April 2015 by McMahon Group

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 66, Number 4 • April 2015

Gastro G Groups Aim For Clean Fo ner Scopes After Dea Af adly Outbreak

Free Colonoscopies Save System Money NYC hospital finds no-cost screening avoids costly cancers

NEW YORK—Need a blender? Lawrence J. Brandt, MD, a contemporary pioneer and proponent of fecal microbiota transplant (FMT) has a surplus, brought in by patients about to undergo the somewhat radical but overwhelmingly successful treatment for recurrent Clostridium difficilee infection (CDI).

NEW YORK—Cost is recoggnized as one of the barrierss to screening colonoscopyy, the uptake of which hoverss at around 65% of the eligiblee population in the United States. Although it may seem counterintuitive in today’s cost-conscious medical landscape, offering screening colonoscopy free of charge may be a feasible way around this obstacle. In 2006, a collaborative effoort between Maimonides Medical Center, in New York City, and NYC Department of Health to raise awaareness of the value of colorectal cancer (CRC) scrreening began offering colonoscopy to patients regarrdless of their ability to pay. The program has proved quite successful, according to data presented at the pooster session of the New York Society for Gastrointesttinal Endoscopy’s 2014 annual meeting. “It’s an interesting study and a very worthwhile program,” said Sidney Winaawer, MD, professor of medicine at Weill Cornell Medical College and Paul Sherlock Chair in Medicine at Memorial Sloan-Kettering Cancer Center, both in n New York City.

see FMT, page 34

see No cost, page 12

he outbreak of o superbug infections linked to contaminate duodenoscopes that sickened at contaminated least seven p pattients in Los Angeles and left two dead has haas sspurred rred gaastrroenterology practices nationwide too implement i lement em meas measurees to bolster their scope reprocessin ng practices. ct The infections, Th i f i involving in i l carbapenem-resistant Enterobacteriaceae (CRE), were tracked back to contaminated duodenoscopes used for endoscopic retrograde cholangiopancreatography (ERCP) procedures in Los Angeles, Illinois and elsewhere. CRE reportedly has a mortality rate see Scope, page 24

Fecal Transplants: An Insider’s Guide

I N S I D E

Doubling Up on IBD Therapy Does Not Appear To Raise Infection Risk

EXPERT ROUNDTABLE Frank G. Gress, MD

PHILADELPHIA— —The combination of vedolizumab and another immunosuppressive agent does not appear to increase a patient’s risk for infection, new data show. That finding comes after the placebo-controlled GEMINI I and II trials, investigating vedolizumab (VDZ; Entyvio, Takeda) as treatment for Crohn’s disease (CD) and ulcerative colitis (UC), indicated that the drug might put some patients at risk for certain infections, such as nasopharyngitis. However, the new research suggests the infection rate is similar whether patients receive VDZ alone or in combination with other therapies. see VDZ, page 26

Sidney Winawer, MD Felice Schnoll-Sussman, MD David Greenwald, MD

How Long Is s Too Long Between Surveillance e Colo onoscopies?.......... page 20

Managing C. difficile infections .................... page 4

PRINTER-FRIENDLY VERSION AVAILABLE V AT GASTROENDONEWS.COM A

OPT IN

to receive your free e-Newsletter at Register @ gastroendonews.com/enews

The Microbiome for Gastroenterologists

EDUCATIONAL REVIEW

AMIT DUTTA T , MD Aberdeen Royal Infirmary Forsterhill, Aberdeen, United Kingdom

Vegetarian diet tied to lower CRC risk k....... page 10

EMAD M. EL-OMAR, MD, FRCP Division of Applied Medicine Institute of Medical Sciences School of Medicine & Dentistry Aberdeen University Foresterhill, Aberdeen, United Kingdom

see insert after page 36

The Microbiome for Gastroenterologists

Simple bilirubin test for biliary atresia ....... page 31 Drs. Dutta and El-Omar report no relevant financial conflicts of interest.

icroorganisms are present on almost all parts of the human body that come in contact with the external environment including the gut, skin, oral cavity, genitourinary tract, and airway.1

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • A P R I L 2 0 1 5

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Gastro & Endo News @gastroendonews Follow us on Twitter

Heard Here First See page 31

Careful follow-up of family y members when hereditary colorectal cancer syndromes are found makes the diagnosis cost-effective and can dramatically alter the natural history of the disease. With colonoscopies and some occasional extra surgery, [clinicians] can turn Lynch syndrome into a fairly ‘boring’ disease— without the big surprise of cancer.

Vol. 66, No. 3 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

GARY R. LICHTENSTEIN, MD

Houston, Texas

Philadelphia, Pennsylvania

ALAN F. CUTLER, MD

NIRMAL S. MANN, MD, PHD

Farmington Hills, Michigan

Sacramento, California

FREDRIC DAUM, MD

PETER R. MCNALLY, DO

Mineola, New York

Fort Carson, Colorado

STEVEN M. FABER, MD

TARUN MULLICK, MD

Elizabeth City, North Carolina

St. Charles, Illinois

RONNIE FASS, MD

JOEL E. RICHTER, MD

Cleveland, Ohio

Tampa, Florida

BARBARA B. FRANK, MD

DAVID ROBBINS, MD

Philadelphia, Pennsylvania

New York, New York

FRANK G. GRESS, MD

ELLEN J. SCHERL, MD

New York, New York

CHRISTOPHER JOLLEY, MD

PRATEEK SHARMA, MD

Gainesville, Florida

Kansas City, Kansas

MYRON LEWIS, MD

JEROME H. SIEGEL, MD

Memphis, Tennessee

New York, New York

March 2015

DAN RADEBAUGH, Director of Production and Technical Operations

EDITORIAL STAFF

SALES STAFF

ADAM MARCUS, Managing Editor, amarcus@mcmahonmed.com

BRIAN J. HIGGINSON, Publication Director, bhigginson@mcmahonmed.com

JAMES PRUDDEN, Group Editorial Director

MATTHEW SPOTO, Senior Account Manager, mspoto@mcmahonmed.com

MCMAHON PUBLISHING

CRAIG WILSON, Classified Advertising Sales, cwilson@mcmahonmed.com

VAN VELLE, President, Partner

DAVID BRONSTEIN, DONALD M. PIZZI, Editorial Directors ROBIN B. WEISBERG, Manager, Editorial Services ELIZABETH ZHONG, Associate Copy Chief

ART AND PRODUCTION STAFF MICHELE MCMAHON VELLE, Creative Director

BRANDY WILSON, Circulation Coordinator

RAYMOND E. MCMAHON, Publisher and Managing Partner

MATTHEW MCMAHON, General Manager, Partner LAUREN SMITH, MICHAEL P. MCMAHON, MICHELE MCMAHON VELLE, ROSANNE C. MCMAHON, Partners

JEANETTE MOONEY, Y Senior Art Director JAMES O’NEILL, Senior Systems Manager

Subscription to Gastroenterology & Endoscopy News Gastroenterology & Endoscopy Newss obtains its mailing list from the American Medical Association (AMA) and the American Osteopathic Association (AOA). You do not have be a member of the AMA or AOA to receive the publication, but you do need to be correctly listed on the appropriate organization’s file, with a designated specialty of “gastroenterology,” “hepatology” or “colon and rectal surgery.” All U.S. gastroenterologists, hepatologists and colorectal surgeons should receive Gastroenterology & Endoscopy News free of charge. If you are a U.S. gastroenterologist, hepatologist or colorectal surgeon and you are not receiving Gastroenterology & Endoscopy News, or if you are changing your name, address or professional specialty, contact the AMA at (800) 262-3211 or the AOA at (800) 621-1773 and notify them

of your name, address and professional specialty.

Educational & Commercial Reprints

If you are not a U.S. gastroenterologist, hepatologist or colorectal surgeon and would like to subscribe, please send a check payable to Gastroenterology & Endoscopy Newss to: Circulation Coordinator, Gastroenterology & Endoscopy News, 545 West 45th Street, 8th Floor, New York, NY 10036. Annual subscription: $70.00 (outside U.S.A., $90.00). Single copies: $7.00 (outside U.S.A., $10.00). Please allow 8-12 weeks for delivery of the first issue. Further questions may be addressed to the Circulation Coordinator at (212) 957-5300, ext. 362, or bwilson@mcmahonmed.com.

Reprints of articles appearing in Gastroenterology & Endoscopy Newss are available in minimum quantities of 500. Reprints can be ordered in black and white or four-color versions and are printed on 80-lb. glossy stock paper. Standard turnaround time is 4 weeks. For specific price quotes, contact Brian J. Higginson at (212) 957-5300, ext. 241, or bhigginson@mcmahonmed.com.

McMahon Publishing is a 43-year-old family-owned medical publishing and medical education company. McMahon publishes monthly clinical newspapers, annual and semi-annual Special Editions, and continuing medical education and custom publishing pieces. INFECTIOUS DISEASE SPECIAL EDITION

What You Need to Know about Elastography View the latest clinical educational materials from Siemens.

GA A STROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Overview of the Management of Clostridium os diffficile Infections Julia Garcia-Diaz, MD, MSc, FIDSA Program Director, Infectious Disease Fellowship Program Ochsner Clinic Associate Professor University of Queensland/Ochsner School Clinical Associate Professor of Medicine Tulane University, New Orleans, Louisiana

lostridium difficile infection (CDI), a common cause of infectious diarrhea, has become increasingly prevalent in the acute care setting.1 CDI is associated with increased morbidity and more recently with increased mortality,2,3 and it has surpassed methicillinresistant Staphylococcus aureuss (MRSA) as the leading cause of hospital-acquired infections (HAIs).2,4 CDI also increases hospital length of stay (LOS) and care costs. A well-known cause of antibiotic-associated diarrhea, it is estimated to account for 15% to 25% of all diarrheal episodes.2 No longer only associated with health care facilities, CDIs are an emerging threat in the community.

Arnab Ray, MD Gastroenterologist Ochsner Clinic New Orleans, Louisiana

Karla Rivera Rivera, MD Infectious Disease Fellow Ochsner Clinic New Orleans, Louisiana

extra health care costs annua ually. Yet, others have estimated the cost for CDI treatment to be as high as $4.9 billion in the acute acu care setting.10 Although once thought tho to be strictly an HAI, there is an increasing numb mber of community-acqu quired C. difficile infections ns (CaCDI). Some reports estimatee that t 30% to 40% of all CDI cas ases are CaCDI.11,12 Of note, Khanna na et al demonstrated that 22% of patie atients had no antibiotic exposure in the he 90 days before the onset of CaCDI.12

Epidemiology

Pathogenesis of Hypervirulent Strains

C. difficile is responsible for 12% of all HAIs in 10 geographically diverse states (Figure 1). This translated to an estimated 80,400 cases of hospital-onset infections.5,6 The Centers for Disease Control and Prevention (CDC) national and state HAI progress report estimated that there were 107,700 hospital-onset CDIs nationwide in 2011 (the most recently reported data from 2012 showed a 2% decline in reported cases).4 Once thought to have a low attributable mortality rate, recent data have estimated CDI mortality to be 6.9% at 30 days after diagnosis and 16.7% at 1 year.6 The infection accounts for approximately 14,000 deaths annually, and there was a 400% increase in CDI-related deaths from 2000 to 2007, with most deaths occurring in older individuals.7,8 It is estimated that half of all CDIs occur in people younger than age 65 years. However, 90% of CDI-related deaths occur in those who are 65 and older. Furthermore, about 25% show initial symptoms in the hospital versus 75% in nursing homes, doctors’ offices, and clinics; hence, 94% of all CDIs are linked to medical care.8 Not only is this a concern for patient safety, it is also a concern for health care costs nationwide, which indirectly affect patient care. Scott demonstrated an average attributable per-patient cost of $9,124 for CDI, higher than catheter-associated urinary tract infections, which occurred at a higher rate at the time of the study.9 This translates to approximately $1 billion in

As the rates of CDI increased in 2000, the North American Pulsed Field type 1 strain (NAP1), or PCR ribotype 027 emerged; this strain was responsible for the Pittsburgh, Atlanta, and Montreal CDI outbreaks.2 This strain has increased production of the classic A (enterotoxin; 16-fold) and B (cytotoxin; 23-fold) toxins, and also an additional binary toxin currently under study; the latter is associated with a more severe diarrheal illness. It is also inherently resistant to fluoroquinolone (FQ) antibiotics, likely secondary to their increasing and widespread use. Although FQs are not recommended for the treatment of CDI, their use is an important epidemiologic risk factor for the spread within health care facilities. Metronidazole (various) is the current recommended choice for mild to moderate disease and those with NAP1 infections see high failure rates,13 thought to be secondary to the severity of the disease, low concentration levels in the fecal material, and poor tolerance. The NAP1 or ribotype 027 strains were associated with an increase in recurrences and a more complicated clinical course, therefore higher morbidity and mortality rates.14 Another strain sharing hypervirulence is C. difficile PCR ribotype 078. Keel et al demonstrated that this was the most commonly isolated strain in swine and calves.15 Also frequently found in meat products, ribotype 078 is a possible risk factor for animal-to-human transmission, as well as a source for CaCDI.15 In the

United State States, ribotype pe 078 is reported to be the third most com mmonly isolated strain in CaCDI.16 It sharees toxin A and B production as well as a binar nary toxin. In general, CaCDI may prese esent with a more severe infection; patients ar are less likely to receive antibiotics and more likely to be younger and have a greate ter proportion of PCR ribotype 078 than those with CDI acquired in a hospital setting.17 More vigilance is required to detect these cases in the community which may not present with the traditional predisposing factors.

Risk Factors As the leading cause of HAIs, there is a need for understanding risk factors associated with CDI. The CDC has confirmed advanced age (≥65) and antibiotic exposure as risk factors for CDI and CaCDI primary and recurrent infections.8 Multiple meta-analyses have confirmed older age, continued antibiotic exposure, and concomitant use of H2 blockers and proton pump inhibitors (PPIs) as risk factors for recurrent CDI as well as comorbid conditions, previous CDI recurrence, CDI acquired in the hospital setting, and prolonged hospital LOS.18 Although it is generally agreed that exposure to certain antibiotics (particularly FQs) increases the risk for CDIs, there has been some conflicting data as to what classes of drugs yield the greatest risk. Goorhuis et al, for example, found FQ treatment to be an independent risk

factor for CDI due to ribotype 078. Ribotype 027 also had

h had therap apy.14 Howe use of tetra to lower risk isk for CDI,18 Keessen et al found that clindamycin (various) exposure was also a major risk factor, in add addition to exposure to cephalosporin cephalosporins and FQs, specifically for CDI due to ribotype 078.19 Yet another study showed that in addition to the aforementioned risk factors, hospital LOS was a risk factor for colonization with C. difficile leading to CDI.20 Additional studies have highlighted treatment with PPIs as a novel risk factor for CaCDI in military active duty personnel (this study also revealed higher morbidity and mortality rates among older individuals plus those once considered low-risk groups for CaCDI, including community dwellers, pregnant women, and children).21

Treatment Approaches In general, strategies for treatment should be tailored according to the patient’s age and underlying comorbidities (Table 1).

GAST ROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

FDA A-Approved Options Mettronidazole and Vancomycin Metronidazole is a nitroimidazole w broad activity against anaerobic with baacteria, including C. difficile. It is curreently recommended as the drug of ch hoice for mild to moderate CDI.22 Vancomycin is a glycopeptide that is V noot absorbed when given orally. Vancoomycin is currently recommended for th he first episode of moderate to severe CD DI or in cases of metronidazole therapyy failure or potentially life-threatening CDI. C 22 Although early studies demonstrated A sim milar efficacy between the 2 agents,23 studies since 2004 have shown an increeased rate of treatment failures associateed with metronidazole (16%-38%), wheereas vancomycin failures remained thee same (1%-6%).24 Zar et al was the first study to compare the drugs the directly, in a prospective manner, in tthe treatment of C. difficile-associat iated diarrhea (CDAD). Among the pa patients with mild CDAD, tre reatment with metronidazole or va vancomycin resulted in clinical cure in n 90% and 98% of the patients, respectiv tively (P P=0.36). The

critical results from this study were that among the patients with severe CDAD, clinical cure was 76% for metronidazole and 97% for vancomycin (P=0.02). P Recurrence rates were similar (15% and 14%) between the 2 groups.24 Oral metronidazole is completely absorbed in the gastrointestinal tract but fecal penetration is poor, leading to low luminal concentrations (range 0.8-24 mcg/g; the susceptible range is 0.2-2.0 mcg/mL). IV metronidazole also has been shown inferior (P<0.001) to both oral metronidazole and oral vancomycin.25 Fidaxomicin Fidaxomicin (FDX; Dificid, Cubist) is the most recent CDI treatment to receive FDA approval. It is a macrocyclic antibiotic that is highly active against C. difficile (MIC90, 0.25 mcg/mL), including the epidemic strain. Results from 8 in vitro studies comprising 1,323 C. difficile isolates showed the minimum inhibitory concentration (MIC) range of FDX to be greater than 0.001 to 1 mcg/mL, with a MIC90 of 0.5 mcg/mL. No resistant isolate has been reported, although a single strain was recovered from a cured patient who had

an elevated MIC of 16 mcg/mL at the time of recurrence.26 In the pivotal trial of FDX versus vancomycin, clinical cure rates were similar and FDX was noninferior to vancomycin (92.1% and 89.8%, respectively). However, patients treated with FDX had lower recurrence (13.3% vs 27 24%; P=0.004). P Additionally, data from the 2 Phase III trials showed that FDX, when administered concomitantly with other antibiotics, has a higher cure rate (46 of 51 [90.2%]) than vancomycin (33 of 45 [73.3%]; P P=0.031) and that overall treatment with FDX compared with vancomycin was associated with lower recur28 rence rates (16.9% vs 29.2%; P=0.048). P The lower recurrence rates associated with FDX may be due to the drug’s ability to preserve the normal gut microbiome and completely resolve the underlying CDI pathogen, or both. A randomized clinical trial assessed the microflora-sparing properties of FDX by examining fecal samples for quantitative cultures for C. difficile and cytotoxin B fecal filtrate concentrations against normal microbiota. FDX and vancomycin rapidly killed C. difficile and neutralized toxin; however, FDX preserved the microbiome during and after CDI treatment.27

Barrier precautions and environmental cleaning STOP ACQUISITION OF TOXIGENIC C. DIFFICILE STRAIN (ingestion of spores)

UNNECESSARY ANTIMICROBIAL USE ACQUISITION OF C. DIFFICILE

C. DIFFICILE E INFECTION (community-acquired)

ASYMPTOMATIC C. DIFFICILE COLONIZATION

ANTIMICROBIALS (alter the gut microbiome)

HOSPITALIZATION

Vaccines (if risk factors), monoclonal antibodies

Restore gut flora or colonize with nontoxigenic C. difficile ANTIBIOTIC TREATMENT (minimize disruption of gut flora) +/• Vaccines (boost immunity) • Monoclonal antibodies (passive immunity) • Nontoxigenic C. difficile

Because results with currently available treatments have been suboptimal—with high rates of recurrence—new modalities and treatments have been pursued. Rifaximin Rifaximin (Xifaxan, Salix) is a semisynthetic derivative of rifamycin approved for the treatment of traveler’s diarrhea; it is also used off label for irritable bowel syndrome and hepatic encephalopathy. It has in vitro activity against aerobic and anaerobic gram-positive and gram-negative bacteria. After 3 days of therapy, the fecal level of the drug reaches 8,000 mcg/g.29 C. difficile resistance to rifampin (a surrogate for rifaximin) has been observed in several studies. The prevalence of rifampin resistance among 470 C. difficile isolates from a large teaching hospital was analyzed and was observed in 173 patients (36.8%), including 167 of 205 (81.5%) with epidemic clone (BI/NAP1) isolates (P<0.001). Of 8 patients who were exposed to rifamycin, 7 had rifampin-resistant C. difficile compared with 166 of 462 unexposed patients (relative risk, 2.4).30 In an open-label trial, 8 of 13 enrolled patients received rifaximin; all patients reported symptom resolution; 7 had no relapse at follow-up (median 162 days).31 Overall, more attention has been given to use of rifaximin as a “chaser” rather than as first-line therapy. In one study, for example, patients were given rifaximin versus placebo immediately after finishing standard anti-CDI antibiotics. CDI recurrence was lower in the rifaximin arm 32 versus placebo (15% vs 31%; P=0.11). P A randomized placebo-controlled trial testing the hypothesis that rifaximin given in a decreasing dose over 4 weeks after successful CDI treatment will reduce relapse is currently ongoing. Nitazoxanide

CDI (mild, moderate, severe; first episode, recurrence)

FECAL MICROBIOTA TRANSPLANTATION

Figure 1. Overview of the current hospital epidemiology and management strategies to prevent and treat CDI. CDI, Clostridium difficile Adapted from Gerding DN, Johnson S. Management of Clostridium difficile infection: thinking inside and outside the box. Clin Infect Dis. 2010;51(11):1306-1313.

