enteric-coated minimicrospheres Creon 3,000

3,000

15,000

9,500

Creon 6,000

6,000

30,000

19,000

Creon 12,000

12,000

60,000

38,000

Creon 24,000

24,000

120,000

76,000

Ultresa 13,800

13,800

27,600

Ultresa 20,700

20,700

41,400

Ultresa 23,000

23,000

46,000

Zenpep 3,000

3,000

16,000

10,000

Zenpep 5,000

5,000

27,000

17,000

Zenpep 10,000

10,000

55,000

34,000

Zenpep 15,000

15,000

82,000

51,000

Zenpep 20,000

20,000

109,000

68,000

Zenpep 25,000

25,000

136,000

85,000

Pancreaze 4,200

4,200

17,500

10,000

Pancreaze 10,500

10,500

43,750

25,000

Pancreaze 16,800

16,800

70,000

40,000

Pancreaze 21,000

21,000

61,000

37,000

Enteric-coated minitablets

Enteric-coated beads

Enteric-coated microtablets

Bicarbonate-buffered enteric-coated microspheres Pertzye 8,000

8,000

30,250

28,750

Pertzye 16,000

16,000

60,500

57,500

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therapy, pancrelipase preparations can survive transit through the stomach and effectively decrease steatorrhea.20 CF patients with PEI exhibit a marked decrease in the pancreatic secretion of bicarbonate needed to neutralize gastric acid. Suboptimal bicarbonate secretion results in increased acidity in the gastrointestinal tract, including the duodenum, which may prevent or slow the dissolution of enteric-coated microcapsules, which dissolve over a variable period of time at a pH exceeding 5.5 to 6.0.6,21 Bicarbonate-buffered enzyme preparations have been shown to be effective in CF and may improve activity of delivered enzymes.22,23 The role of bicarbonate is to increase the duodenal pH to 8.5 to 9.0, potentially allowing optimal lipase bioactivity and consequently decreased doses of PERT.24,25 These theoretical advantages require further clinical study and documentation before being recommended as standard initial therapy.

Dosing Strategies and Guidelines PERT should be individualized to achieve a balance between minimizing steatorrhea and maximizing nutritional status.26 Guidelines for the dosing of PERT have been issued by the Cystic Fibrosis Foundation (CFF). Weight-based dosing recommendations for PERT, promulgated by the CFF, require adjustment in relation to disease severity and clinical response to optimize fat absorption.26 Pancreatic lipase enzymes are susceptible to acidic deactivation; in order to restore nutrient digestion in patients with PEI, enzymes must be delivered into the duodenal lumen in sufficient quantities and synchronized with meals.26 In adults, intraluminal lipase activity requires a minimum of 40 to 60 IU lipase per minute in postprandial chime throughout the digestive period, corresponding to approximately 25,000 to 40,000 USP units of lipase needed for the digestion of a regular meal. Such doses should reduce steatorrhea to less than 15 g per day of fat.27,28 Unprotected immediate-release uncoated lipase is quickly rendered inactive in the low pH of the gastric environment; up to 10-fold more lipase must be given orally to reach the duodenum and correct steatorrhea.27 There are several enzyme preparations and methods of enzyme delivery designed to avoid gastric inactivation of enzymes. First, administration of a higher-dose preparation may facilitate greater active enzyme delivery to the duodenum; however, the benefits of higher-dose preparations must be weighed against potential adverse effects, including bloating, diarrhea, flatulence, hyperuricosuria, and colonic strictures.27,29-32 Second, the administration of acidsuppressing agents such as histamine-2 (H2) receptor blockers or PPIs enables an increase in gastric pH

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(>4.0) to prevent acid-induced deactivation; however, this approach increases treatment costs, and reported studies have not demonstrated a clear benefit associated with this strategy.28,33-35 Third, the introduction of enteric-coated preparations, which dissolve in a pH greater than 5.5, allows enzyme release to be targeted to the small intestine.5 The CFF consensus-based guideline for the nutrition-related management of adults with CF and PEI was readdressed in 2008.36 The recommended doses include 500 to 2,500 units of lipase per kilogram of body weight per meal or less than 10,000 units of lipase per kilogram of body weight per day, or less than 4,000 units of lipase per gram of dietary fat per day.36 As lipase is the lead enzyme within individual preparations, it is the most important determinant of efficacy in the treatment of steatorrhea. Lipase possesses specific biochemical properties including: 1) a marked decrease in synthesis compared with other enzymes in early pancreatic insufficiency fat malabsorption; 2) denaturation secondary to diminished pancreatic bicarbonate secretion; 3) minimal extra-pancreatic lipolysis; and 4) a short intraluminal survival time compared with other enzymes.27,37 In most adults with CP, a minimum of 30,000 USP units of lipase per meal allows adequate intraluminal digestion of fat and protein.27,37 The dose may need to be titrated to as much as 60,000 to 80,000 USP units lipase per meal because not all of the lipase may reach the proximal small intestine in the active form.27,37 Many patients with CF will require numerous PERT capsules dailyâ&#x20AC;&#x201D;doses of 15 to 25 capsules are commonâ&#x20AC;&#x201D;but doses of lipase in excess of 75,000 units per meal are not recommended.27,37 The timing of PERT ingestion is subject to dietary and individual considerations. Enzymes may be taken before, during, or after the meal or snack. To maximize fat absorption, enzymes may be taken before and during, or during and after, the meal. A recent trial demonstrated that administration of enzymes was most effective when given during or after the meal.38 A nutritional consultation with a registered dietitian knowledgeable in CF care should be available for PEI patients and family members to assist with proper use and understanding of PERT.5 Several drinks and foods (eg, coffee/tea, lollipops, gum, jelly beans, and popsicles, that contain simple carbohydrates and minimal nutritional value, as well as fruit and select fruit juices) do not require PERT.19 Usually, half of the standard PERT dosage is administered with snacks, and slightly higher than standard doses may be appropriate for fried foods, pizza, or other high-fat foods.19 The total PERT daily dose should be based on 3 meals and 2 to 3 snacks.5,15,39 Recommended enzyme dose, based

on lipase units per kilogram, is decreased for older patients as they weigh more and typically ingest less fat per kilogram of body weight.39 For patients who are unable to swallow capsules, they may be opened and the contents mixed with applesauce, rice cereal, bananas, or an alternate non-alkaline food to facilitate ingestion.14 Because of the risk for micro-coating disruption, the microcapsules cannot be crushed, chewed, or mixed with food for an extended period of time.14 Instead, the capsule beads are to be sprinkled on the food immediately before ingestion. Pancreatic enzyme products are biologic extracts that contain, in addition to the active ingredients, protein and other substances that introduce the potential for enzyme activity to vary from batch to batch.10 Enzyme activity also may vary due to environmental factors and a decline in potency over time, especially with exposure to sunlight, heat, and humidity.10 Enzymes should be stored in a cool, dry environment, and checked consistently for expiration dates.

Adverse Effects of PERT PERT is generally well tolerated at typical therapeutic doses; however, high doses of PERT have been shown to induce nausea, vomiting, and diarrhea associated with transient intestinal upset, as well as hyperuricemia.5 In the past, the use of powdered preparations of PERT has caused hypersensitivity reactions in some patients.40 Fibrosing colonopathy—a condition associated with ingestion of high doses of PERT—can progress to colonic strictures at its most advanced stage. Highstrength microencapsulated products (>20,000 units of lipase) were first commercially available in 1991; 3 years later, the first colonic strictures were reported in patients with CF, suggesting a temporal relation to the introduction of high-strength pancreatic enzyme replacement products. It has been hypothesized that the protease content of the pancreatic enzyme replacement products may cause fibrosing inflammation in some predisposed patients at ultra-high doses.15 Recent studies have suggested that methacrylic acid copolymer, which is used as the acid-resistant coating on certain brands of microencapsulated enzymes, may be the cause of fibrosing colonopathy. Until the cause of fibrosing colonopathy can further be ascertained, it is prudent to avoid excessive doses of microencapsulated products and instead attempt combination therapy with an uncoated product and a PPI or H2-receptor antagonist.26,29 Fibrosing colonopathy should be considered in patients receiving PERT who have evidence of obstruction, bloody diarrhea, or chylous ascites, as well as in patients with abdominal pain and persistent

diarrhea, poor weight gain, or a combination thereof. The relative risk for developing this condition in the setting of high-dose pancreatic enzymes ranges from 10 to 200, increasing in a dose-dependent manner. Patients at high-risk for developing fibrosing colonopathy include those administered enzyme doses exceeding 6,000 lipase units per kilogram per meal for more than 6 months, or patients with a history of meconium ileus, distal intestinal obstruction syndrome, recent intestinal surgery, or inflammatory bowel disease.15,26,29-31 Overall, PERT is safe, well-tolerated, and produces few adverse effects if dosed and monitored based on a specific individual’s signs and symptoms.