Other Options

Nitazoxanide (NTZ) is a synthetic nitrothiazole benzamide approved for the treatment of Cryptosporidium and Giardiaa species. It has excellent in vitro activity against C. difficile with an MIC90 of 0.125 mcg/mL. A prospective, randomized, double-blind study compared NTZ (7 and 10 days) with metronidazole (10 days) in hospitalized patients with C. difficile colitis. Response rate at 1 month for metronidazole was 57.6% compared with 65.8% (7 days) and 74.3% (10 days; P=0.34) for NTZ.33 P In another study, patients who had failed metronidazole treatment were given NTZ; 74% responded, although 7 later had recurrent disease (54% cure rate). Three who initially failed and 1 who had recurrent disease were retreated with NTZ and responded, yielding an see C. diff, page 6

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

C. diff continued from page 5

aggregate cure rate of 66% in this difficult-to-treat patient population.34 No clinical trials are currently ongoing. Tigecycline Tigecycline (Tygacil, Pfizer) has activity against a broad spectrum of grampositive and gram-negative aerobes and anaerobes, including C. difficile (MIC90 of 0.06-0.25 mcg/mL).35 Multiple case reports and small case series using IV tigecycline as adjunctive therapy to other treatment options for severe, refractory CDI in critically ill patients have reported some success. A prospective clinical trial assessing the safety of tigecycline added to standard oral therapy (vancomycin or metronidazole) was completed recently and results are pending.

New Drugs in Development LFF571 LFF571 (Novartis) is a novel semisynthetic thiopeptide antibiotic with potent activity against a variety of grampositive pathogens, including C. difficile. In a hamster model, LFF571 was more efficacious and had fewer recurrences than vancomycin.36 A study investigating

the safety and pharmacokinetics of single- and multiple-ascending oral doses in healthy individuals reported that the drug was generally safe and well tolerated.37 A Phase II study of the safety and efficacy of multiple daily dosing of oral LFF571 in patients with moderate CDIs was completed recently and data are pending. Surotomycin Surotomycin (CB-183,315, Cubist) is an orally available lipopeptide antibiotic that is structurally related to daptomycin.38 Surotomycin has shown good potency against C. difficile isolates (including 027/NAP1/BI isolates) as well as those with high MICs to metronidazole, moxifloxacin, and vancomycin. It lacks activity against Enterobacteriaceae and species of the Bacteroides group (MIC90 >8,192 mcg/mL); this suggests that this compound will minimize disruption and lead to rapid recovery of the normal gut flora.39,40 Surotomycin has successfully completed a Phase II trial in patients with CDI. It also showed better sustained cure rates than vancomycin as well as reduction and delay in recurrence (17% for surotomycin vs 36% vancomycin) of CDAD episodes.38 Phase III trials are ongoing.

SMT 19969 SMT 19969 (Summit) is a bis-benzimidazole tetrahydrate compound that has demonstrated potent activity against C. difficile isolates with MIC90 values 2-, 8-, and 16-fold lower than FDX, metronidazole, and vancomycin, respectively. SMT 19969 has shown limited activity against gram-positive and gram-negative anaerobes, including Bacteroides species, Bifidobacterium species, and others (with the exception of Clostridia). This suggests that SMT 19969 would have minimal disruption in the gut flora and preservation of the normal gut microbiome.41,42 SMT 19969 was safe and well tolerated at all dosages in the recent Phase I trial.41 A Phase II trial is ongoing. Cadazolid Cadazolid (CDZ; ACT-179811, Actelion) is a new quinolonyl-oxazolidinone with structural elements of the oxazolidinone as well as the quinolone class. It is a strong inhibitor of C. difficile protein synthesis that leads to the suppression of toxin and spore formation. A recent study showed CDZ was active against all (including linezolidand moxifloxacin-resistant) C. difficile strains (MIC90 0.125, range 0.03-0.25 mg/L). The CDZ geometric mean MIC

Table 1. Treatment Options for Clostridium difficile Infection FDA-Approved

Off-Label Options

New Drugs in Development

Biotherapeutics

Metronidazole

Rifaximin (Xifaxan, Salix)

LFF571 (Novartis)

Fecal microbiota transplantation

Vancomycin

Nitazoxanide

Surotomycin (CB-183,315, Cubist)

VP20621 (ViroPharma)

Fidaxomicin (Dificid, Cubist)

Tigecycline (Tygacil, Pfizer)

SMT 19969 (Summit)

Probiotics

Cadazolid (ACT-179811, Actelion) Oritavancin (LY333328, The Medicines Company) Cholate meta-benzene sulfonic derivative

Table 2. Clostridium difficile Vaccines and Immunologics Product

Antigen

Formulation

Clinical Trials

ACAM-CDIFF Vaccine (Sanofi Pasteur)

Formalin inactivated toxins A and B from VPI 10463

± Alum-adjuvant IM injections 0, 7, and 28-30

Phase I volunteer safety and immune response Phase II for CDI Phase II for CDI prevention (ongoing)

Intercell IC84 Vaccine

Recombinant fusion protein of toxin A and B binding regions

± Aluminum salt adjuvant IM injection days 0, 7, and 21

Phase I volunteer safety and immune response

Clostridium difficile vaccine (Pfizer)

Molecularly and chemically inactivated toxins A and B

Vaccine with or without unnamed adjuvant, 3 ascending doses

Phase I volunteer safety and immune response

Monoclonal antibodies: MK-6072 and MK-3415A (Merck)

Monoclonals targeting toxin-binding epitopes

Human monoclonal antibody IV

Two Phase III clinical trials

CDI, Clostridium difficile infection

was 152-, 16-, 9-, and 7-fold lower than those of moxifloxacin, linezolid, metronidazole, and vancomycin, respectively. CDZ levels persisted at 50- to 100-fold supra MIC for 14 days after dosing. Inhibition of gut microflora was limited with the exception of bifidobacteria; Bacteroides fragiliss group and Lactobacilluss species counts were not affected.43 In Phase I trials, CDZ was well tolerated and systemic exposure was low. Most of the compound was recovered unchanged in the feces, resulting in high concentrations in the colon.44 A Phase II study evaluated the efficacy, safety, and tolerability of CDZ in patients with CDAD. The results of this study indicate that the cure rates for all twice-daily doses of CDZ (76.5% [250 mg]; 80% [500 mg]; 68.4% [1,000 mg]) were similar to or better than those for vancomycin (68.2%). Recurrence rates were lower for all twicedaily doses of CDZ (18.2% [250 mg]; 25% [500 mg]; 22.2% [1,000 mg]) compared with vancomycin (50%).45 Phase III clinical trials are underway. Oritavancin Oritavancin (ORI; LY333328, The Medicines Company) is a lipoglycopeptide with activity against C. difficile. In vitro, it was found to be at least 4-fold more potent than vancomycin against C. difficile strains tested.46 When tested for the treatment of PCR ribotype 027 in a human gut model, it was found that both ORI and vancomycin were effective in treating CDI, but only ORI appeared active against spore forms of C. difficile. Overall, ORI therapy may be more effective in treating CDI than vancomycin because it may prevent recrudescence of C. difficile spores.47 In a simulated CDI human gut model, Chilton et al demonstrated that ORI short-course therapy (4-day) might be an effective CDI treatment.48 More recently this same group showed that ORI might adhere to spores, potentially causing early inhibition of germinated cells and preventing subsequent vegetative outgrowth and spore recovery. Again, this may prevent some recurrences of CDI that are due to germination of residual spores after antibiotic therapy.49 Despite all the information thus far available, no clinical trials are ongoing. CamSA Cholate meta-benzene sulfonic derivative (CamSA) is a bile salt analog that inhibits C. difficile spore germination in vitro. Howerton et al infected mice with massive inocula of C. difficile spores and treated them with different concentrations of CamSA. A single 50-mg/kg dose of CamSA prevented CDI without any toxicity. This is a novel approach see C. diff, page 8

TURNING RESEARCH INTO RECOVERY — FASTER.

At Houston Methodist, our physicians are committed to translational and multidisciplinary research to directly beneﬁt our patients. Through more than 700 clinical studies at Houston Methodist, including national studies we exclusively offer in Texas, we are discovering new technologies and treatments for some of medicine’s toughest challenges. And we’re getting them to our patients — faster. Visit houstonmethodist.org/ri and explore all the ways we’re leading medicine.

CANCER • CARDIOLOGY & HEART SURGERY • DIABETES GERIATRICS • GYNECOLOGY • NEPHROLOGY • NEUROLO OGY & NEUROSURGERY • ORTHOPEDICS • PULMONOLOGY • UROLOGY

continued from page 6

and would add to the treatment of CDI without compromising the microbiota in these patients.50 CamSA’s in vitro stability, distribution, and cytotoxicity are currently being characterized. Monoclonal Antibodies MK-3415A (Merck) is a combination of monoclonal antibodies (mAbs) to C. difficile toxin A (MK-3415) and toxin B (MK-6072). A Phase II study showed favorable results when C. difficile human mAbs were administered to patients with C. difficile infection after being treated with metronidazole or vancomycin. This clinical trial showed significant reduction in the rate of recurrence of C. difficile among patients treated with the mAbs (7% vs 25%; P<0.001). The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P=0.06); P among patients with more than one previous episode of CDI, recurrence rates were 7% and 38%, 51 respectively (P=0.006). P Phase III trials are ongoing.

Biotherapeutics Fecal Microbiota Transplantation There has been a lot of attention surrounding the success of fecal microbiota transplantation (FMT) in the treatment of recurrent CDI. To date, numerous studies have shown superior efficacy of FMT over traditional antibiotics. The landmark study published by van Nood et al randomized patients with recurrent CDI to FMT via nasoduodenal infusion, vancomycin, and vancomycin with bowel lavage. The study was halted at interim analysis because the FMT arm showed a superior success rate (81%) compared with the vancomycin (31%) and vancomycin with bowel lavage arms (23%). Two of the 3 treatment failures in the FMT arm resolved with a second infusion from a different donor, bringing the overall success rate to 93.75%.52 This is consistent with meta-analyses of the success rate of FMT for CDI worldwide, which is 91%, regardless of the route of administration.53 Additionally, after the donor-feces infusion, patients showed an increased fecal bacterial diversity very much similar to the donors (Figure 2). In 8 patients from whom samples were available, the diversity of fecal microbiota could not be distinguished from that of the donors during the follow-up period.52 Although concerns have been raised regarding the safety of FMT, numerous literature reviews have reported no serious adverse events (AEs) or infectious transmissions directly attributable to

FMT.54 There are, however, legitimate concerns regarding the safety of FMT in patients with compromised immune systems. Immunocompromised patients seem to be at increased risk for developing recurrent CDI due to repeated antibiotic treatment, prolonged hospital LOS, and decreased ability to eradicate the infection. A multicenter retrospective study of FMT in 75 immunocompromised adults found similar efficacy (89%) to other studies and no infectious complications directly attributable to FMT, with follow-up to 11 months. Patients included were solid organ transplants, HIV/AIDS, patients undergoing chemotherapy, and those receiving immunosuppressive treatment for inflammatory bowel disease.55 Cost is also an issue with FMT. An analysis of FMT versus vancomycin for recurrent CDI found that FMT had an incremental cost-effectiveness ratio of $17,016 relative to vancomycin. More specifically, FMT via colonoscopy was felt to be the most cost-effective route of administration compared with duodenal infusion or enema.56 FMT has proven to be safe and efficacious, but it remains a time-consuming and nonstandard process. Although the major gastrointestinal societies and the Infectious Diseases Society of America released a joint statement on donor screening guidelines in July 2013, the recommendations are not evidence-based.57 Finding and screening a donor can be a time-consuming, expensive, and embarrassing process for the patient. In the inpatient setting with a critically ill patient, there is not always time to properly identify and screen a donor. Multiple techniques have been developed to try to work around these inherent difficulties in an attempt to standardize and speed up treatment, including frozen stool protocols and open-access stool banks. In frozen stool protocols, donor stool is blended, filtered, and then processed with glycerol before freezing at –80°C for later usage. Before use in FMT, the frozen slurry is thawed in an ice bath. A series of 43 patients treated with the frozen protocol showed an 86% treatment success rate, but it should be noted that 30% of the patients had underlying inflammatory bowel disease.58 More recently, Youngster et al conducted an open-label, randomized, controlled pilot study using frozen inoculum from unrelated donors.59 Overall cure rate was 90% at 8 weeks. North York General Hospital in Toronto, Canada, has begun offering patients the option to bank their own stool before hospital admission in the event they become infected with hospital-acquired CDI. This approach offers the advantages

250 Simpson’s Reciprocal Index

C. diff

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

200

150

100

0 Donors

Patients before Patients after infusion infusion

Figure 2. Microbial diversity in patients before and after infusion of donor feces compared with diversity in healthy donors. Adapted from reference 52.

of not requiring a donor or screening testing. This program is a pilot study and no efficacy data are available yet.60 OpenBiome, meanwhile, is a nonprofit “stool bank” developed at Massachusetts Institute of Technology in Cambridge. A selected few “healthy donors” have undergone extensive screening for common infectious diseases beyond the consensus screening guidelines, and serially collected and frozen the stool, making it commercially available for hospitals. Anecdotal reports thus far have been positive, and data collection is currently underway to publish safety and efficacy data. There is concern from the FDA regarding oversight and regulation of stool banks, although OpenBiome operates under an institutional review board. The ultimate goal is to remove the “fecal” from FMT, and this may be accomplished via stool substitute transplant therapy. Queen’s University in Canada has successfully reproduced 33 purified intestinal bacterial cultures under anaerobic conditions into a synthetic mixture, which was then instilled into the colons of 2 patients with recurrent CDI due to a hypervirulent ribotype 078 strain. Both patients had resumption of normal bowel habits within 3 days with durability of cure at 6 months.61 The “holy grail” of FMT is to develop a pill that would reconstitute the colonic microbiome and eradicate C. difficile. Louie presented a pilot series of 31 patients treated with 24 to 34 pills of fecally derived bacteria covered in gelatin to survive gastric acid and deliver the

contents to the colon; 30 of 31 patients enrolled were cured with no significant AEs noted.62 VP20621 VP20621 (ViroPharma), spores of nontoxigenic C. difficile (NTCD) strain M3, have been shown to be protective against challenge with toxigenic strains in hamsters.63 Human administration and colonization by VP20621 may prevent primary CDI or recurrent CDI. Phase I clinical safety testing was completed in 2010. Healthy adults received single or multiple doses of an oral suspension of VP20621 or placebo. All doses were well tolerated, and no serious AEs were reported and no discontinuation due to AEs occurred. Participants did not experience diarrhea or change in bowel habits. Persistent colonization with VP20621 was detected in stools on days 21 to 28 in 44% of participants. VP20621 was able to colonize the gastrointestinal tracts of those pretreated with vancomycin.64 A Phase II clinical trial in recurrent CDI is underway. Probiotics A Cochrane meta-analysis of 31 randomized studies and 4,492 participants concluded that taking probiotics with antibiotics reduced the risk for developing CDAD by 64%. The use of probiotics appeared to be safe and effective in patients who were not immunocompromised.65 There are a number of clinical trials currently ongoing to determine the role of probiotics in the prevention of CDI and/or CDI recurrence.

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Vaccines

References

The only currently available antibody treatment for CDI is pooled intravenous immunoglobulin (IVIG); IVIG preparations contain neutralizing levels of IgG antibody to toxin A and B. To date, no studies have provided conclusive evidence for any clinical benefit of IVIG. Active immunization rather than passive is appealing, as this would confer durable protection against CDI. Vaccines for CDI have been in development for more than 2 decades. Torres et al showed that a formalin-inactivated C. difficile culture filtrate protected hamsters when given by nasal, intraperitoneal, and subcutaneous routes.66 Currently there are 3 vaccines in clinical development. ACAM-CDIFF (Sanofi-Pasteur) is a mixture of formalin-inactivated toxin A and B that is given 3 times IM. The vaccine has been shown to be safe, well tolerated, and immunogenic in healthy adults. Phase II trials have been completed in the therapeutic setting and additional trials in the prophylactic setting are ongoing. Due to the fact that the vaccine addresses an important unmet medical need, ACAM-CDIFF has been fasttracked by the FDA.67 A second injectable vaccine, IC84, is a subunit recombinant protein vaccine consisting of 2 truncated toxins A and B from C. difficile. IC84 has undergone Phase I safety and immunogenicity testing in volunteer subjects and also has been shown to be highly immunogenic in elderly subjects.68 In addition, a vaccine derived from molecularly and chemically inactivated toxins A and B is currently undergoing Phase I clinical trials.

Conclusion

12.

The incidence of CDI has increased dramatically over the past 2 decades and we have seen the emergence of epidemic strains with new resistance patterns, which have resulted in high morbidity and mortality. Despite the treatment advances in recent years, several challenges are still present: appropriate treatment of severe complicated/fulminant CDI; the management of CDI recurrence; proper management of repeat episodes and the BI/ NAP1/027 strain; and, lastly, the role of vaccines, immunologics, and other biotherapeutics. The use of biotherapeutics to restore normal flora seems a novel and successful approach. There is a great need to continue to explore and develop new agents in the antimicrobial arena that spare the normal flora and perhaps most of all, avoid using antimicrobials altogether, whenever possible.

6. 7.

10. 11.

13. 14. 15. 16. 17. 18.

19.

20.

21. 22.

Centers for Disease Control and Prevention. MMWR quickstats: rates of Clostridium difficilee infection among hospitalized patients aged >65 years by age group—National Hospital Discharge Survey, United States, 1996-2009. CDC. 2011;60(34):1153-1185. Centers for Disease Control and Prevention. Clostridium difficilee FAQs (online). http://www.cdc.gov/HAI/organisms/ cdiff/Cdiff_faqs_HCP.html. Accessed July 1, 2014. Virginia Department of Health. Clostridium difficilee (C. difficile) infections. http:// www.vdh.virginia.gov/epidemiology/surveillance/hai/cdiff.htm#Citation2. Arnold K, Avery L, Bennett R, et al. National and state healthcare-associated infections progress report. http://www. cdc.gov/HAI/pdfs/progress-report/haiprogress-report.pdf. Magill SS, Edwards JR, Bamberg W, et al. N Engl J Med. 2014:370(13): 1198-1208. Dubberke ER. Infect Control Hosp Epidemiol. 2014;35(6):628-645. Centers for Disease Control and Prevention. Investigating Clostridium difficile infections across the US—emerging infections program—healthcare-associated infections community interface activity. http://www.cdc.gov/hai/eip/pdf/ Cdiff-factsheet.pdf. Centers for Disease Control and Prevention. CDC vitalsigns. http://www.cdc. gov/vitalsigns/pdf/2012-03-vitalsigns.pdf. Scott RD. The direct medical costs of healthcare-associated infections in US hospitals and the benefits of prevention. http://www.cdc.gov/hai/pdfs/hai/ scott_costpaper.pdf. Dubberke ER, Olsen MA. Clin Infect Dis. 2012;55(suppl 2):S88-S92. Leffler DA, Lamont JT. Am J Gastroenterol. 2012;107(1):96-98. Khanna S, Pardi DS, Aronson SL, et al. Am J Gastroenterol. 2012;107(1):89-95. Kuijper EJ, Wilcox MH. Clin Infect Dis. 2008;47(1):63-65. See I, Mu Y, Cohen J, et al. Clin Infect Dis. 2014;58(10):1394-1400. Keel K, Brazier JS, Post KW, et al. J Clin Microbiol.l 2007;45(6):1963-1964. Goorhuis A, Debast S, van Leengoed L, et al. J Clin Microbiol. 2008;46(3):1157. Rupnik M, Widmer A, Zimmermann O, et al. J Clin Microbiol. 2008;46(6):2146. Brown KA, Khanafer N, Daneman N, et al. Antimicrob Agents Chemother. 2013;57(5):2326-2332. Keessen E, Hensgens M, Spigaglia P. Antimicrob Resist Infect Control. 2013;2:14. Eyre DW, Walker AS, Wyllie D, et al. Clin Infect Dis. 2012;55(suppl 2):S77-S87. Gutiérrez R, Riddle M, Porter K. BMC Infect Dis. 2013;13:609. Cohen SH, Gerding DN, Johnson S, et al. Infect Control Hosp Epidemiol.

2010;31(5):431-455. 23. Teasley DG, Gerding DN, Olson MM, et al. Lancet. 1983;2(8358):1043-1046. 24. Zar FA, Bakkanagari SR, Moorthi KM, et al. Clin Infect Dis. 2007;45(3):302-307. 25. Wenisch C, Parschalk B, Hasenhündl M, et al. Clin Infect Dis. 1996;22(5):813-818. 26. Goldstein EJ, Citron DM, Tyrrell KL, et al. Antimicrob Agents Chemother. 2013;57(10):4872-4876. 27. Louie TJ, Miller MA, Mullane KM, et al. N Engl J Med. d 2011;364(5):422-431. 28. Mullane KM, Miller MA, Weiss K, et al. Clin Infect Dis. 2011;53(5):440-447. 29. Adachi JA, DuPont HL. Clin Infect Dis. 2006;42(4):541-547. 30. Curry SR, Marsh JW, Shutt KA, et al. Clin Infect Dis. 2009;48(4):425-429. 31. Rubin DT, Sohi S, Glathar M, et al. Gastroenterol Res Pract. 2011;2011:106978. 32. Garey KW, Ghantoji SS, Shah DN, et al. J Antimicrob Chemother. 2011;66(12):2850-2855. 33. Musher DM, Logan N, Bressler AM, et al. Clin Infect Dis. 2009;48(4):e41-e46. 34. Musher DM, Logan N, Mehendiratta V, et al. J Antimicrob Chemother. 2007;59(4):705-710. 35. Hecht DW, Galang MA, Sambol SP, et al. Antimicrob Agents Chemother. 2007;51(8):2716-2719. 36. Trzasko A, Leeds JA, Praestgaard J, et al. Antimicrob Agents Chemother. 2012;56(8):4459-4462. 37. Ting LS, Praestgaard J, Grunenberg N, et al. Antimicrob Agents Chemother. 2012;56(11):5946-5951. 38. Mascio CT, Chesnel L, Thorne G, et al. Antimicrob Agents Chemother. 2014;58(7):3976-3982. 39. Citron DM, Tyrrell KL, Merriam CV, et al. Antimicrob Agents Chemother. 2012;56(3):1613-1615. 40. Chilton CH, Crowther GS, Todhunter SL, et al. J Antimicrob Chemother. 2014 May 9. [Epub ahead of print]. 41. Vickers R, Robinson N, Best E, et al. Presented at the 53rdd Interscience Conference Antimicrobial Agents and Chemotherapy. Denver, CO: September 10-13, 2013. Abstract F-626. 42. Vickers R, Tinsley J, Storer R, et al. Presented at the 51st Interscience Conference Antimicrobial Agents and Chemotherapy. Chicago, IL: September 17-20, 2011. Abstract B-1194. 43. Chilton CH, Crowther GS, Baines SD, et al. J Antimicrob Chemother. 2014;69(3):697-705. 44. Baldoni D, Gutierrez M, Timmer W, et al. J Antimicrob Chemother. 2014;69(3):706-714. 45. Locher HH, Seiler P, Chen X, et al. Antimicrob Agents Chemother. 2014;58(2):892-900. 46. O’Connor R, Baines SD, Freeman J, et al. J Antimicrob Chemother. 2008;62(4):762-765.

47. Baines SD, O’Connor R, Saxton K, et al. J Antimicrob Chemother. 2008;62(5):1078-1085. 48. Chilton CH, Freeman J, Crowther GS, et al. J Antimicrob Chemother. 2012;67(10):2434-2437. 49. Chilton CH, Freeman J, Baines SD, et al. J Antimicrob Chemother. 2013;68(9):2078-2082. 50. Howerton A, Patra M, Abel-Santos E. J Infect Dis. 2013;207(10):1498-1504. 51. Lowy I, Molrine DC, Leav BA, et al. N Engl J Med. d 2010;362(3):197-205. 52. van Nood E, Vrieze A, Nieuwdorp M, et al. N Engl J Med. d 2013;368(5):407-415. 53. Brandt LJ, Aroniadis OC, Mellow M, et al. Am J Gastroenterol.l 2012;107(7):1079-1087. 54. Kassam Z, Lee CH, Yuan Y, et al. Am J Gastroenterol.l 2013;108(4):500-508. 55. Kelly CR, Ihunnah C, Fischer M, et al. Am J Gastroenterol.l 2014 Jun 3. [Epub ahead of print]. 56. Konijeti GG, Sauk J, Shrime MG, Gupta M, et al. Clin Infect Dis. 2014;58(11):1507-1514. 57. ACG, AGA, ASGE, IDSA, NASPGHAN. Current consensus guidance on donor screening and stool testing for FMT. http://www.gastro.org/research/ Joint_Society_FMT_Guidance.pdf. 58. Hamilton MJ, Weingarden AR, Unno T, Khoruts A, Sadowsky MJ. Gut Microbes. 2013;4(2):125-135. 59. Youngster I, Sauk J, Pindar C, et al. Clin Infect Dis. 2014;58(11):1515-1522. 60. North York General Hospital. Spotlight on research: Sumit Raybardhan, infectious diseases pharmacy practitioner. http://www.nygh.on.ca/Default. aspx?cid=2492&lang=1. Accessed July 1, 2014. 61. Petrof EO, Khoruts A. Gastroenterology. 2014;146(6):1573-1582. 62. Louie T, Cannon K, O’Grady H, et al. Presented at IDWeek; October 2-6, 2013; San Francisco, CA. Abstract 89. 63. Merrigan MM, Sambol SP, Johnson S, et al. Int J Antimicrob Agents. 2009; 33(suppl 1):S46-S50. 64. Villano SA, Seiberling M, Tatarowicz W, et al. Antimicrob Agents Chemother. 2012;56(10):5224-5229. 65. Goldenberg JZ, Ma SS, Saxton JD, et al. Cochrane Database Syst Rev. 2013;5:CD006095. 66. Torres JF, Lyerly DM, Hill JE, Monath TP. Infect Immun. 1995;63(12):4619-4627. 67. Leuzzi R, Adamo R, Scarselli M. Hum Vaccin Immunother. 2014;10(6):1466-1477. 68. Valneva website. http://www.valneva. com/?page=85. Accessed June 28, 2014. Drs. Ray and Rivera Rivera reported no relevant financial conflicts of interest. Dr. Garcia-Diaz has received grant and/or research support for pharmaceutical trials from Astellas, Cubist, GlaxoSmithKline, and Sanofi-Aventis, and serves on the speakers’ bureau at Astellas.

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Vegetarian Diet Linked to Lower CRC Risk Eating fish, but not red meat, most beneficial

utting meat from one’s diet may reduce the risk for colorectal cancer (CRC) by about 20% compared with regular meat eaters, new research shows. The findings, from a population study of more than 77,600 people, suggest that a vegetarian diet, or a diet that includes protein from fish rather than red meat, provides at least some protection against CRC, although the size of the effect varies significantly. But the latest results should come with a side order of caution. The magnitude of the benefit is rather small and the participants belong to a religious group that abstains from the use of alcohol and tobacco, meaning extrapolation to the general population might be difficult. Still, the researchers said their findings could be broadly applicable. “If such associations are causal, they may be important for primary prevention of colorectal cancers,” said study leader Michael J. Orlich, MD, a public health researcher at Loma Linda University, in Loma Linda, Calif., in a statement. “The evidence in this … article that vegetarian diets similar to those of our study participants may be associated with a reduced risk of colorectal cancer should also be considered carefully in making dietary choices and in giving dietary guidance.”

They then divided the study population into five groups based on the nature of their diet: meat eaters and four “vegetarian” categories, including vegans—generally no animal proteins; vegetarians who ate eggs and dairy; pesco-vegetarians who ate fish occasionally but no other meats; and those who ate mostly vegetables but consumed meat or fish less than once a week. Vegetarians as a group had a 22% lower

risk for developing CRC than did meat eaters—19% lower for colon cancer and 29% lower for rectal cancer—according to the researchers. Within the vegetarian group, the effect was greatest for pescovegetarians, who had 43% lower risk for developing CRC than did meat eaters, a reduction the Loma Linda researchers called “noteworthy and interesting.” “The strength of this association

Now available! The ALL NEW

FREE iPad App Explore the features of the new app on your iPad.

Previous Data Inconsistent The new study joins a conflicting chorus of data on the effects of vegetarianism on the risk for CRC. A 2009 study from the United Kingdom found that vegetarians had a 50% greater risk for CRC than meat eaters ((Am J Clin Nutr 89:1620S-1626S). However, that finding evaporated in a larger follow-up analysis (Br J Cancerr 2009;101:192-197). More recently, Korean investigators reported that meat eaters are at roughly 50% higher risk for developing colorectal adenomas, and nearly a threefold greater risk for developing advanced adenomas compared with vegetarians (Dig Dis Sci 2014;59:1025-1035). Dr. Orlich’s group published its findings online in JAMA Internal Medicine. The research comes from the ongoing Adventist Health Study 2, which recruited more than 96,000 men and women from that church across the country between 2002 and 2007. The latest analysis included 77,659 participants, followed for a mean of about seven years. Using state cancer registries and, when necessary, phone interviews with study participants, the researchers identified 490 cases of CRC, for a rate of 86 cases per 100,000 people—much higher than the national average of about 44 per 100,000.

Three ways to download: 1. Go to the iTunes App Store and search for Gastroenterology & Endoscopy News. 2. Go to gastroendonews.com/apps and click on the “Available on the App Store” icon. 3. Scan this QR code with your iPad and download the App from iTunes.

Read the #1 gastroenterology publication. Anytime. Anywhere.

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

suggests that future analysis by fish and long-chain omega-3 fatty acid consumption may be beneficial,” they wrote. “Such analysis may elucidate whether the reduced risk seen in the pesco-vegetarian group is attributable to fish consumption or to other aspects of the diet.” “A vegetarian diet defined as a diet which does include fish did appear to be associated with the lowest risk for colorectal cancer,” said Andrew T. Chan, MD, of the Division of Gastroenterology at Massachusetts General Hospital and Harvard Medical School, in Boston. “This is intriguing data

and would support studies which show that fish may also have an independent beneficial effect on carcinogenesis. This may be mediated by its content of omega-3 fatty acids, which are hypothesized to have an anti-inflammatory effect.” Dr. Chan, a co-author of a recent review in Gastroenterologyy on the link between diet and colorectal cancer (2015 Jan 6. [Epub ahead of print]), praised the Loma Linda study for its methodology, particularly in its use of a more flexible definition of “vegetarianism.” “These categories are very reasonable

given that very few individuals are absolute in their diets. In addition, a strength of the study was that the investigators did not rely on individuals self-identifying themselves as ‘vegetarian,’ a term which means different things to different people,” Dr. Chan said. “Instead, they used surveys of the actual dietary patterns provided by the individuals to make these classifications. This approach is less prone to bias.” The researchers said they plan to take a closer look at how particular foods might affect CRC risk. —Adam Marcus

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

No Cost continued from page 1

Maimonides had a few reasons for initiating a no-cost colonoscopy program, explained Rabin Rahmani, MD, director of medical education and research in the Division of Gastroenterology of Maimonides and a co-author of the study. One was to raise awareness of the fact that most CRCs are preventable and/ or curable when caught in early stages. Another was to address the underuse of screening colonoscopy among Brooklyn

residents. “At the time, only about 35% to 40% of the borough’s eligible population were getting screened,” said Dr. Rahmani, who is also medical director at Gastroenterology Associates in Brooklyn. “Lack of insurance coverage is recognized as an impediment to screening colonoscopy, so we started this program.”

‘A Lot of Legwork’ Pays Off The hospital took a multipronged

approach to publicize the program throughout Brooklyn’s many diverse ethnic communities. “It takes a lot of legwork,” Dr. Rahmani said. “We were supported in our efforts by public service announcements in many media outlets,

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

The Independent Monthly Newspaper for Gastroenterologists

Real-World Data Mimic Trial Findings For HCV Treatment BOSTON—Drugs often fall short of the expectations set in clinical trials, because the trials often exclude patients with various comorbidities and the sickest of the sick. This does not seem to be the case with the latest generation of medications to treat hepatitis C virus (HCV) infection, which so far are meeting the high bar they set in pre-approval trials. see Real World, page 28

‘Normal’ Stomach On Endoscopy May Be Anything But Precautionary biopsies make sense PHILADELPHIA A—Nearly 30% of stomachs that appear to be normal during endoscopy in fact may have significant gastric pathology, according to a new study, which suggests that endoscopists may want to consider taking more biopsies as a precaution. see Biopsy, page 38

Falling Through the Cracks: Mothers With Hepatitis B Receive Inadequate Treatment, Follow-up

ore than on ne-third of women with the hepatitis B virus (HBV) are initially diagnoosed with the infection at their first prenatal care visit, but they do not receive follow-up care for the infection after their pregnaancy, researchers have found. The retrospective stud dy examined the medical records of 243 women with HBV who receiveed prenatal care at facilities under th he umbrella of Massachusetts Gen neral Hospital (MGH). “It’s clear from the data that these women are getting lostt to followup or not getting ap ppropriate care to begin with,” saaid Ruma Rajbhandari, MD, MPH, a gastroenterology and hepatology fellow at MGH H, in Boston, who led the sttudy. “It’s a real shame. It is siimilar to getting diagnosed with HIV and not receiving any follow-up care for it.”

The researchers presented theeir findings at the 2014 Liver Meetin ng of the American Association for th he Study of Liver Diseases (AAS SLD), in Boston (abstract 1552). In 1990, the Centers for Disease Control and Prevention created the U.S. Perinatal Hep patitis B Prevention Program (P PHBPP) in an effort too reduce perinatal trransmission of the disease. Under the P PHBPP, pregnantt women are rroutinely screened for H HBV and their inffants are treated an nd monitored approopriately. The prograam has resulted in a sharp reduction of p perinatal infections with HBV. see Hep B, page 36

I N S I D E

Are We There Yet? Women still feel gender disparities in pediatric gastroenterology

hen it comes to compensation, mentoring and promotions, women in pediatric gastroenterology believe they continue to lag behind their male peers, a new survey has found. see Disparities, page 24

-/Ê" Ê ÊÓä£{\Ê* ,/ÊÓ 8* ,/-½Ê* -Ê More of the Best of the American College of Gastroenterology annual meeting.................... «>}iÊ£{

Gary Lichtenstein, MD

*iÌiÀÊ }} Ã]Ê MD

Rajiv Chhabra, MD

PRINTER-FRIENDLY VERSION AVAI A LABLE AT A GASTROENDONEWS.COM

Now available! À> `Ê iÜÊ *>`Ê ««

OPT IN

EDUCATIONAL REVIEW

Hemorrhoids: Evaluation and Management for the Office-based Clinician ERIC FONTENOT, MD

to receive your free monthly e-Newsletter at www.gastroendonews.com

see insert at page 20

STEPHEN W. LANDRENEAU, MD

Louisiana State University School of Medicine Department of Medicine Section of Gastroenterology New Orleans, Louisiana

The authors report no relevant financial conflicts of interest.

Hemorrhoids: Evaluation and Management for the Office-based Clinician

he medical literature on hemorrhoidal disease dates back at least as far

as Hippocrates, who described techniques that will be familiar to practitioners even today. This article will cover the epidemiology,

Internal hemorrhoidal plexus

normal anatomy and physiology, pathophysiology, and classification of

Dentate line

hemorrhoids, with a particular focus

External hemorrhoidal plexus

on the office-based physician. Epidemiology Hemorrhoids are a common problem, estimated in a large epidemiologic study to have an overall prevalence of as much as 4.4% in the United States.1 Both sexes demonstrate a peak prevalence in the age range of 45 to 65 years, with increased rates associated with higher socioeconomic status.1 However, the true prevalence of hemorrhoidal disease may be underestimated because many patients do not seek medical attention, or overestimated because some patients erroneously attribute any anorectal problem to “hemorrhoids.”2

Anatomy The anal canal (Figure 1) consists of the approximately 4 cm between the distal rectum and the anal verge. In the approximate midpoint of the canal is the dentate line, an important anatomic landmark in the

Figure 1. Normal anorectal anatomy. Courtesy of Iain Cleator MD, Vancouver, BC, Canada

evaluation and treatment of hemorrhoidal disease. The dentate line represents the junction between the embryologic endoderm and ectoderm and is the point that the mucosa of the anal canal changes from the insensitive columnar epithelium of the rectum to the highly sensitive squamous epithelium of the anoderm. Found proximally to the dentate line, the internal hemorrhoids are a specialized collection of 3 fibrovascular “cushions” arranged in a left lateral, right anterior, and right posterior configuration.3 They are composed of an arteriovenous plexus where branches of the superior, middle, and, to a lesser extent, inferior hemorrhoidal

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • JA N UA RY 2 0 1 5

For iPad

and many elected officials spread the word to their constituents. We have a patient navigator who continuously gets word out into our communities and leads patients through the program, and a number of doctors who screen and follow up with the patients.” Insured patients are billed as usual. Those without insurance are assisted by Maimonides’ patient navigator and support staff to investigate whether or not they qualify for coverage under a government plan. All others are screened at no charge, and when clinical treatment for CRC is mandated, they receive that at no cost as well. During the five-year study period, the program’s gastroenterologists administered screening colonoscopy to 643 patients with an average age of 57 years. Adenomatous polyps were found in 29.3%, and seven patients (1.1%) had early-stage adenocarcinoma amenable to surgical resection. The study authors concluded that without access to this, many of these patients would have progressed to CRC or to later-stage and larger, possibly unresectable, colorectal tumors. Dr. Rahmani offered several explanations for why the prevalence of adenomas was higher than the national average in the no-cost colonoscopy patients. One is that the study population had a higher proportion of black and Asian patients than is typical for national studies. Those

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Containing Cost Anyone familiar with the expense of colonoscopy, particularly in New York, where the procedure costs at least $740 and can be more than 10 times that depending on the setting, may wonder how any medical facility can pull off nocost colonoscopy. The hospital shoulders the bulk of the cost, which varies from year to year depending on how many uninsured patients are screened and, if necessary, undergo CRC treatment. Maimonides “feels that it’s a worthwhile endeavor. We doctors volunteer our time so the patients don’t get billed,” Dr. Rahmani said. Sedation costs are minimized by using nurse-administered midazolam with meperidine or fentanyl. “When patients require more intensive anesthesia services, we file a special application through the anesthesia department and anesthesia services will waive the cost,” Dr. Rahmani said.