Vitamin Replacement Therapy Comprehensive management of patients with PEI includes assessment of potential vitamin deficiencies and the use of over-the-counter fat-soluble vitamin supplements.5 Steatorrhea often is associated with malabsorption of the fat-soluble vitamins A, D, E, and K. Vitamin deficiencies may develop as a consequence of fat maldigestion and malabsorption, for which patients with CF and CP are at risk. Nearly half of all patients diagnosed with CF are deficient in vitamins A, D, and/or E.41,42 In particular, vitamin D deficiency can lead to complications such as osteoporosis. The odds ratio for fracture in patients with CP is comparable to that for other gastrointestinal diseases associated with a high fracture risk.43 Although all patients with severe PEI should receive a bone scan, it may be more practical to establish a baseline bone mineral density in menopausal patients with PEI, particularly if there is a family history of osteoporosis. Young adults, adolescents, and children with CF often have low levels of vitamin D despite taking daily supplements and consequently also are at high risk for metabolic bone disease.42,44 Although most vitamin deficiencies are not clinically observed, bone demineralization is commonly seen in patients with CF and also may be a reflection of general malnutrition and corticosteroid treatment. Metabolic bone disease has been described in patients with CP, but prospective studies are needed to accurately determine its incidence and prevalence. There is a clinical consensus that a multivitamin and additional dietary supplementation of fat-soluble vitamins A, D, E, and K typically results in rapid normalization of serum markers of malnutrition (albumin) and vitamin deficiency.45

Increased Caloric Requirement And High-Fat Diet Patients with PEI should consume a high-caloric diet with unrestricted fat content that is appropriate

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APRIL 2013

for age and clinical status.45 Patients with CF may require anywhere from 20% to 50% more calories than a healthy individual.19 Additional calories are required for catch-up growth, and nutritional assessment should accompany evaluation in all patients.45 The CFF recommends that nutritional status be appropriately managed to avoid unintentional weight loss in patients older than 20 years.36 Additionally, as PEI in CF generally does not represent a risk factor for developing hyperlipidemia, the abundance of dietary fat—the highest density source of calories—is not particularly concerning.46 Meals can be complemented with store-bought nutritional supplements and homemade milkshakes, but these additions should not serve as primary sources of nutrition.19

12.

Keller J, Runzi M, Goebell H, et al. Duodenal and ileal nutrient deliveries regulate human intestinal motor and pancreatic responses to a meal. Am J Physiol. 1997;272 (3 Pt 1):G632-G637.

13.

Layer P, von der Ohe MR, Holst JJ, et al. Altered postprandial motility in chronic pancreatitis: role of malabsorption. Gastroenterology. 1997;112(5):1624-1634.

14. Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of intestinal malabsorption in cystic fibrosis. Pediatr Pulmonol. 2006;41(1):35-49. 15.

FitzSimmons SC, Burkhart GA, Borowitz D, et al. Highdose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. N Engl J Med. 1997;336(18):1283-1289.

16.

Giuliano CA, Dehoorne-Smith ML, Kale-Pradhan PB. Pancreatic enzyme products: digesting the changes. Ann Pharmacother. 2011;45(5):658-666.

17.

Gow R, Bradbear R, Francis P, et al. Comparative study of varying regimens to improve steatorrhoea and creatorrhoea in cystic fibrosis: Effectiveness of an enteric-coated preparation with and without antacids and cimetidine. Lancet. 1981;2(8255):1071-1074.

18.

Ansaldi-Balocco N, Santini B, Sarchi C. Efficacy of pancreatic enzyme supplementation in children with cystic fibrosis: comparison of two preparations by random crossover study and a retrospective study of the same patients at two different ages. J Pediatr Gastroenterol Nutr. 1988;7(suppl 1):S40-S45.

19.

Maguiness K, Casey S, Fulton J, et al. Nutrition: Pancreatic Enzyme Replacement In People with Cystic Fibrosis. www.cff.org/UploadedFiles/LivingWithCF/ StayingHealthy/Diet/Nutrition-Pancreatic-EnzymeReplacement.pdf. Accessed March 21, 2013.

References 1.

Schibli S, Durie PR, Tullis ED. Proper usage of pancreatic enzymes. Curr Opin Pulm Med. 2002;8(6):542-546.

Strausbaugh SD, Davis PB. Cystic fibrosis: a review of epidemiology and pathobiology. Clin Chest Med. 2007;28(2):279-288.