Beyond the program’s strategies for keeping it as affordable as possible up front, a study the center conducted after the program completed its second year suggested that an investment in free screening more than pays for itself ((Am J Gastroenteroll 2008;103:S405). “Based on the number of cancers we found and aggressive polyps that would have progressed to colorectal cancer, we calculated that for every $390 we spent,

we saved about $800,” Dr. Rahmani said. “Our thought at that time was that the government should cover screening colonoscopies at age of 50 for patients who will be Medicare-eligible at 65, because during that 15-year time period, a lot of people won’t get screened properly and will end up costing the government a lot more money.” —Monica J. Smith

CONTACT THE

EDITOR amarcus@ mcmahonmed.com

THRIVING IN A CHANGING HEALTH CARE DELIVERY SYSTEM THE PRACTICE MANAGEMENT CONFERENCE

LEARN KEYNOTE SPEAKERS CONGRESSMAN PHIL ROE, MD United States House of Representatives Tennessee District 1 G. ANTON DECKER MBBCH, MRCP, FACG, MHA, CPE President Mercy Health Physicians Cincinnati, OH JULIE MICHELLE DAWSON Power Negotiating Institute Santa Barbara, CA CHRISTOPHER A. HOLDEN President and CEO AmSurg Nashville, TN

ADAPT

THRIVE

Physicians are being faced with unprecedented changes in the health care delivery system. Moving from a payment model focused on fee-forservice to value-based payment will challenge GI practices to evaluate their current reimbursement landscape and adapt to multiple new approaches to stay viable in this changing health care delivery system. GI Outlook 2015 will provide you with the necessary tools and new approaches to help your GI practice easily adjust and be at the forefront of GI practices operating under this new paradigm in health care delivery. GO 2015 faculty will discuss the most pressing topics affecting GI practices in the coming years, including: • The value of physician services • New innovative payment delivery models • The importance of patient-centered care • The demonstration of value and quality of care • Approaches to assess your practice and market • Negotiation strategies: a core business skill for GI practices.

Register for GO 2015 and receive the tools and approaches necessary to stay viable – and thrive – in the changing health care delivery system.

AUGUST 7–9, 2015

FAIRMONT CHICAGO MILLENNIUM PARK | CHICAGO, IL CO-SPONSORED BY ASGE AND THE AGA INSTITUTE

EARLY REGISTRATION DISCOUNTS END JULY 9, 2015 | WWW.ASGE.ORG/GO2015

pop pulations tend to have a h higher incidence of adeenomas and CRC. The other is that these patients werre simply better preparred than patients outside the no-cost program. ““It’s such a comprehen nsive program, with a llot of patient support an nd phone calls to help theem make sure they’re dooing things right the first time,” Dr. Rahmaani said. “They’re deeply appreciative of th he fact that they’re geetting a necessary and heelpful test for free, so th hey’re very complian nt with preparation in nstructions.” Dr. Winawer, howeever, cautioned against rreading too much intoo the higher adenoma rate. “It is a retrospective study, and although it is a screenin ng study, one cannot be certai certain that the group did not have many symptomatic or high-risk patients. However, the people came in, and the [program] did uncover a lot of pathology, which is good.” He also noted that there are other nocost colonoscopy programs in a number of Manhattan hospitals and gastroenterology centers sponsored by the city’s Department of Health, the American Cancer Society and New York’s Citywide Colon Cancer Control Coalition.

ONE HE’S BEEN WAITING FOR IS HERE

One tablet contains ledipasvir and sofosbuvir

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Med Records as Advertising Medium? One Company Sees Big Business Opportunity

ow does a free electronic health record system (EHR) sound? How does it sound if the price of “free” is a periodic pop-up alert on behalf of a drug company, insurer or other customers? Practice Fusion, a startup EHR firm, gives away its software, charges no implementation fee and offers a no-cost

patient portal and other perks. In return, users receive real-time notifications that encourage them to speak with patients about vaccinations and other health services. The company, which has approximately 112,000 users and access to some 100 million patient records, says its product benefits patients. One example:

It recently partnered with the vaccines division of Merck to send alerts about inoculations to Practice Fusion customers. During a four-month study period, the alerts spurred a 73% increase in vaccinations, or some 25,000 additional inoculations, according to the Wall Street Journal. l (Merck, which declined to disclose how much it paid for the deal, told

• Recommended by Gastroenterologists 2X MORE than any other probiotic‡ • #1 Gastroenterologist-recommended probiotic 6 YEARS IN A ROW‡ Only Align contains the patented, pure strain Biﬁdobacterium infantis 35624, a probiotic strain that fortiﬁes the digestive system with healthy bacteria 24/7.§ * B. infantis 35624 is a unique, well-studied probiotic tic strain, with over 10 years of research and over 50 publications and abstracts. Although some store brands compare themselves to Align, none contain the same strain as Align.

Recommend Align with conﬁdence. ®

Visit pghealthsamples.com today for FREE samples! * These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. ‡ Among gastroenterologists who recommended a brand of probiotic in Symphony Health Solutions 2008–2013 surveys. §

With continued daily use.

PHC-13784

the newspaper it was so pleased with the results that it wanted to explore more opportunities.) Despite this success, not everyone is happy about the arrangement. According to the newspaper, some experts have questioned whether subsidized alerts might be improper incentives that fall on the wrong side of anti-kickback statutes. Other EHR vendors, including Epic Systems, offer pop-up alerts, although without the sponsorship arrangements. So too with gMed, which specializes in software systems for gastroenterologists. “We always think about the workflow of the physician or endoscopist, and how to effectively and safely speed their process up,” said Matthew Schreiber, vice president of sales and marketing for the Weston, Fla.-based firm. “Advertising pop-ups would both irritate them and slow them down.” Mr. Schreiber said gMed does provide users with alerts “to ensure the physician is aware of a particular critical item. Having a fully integrated system ensures this takes place in both the endoscopy center and/or the physician’s office, significantly increasing the relevance of the alert.” Mr. Schreiber said gMed has been approached by other companies seeking to advertise their products through clinical alerts. “Based on the frequency of these conversations, we believe it is a growing revenue stream for some companies in the industry,” he said. “gMed will continue to review these opportunities, and if there is one that is not intrusive in the workflow of the physician, and can truly contribute to a patient’s clinical outcome, we may engage in further conversations.” —Adam Marcus

Know the difference. Make a difference.

a potent probiotic medical food VSL#3 provides clinically proven beneﬁts in the dietary management of UC and an ileal pouch.Recognized by the ACG Practice Parameter Committee1 and the Cochrane Library2 as an effective tool for the management of pouchitis. VSL#3 adds billions of bacteria to the microbial barrier restoring balance and diversity in the GI tract.3 The research of the Human Microbiome Project [http://hmpdacc.org/] is investigating key links between human health and the balance of speciﬁc microbes in the human gut. Knowing the difference makes all the difference when it comes to probiotic health. References: 1. Kornblut A, et al. Am J Gastroenterol. 2004;99(7):1371-1385. 2. Holubar SD, et al. The Cochrane Library. 2010, Issue 6. 3. Gionchetti P, et al. Gastroenterology, 2000;119(2):305-309.

VSL#3 is a high potency probiotic medical food that must be used under medical supervision. Made in U.S.A. Distributed by Sigma-Tau Pharmaceuticals, Inc. Gaithersburg, M.D. ©2014 Sigma-Tau Pharmaceuticals. All rights reserved V1166 03/15

www.vsl3.com

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Plasma-Based Biopsies Can Help Guide Therapy

new type of blood biopsy tracks the evolving genetic fingerprint of a patient’s cancer by measuring circulating tumor DNA in plasma. The tool may be particularly beneficial for patients who cannot undergo conventional tissue biopsies. Guardant360 is one of nearly a dozen “liquid biopsy” assays now available or in development in the United States. In studies presented at oncology meetings in summer and fall 2014, researchers reported that Guardant360 accurately assesses the genomic profile of a tumor, using 54 clinically actionable genes. Oncologists can use this information to identify tumor-specific genomic alterations that can help drive treatment options.

colorectal cancer patients.” Dr. Kopetz has conducted research using Guardant360 and other blood-based assays but has not received funding from the makers of Guardant360 or other companies that develop similar tests. At MD Anderson, Dr. Kopetz uses the Guardant360 assay for patients with colorectal cancer in whom it is difficult to get tissue. “In these patients, we need to understand their KRAS S or NRAS S status to make decisions about treatment with monoclonal antibodies. We’ve used Guardant to understand whether patients have developed resistance to these antibodies and should no longer be receiving them.” It also is useful in patients with

‘For physicians who are looking to rapidly get results of KRAS, NRAS and BRAF for routine clinical decision making, this provides a very convenient and rapid assay that has been accepted by insurance companies.’ —Scott Kopetz, MD, PhD

Although such blood biopsies do not provide the details of hundreds of genes that a conventional biopsy can, and circulating tumor DNA is not detectable in about 5% to 15% of patients with advanced cancer, in selected patients genomic sequencing can aid clinical decision making and identify targeted therapies and experimental clinical trials suitable for patients. “I’ve been very impressed with the ability of the Guardant360 to provide rapid information on mutation status of over 50 genes as well as copy number information on several genes,” said Scott Kopetz, MD, PhD, associate professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, in Houston. “This is information that I’ve used to change the management of metastatic

amplifications of the MET T gene, said Dr. Kopetz. “These are things that occur later in treatment and are not present in the primary tumor. If we just rely on the archival tissue, we would not see this information and would not have been able to get these patients onto clinical trials based on these results.”

Validation Studies The assay has been validated in breast, lung, colorectal, skin and prostate cancers. It was formally launched in June 2014 after a series of clinical validation studies were presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO). In one of the studies, which was conducted by Guardant (abstract e22041), 86% of 300 patients evaluated had detectable somatic genomic alterations in

circulation, and the concordance of tumor biopsy–derived alterations and those in blood was 93% when tumor biopsies were taken concurrently with the blood draw. Another study, conducted at the John Wayne Cancer Institute, in Santa Monica, Calif., looked at the results of circulating tumor DNA analysis in 18 patients with metastatic melanoma (abstract 9018). Again, the circulating tumor DNA mutations detected matched those from paired metastatic tumor tissues resected after the blood draw. The mutations detected included well-known melanoma mutations, BRAF F and TP53, but also mutations that are more rare, such as CDKN2A, NRAS, PTEN, N NOTCHI, I EGFR R and JAK2. “This Thi is taking next-generation sequeencing to a whole new level by loooking at blood. Once you’ve id dentified that a patient has ccancer and you start treatment, yoou still need to follow treatmen nt response. This assay provides that m mechanism,” said investigator Dave S.B. Hoon, PhD, director of the M Molecular Oncology Department and Sequencing Center at the John Wayne Cancer Institute. “Liquid biopsies b have been around for deccades. Now, it’s taken to a whole neew level in terms of how it’s doone and the accuracy of it.” Dr. Hoon, who has been investigating the role of circulating tumor cells in n melanoma since the 1990s, also servees on the board of Guardant. Another study presented at A AS SCO (abstract 11093) assessed Gu uardant360 in patients with metastatic breast cancer. Eighteen women with locally ad dvanced or metastatic breast can ncer who failed standard therapies had plasma analyzed for apie alterations lterati in circulating tumor DNA. All women wo were found to have circulating tumor DNA, including alterations in TP53 (44%), PIK3CA A (44%), ALK (39%) and EGFR (28%). Based on the results, three women were continued on HER2-targeted therapy after circulating tumor DNA confirmed ERBB2 alteration or amplification. Two HER2negative women were started on HER2targeted therapy after tests revealed ERBB2 mutations. The test is not designed to diagnose cancer, said AmirAli Talasaz, PhD, Guardant’s president and chief technology officer. It’s intended to monitor the evolution of a tumor over time by measuring 18 actionable cancer-related genes and the “hot” exons of an additional 36 onco-tumor suppressor genes. In one patient, the test corrected

a misdiagnosis of pancreatic cancer, according to a poster presented at the 2014 annual meeting of the American Society of Human Genetics (abstract 3422S). The researchers, from the University of California, San Francisco Medical Center, doubted the accuracy of the patient’s initial pancreatic cancer diagnosis after the woman was referred to their facility. The team used a blood biopsy after a conventional biopsy failed to provide adequate tissue. The results, along with other tests, led to a diagnosis of ovarian cancer. “They started treating the patient [for] ovarian cancer with ... chemotherapy, and after three cycles of treatment the disease became resectable,” Dr. Talasaz said.

Obtaining Liquid Biopsy Results When using Guardant360, an oncologist submits two tubes of a patient’s blood, which are sequenced at Guardant’s CLIA-certified laboratory. Analysis identifies genomic alterations and associated treatment options, and a report is generated and reviewed by Guardant’s molecular tumor board before being sent to the oncologist within two weeks. The report does not recommend specific treatments. It quantitatively reports variants found in the blood, saying, for instance, “BRAF V600E mutation at 0.5% level.” The tumor board outlines any association between variants and treatments in publicly reported literature or experimental clinical trials. Dr. Kopetz said blood biopsies using circulating tumor DNA could be particularly helpful for community oncologists. “For physicians who are looking to rapidly get results of KRAS, NRAS S and BRAF F for routine clinical decision making, this provides a very convenient and rapid assay that has been accepted by insurance companies to allow treatment with cetuximab [Erbitux, Bristol-Myers Squibb] and panitumumab [Vectibix, Amgen],” he said. It also can help physicians who are considering referring patients to academic centers or signing patients up for clinical trials, he said. “This assay has been used to help decide whether or not there are particular therapies that may benefit a patient in a research setting. It may be that oncologists order this to help decide whether a trip out of state may be worthwhile for a patient.” Guardant360 lists at a price of $4,900. Oncologists and Guardant representatives said that insurance companies frequently cover the test in cases where genomic profiling is needed and conventional biopsy is not an option, although the review cycle takes many months. —Christina Frangou

A new generation has arrived. Introducing Fuse® Generation 2 FuseView™ 4K Ultra HD Viewing Experience | FuseBox® Advancements | C38s Slim Colonoscope | StrataFlex™ Technology

To schedule a Fuse demo, please email fuse@endochoice.com or call 888.682.3636 x5. EndoChoice.com/Fuse | FuseColonoscopy.org | FuseCases.com

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

How Long Is Too Long Between Su urveillance Colonoscopies? Frank G. Gress, MD

Sidney Winawer, MD

Professor of Medicine and Clinical Chief of the Division of Digestive & Liver Diseases at Columbia University Medical Center, in New York City

Professor of Med edicine at Weill Cornell Medical College and Paul Sherlock k Chair C in Medicine at Memorial Sloan-Kettering Cancer Cente nter, in New York City

Felice Schnoll-Sussman, MD

David Greenwald, MD

Associate Professor of Clinica nical Medicine at Weill Cornell Medical College Col and Director of the Jay ay M Monahan Center for Gastrointestinal nal Health at NewYorkPresbyteria yterian Medical Center, in New York City

Director of Endoscopy at the Henry Janowitz Division of Gastroenterology in the Samuel Bronfman Department of Medicine at the Mount Sinai Hospital, in New York City

Compiled and edited by Monica J. Smith

t the New York Society for Gastrointestinal Endoscopy’s annual course of 2014, Sidney Winawer, MD, gave a presentation on endoscopists’ adherence to guidelines for surveillance colonoscopy, which a survey suggests is overused by 40% of endoscopists. Dr.

Winawer s talk sparked lively participation from the audience during the question Winawer’s question-and-answer and answer panel that followed, but this discussion was limited by time constraints. Gastroenterology & Endoscopy

GEN: A meeting attendee commented that many of his colleagues, uncomfortable with the 10-year surveillance interval, call their patients back in five years. Would shortening surveillance ill intervals i t l to t five fi years in i low-risk l i k patients reduce the risk for interval cancers?

News invited experts to explore the issues further. GEN: Schoen and colleagues (Gastroenterologyy 2010;138:73-85) found that 25% of endoscopists recommended a repeat colonoscopy at five years for patients with no adenomas, and that 40% recommended follow-up at less than five years for patients with small adenomas. What are the drawbacks to bringing these patient populations back early? Are there any advantages? Dr. Gress: The main disadvantage is the increased cost to the health care system. Another drawback could be the additional risk that may be added to the patient having a more frequent screening interval. The only advantage I can see would be that more frequent screening might detect missed lesions earlier. There are still many gastroenterologists who want to see more data before changing their practice to a seven- or 10-year screening interval.

GEN: Conversely, 40% of the endoscopists surveyed recommended no colonoscopy within five years for patients with polyps considered at increased risk for becoming advanced adenomas—a dramatic

underutilization of surveillance colonoscopy. What might be the reasons for this? Are there any advantages? Dr. Gress: The authors mentioned in their discussion that it remains unclear why a significant number of individuals with advanced adenoma did not have the appropriate follow-up interval for surveillance. They postulated that it could be due to significant comorbidities or advanced age in these patients.

GEN: Adenoma detection rates (ADR) among endoscopists vary widely, and studies have reported a 20% miss rate. How can endoscopists be comfortable with a 10-year surveillance interval even in patients with no polypectomy? Dr. Gress: Data show that the optimal ADR is achieved by reaching the cecum and spending a minimum of six minutes on the way out, looking for polyps. The more time you spend looking, the more likely you’re going to find polyps. Also, there is a new endoscope system [FUSE, Endo Choice] that, based on some studies, yields a 60% ADR. This technology uses LED lighting and three viewing screens, providing a panoramic 330-degree field of view.

Dr. Winawer: Data indicate that most interval cancers occur early, in three years or less. So shifting from 10 years to five years is not really going to help avoid interval cancers. But I missed a great opportunity when that question came up. When we first started doing colonoscopy with polypectomy and surveillance in the 1970s, the common practice was to bring patients back every year. Then National Polyp Study data demonstrated we could defer surveillance colonoscopy to three years, and further studies stratified patients into high- and low-risk and suggested we could put low-risk patients off for five years. Now, the latest guidelines say the risk for those patients is so low we can put them off for five to 10 years based on clinical judgment. So that question filled me with joy. The attendee said, ‘We’re uncomfortable with 10, we should see patients at five years.’ That statement, and the applause that followed, was beautiful. It told me that clinicians are getting comfortable with five years instead of the initial interval of one year and the more recent interval of three years. That’s a major change. It will take time to get comfortable shifting to 10 years in some of their patients.

GEN: With new technology, better bowel preparations, retroflexion and improved imaging, some endoscopists are achieving an ADR of 40% to 50%. How might this affect surveillance?

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Dr. Winawer: I think we need to be careful about this now. If you look at the data on new technology increasing ADR, the additional adenomas being found are very small. We will have to see what is being found in terms of pathology, the impact on reduction of colon cancer incidence and mortality, the increased cost of removing those polyps, the increased risk for polypectomy, and the burden of increased surveillance that will be created by finding more people with adenomas that may have little significance. New technology needs to focus on reducing interval cancers that arise from missed polyps, especially the large serrated proximal polyps.

GEN: If endoscopists are not using wellestablished guidelines to direct their surveillance decisions, what are they using? In what situations would you perform surveillance colonoscopy contrary to the guidelines? Dr. Winawer: Guidelines are really meant to assist clinicians in their judgment in practice. They certainly can deviate from the guidelines, but it’s important that they indicate in their note why they’ve deviated. There are many reasons for deviating, and I’ve done so a number of times myself over the years. For instance, a patient may have comorbidities that keep the clinician from feeling comfortable recommending a three- or five-year follow-up. But a clinician may recommend a shorter surveillance interval if he or she lacked confidence in the exam, whether due to a difficult colon, suboptimal preparation, or if the endoscopist wasn’t satisfied that the colon had been cleared of polyps or that a large polyp had not been completely removed.

GEN: The surveillance guidelines are long established and well known, yet many endoscopists call patients back much sooner. Will there be financial ramifications if adherence to surveillance is a quality measure taken into account by the Centers for Medicare & Medicaid Services (CMS) and other payors? Dr. Schnoll-Sussman: We’re at a juncture in medicine where physicians need both to comply with the rules and to prove that they are, and I do think that cost-conscious physicians especially will think twice about bringing someone back earlier. The reality is we have all seen interval cancers. We bring patients back out of concern. The motive is pure. Doctors are not bringing patients back early because they want to make more money. The problem is the guidelines are the only things CMS and other payors have to direct their decisions. Are the majority of people doing 10-year surveillance intervals? They’re not. Are there reasons for that? Of course. I do think there may be financial ramifications.

GEN: Do you think the emerging data showing a rise in young-onset colorectal cancer (CRC) should prompt a reassessment of screening colonoscopy in this population?

Dr. Schnoll-Sussman: First, 10% of CRC is diagnosed in people under the age of 50 years. A lot of these people have a family history, and the guidelines recommend that we start screening sooner in these patients. But patients don’t come to gastroenterologists if they are under 50. We are dependent on the gatekeepers—the gynecologists, internists and primary care physicians—to get this family history and refer patients appropriately. Part of this call to action is educating the gatekeepers. Second, doctors tend not to suspect CRC in people under 50, but patients with symptoms need to be sent for attention. A patient’s anemia may not have to do with her period, and rectal bleeding may not be due to hemorrhoids. Finally, most young-onset cancers are in the distal colon or rectum. If this trend of more early-onset CRC continues, one consideration may be to perform a flexible sigmoidoscopy at age 40. If we find something, we deal with it; if not, we hold off until they’re 50 for a colonoscopy. This could be cost-effective. Many family practitioners do flexible sigmoidoscopy, the preparation isn’t too bad, and it can usually be done without sedation.

GEN: The matter of screening based on age is controversial. The U.S. Multi-Society Task Force on Colorectal Cancer recommends decisions be individualized, but the risk for complications goes up with age. At what point should you stop screening older adults? Dr. Schnoll-Sussman: This is controversial because anytime you question whether someone deserves something based on age, it always feels like an age bias. When we look at the older population today, 75 now is what 60 used to look like. They are vibrant and active and look amazing. But sometimes, in these 75-year-olds who look amazing, when something bad happens, like a perforation, they look bad in a second. If something bad happens to a 50-year-old, they can undergo surgery and bounce back. But with the 75-year-old, the subtleties of their age start to show. With these patients, I always consider how they will cope if something bad happens. A patient who’s reached 75 has probably already had two or three colonoscopies, and if they have no family history of colon cancer or personal history of polyps, the chance of their getting cancer is extremely low. If they have a family history and have had polyps, you are doing them a service considering colonoscopy. But you also have to consider longevity. Do you think this patient will live to 85, and is colonoscopy worth the risk?

GEN: More than 23 million people in the United States currently are unscreened. Would better adherence to surveillance guidelines shift resources and foster greater uptake of CRC screening and diagnosis? Dr. Greenwald: Surveillance intervals for colonoscopy exist to guide practitioners in the management of patients found to have colorectal polyps on previous examinations. Some have suggested that more surveillance exams are being done than are necessary, and that resources being used for these surveillance

exams could be redirected toward screening the currently unscreened. Adherence to surveillance guidelines is important in its own right, as guidelines were developed using the best available evidence concerning the time of progression from “normal” tissue to adenoma to carcinoma. All practitioners should be familiar with surveillance guidelines and adhere to them. Whether increased adherence to surveillance guidelines would lead to an increase in resources available for screening is not clear. Most important, however, is to use whatever resources are available to reach the unscreened populations and try to engage them in proper screening, starting with an accurate assessment of the specific barriers to screening and then working toward solutions to overcome those barriers.

GEN: Does expanded consent—informing patients that colonoscopy is not perfect and cancer might still happen—protect the endoscopist if a lawsuit should arise in the case of an interval cancer? Dr. Greenwald: Consent is a process, not simply words on a piece of paper. Consent for colonoscopy between a caregiver and a patient is the sum total of all the interactions that occur in preparation for that planned procedure. Disclosure of the risks, benefits and alternatives for a procedure comprises the essential portion of informed consent for a colonoscopy. Many practitioners have chosen to include the words “missed lesions” in their consent process, recognizing studies that have shown “miss rates” during colonoscopy. Such an acknowledgment during the consent process will not necessarily protect an endoscopist in the case of a lawsuit if an interval cancer is detected, but it does indicate that the provider is informing the patient that colonoscopy is associated with a known and welldescribed miss rate. Endoscopists should strive to always perform highquality exams; one way to demonstrate that is for the colonoscopist to meet quality benchmarks such as cecal intubation rates and adenoma detection rates.

GEN: What are the strongest arguments or evidence an endoscopist can present in court to defend himself or herself when brought to trial for missed cancers? Dr. Greenwald: It is crucial that practitioners always perform high-quality exams. Metrics to define high-quality colonoscopic exams have been developed and validated. These include measures such as cecal intubation rates and ADR. The strongest defense for a gastroenterologist in a lawsuit is always that the procedure was done for an indicated reason, that the procedure was performed in accordance with the standard of care, and if a complication occurs, that it was recognized as quickly as is reasonable and treated appropriately. In the case of a missed cancer, endoscopists are best prepared to defend themselves if they can show that they consistently perform procedures that are indicated and that they consistently perform them in a high-quality way. One way to do that is to participate in a quality registry, regularly submit data on all their procedures and assess their performance against recognized quality benchmarks.

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Rectal Cancer:

What’s Optimal Timing for Surgery After Radiation? SAN FRANCISCO—Although an interval up to 75 days between radiation and surgery may achieve higher rates of pathologic complete response (pCR), a delay of more than 60 days from radiation to surgical resection decreases overall survival in patients with rectal cancer, according to data presented at the 2015 Gastrointestinal Cancers Symposium (abstract 510). “In patients with locally advanced rectal cancer, there was a significant difference in complete pathologic response, positive margin status and survival before and after 60 days’ interval between radiation and surgery,” said Jonathan C. Salo, MD, a surgical oncologist at the Levine Cancer Institute at Carolinas Medical Center, in Charlotte, N.C. “A radiation–surgery [R-S] interval of less than 60 days was associated with greater eater overall survival than an interval of greater than 60 days.” The optimal timing of surgery relative to the conclusion of neoadjuvant therapy has been ambiguous, according to Dr. Salo, who presented the reesults of the retrospective study that was led by Ciara R. Huntington, MD, a general surgeon at Carolinas Medicaal Center. “Other studies have shown that in treeatment of locally advanced rectal adenocarcinoma, an increased time interval of six to 12 weeks frrom the end of radiation therapy to surgery maay increase the rate of pCR,” Dr. Salo said. “Butt the optimal time interval with respect to survival has not been established. This study evaluated the impact of time delay on overall mortality.” The National Cancer Data Base was queried for patients with adenocarcinoma of the rectum and no evidence of metastasis at diagnosis, who underwent preoperative chemoradiation followed by radicall surgical resection from January 2004 through h December 2006. The cohort consisted of 6,805 patients, who generally were treated with low anterior resection (57.3%), colon-anal reanastomosis (8.4%) or abdominoperineal resection (28.4%). They had a median survival of 66.6 months..

Dr. Salo outlined the following findings: • Overall survival was equivalent in groups with R-S interval less than 60 days. • Overall survival was shorter for a R-S interval of more than 60 days compared with less than 60 days (hazard ratio, 1.25). • The pCR rate increased up to 75 days after radiation, and did not increase further thereafter (P=0.0003). • Positive surgical margins occurred at equivalent rates for all groups of R-S interval less than 60 days. • Positive surgical margin rate increased after 60 days following radiation (P=0.0067).

“There was a significant relationship between radiation–surgery interval and complete pathologic response [P=0.0002],” P he emphasized. “Additionally, a radiation–surgery interval of more than 60 days was associated with 20% greater risk for mortality. This effect became more pronounced with increasing intervals; an interval of greater than 75 days was associated with 28% increased risk of mortality, while patients with an interval of less than 60 days saw a survival benefit,” he said. Other significant predictors of survival were age, surgical margins, cormorbidity index, time to discharge after surgery, pathologic staging, surgical volume and patient income (P<0.05 for all values). Nancy Kemeny, MD, an attending physician at Memorial Sl Sloan-Kettering Cancer Center and professor of med dicine at Weill Cornell Medical College, both in New w York City, noted several limitations of the study: Th he data could be outdated due to improvements in chem motherapy and surgery; some patient- and treatment-rellated specifics were lacking or not reported; and the oveerall pCR rate of 6.8% is lower than most current reports r (12%-28%). How wever, Dr. Kemeny added that the large retroospective analysis “has given support to the con ncept that a longer interval from the end oof chemoradiation to surgery is necessary to increase the chance of complete response, but waiting more than 60 days decreases overall survival.” Although it may take time to develop a complete response, in the absence of a tumor response, these longer intervals may actually be harmful, she said. “An increased time delay could facilitate local tumor growth and metastasis, enhance ffibrosis, and delay the resumption of postop perative chemotherapy,” Dr. Kemeny said, sugggesting that the optimal strategy might be “meaasuring response more frequently.” —Chase Doyle Drs. Salo and Kemeny reported no relevant financial conflicts of interest.

New Code Set for Transoral Fundoplication Procedure he American Medical Association (AMA) has created a new identification code for a transoral incisionless fundoplication procedure for reconstruction of a defective gastroesophageal valve. The Category I Current Procedural Terminology (CPT) code, 432XX1, will enable physicians to effectively communicate information to payors about the procedure, which is used to treat patients with chronic gastroesophageal reflux disease (GERD). The application for the new code was jointly sponsored by

four specialty medical societies: the American Gastroenterological Association, the American College of Gastroenterology, the American Society for Gastrointestinal Endoscopy and the Society of American Gastrointestinal and Endoscopic Surgeons. “AMA’s CPT editorial panel’s decision to add this Category I code in 2016 is significant, as it enables health care providers better access to coding and payment structures in the U.S. than are currently available,” said Philip Macdonald, vice president of

Healthcare Economics, Policy, and Reimbursement at EndoGastric Solutions, in a statement. “This not only increases procedure choice for physicians but expands patient access for new technology for GERD patients.” EndoGastric Solutions markets EsophyX for the GERD procedure, as does Medigus, maker of the MUSE device. The Summary of Panel Actions is preliminary. New and revised code descriptions may be further refined

prior to implementation, scheduled for Jan. 1, 2016, according to the press release. —Paul Bufano

GaviLyt y e-H

GASTROENTEROLOGY & END DOSCOPY NEWS • APRIL 2015

Scope continued from page 1

of at least 40% among patients ents who develop bloodstream infections ns with the microb obe. b Be Before the latest outb utbreak, which h offi officials say exposed as many as 179 patients nts at Ronald Reagan Medical Me Center to infection and as many as 67 more at nearbyy Cedars-Sinai C Medical Center er, infections had been attributab able to lapses in adherencee to t cleaning protocols, which includ ude manual washing and nd brushing in detergent followed by h high-level disinfectioon. The latter may be done using an au utomatic endoscop pe reprocessor or ethylene oxide gas. But th he recent infection ons—the latest reported March 4 at Cedars--Sinai— occurreed without any known reprocessing slip-ups,, casting doubt on the disinfection protocols themselves. In mid-March, USA Todayy reported that thee scopes involvved in CRE outbreaks since 2013 underwen nt decontamin nation by automated endoscope reprocessors rs (AERs). The FDA has been reviewing the machines,, which are rated to destroy 99.9999% of bacteria on scop pes, for more than a year, according to the newspaper, butt only recently asked th he manufacturers of the devices for fo new data on their effect ctiveness. Craig Smi mith, senior vice president of regulatory affairs and quality assurance assuurance for Cantel M Medical, the parent Me company of AER AER manufacturer er Medivato divators, said id the FDA conta ontacted his firm m recently recen ntly with a reques request est st fo for seven specific ific items. “What the he FDA F is wondering is, is have man anufacturers of AERs ERs that have been cleared for or several years done era ne any anything to revalidate scopes that are new ne to the market? mark Many of these scope reprocessors were re cleared in the 1990s, and even longer ago, and there have been a lot of technological changes to scopes since then.” Medivators has had “an ongoing validation program in place since before 1999,” Mr. Smith added. As for the safety of duodenoscopes, Mr. Smith said, “I think that perhaps everyone acknowledges that the elevator wire channel is complex. If you have a scope that is not in good clinical condition and you don’t follow the manufacturer’s guidelines for pre-cleaning and disinfecting, I think everyone knows you could have problems.” Mr. Smith said data from his company show that about 90% of duodenoscopes in use in the United States es undergo an AER cycle. The outbreak has triggered at least two lawsuits ag against Olympus. It also has prompted a flurry of reaction ons from

governm government health agencies. In early 2014, following a 2013 CRE E outbreak ou traced to a contaminated duodenoscope at an Illinois nois hospital, the FDA asked the three duodenoscope manufact facturers Olympus, Pentax and Fujifilm to submit results of te tests of theirr duodenoscope-cleaning duodeno protocols, the Reuterss news ws agency reported. report The FDA concluded that the tests w were either improperly improper conducted or the disinfection ction protoccols failed, but the age gency did not report these findings. Af news of the Caliifornia infections broke After ke in February ry, the FDA issued a new safety alert that d duodenoscop opes, by their design n, may be difficult to clean an and therefor ore prone to infecttion. The report mentioned that t the duode denoscope’s elevvator, which moves up and dow wn to maneuve ver instrumen ents near the bile and pancreatic ic ducts, contai ains micros oscopic crevices that brush bristles may not be abl ble to rea each. Despite concerns over efficacy of manufacturer ers’ cl cleaning guidelines, the FDA recommended adhering ngg to them. Furthermore, e, reports rep have stated that the FDA had not approved onee of o the he scopes in question, Olympus’ most recent mode del TJF-Q1 Q180V; in fact, Olympus put in its 501(k) last year at the ag agency’s request, CNN reported.

‘We’re concerned about whether culturing the tip of the scope and having a negative culture truly means that that scope is not contaminated. Traditionally, a negative culture means that nothing continued to grow out on the culture, but that doesn’t mean that there isn’t some CRE on the scope.’ —Neil Gupta, MD, MPH

On March 4, the he F FDA updated its earlier safety coomm munication to address ss this issue: “At this time, FD DA has no evidence that thee lack of a 510(k) clearance was h w aassociated with the infectio ions,” according to the agen ncy.

Infections were associated with d duodenoscopes from all three manufacturers, not just thee unapproved Olympus model, the update said. The FDA A said it would not pull the scopes from the market out off concern that doing so would risk creating a duodenoscop pe shortage. The FDA, which has rejected d recalling the scopes, revisited the issue on March 12. In n a “final guidance,” the agency said it will require scope makers m to demonstrate that reusable devices can be safelyy cleaned before it will approve new instruments. The poolicy does not apply to scopes already on the market, how wever. Officials also sought to reassu ure clinicians and the public about the safety of the scop pes. “Despite the recent concerns about multidrug-resistaant bacteria infections associated with duodenoscopes, p patients and health care providers should know that the risk of acquiring an infection from a reprocessed medical d device is low,” said William Maisel, MD, MPH, chief sciientist at FDA’s Center li for or Devices and Radiological Heaalth. Meanwhile, the Centers for Disease Control and M Preven vention (CDC) has released an a interim protocol for facilities ies that at want to test their scop pes for evidence of contaminatio tion. on. Writing on the agenccy’s blog, Michael Bell, MD, de depu puty director of CDC DC’s Division D of Healthcare Quali ality Pro romotion, said: “Thiss is is not a replacement for ong ngoing train ining and oversight to to ensure that cleaning an nd disinfectioon steps are all perffor ormed correctly. But it might be a wayy to t detect contamiinat ation, whether due to lack of adherencee to manufacturerr-rec ecommended reprocessing practices ices or any other reason r on, and to prompt follow-up up act action to protect patients if needed.” n

How Practices Are Testing H For Bacterial Activity The endoscopy department at Brigham m and Women’s Hospital, in Boston, has added a steep to its cleaning c protocol for duodenoscopes. After manuually clean ning the scopes, they now use a device to check for adenosin ne triphosphate (ATP) activity, which is a sign of livve bacteriia, before moving on to automatic reprocessingg, said Joohn Saltzman, MD, the hospital’s director of end doscopy. Iff ATP activity is found “you can keep processing tthe scope to t see if you’ve manually cleaned out everything th hat can be detected. This strategy has not been proven yet,” D Dr. Saltzm man continued. “There’s no data [telling] us that th hat necessarily adds anything more to what we have been d doing.” see Scope, page 28

FDA’s Recommendatio ons forr Facilities and Staaff That Repro rocess ERCP Duoden nosccopes Follow closely all manufacturer instructions for cleaning and processing.

Follow these additional general best practices:

• The FDA recommends adherence to general endoscope reprocessing guidelines and re reprocessing prac actices established by the infection tion control community and endoscopy y professionals. In addition, it is important to follow specific reprocessing instructions in the manufacturer’s labeling for each device.

risk k for infection. Deviations from the manufacturer’s instructions th for reprocessing may contribute to contamination. The benefit of using cleaning accessories not specified in the manufacturer’s instructions, such as channel flushing aids, brushes, and ne cleaning eaning agents, is not known.

• Meticulously clean the e elevator mechanism and the rec cesses surrounding the elevato or mecha or mechanism by hand, even when en using an automated endoscope e reprocessor (AER). Raise and low ower the elevator throughout the manual cleaning process to allow brushing of both sides.

• Report rt problems with repro reprocessing the device evice to the ma manufacturer and to the FDA.

• Implement a comprehensive quality control program for reprocessing duodenoscopes. Your reprocessing program should include written procedures for monitoring training and

• Even though duodenoscopes are inherently difficult to reprocess, strict adherence to the manufacturer’s reprocessing instructions will minimize the

adherence to th he prrogram, and documentation of equipment e tests, processe tests processes and a quality monitors used du uring the reprocessing procedu ure. • Refer to the Multisociety M Guideline on Repro rocessing Flexible Gastrointes testinal Endoscopes: 2011 consensus con document ffor evidence-based recommendations for endoscope reprocessing.

H E M OS TA S I S

Case closed. To complete any endoscopic clipping procedure, you need a clip with a tight grip that won’t buckle under pressure. You need Instinct. Its distinctive anchoring tips improve your tissue grasping capability while the ed jaws give you added extra-thick, nitinol reinforced stability. This is the kind of strength and security that leads to the outcomes you expect. hanced patient care. Trust your instincts for enhanced

Instinct

™

ENDOSCOPIC HEMOCLIP

www.cookmedical.com

Image courtesy of Shou Jiang Tang, MD, University of Mississippi Medical Center, Jackson, MS.