Montalto G, Soresi M, Carroccio A, et al. Lipoproteins and chronic pancreatitis. Pancreas. 1994;9(1):137-138.

Boreham B, Ammori BJ. A prospective evaluation of pancreatic exocrine function in patients with acute pancreatitis: correlation with extent of necrosis and pancreatic endocrine insufficiency. Pancreatology. 2003;3(4):303-308.

Ferrone M, Raimondo M, Scolapio JS. Pancreatic enzyme pharmacotherapy. Pharmacotherapy. 2007;27(6):910-920.

DiMagno EP, Malagelada JR, Go VL, et al. Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. N Engl J Med. 1977;296(23):1318-1322.

20. DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme ouputs and malabsorption in severe pancreatic insufficiency. N Engl J Med. 1973;288(16):813-815.

Park RW, Grand RJ. Gastrointestinal manifestations of cystic fibrosis: a review. Gastroenterology. 1981;81(6):1143-1161.

21.

Keller J, Layer P. Pancreatic enzyme supplementation therapy. Curr Treat Options Gastroenterol. 2003;6(5):369-374.

FitzSimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr. 1993;122(1):1-9.

10. Durie P, Kalnins D, Ellis L. Uses and abuses of enzyme therapy in cystic fibrosis. J R Soc Med. 1998;91 (suppl 34):2-13. 11.

Holtmann G, Kelly DG, Sternby B, et al. Survival of human pancreatic enzymes during small bowel transit: effect of nutrients, bile acids, and enzymes. Am J Physiol. 1997;273(2 Pt 1):G553-G558.

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Dutta SK, Russell RM, Iber FL. Impaired acid neutralization in the duodenum in pancreatic insufficiency. Dig Dis Sci. 1979;24(10):775-780.

22. Konstan MW, Strausbaugh SD, Ahrens RC, et al. Pediatr Pulmonol. 2008;43(S31):425. 23. Konstan MW, et al. A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Cross-Over Study to Evaluate the Effectiveness and Safety of a Novel Pancrelipase (PANCRECARB® MS-16) in Reducing Steatorrhea in Children and Adults with Cystic Fibrosis. 2008 North American Cystic Fibrosis Conference. Abstract 618. 24. Brady MS, Garson JL, Krug SK, et al. An enteric-coated high-buffered pancrelipase reduces steatorrhea in patients with cystic fibrosis: a prospective, randomized study. J Am Diet Assoc. 2006;106(8):1181-1186.

25. Kalnins D, Ellis L, Corey M, et al. Enteric-coated pancreatic enzyme with bicarbonate is equal to standard enteric-coated enzyme in treating malabsorption in cystic fibrosis. J Pediatr Gastroenterol Nutr. 2006;42(3):256-261. 26. Layer P, Keller J, Lankisch PG. Pancreatic enzyme replacement therapy. Curr Gastroenterol Rep. 2001;3(2):101-108. 27. Layer P. [Intestinal regulation of pancreatic enzyme secretion: stimulatory and inhibitory mechanisms]. Z Gastroenterol. 1992;30(7):495-497. 28. DiMagno EP LP, Clain JE. Chronic Pancreatitis. In: Go VL ea, ed. The Pancreas: Biology, Pathobiology and Disease. 2nd ed. New York, NY: Raven Press, Ltd, 1993. 29. Lebenthal E. High strength pancreatic exocrine enzyme capsules associated with colonic strictures in patients with cystic fibrosis: “more is not necessarily better.” J Pediatr Gastroenterol Nutr. 1994;18(4):423-425. 30. Mac Sweeney EJ, Oades PJ, Buchdahl R, et al. Relation of thickening of colon wall to pancreatic-enzyme treatment in cystic fibrosis. Lancet. 1995;345(8952):752-756. 31.

Bansi DS, Price A, Russell C, et al. Fibrosing colonopathy in an adult owing to over use of pancreatic enzyme supplements. Gut. 2000;46(2):283-285.

32. Stapleton FB, Kennedy J, Nousia-Arvanitakis S, et al. Hyperuricosuria due to high-dose pancreatic extract therapy in cystic fibrosis. N Engl J Med. 1976;295(5):246-248. 33. Regan PT, Phillips SF, Dimagno EP. Pancreatic insufficiency and Menetrier’s disease. Report of a case with clinical response to pancreatic enzyme replacement. Am J Dig Dis. 1978;23(8):759-762. 34. Carroccio A, Pardo F, Montalto G, et al. Use of famotidine in severe exocrine pancreatic insufficiency with persistent maldigestion on enzymatic replacement therapy. A long-term study in cystic fibrosis. Dig Dis Sci. 1992;37(9):1441-1446. 35. Heijerman HG, Lamers CB, Bakker W. Omeprazole enhances the efficacy of pancreatin (pancrease) in cystic fibrosis. Ann Intern Med. 1991;114(3):200-201. 36. Stallings VA, Stark LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108(5):832-839.