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

VDZ continued from page 1

“This study is groundbreaking,” said Ellen Scherl, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease and professor of clinical medicine at Weill Cornell Medical College, in New York City. “A Mayo Clinic study suggested that if you have more than one immunosuppressant—whether it be corticosteroids, a biologic or an immunomodulator—you are likely to have an immune-compromised

state with infections or serious adverse infections [Gastroenterologyy 2008;134:929936]. This research showed that two therapies did not increase the likelihood of infection,” Dr. Scherl said. To investigate the rates of infection adverse events and infection serious adverse events, researchers evaluated data on GEMINI I and II patients who received 300 mg of VDZ in the induction phase and throughout the maintenance phase. The cohort included 1,434 patients: 445 who received VDZ

monotherapy, 506 who received VDZ and corticosteroids at baseline, 247 who received VDZ and baseline immunomodulators, and 236 who received VDZ and both therapies concomitantly. “For each subgroup, the percentages of patients who experienced an infection [adverse event or serious adverse event] were calculated, and then time-adjusted incidence rates were determined,” said Edward V. Loftus Jr., MD, professor of medicine and director of the Inflammatory Bowel Disease Interest Group in

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

www.CMEZone.com

Release Date: February 10, 2014

Expiration Date: August 11, 2015

Chair

Statement of Need

Intended Audience

William D. Chey, MD

Probiotics can be powerful tools in managing a number of medical conditions. However, efficacy may be suboptimal if these agents are not used appropriately. As public interest in the benefits of probiotics increases, so does the need for clinical education. Many physicians and patients are unfamiliar with the nuances of probiotic pharmacology, or—with many probiotics available for over-the-counter purchase— may not be aware that their patients are selecting ineffective therapies. Thus, it is important for health care professionals to familiarize themselves with the latest research data on probiotic use.

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

Professor of Internal Medicine Director, Gastrointestinal Physiology Laboratory Co-Director, Michigan Bowel Control Program H. Marvin Pollard Institute Scholar Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

Faculty Brooks Cash, MD Professor of Medicine Division of Gastroenterology University of South Alabama Mobile, Alabama

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

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

Learning Objectives Upon completion of this activity, the participant will be better prepared to do the following: 1 Review key diﬀerentiating characteristics of various probiotic therapies, including mechanism of action. 2 Describe the importance of strain speciﬁcity in the clinical applicability of probiotic therapies.

Estimated Time for Completion 1 hour

Course Format Monograph

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

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

3 Discuss the role of probiotic therapy in clinical digestive ailments. 4 Review strategies for appropriate patient selection and education in the use of probiotic therapies.

Jointly sponsored by AKH Inc. and Applied Clinical Education

Supported via an educational grant from Procter & Gamble

Distributed via CMEZone and Gastroenterology and Endoscopy News

the Division of Gastroenterology and Hepatology at Mayo Clinic, in Rochester, Minn. He presented the research at the 2014 annual meeting of the American College of Gastroenterology (abstract 16). All four groups were fairly well matched with respect to mean age, prevalence of narcotic use, mean albumin levels, mean body weight, mean disease duration, baseline activity scores and extent of disease, according to the researchers. “Overall, roughly 42% to 45% of patients experienced at least one infection” adverse event, Dr. Loftus said. “But among the four groups, there was no signal of an increased rate of infection AEs in patients on combination therapy” compared with those on VDZ monotherapy. This finding persisted when the researchers looked at individual infections, such as nasopharyngitis, sinusitis, upper respiratory tract infection, bronchitis and urinary tract infections. The researchers found no increase in infection events in the combination group over time; rates remained the same between the two groups. Regarding serious infections—those significant enough to result in hospitalization, require IV therapy or have the potential to cause disability or death— the rate was again similar across the four groups, at 3% to 5%, Dr. Loftus said. “When we look at individual [serious infections], there are no signals that they are more common in patients on combination therapy.” The same outcome was seen in the time-adjusted incidence rates. The rarity of serious infections was reassuring, but also was a limitation of the study. “It makes it harder to interpret the data because there just aren’t enough events occurring to compare across the groups,” Dr. Loftus said. However, he said, the data show that infection events in patients with UC or CD were similar whether vedolizumab was used as monotherapy or with other therapies. The reason for that similarity likely reflects the fact that although vedolizumab is administered systemically, it works topically, Dr. Scherl explained. “It blocks only the circulating white blood cells that are going to the intestine. It is not addressing white blood cells elsewhere, so it doesn’t compromise immunity,” she said. “VDZ allows all of the immune function of the lymphocytes in the body to stay intact except for the 1% of circulating lymphocytes targeting the gastrointestinal tract. So one would predict that, due to this topicalizing effect, there would be a lower infectious risk.” —Monica J. Smith Dr. Loftus receives research support from Takeda and other pharmaceutical companies. Takeda manufactures vedolizumab and sponsored the study.

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Managing Hereditary CRC Syndromes A thorough history, genetic testing and enhanced screening often can forestall advance of disease SAN FRANCISCO—Close screening and follow-up of patients with genetic predispositions to colorectal cancer syndromes have major implications for the prevention and treatment of these syndromes, according to findings presented at the 2015 Gastrointestinal Cancers Symposium. “Careful follow-up of family members when hereditary colorectal cancer syndromes are found makes the diagnosis cost-effective and can dramatically alter the natural history of the disease,” said C. Richard Boland, MD, chief of gastroenterology at Baylor University Medical Center, in Dallas. “With colonoscopies and some occasional extra surgery, [clinicians] can turn Lynch syndrome into a fairly ‘boring’ disease—without the big surprise of cancer.” Dr. Boland reported that the first step in evaluating familial clusters is determining whether it is a colonic or intestinal polyposis syndrome or one of the nonpolyposis syndromes. However, such classification is rarely as straightforward as it might sound. “There’s not a simple black line between polyposis and nonpolyposis,” Dr. Boland said. Focusing his presentation on two polyposis syndromes—familial adenomatous polyposis (FAP) and MutYHH associated polyposis (MAP)—as well as on the nonpolyposis Lynch syndrome, Dr. Boland explained that “classic polyposis is more than 100 polyps, and in the case of [FAP] and [MAP], they’re all adenomatous polyps.” But, he added, “attenuated forms of FAP and a lot of MAP [cases] have fewer than 100.” With Lynch syndrome, he said, generally patients have “about three polyps by age 30 and about six polyps by age 50, but there are often patients who have more than this.” FAP is caused by inactivating germline mutations in the APC C gene (Figure). Noting that APC C is a large gene, with 2,843 codons, Dr. Boland said, “Such a big target is an invitation for genetic trouble.” FAP is a systemic disease, with an associated likelihood of periampullary cancer somewhere between 5% and 8%. Patients can develop duodenal adenomas, which are true neoplasms and lead to cancer; fundic gland polyps, which are not neoplasms although they look like they are to many pathologists; desmoid tumors; as well as other forms of cancer. MAP is caused by mutations in MutYH, H a base-excision repair gene (Figure). “Mutations are usually missense,” Dr. Boland said, “and the mutations are dominated by founder mutations.” According to Dr. Boland,

the two most common mutations in the MutYH H gene for whites are a very inactive allele and a hypomorphic allele. The interaction between the two accounts for the heterogeneity of the syndrome. “A typical diagnostic strategy [for Europeans] is to look for these two mutations first,” he explained, “and if one of them is found, then … sequence the whole gene looking for the other. However,

if it’s not a European, then you probably have to ask for the whole gene to be sequenced,” he added, noting that “with next-[generation] techniques, that is probably going to [become] the standard.” Lynch syndrome is autosomal dominant and caused by a germline mutation in one of four DNA mismatch repair genes. “Almost all the tumors have

microsatellite instability (MSI),” he said, “and the tumors show absence of the expression of the mutating gene, so these are always inactivating mutations.” More than two-thirds of the cancers caused by Lynch syndrome occur in the proximal colon, but there’s an increased risk for other tumors, too, including endometrial, gastric and urinary tract tumors. see Hereditary, page 33

Endoscopy Report Writer gGastro is the only fully integrated procedure reporting platform that combines the attributes of an electronic health record and report writer in one easy-to-use solution. By providing previously documented information from the hospital EHR at the time of the procedure, your team can utilize and update critical existing patient information without duplicate entries, streamlining your operation and promoting safety. gGastro provides advanced tools to promote quality of

Integrate images, Export procedure report to primary EHR Diagnostic, Therapeutic, and Pediatric Endoscopy Advanced procedures (EUS, ERCP, Enteroscopy) Pulmonology (Bronchoscopy, Chest tube placement) Content Flexibility (Urology, Pain Management)

ity care and full compliance with hospitals and community se information exchanges required by Meaningful Use cal and Healthcare Reform. Through gGastro’s clinical an support and nursing documentation, your team can easily meet Meaningful Use Stage 2 requirements at the hospital and ambulatory surgery center.

To speak with a gMed Sales Representative, please contact: 888.577.8801 | salesteam@gmed.com

gMed.com

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Scope continued from page 24

St. Joseph’s/Candler Healthcare, in Savannah, Ga., also tests for ATP production, said Nicholas Costrini, MD, PhD, MBA, director of gastroenterology at the institution. If concerns about bacterial contamination remain after testing, staff may try to culture swabs from the device in question, Dr. Costrini said. Culturing Samples In response to the infections, Gastroenterology Associates of Laredo, Texas,

started culturing samples taken from the duodenoscope elevator, its channel and the fluid in the channel, to monitor bacterial exposure after each use, said Monte Allen, DO, one of the small practice’s two physicians. The clinic plans to continue culturing swabs from the scopes for the next six months, then assess the data. Dr. Allen said he and his colleagues do not keep their duodenoscopes out of use while awaiting culture results. ECRI Recommendations In culturing their duodenoscopes, the

Laredo practice is in line with recommendations from the ECRI Institute, a nonprofit health care standards organization. In early March, ECRI suggested that practices take swabs from each scope and culture them for 48 hours after reprocessing. Doing so takes duodenoscopes out of service for much longer than the hour or so that is typical for cleaning with an automatic reprocessor. One possible concern mentioned in the ECRI report about culturing duodenoscope samples for 48 hours before reusing the instruments is that practices might need to buy

The New GESAP VIII

The Next Level of Endoscopy Self-Assessment ASGEE is proud to introduce the new Gastrointestinal Endoscopy Self-Assessment Program VIII (GESAP VIII). The latest version of ASGE’s award-winning GESAP line Pro is bigger and better than ever, and continues the tradition of being your best resource for assessing endoscopy knowledge, preparing for certification exams and earning points for ABIM Maintenance of Certification (MOC).

Take a look at these NEW highlights from GESAP VIII:

One Online Resource that Does it All!

• More Content! – Additional peerreviewed questions, as well as numerous new videos and images

GESAP VIIII is an online product that delivers the most robust learning experience in GI endoscopy. Take advantage of a fully-interactive format with images and videos, 360+ peer-reviewed questions offered as 10 study modules by topic area, real-life scenarios, a rationale for each correct answer, as well as references. With GESAP VIII, you can also earn up to 113 Maintenance of Certification (MOC) points, while earning AMA PRA Category 1 Credits™.

• More MOC! – Earn up to 113 MOC points

• Latest Guidelines! Updated references and explanations to reflect the most current guidelines and recommendations

• Comprehensive Suite — The ultimate study and self-test package th hat is also your BEST VALUE. Ideal for those looking for a complete self-study ressource.

• Enhanced Learning! Links to other ASGE resources that will enhance your understanding of each question, such as recorded courses, author interviews, and more

• Individual Modules — Choose and purchase individual modules. Ide eal for those looking to study specific topics.

• Education Fulﬁllment! Meets new patient safety requirement for MOC

Select from these convenient online formats:

• MOC Packages — Purchase modules available for MOC only. Ideal for those looking to earn ABIM MOC points.

With a host of great features, you can tailor GESAP VIII to your own personal learning style, and maximize your time. ✓ Track your progress and return at any time ✓ See how your answers compare to your peers ✓ Earn CME and print certificates from your account ✓ Submit MOC points directly to ABIM ✓ Access self-test module with the same 360+ questions in random order for a true self-assessment experience

Newest content on key endoscopic topics: Biliary

• Patient Prep, Monitoring & Sedation

• Colorectal

• Pediatrics

• Esophagus

• Small Intestine

• Nutrition

• Stomach

• Pancreas

• GIE Focal Points

Close-up view of an ERCP endoscope tip.

more endoscopes to keep up with demand. ECRI therefore recommends that if culturing after each reprocessing is impossible, practices culture their scopes over the weekend. At Chicago’s Loyola University Health Center, the endoscopy department has been revamping its duodenoscope cleaning procedure since the 2013 CRE outbreak at Advocate Lutheran General Hospital, in Illinois, said Neil Gupta, MD, MPH, the hospital’s director of endoscopy and assistant professor at Loyola University of Chicago’s Stritch School of Medicine. “It has been an ongoing process,” Dr. Gupta said.

‘You can keep processing the scope to see if you’ve manually cleaned out everything that can be detected. This strategy has not been proven yet. There’s no data [telling] us that that necessarily adds anything more to what we have been doing.’ —John Saltzman, MD

Loyola has been double-checking to ensure that it follows the Olympus guidelines, a process that includes having company employees retrain the technicians who clean the instruments. Loyola is not culturing its scopes, however, out of concern for accuracy. “We’re concerned about whether culturing the tip of the scope and having a negative culture truly means that that scope is not contaminated,” Dr. Gupta said. “Traditionally, a negative culture means that nothing continued to grow out on the culture, but that doesn’t mean that there isn’t some CRE on the scope, and that’s one of the reasons that we have not implemented cultures yet: We don’t know if that’s an accurate way to ensure that the scope is correctly processed.” More Frequent Reprocessing

Whether you are in need of MOC points, preparing for certification, or interested in an evaluation of your knowledge in toda ay’s GI field, look to GESAP VIIII, your online resource ce e for a complete endoscopy self-assessm ment!

GESAP VIII is scheduled for release in May 2015. Visit www.asge.org/gesap.

At Yale-New Haven Hospital, in New Haven, Conn., the endoscopy department also cultured samples from its reprocessed scopes after the recent outbreak; how

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Crohn’s-Related Growth Delays Improve With Adalimumab

reatment with adalimumab (Humira, AbbVie) is associated with significant improvements in the growth rate of pediatric patients with Crohn’s disease who experience growth delays, researchers have found. The association persisted, regardless of disease severity or recent use of corticosteroids, according to the investigators. With as many as half of all pediatric Crohn’s patients experiencing delays in growth ((J Clin Gastroenterol

‘In such children and adolescents, it is important to choose an agent that will rapidly induce remission, effectively maintain disease remission and not inherently inhibit linear growth.’

—Thomas Walters, MBBS

frequently it will do this in the future is unclear, said Priya Jamidar, MBChB, the hospital’s director of endoscopy and professor at the Yale School of Medicine. However, Yale has increased how often it reprocesses its duodenoscopes. Before the CRE outbreak, it reprocessed the scopes once per week if they were unused, or after each use. “We have started to reprocess all our scopes first thing in the morning before we do any ERCPs. We also reprocess scopes immediately after doing ERCPs,” Dr. Jamidar said. “The scopes basically cut the queue and are at the head of the line compared with other scopes, so they’re reprocessed immediately.” A 2014 study from the Medical University of South Carolina, in Charleston, found that duodenoscopes could be stored for as long as 21 days without developing growth of pathogenic bacteria (Gastrointest Endoscc 2014 Dec 4. [Epub ahead of print]). Longer reprocessing intervals would save money, the authors pointed out.

Liver Stiffness Guided HCV Management

Security Uncertain

• Determine treatment urgency

Given that it’s unclear if following manufacturers’ reprocessing guidelines to the letter can prevent contamination, uncertainty reigns over what the best reprocessing methods are, with hospitals trying many different approaches. “I think it’s unclear to everyone what is the right thing to do with regard to culturing or with regard to gas sterilization [another disinfection method under consideration] because there are pros and cons to both,” Dr. Gupta told Gastroenterology & Endoscopy News. After the 2013 infections, Advocate Lutheran switched from automatic reprocessing to ethylene gas sterilization and had no more infections ( (JAMA A 2014:312;1447-1455). However, concerns have arisen about the wear and tear that sterilization with ethylene oxide gas causes to instruments and also about whether or not repeated exposure to the gas is safe for technicians. Fine-tuning these reprocessing methods for best results, Dr. Jamidar said, is “a work in progress.” —Ashley P. Taylor

• Identify candidates for HCC and varices screening • Establish baseline stiffness for tracking disease FibroScan... the world’s most validated liver assessment technology… For more information, call us at 800.468.4556, or visit us at ﬁbroscan502touch.com

2012;46:581-589), one expert said the results are clinically significant. “Improving linear growth is a huge treatment goal in the management of pediatric patients with inflammatory bowel disease,” said Genie Beasley, MD, assistant professor of pediatric gastroenterology, hepatology and nutrition at the University of Florida Health, in Jacksonville. “Delayed growth leads to diminished overall adult height and pubertal see Growth, page 30

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Table. Changes in Growth Velocity With 26 and 52 Weeks Of Adalimumab Treatment in Crohn’s Disease

Growth

Baseline

continued from page 29

delay, and impacts self-esteem and quality of life.” Dr. Beasley was not involved in the latest research. An international team led by Thomas Walters, MBBS, co-director of the pediatric inflammatory bowel disease program at the Hospital for Sick Children, in Toronto, Ontario, Canada, retrospectively analyzed growth velocity data from the IMAgINE 1 trial of adalimumab (Gastroenterology 2012;143:365-374).

In the Phase III, double-blind trial, 192 patients with moderate to severe Crohn’s disease between the ages of 6 and 17 years received treatment adjusted for their body weight. Children weighing less than 40 kg first received 80 mg of adalimumab followed by 40 mg two weeks later; patients weighing more than 40 kg received 160 mg and 80 mg two weeks later. Lighter-weight patients were then randomized to receive either 10 or 20

Low dose High dose Infliximab-naive Infliximab-experienced Corticosteroid use at baseline No corticosteroid use at baseline Moderate diseasec Severe diseasec a

Change measured relative to baseline and expressed in standard deviations; P<0.001 for all changes. P<0.05 for infliximab-naive versus infliximab-experien nced at week 26. Disease severity defined by Pediatric Crohn’s Disease e Activity In Index scores, w where <40 is moderate o and ≥40 is severe. c

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

Change at Week 52a 3.4 3.3 3.8 1.4 4.3 2.3 3.0 3.8

INCREASE YOUR ADENOMA DETECTION RATE.

MEDIVATORS.COM

–3.0 –2.8 –3.1 –2.3 –2.8 –2.9 –3.2 –2.7

Change at Week 26a 2.5 2.3 2.7b 1.7 2.5 2.3 2.7 2.3

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

mg of adalimumab every other week, and patients weighing at least 40 kg received 20 or 40 mg. The current analysis included data from 89 patients with delayed height growth, whose median velocity of growth in height at baseline was 2.9 standard deviations less than that of their ageand sex-matched peers in the general population. According to Dr. Walters, 26 and 52 weeks after starting treatment with adalimumab, median height growth velocity increased by 2.4 and 3.3 standard deviations, respectively, compared with baseline (P<0.001 for both; Table). Subgroup analyses showed that patients with growth delays at baseline experienced significant improvements regardless of the dose of adalimumab they were administered, whether they had been receiving corticosteroids at the start of the study and independent of the severity of their disease. The only between-group difference was seen among those who had or had not previously been administered infliximab (Remicade, Centocor), Dr. Walters reported. Dr. Walters, who presented the findings at the 2014 annual meeting of the North American Society for Pediatric Gastroenterology and Hepatology (abstract 1), said the results show that effective and rapid control of inflammation in younger patients with growth impairment is “paramount. In such children and adolescents, it is important to choose an agent that will rapidly induce remission, effectively maintain disease remission and not inherently inhibit linear growth.” Treatments such as corticosteroids have a “less than ideal impact on growth,” Dr. Beasley added. Therefore, pediatric gastroenterologists are increasingly following a “top-down approach,” in which biologic treatments are used first. —David Wild

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

Newborn Screen Can Detect Biliary Atresia

simple and widely available screening test can identify biliary atresia in newborns with high sensitivity, researchers have found. Biliary atresia (BA) is the leading indication for pediatric liver transplantation worldwide. The disease affects approximately one in 10,000 infants in the United States, and is characterized by rapid liver scarring. Although some countries use a stool color card to screen for BA, no such tool exists in the United States. The sole accepted treatment for the disease, the Kasai operation, directly connects the liver to the intestines, bypassing the blocked biliary ducts. Children who undergo Kasai surgery earlier have better outcomes—clearance of jaundice and delayed need for liver transplants—than those whose treatment is delayed. But prompt detection is an important factor for success, experts said. “In this study, we show that newborn direct or conjugated bilirubin measurements can help identify infants with biliary atresia in the first two to three weeks of life,” said Sanjiv Harpavat, PhD, MD, assistant professor of pediatrics at Baylor College of Medicine, in Houston, who led the work. “There’s a real value in catching it early, possibly delaying the liver transplant.” The researchers presented their findings at the 2014 annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (abstract 330). A previous study by Dr. Harpavat and his colleagues in Pediatricss showed that at birth, infants with BA all had concentrations of direct bilirubin (DB) or conjugated bilirubin (CB) that were above the upper limit of age-related reference intervals set by their individual hospitals, which, in contrast to the traditional cutoff of 2 mg/dL, was about 0.5 mg/dL (2011;128:e1428-e1433). In the new study, Dr. Harpavat’s group prospectively evaluated 11,636 infants born between July 2013 and September 2014 in four Houston hospitals that routinely measure DB or CB levels in newborns. Those with high newborn DB or CB levels were re-measured at their two-week well-child visits. Infants were considered positive if they had elevated concentrations of DB or CB as newborns that increased with the repeat test at 2 weeks of age. Of the children studied, 121 had DB or CB levels that were considered high. On retesting at two weeks, 12 continued to have high levels. Ultimately, two of these infants were identified as having BA. “This disease is the most devastating and important liver disease in infants that we take care of. It has a great financial

and emotional toll. We talk about it being rare, but it is 10 times more common than some of the diseases we currently do newborn screening for,” said Ron Sokol, MD, section head of gastroenterology, hepatology and nutrition at Children’s Hospital Colorado, in Aurora. “When an infant has elevated DB/CB levels in the first five days of life, it’s something that needs to be followed up.” Stool color cards are being used in several countries and being tested in

others, and appear to be effective compared with no screening, Dr. Sokol said. “In Taiwan and Japan, the stool color card seems to get the children to Kasai surgery before 45 days on average, which is very good,” he said. Using DB or CB levels as a screening tool will require more study to assess its overall cost-effectiveness, he said. “This is an early study, but it’s promising,” Dr. Sokol said. “There’s no reason we shouldn’t be screening for BA, it’s just

that we haven’t had a way to do it.” Dr. Harpavat and his research team are performing those studies now, as well as spreading the screening program to other hospitals and health care systems that have expressed interest in it. “Our work emphasizes that high DB/ CB levels in newborns should be taken seriously,” Dr. Harpavat said. “It could be the one clue that helps make the BA diagnosis on time.” —Keely Savoie

ADD REVENUE TO YOUR PRACTICE WITH ANORECTAL MANOMETRY

Ask about our new biofeedback software

“mcompass is a real game changer, it really brings testing within reach of the private practice market. But hospitals can benefit from it too.” -Dr. Keith Munson, MD

I t ’s A b o u t Ti m e . . . D i a g n o s t i c Confidence...and Expanding

N E W O P T I O N F O R PAT I E N T S S U F F E R I N G FROM FECAL INCONTIENCE OR C H R O N I C C O N S T I PAT I O N 1 in 3 women will suffer from fecal

The mcompass is the only manometry

incontinence/chronic constipation in their

device optimized exclusively for anorectal

lifetime. Anorectal manometry is a

applications, and for the first time ever,

diagnostic test that can give physicians an

makes in-office manometry and sensation

understanding of why the patient is

testing practical and profitable.

suffering from these debilitating issues.

The mcompass simplifies this procedure

Medspira along with the Mayo Clinic

while still maintaining all of the industry

have created the mcompass to bring

standards of testing/accuracy. As a result,

- Disposable Catheter with easy insertion

anorectal manometry to offices who may

the mcompass system is being utilized by

tip for fast and convenient patient care

have been concerned about cost, time

colorectal surgeons, gastroenterologists,

constraints, space, etc.

URO/GYNs, OB/GYNs and physical

Patient Care - Complete exams in as little as 15 minutes - Portable, wireless system eliminating the need for a cart and dedicated room - Cost efficient mobile technology enables testing in any office setting

- Easy emailing using built-in WiFi - Developed by the Mayo Clinic

2718 Summer Street NE Minneapolis, MN 55413

therapists worldwide.

Contact sales@medspira.com and mention “GE01” and receive 5% savings

Tel 800.345.4502

Fax 612.789.2708

WWW.MEDSPIRA.COM/MCOMPASS

CLASSIFIEDS

APRIL 2015

Gastroenterologist Opportunity Geisinger Health System (GHS), a national leader in quality and integrated healthcare is seeking a BC/BE Gastroenterologist with an interest in ERCP, motility or IBD to join its innovative practice at Geisinger Medical Center in Danville, PA. Ability to perform ERCP will be supported in a new state-of-the-art endoscopy suite with 3 dedicated advanced procedure rooms. Become part of a closely integrated department comprised of more than 23 gastroenterologists, 3 hepatologists and 10 fellows with some of the best resources available for academic and clinical practice. Call is equally shared and is no more than 5 to 6 weeks per year. Transplant Hepatology, and our Gastroenterology and Advanced Endoscopy fellowship programs are located at Geisinger Medical Center. As a part of Geisingerâ&#x20AC;&#x2122;s team, you will work in an academic environment, backed by the resources of one of the nationâ&#x20AC;&#x2122;s most progressive integrated health systems. Enjoy the balance of a favorable call

schedule with the collegiality of a unique practice and surrounding community that offers a low cost of living, superb public schools, numerous outdoor and cultural activities, and easy access to major metropolitan areas including New York City, Baltimore, Philadelphia and Washington, D.C. Geisinger Health System serves nearly 3 million people in Northeastern and Central Pennsylvania and has been nationally recognized for innovative practices. A mature electronic health record connects a comprehensive network of 9 hospital campuses, 43 community practice sites and more than 1,200 Geisinger primary and specialty care physicians. Discover for yourself the Geisinger difference.

For more information visit geisinger.org/careers or contact: Mathew McKinney, &GRCTVOGPV QH 2TQHGUUKQPCN 5VCHĆ&#x201A;PI CV QT OYOEMKPPG["IGKUKPIGT GFW

PRESBYTERIAN PRESBYTERIAN HEALTHCARE SERVICES Albuquerque, NM Presbyterian Healthcare Services is seeking Board CertiďŹ ed Gastroenterology trained physicians to join our established practice of 11 physicians, 2 Gastroenterology Hospitalists and 7 advanced practitioners. Our medical group employs more than 600 primary care and specialty providers and is the fastest growing employed physician group in New Mexico. Presbyterian Healthcare Services is a locally owned, not-for-proďŹ t organization based in Albuquerque. Our integrated healthcare system includes eight hospitals in seven New Mexico cities, a medical group, multispecialty clinics and a health plan (over 400,000 members). We have been proudly providing care to New Mexicans for 105 years. In addition to a guaranteed base salary we also offer a sign on bonus, incentive bonus, malpractice, relocation, house hunting trip, health, dental, vision, 403(b) w/ contribution from PHS 457(b), short & long term disability, CME allowance, etc. Albuquerque thrives as New Mexicoâ&#x20AC;&#x2122;s largest metropolitan center with a population of 700,000. Albuquerque has been listed as one of the best places to live in the United States by Newsweek, U.S. News & World Report, Money and Entrepreneur Magazines! Albuquerque is considered a destination city for most types of outdoor activities with 310 days of sunshine. A truly diverse and multicultural city, Albuquerque offers you and your family a great variety of activities and entertainment including national theater productions, sporting events, golf courses ranked among the best in the country, the largest hot air balloon festival in the US, American Indian Cultural activities and much more.

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

CLASSIFIEDS

APRIL 2015

Career Opportunities

Got Job Openings? Promote your positions to the largest audience Contact Craig Wilson, Sales Associate, Classiﬁeds 212-957-5300 xĂăĆƫƫđƫƫcwilson@mcmahonmed.com

Hereditary continued from page 27

Treatment Approaches “We treat FAP with a prophylactic colectomy in the late teens or early 20s,” Dr. Boland said. “It’s important for the child to be fully grown to be able to tolerate the surgery … but you want to get the colon out as early as possible.” After the colectomy, it is important to assess “the duodenum for adenomas and cancer and [follow] the germline mutation through the family,” he said. Even with a colectomy, however, patients are still at risk for pancreatic and gastric cancers. A prophylactic colectomy also is an option for patients with MAP, but in milder cases of the syndrome, an annual colonoscopy can suffice, according to Dr. Boland. “Treatment has to be individualized based on the patient’s willingness and availability to get follow-up and tolerate some degree of uncertainty in exchange for keeping the colon in place,” he said. “For Lynch syndrome, we don’t usually go to a prophylactic colectomy; an annual colonoscopy will do,” Dr. Boland said. “For women with this disease,” he said, “removal of the uterus and ovaries after childbirth is recommended, especially in Lynch syndrome MSH6 type.”

Familial adenomatous polyposis

If colon cancer is found in conjunction with Lynch syndrome, however, Dr. Boland suggested a colectomy preserving the rectum, and an ileorectal or ileosigmoid anastomosis. He also noted that patients with Lynch syndrome, and possibly others with MSI, may not respond to 5-fluorouracil–based chemotherapy.

MutYH-associated polyposis

MutYH gene 1p34 p

Interpretation Lags Behind Gene Sequencing Despite the obvious advantages of screening, Dr. Boland concluded his presentation by discussing some of the issues concerning diagnostic testing panels. Testing of multiple genes, for example, may uncover sequence variations that suggest a functional change in the gene, but it may not be causing the cancer— or cancer risk—in that patient or family. “We can now sequence many genes that we cannot interpret,” he cautioned. Thomas Seufferlein, MD, from Ulm University Hospital, in Germany, said screening should be performed routinely. “The trouble is,” he said, “it starts with taking proper history of patients, which is not often done or done correctly. The simple things are those that are usually

APC gene 5q21 q

Figure. APC and MutYH H genes. Source: http://www.genetics4medics.com/familial-adenomatous-polyposis.html.

forgotten. We are prone to say, ‘let’s get this to pathology,’ but taking the family history first is critically important. You have to know what you actually want. Because there are many ‘pseudo types’ that are not actually Lynch syndrome,

you must talk to the patient to help determine this. Nothing makes sense until you have family history.” —Chase Doyle Drs. Boland and Seufferlein reported no relevant financial conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

FMT continued from page 1

“They never want the blender back,” said Dr. Brandt, professor of medicine and surgery at Albert Einstein College of Medicine and emeritus chief of the Division of Gastroenterology, at Montefiore Medical Center, in New York City. Interest in FMT has ramped up considerably in the past few years, but the concept dates to fourth-century China, when doctors administered a fecal suspension by mouth for food poisoning or severe

diarrhea. “By the 16th century, there was a menu of ways to take stool, and it was given for a variety of disorders: diarrhea, pain, vomiting, constipation,” Dr. Brandt said. Contemporary use of FMT dates to 1958, when it was administered by enema to treat four patients with pseudomembranous colitis. It was first used to treat CDI in 1983, and in 2013 the American College of Gastroenterology included consideration of FMT in its guidelines as a treatment for recurrent CDI. “The rationale is that we can avoid another course of the anti-C. difficile

antibiotics that, for example, in the case of vancomycin, is really maintaining the condition for which you were given it in the first place: a disturbance in the microbiota, or dysbiosis,” Dr. Brandt said, “FMT can immediately re-establish the normal diversity of the intestinal microbiome and thus restore the ability of the microbiota to resist colonization.”

How It’s Done The first step is choosing a donor, who can be any healthy person. “Whether you’re dealing with a spouse or family member,

treatment for hemorrhoids to your practice. (And smiles to your patients’ faces.)

Half of your patients will experience symptomatic hemorrhoids by age 50. Why not start treating them? It’s also now being performed by more than 1,800 physicians at 600 practices across the country. Join your colleagues and get started today by scheduling a free physician-physician training session at your practice. For more information, call 866.473.3024 x 1023 or visit www.crhmedicalproducts.com Your patients will thank you.

household contact or total stranger, the results are basically the same, raising the whole concept of a universal donor,” Dr. Brandt said. “People don’t seem to have much difficulty accepting stool from someone they know or don’t know if they’re sick enough, and these people are sick enough.” The next step is thorough screening. Donor stool is tested for parasites, C. difficile, Giardia, Cryptosporidium, Isospora and norovirus; the donor also is tested for syphilis; hepatitis A, B and C; HIV infection; and other blood-borne infections. Some donor exclusions include recent use of antibiotics, diarrhea, constipation, inflammatory bowel disease, colorectal cancer, immunocompromise, use of anticancer drugs, high-risk sexual behaviors and recent body piercing or tattoos. Other exclusions include diabetes, obesity, atherosclerotic cardiovascular disease and mood and neurologic disorders.

‘I sometimes give the donor a gentle laxative the night before. I like to use stool that’s fresh, passed within six hours—it does not need to be refrigerated.’ —Lawrence Brandt, MD Preparation for the recipient includes discontinuing anti-C. difficile antibiotics two to three days before the procedure, and undergoing a large-volume colonoscopy bowel preparation the evening before. “I give them some loperamide right before I put the stool in so that they hold it for at least four, preferably six hours,” Dr. Brandt said. “I sometimes give the donor a gentle laxative the night before. I like to use stool that’s fresh, passed within six hours—it does not need to be refrigerated.” Dr. Brandt suspends the stool in nonbacteriostatic saline and filters it through gauze into a canister; it can be mixed by hand or by blender. With a cathetertipped syringe connected to the accessory channel of the colonoscope, he administers 300 mL into the ascending colon, or terminal ileum if easily intubated. Colleen Kelly, MD, clinical assistant professor of medicine at Brown University, in Providence, RI, also administers FMT during colonoscopy in patients who are healthy enough to undergo the procedure and who have not had a recent colonoscopy. Otherwise, she uses flexible sigmoidoscopy to place the stool. “It’s a less invasive procedure and, in my opinion, works as well as colonoscopy,” she said.

Increasing Popularity Dr. Kelly has seen a definite change in the degree to which FMT is now being

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2015

offered for CDI, particularly since the publication of a landmark paper that demonstrated a response rate of 82% in patients with CDI who received a nasoduodenal infusion of stool, compared with 31% in those who received vancomycin alone (N Engl J Medd 2013;368:407-415). “That changed a lot of people’s minds,” Dr. Kelly said. “That, and the FDA’s decision to enact a policy of enforcement discretion last summer.” The FDA had formerly required investigational new drug permission for anyone using stool as a treatment. “That really put the kibosh on the use of FMT,” Dr. Brandt said. “So we had a public workshop, made impassioned speeches, a couple of our patients made impassioned speeches, and then in July [2013], the FDA said that for CDI that does not respond to standard therapy, they will exercise enforcement discretion. They are not going to come after you as long as you give the patient adequate informed consent, tell them that this is an experimental investigative therapy and explain the potential risks.” Dr. Brandt added that he was thrilled and impressed with the FDA because the agency changed the direction of its policy in response to public sentiment, which was bolstered by the positive experiences with FMT to date. In addition to The New England Journal of Medicinee article and the FDA’s enforcement discretion policy, a couple of other developments evolved last year to help expand the use and investigation of FMT. One is the Fecal Transplant Foundation, a website started by a patient that contains a list of FMT providers in both the United States and abroad.

Dr. Brandt said researchers are interested in the technique’s potential to treat conditions unrelated to the gastric tract. “Insulin resistance, obesity, Parkinson’s, multiple sclerosis, autism: There are bits of scattered data out there that suggest there may be something to this,” he said. Fecal transplant, however, is only the first step in the probiotic journey. “People have used frozen fresh material, an extract of stool that it is added to water and diluted; it has exactly the same effect as [fresh] feces,” Dr. Brandt said. A small study showed that a mixture of 33 strains

1978

—

of bacteria derived from normal stool and synthesized into a “living liquor” was able to cure patients of recurrent CDI. “And then there are the poop pills in Canada, 27 to 34 pills [each] that cured them of their disease,” he said. “So we’re now looking at stool and at different types of derived preparations. We start with a lot [of bacterial strains], we then go to a few, we may soon even go to a single strain, and perhaps one day we won’t even give the bacteria, maybe just the metabolic products of those bacteria.” —Monica J. Smith

GASTROENTEROLOGY & ENDOSCOPY NEWS, the independent monthly newspaper for gastroenterologists, has been providing physicians with comprehensive and objective information since 1978. The newspaper is circulated to more than 17,500 gastroenterologists, colorectal surgeons, and hepatologists, and GI-specific physician assistants and nurse practitioners (as reported to BPA Worldwide, Publishers Audit, based on circulation data as of July 2013). Gastroenterology & Endoscopy News (ISSN 0883-8348) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Please send address changes to Gastroenterology & Endoscopy News, 545 W. 45th Street, 8th Floor, New York, NY 10036. Copyright © 2015 by McMahon Publishing.

37th Anniversary — 2015

2015 2014

The Independ Independent Monthly Newspaper for Gastroenterologists

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

OpenBiome Another is the nonprofit OpenBiome, a stool bank developed by a group of researchers from MIT (see Gastroenterology & Endoscopy News, November 2014, page 1). “OpenBiome recruits donors, screens the stool and centralizes the whole process,” Dr. Kelly said. They began in 2013 and have now sent more than 1,000 doses to more than 100 sites, including some to providers who don’t perform FMT often enough to establish a donorscreening protocol, she said. OpenBiome charges a user fee of $250 per dose, significantly less than the cost of donor screening, which can run to $1,000 or more. “They’ve been really successful in helping providers and researchers. I think their hope is to help people who want to do FMT research obtain materials for their study,” Dr. Kelly said. Researchers are already looking into FMT as a treatment for various gastrointestinal disorders; several papers were presented at Digestive Disease Week 2014 (see Gastroenterology & Endoscopy News, August 2014, page 1).