37. DiMagno EP, Go VL, Summerskill HJ. Intraluminal and postabsorptive effects of amino acids on pancreatic enzyme secretion. J Lab Clin Med. 1973;82(2):241-248. 38. Domínguez-Muñoz JE, Iglesias-García J, Iglesias-Rey M, et al. Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005;21(8):993-1000. 39. Borowitz DS, Grand RJ, Durie PR. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995;127(5):681-684. 40. Whitcomb D, Lowe M. Hereditary and Childhood Disorders of the Pancreas, Including Cystic Fibrosis. In: Feldman M, Friedman L, Brandt L, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease Pathophysiology/Diagnosis/Management Volume 1. 9th ed. Philadelphia, PA Saunders, 2010. 41. Layer P, Keller J. Lipase supplementation therapy: standards, alternatives, and perspectives. Pancreas. 2003;26(1):1-7. 42. Rovner AJ, Stallings VA, Schall JI, et al. Vitamin D insufficiency in children, adolescents, and young adults with cystic fibrosis despite routine oral supplementation. Am J Clin Nutr. 2007;86(6):1694-1699. 43. Tignor AS, Wu BU, Whitlock TL, et al. High prevalence of low-trauma fracture in chronic pancreatitis. Am J Gastroenterol. 2010;105(12):2680-2686. 44. Caldeira RJ, Fonseca Vde M, Gomes SC, Jr., et al. Prevalence of bone mineral disease among adolescents with cystic fibrosis. J Pediatr. (Rio J) 2008;84(1):18-25. 45. Ramsey BW, Farrell PM, Pencharz P. Nutritional assessment and management in cystic fibrosis: a consensus report. The Consensus Committee. Am J Clin Nutr. 1992;55(1):108-116. 46. Slesinski MJ, Gloninger MF, Costantino JP, et al. Lipid levels in adults with cystic fibrosis. J Am Diet Assoc. 1994;94(4):402-408.

AUTHOR DISCLOSURES—Ms. Suleiman and Drs. Conwell and Kadiyala have no conﬂicts of interest.

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IBS No Longer Only Functional Disorder BY DAVID WILD

Experienced Physicians Offer Tips To Trainees on Landing a Job It’s Never Too Early To Start the Search BY CHRISTINA FRANGOU

LAS VEGAS—For the first time, investigators have documented structural abnormalities in the small bowel of patients with irritable bowel syndrome (IBS). These findings “will fundamentally change our thinking on the disease,” researchers told attendees of the 2012 see IBS, page 8

Mesalamine Elicits Response in IBS BY MONICA J. SMITH LAS VEGAS—Mesalamine, a 5-aminosalicyte acid that is effective for maintenance of remission in patients with ulcerative colitis, also may be effective in relieving and controlling symptoms in irritable bowel syndrome see Mesalamine, page 9

Experts’ Picks

I N S I D E

Best of the American College Of Gastroenterology: Part 2

MDs and DOs Plan Uniﬁed Accreditation System For Graduate Medical Education ............... page 5

EXPERT REVIEW:

Sexual Misconduct by Professionals: A New Model of Understanding

COMPILED AND WRITTEN BY DAVID WILD Gastroenterology & Endoscopy News asked several experts to select their favorite abstracts from the 2012 American College of Gastroenterology (ACG) Annual Scientific Meeting. Inside is a collection of their selections and comments that reflect the varied interests of the experts who we interviewed. (Part 1 of this series appeared in the December 2012 issue of Gastroenterology & Endoscopy News.) see Best of ACG, page 14

BY GREGORY E. SKIPPER, MD, AND STEPHEN SCHENTHAL, MD ..................... page 29

EXPERT REVIEW:

Safeguarding Yourself Against Allegations Of Sexual Abuse or Patient Impropriety BY HARVEY TETTLEBAUM, JD, AND KEVIN MEYERS, JD .................................................................. page 33

PRODUCT ANNOUNCEMENT Clinical Applications of Probiotics in Gastroenterology: Questions and Answers, An Issue of Gastroenterology Clinics see page 37

The Gastric Cancers: Targeted for Personalized Medicine see pages 10-11

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