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.

gastroendonews.com

OPT IN to receive your free e-newsletter from the best-read gastroenterology publication in the country www.gastroendonews.com/renew

Articles from the current monthâ&#x20AC;&#x2122;s issue Articles ahead of print Web-exclusive content

PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

The Microbiome for Gastroenterologists AMIT DUTTA, MD Aberdeen Royal Infirmary Forsterhill, Aberdeen, United Kingdom

EMAD M. EL-OMAR, MD, FRCP Division of Applied Medicine Institute of Medical Sciences School of Medicine & Dentistry Aberdeen University Foresterhill, Aberdeen, United Kingdom

Drs. Dutta and El-Omar report no relevant financial conflicts of interest.

icroorganisms are present on almost all parts of the human body that come in contact with the external environment including the gut, skin, oral cavity, genitourinary tract, and airway.1

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS â&#x20AC;˘ A P R I L 2 0 1 5

Of these microorganisms, more than two-thirds are present in the gastrointestinal (GI) tract.2 Approximately 99% of gut microbes are bacterial species, and it is not surprising that most of the microbiota research has focused on these organisms.3 Major technological advances in molecular biology have greatly expanded our knowledge of the gut microbiota and highlighted the complexity of this system and its crucial role in health and disease pathogenesis.4 The gut “microbiome” is an area of intense research, but current understanding of its role in human disease is still preliminary and largely descriptive. This article will provide a practical view of the composition and function of human gut bacteria and their role in GI and liver diseases.

Tools for Studying the Gut Microbiota In the past, the study of microbiota depended mainly on culture-based techniques. This limitation significantly underestimated the true diversity and complexity of the gut microbiota, as many bacterial species cannot be cultured by standard methods. The advent

of advanced molecular techniques greatly accelerated developments in the field. These tools provide a large amount of information in a short period of time. They may involve detection of a small portion of the nucleic acid of an organism for identification of the species or the entire genome and its products for functional characterization. For example, analysis of 16s ribosomal RNA (16s rRNA) has been used extensively in identifying bacterial species.5 This RNA is small in size but has enough difference in its variable region to allow for differentiation between species, making it an extremely useful target. A similarity greater than 97% is required for bacteria to be grouped into same species. Although 16S rRNA is helpful in the identification of bacteria, it provides no information on genetic structure and function—information critical for the study of how organisms affect human health and the various perturbations that occur in the disease state. The application of “omics” technology can be used to gather this data.6 The bacterial gene pool can be identified by complete sequencing of DNA (genomics). To determine which

Dysbiosis

NOD2/IL-23R/ATG16L1

Gut microbiome Innate immunity Diet Western enterotype

Host factors

IBD Environmentall factors

Barrier function

Geography Parasite exposure Drugs

Figure 1. The overlapping role of the gut microbiome, host, and environmental factors in the pathogenesis of IBD. Dysbiotic changes in the gut microbiome may be influenced by diet and other environmental factors and predispose to IBD. A small proportion of IBD patients have demonstrable genetic susceptibility factors. From Hold et al World J Gastroenterol. 2014 Feb 7; 20(5):1192-1210. IBD, inflammatory bowel disease

G AST R O E N D O N E WS .CO M

genes are actually being expressed, mRNA expression profiling (transcriptomics) can be performed or protein products (proteomics) can be identified. The metabolites produced by bacteria can be measured using mass spectrometry and nuclear magnetic resonance spectroscopy (metabolomics). The data provided by “omics” technology may be enormous and present challenges in interpretation and analysis, but the hope is that they ultimately will provide key insights into disease pathogenesis. Realizing the important but daunting task of characterizing gut microbiota, various consortia have been formed and tasked with assessing human microbiota in health and disease. In 2008, the US National Institutes of Health launched the Human Microbiome Project to study the microbiome in gut, oral cavity, vagina, skin, and respiratory tract.7 From the data obtained, a reference database was established in 2012. The MetaHit (Metagenomics of Human Intestinal Tract) project funded by the European Union was aimed at characterizing gut microbiota.3 Other consortia include the Canadian Microbiome Initiative, the Australian Jumpstart Human Microbiome Project, and the Microbiome Diversity Project in Korea. These developments and initiatives indicate that the scientific community realizes the importance of research in this field and bode well for the future.

Development and Composition of Gut Microbiota Colonization of the GI tract with microbes begins during birth and the complexity and numbers increase progressively.8,9 By about age 2 or 3 years, the microbial composition of the gut starts resembling that of an adult.10,11 The diversity and number of organisms increase until late adolescence, after which they remain stable throughout most of adulthood. Changes may appear again after the sixth decade of life.12 Numerous factors determine the composition of gut microbiota during childhood. These include the mode of delivery, diet, exposure to antibiotics, genetics, and maternal microbiota.13,14 For example, the gut microbiota of infants delivered by cesarean or fed on formula differs in composition from that of children delivered vaginally or fed on breast milk.15,16 The human body harbors roughly 1014 microorganisms—far more than the number of cells in the body. In the GI tract, about 99% of the microbes are bacteria; archae, viruses, and eukaryotes constitute the rest.3 An individual may have an average of 500 to 1,000 bacterial species in his or her gut.3,17 The microbial DNA collectively encodes for more genes than their host.17 With such complexity, comprehending the microbial composition and their metabolism presents researchers a significant challenge. Most of the bacteria are anaerobes; the remainder are facultative anaerobes and aerobes. At the phylum level, about 90% of gut bacteria in

adults belong to Firmicutes and Bacteroidetes.18 Other phyla include Proteobactria, Actinobacteria, Verrucomicrobia, Fusobacteria, Spirochaetes, Tenericutes, and Lentisphaera.18,19 In infants, Proteobacteria and Actinobacteria predominate.9 Adult microbial composition is also affected by several factors including genetics, malnutrition, obesity, smoking, use of antibiotics, and diet.19-22 For example, a diet based on animal fats and proteins increases organisms like Alistipes that are tolerant to bile and decreases the concentration of organisms like Roseburia that metabolize plant carbohydrates.20 It has been proposed that the microbiota of an individual can be classified into 1 of the 3 enterotypes based on the variations in levels of the genera Bacteroides, Prevotella, and Ruminococcus.23 Type 1 enterotype has a high level of Bacteroides, whereas types 2 and 3 are dominated by Prevotella and Ruminococcus, respectively. This classification appears to have a functional significance and does not seem to be influenced by age, body weight, or geographical location; however, long-term diet may have an impact.23 The number and diversity of microbes varies along the length and cross-section of the GI tract.24 The stomach has 10 cells/g of luminal content and these increase to 104 cells in the jejunum and 107 cells in the ileum. The colon has the highest concentration of bacteria at 1011-12 cells/g.4 When present, Helicobacter pylorii is the main species in stomach. Bacillii and Streptococcaceae are prevalent in the small bowel and Bacteroidetes and Lachnospiracea are common in the colon. The dominant bacterial colonies on the epithelial surface of the intestinal tract also differ from those in the lumen.4,25 This has implications when interpreting results from studies based mainly on fecal microbiota because it may not give accurate information about the bacteria on epithelial surface.

Function of Gut Microbiota The commensal bacteria in the human gut play several important roles in the maintenance of health and physiology.11 They affect host gene expression and metabolism26 and they are essential for the development of a healthy immune system in the gut and maintenance of the gut barrier.27,28 Germ-free animals have a defective immune system with underdeveloped lymphoid structures and reduced immunoglobulin A– producing plasma cells.27 The microbiota contribute to maintaining a state of tolerance in the GI tract by influencing host T cells, including regulatory T cells. Considering the large volume of bacteria in the gut, this tolerance to commensals is critical in preventing unwanted immune activation, which would be deleterious for the host. Gut microbes may also influence development of the enteric nervous system, as shown in animal studies.29

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • A P R I L 2 0 1 5

Another important function of gut microbiota is the extraction of energy from undigested food products. Bacteria metabolize many of these products especially fibers to short-chain fatty acids (SCFAs), which include butyric, propionic, and acetic acids.30 SCFAs serve as the energy source for colonic epithelial cells and they also affect cell differentiation and immune functions. The efficient energy extraction also may have the unwanted effect of promoting weight gain. It has been demonstrated that gut microbiota play a role in the development of obesity.30 The bacteria also produce other metabolites from dietary contents like hydrogen sulfide, phenols, and mercaptans, which may have harmful effects.31 Commensal bacteria prevent colonization of intestine by pathogens. This happens through several mechanisms, including competing for space and nutrients and production of antimicrobial substances like bacteriocin, protease, and peroxidase.4 Antibiotics disturb the commensal community and can sometimes lead to overgrowth of pathogens and ill health, including diarrhea. Other functions of gut microbiota include production of vitamins and folic acid, which can be used by the host.32 They may metabolize xenobiotic compounds like antibiotics, which may affect drug bioavailability. They also metabolize a fraction of bile salts in the intestine. Apart from their role in the development and functions of GI tract, gut microbiota also have demonstrated an influence on the development of the cardiovascular, endocrine, and nervous systems, among others.33

Gut Microbiota and GI and Liver Diseases Disturbance in the composition (dysbiosis) and/or function of gut microbiota has been linked to several diseases. However, because of the complexity of the microbiota, pinpointing the role of individual species of bacteria in the pathogenesis of a particular disease is challenging. Although there has been rapid progress, the current understanding of microbiota and human disease remains preliminary. Also, the cause-and-effect relationship has yet to be established for most conditions, as it is unknown whether the altered microbiota is the cause or the consequence of a given disease state.

Faecalibacterium prausnitizi, a firmicute, has antiinflammatory properties and has been shown to be reduced in in patients with IBD36; and Proteobacteria and Actinobacteria are increased.37 Adherent invasive Escherichia colii were found in increased numbers in ileal biopsy specimens in patients with Crohnâ&#x20AC;&#x2122;s disease.38 Similarly, the diversity of species seen in patients with IBD is less than in healthy individuals.39 Dysbiosis may lead to an increase in antigen exposure of gut immune cells, reduction in production of beneficial compounds like SCFAs, increased oxidative stress, and altered metabolism of bile acid, all of which may promote inflammation although the detailed mechanisms remain to be delineated.35,40 Host genetic and environmental factors may be affecting these changes.

GI Cancer Another important focus of microbiota research is its role in development of GI cancer, particularly colorectal cancer (CRC).41,42 The composition of gut microbiota in patients with CRC and adenomatous polyps was found to differ from that of healthy controls.43,44 The bacteria linked to the development of CRC include sulfatereducing Fusobacterium nucleatum and Enterococcus faecalis.45,46 Most CRCs progress through stages of accumulating genetic changes. Microbial dysbiosis can lead to genetic mutations by producing genotoxic metabolites or promoting inflammation. Sulfate-reducing bacteria like Desulfovibrio and Desulfomonas produce hydrogen sulphide and E. faecalis produces reactive oxygen species, both of which appear toxic to epithelial cells.46 Diet may be implicated in the development of CRC through its effects on bacterial metabolism. Proteinrich diets encourage formation of harmful products like nitrosamines and heterocyclic amines by bacteria, whereas fiber in the diet is a source of production of SCFAs, which have protective effects.47 Another important site of cancer in the GI tract is the stomach. The role of H. pylorii in the development of gastric cancer is well established.48 In areas with a high prevalence of gastric cancer, eradication of H. pylorii has been recommended to prevent development of gastric cancer.

Functional Bowel Disease Inflammatory Bowel Disease Gut microbiota is considered a key driver of inflammation leading to inflammatory bowel disease (IBD) in genetically predisposed individuals. Among conditions of the GI tract, IBD has received close attention from microbiota researchers. This is not surprising considering the prevalence of this disorder and the role of gut microbiota in its pathogenesis (Figure 1). Numerous studies have shown that the composition of gut bacteria in patients with Crohnâ&#x20AC;&#x2122;s disease and ulcerative colitis differs from that in healthy people.34,35 There is reduction in Firmicutes and Bacteroides35;

G AST R O E N D O N E WS .CO M

Functional disorders are perhaps the most common GI problems for which people seek medical attention. Dyspepsia and irritable bowel syndrome (IBS) are 2 important conditions in this group. Symptoms are thought to result from abnormal GI motility, increased visceral sensitivity, and abnormal processing of signals in the gutâ&#x20AC;&#x201C;brain axis. Gut microbiota may affect motility and visceral sensation by promoting inflammation and aggravating the enteric nervous system.21,49 There are no consistent observations with regard to actual changes in gut microbiota, but some studies have shown that populations of Firmicutes and Proteobacteria are

increased and Bifidobacteria and Actinobacteria are reduced in patients with IBS.50-52 Interventions like probiotics, antibiotics, and a low FODMAP (Fermentable Oligo-Di-Monosaccharides And Polyols) diet, which are used to treat IBS, likely are beneficial because of their ability to alter microbial composition.21,53,54

Liver Diseases Abnormal function of gut microbiota appears to be a significant factor in the cause and progression of several liver diseases.55 Nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) have been areas of special interest in this regard. Alteration of gut microbiota by diet, alcohol intake, and other environmental factors leads to increased production of proinflammatory substances, including lipopolysaccharide (LPS).55 Exogenous compounds such as alcohol and bacterial products also increase the permeability of the intestinal epithelial barrier. A shift of microbiota toward one with more toxin-producing potential and increased gut permeability may result in significant leakage of bacterial toxins like LPS from the gut into circulation. This leakage would result in activation of Kupffer cells, stellate cells, and hepatocytes and drive inflammation, with resultant tissue damage and, subsequently, fibrosis. Overgrowth of bacteria in the small intestine has been reported in patients with nonalcoholic steatohepatitis and has been associated with raised level of proinflammatory in these patients.56 Bacteroides are reduced in numbers in patients with NAFLD and ALD.57 In ALD, activators of innate immunity like Enterobacteriacea and Proteobacteria are increased.57 Animal studies involving microbiota transfer have shown that dietary factors alone may be insufficient to cause NAFLD and require appropriate microbiota.58 An important factor for NAFLD is obesity, and microbes can influence development of obesity by increasing energy extraction from diet and promoting fat deposition.30 Gut microbes have been linked to hepatic encephalopathy, viral hepatitis, progression of cirrhosis, and development of hepatocellular carcinoma.55 Microbial composition has been shown to be altered in patients with minimal and overt hepatic encephalopathy59— partly explaining the beneficial effect of luminal antibiotics like rifaximin in treating hepatic encephalopathy. The gut microbiota in patients with cirrhosis shows an increased concentration of organisms normally found in the oral cavity,60 although whether this is an artifact or has a role in the progression of the disease is unknown. Overall, data on gut microbiota and liver disease are still emerging and although exciting, at this stage conclusions are elusive.

Other GI Conditions Preliminary data have shown that patients with celiac disease have altered gut microbiota. In a study

of children with the condition, E. colii and Bacteroides vulgatus were seen more frequently, and patients had greater biodiversity than controls.61 Diarrhea caused by Clostridium difficile infection—an important cause of morbidity and mortality, particularly in older and hospitalized patients—often occurs after administration of antibiotics, which is proposed to alter the gut microbial composition and favor overgrowth of C. difficile. Restoration of healthy gut microbiota by fecal microbiota transplantation (FMT) has become an accepted therapy in refractory diarrhea from infection with C. difficile.62 Finally, pancreaticobiliary diseases also have been linked with change in microbiota,63,64 whereas chronic pancreatitis and pancreatic cancer have been associated with differences in salivary microbiota.64

Potential Therapies The expansion in the knowledge of gut microbiota also has provided avenues for developing potential therapies. Various methods of modifying gut bacteria include administration of prebiotics, probiotics, and antibiotics or by FMT.65,66 Examples include antibiotics for treatment of diarrhea-predominant IBS and hepatic encephalopathy, and FMT for treating C. difficile infection.62 Preliminary reports suggest FMT can be successful in patients with ulcerative colitis and probiotics may maintain remission in this condition but the validity of these observations is uncertain.67,68 Animal studies have shown that antibiotics can improve metabolic abnormalities associated with obesity.69 However, until we develop a clear understanding of the specific microbiota involved in the disease process and their pathogenetic mechanisms, therapies will be largely empirical. It also is unlikely that all bacterial species can be classified strictly as either beneficial or harmful because they may have multiple roles. Targeting them for therapies may deprive the host of their beneficial roles and predispose to other diseases. A cautious approach therefore is needed.

Conclusion The gut microbiome doubtless has a major influence on human health and disease. Disturbance of the normal homeostasis of the microbiome (dysbiosis) has been linked to many GI conditions such as IBD and IBS. The role of the microbiota in metabolic pathways leading to obesity, diabetes, cardiovascular disease, and cancer is perhaps the most exciting area of study and offers the biggest challenge and the greatest reward in terms of ultimately reducing the burden of disease in society. Understanding why dysbiosis occurs, how it leads to disease, and how to restore normal homeostasis are major areas of future research. Gastroenterologists are the natural custodians of this research field and it is imperative that we dedicate all our energy, skill, and resources to conquering these challenges.

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • A P R I L 2 0 1 5

References 1.

Ding T, Schloss PD. Dynamics and associations of microbial community types across the human body. Nature. 2014;509(7500):357-360.

21. Simren M, Barbara G, Flint HJ, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut. 2013;62(1):159-176.

2. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124:837-848.

22. Pérez-Cobas AE, Gosalbes MJ, Friedrichs A, et al. Gut microbiota disturbance during antibiotic therapy: a multi-omic approach. Gut. 2013;62(11):1591-601.

3. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59-65.

23. Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature. 2011;473(7346):174-180.

4. Sekirov I, Russell SL, Antunes LCM, et al. Gut microbiota in health and disease. Physiol Rev. 2010; 90(3):859-904.

24. Lavelle A, Lennon G, Docherty N, et al. Depth-dependent differences in community structure of the human colonic microbiota in health. PLoS One. 2013;8(11):e78835.

5. Claesson MJ, O’Toole PW. Evaluating the latest high-throughput molecular techniques for the exploration of microbial gut communities. Gut Microbes. 2010;1(4):277-278.

25. Zhang Z, Geng J, Tang X, et al. Spatial heterogeneity and cooccurrence patterns of human mucosal-associated intestinal microbiota. ISMEJ. 2014;8(4):881-893.

6. Morgan XC, Huttenhower C. Meta’omic analytic techniques for studying the intestinal microbiome. Gastroenterology. 2014;146(6):1437-1448.

26. Bäckhed F. Programming of host metabolism by the gut microbiota. Ann Nutr Metab. 2011;58(suppl 2):44-52.

7. Gevers D, Knight R, Petrosino JF, et al. The Human Microbiome Project: a community resource for the healthy human microbiome. PLoS Biol. 2012;10(8):e1001377. 8. Fouhy F, Ross RP, Fitzgerald GF, et al. Composition of the early intestinal microbiota: knowledge, knowledge gaps and the use of high-throughput sequencing to address these gaps. Gut Microbes. 2012;3(3):203-220. 9. Koenig JE, Spor A, Scalfone N, et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci USA. 2011;108(suppl 1):4578–4585. 10. Kolling G, Wu M, Guerrant RL. Enteric pathogens through life stages. Front Cell Infect Microbiol. 2012;2:114. 11. Ottman N, Smidt H, de Vos WM, et al. The function of our microbiota: who is out there and what do they do? Front Cell Infect Microbiol. 2012;2:104. 12. Hopkins MJ, Sharp R, Macfarlane GT. Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles. Gut. 2001;48(2):198-205. 13. Faa G, Gerosa C, Fanni D, et al. Factors influencing the development of a personal tailored microbiota in the neonate, with particular emphasis on antibiotic therapy. J Matern Fetal Neonatal Med. 2013;26(suppl 2):35-43. 14. Khachatryan ZA, Ktsoyan ZA, Manukyan GP, et al. Predominant role of host genetics in controlling the composition of gut microbiota. PLoS One. 2008;3(8):e3064. 15. Guaraldi F, Salvatori G. Effect of breast and formula feeding on gut microbiota shaping in newborns. Front Cell Infect Microbiol. 2012;2:94. 16. Jakobsson HE, Abrahamsson TR, Jenmalm MC, et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut. 2014;63(4):559-566. 17. Lepage P, Leclerc MC, Joossens M, et al. A metagenomic insight into our gut’s microbiome. Gut. 2013;62(1):146-158. 18. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science. 2005;308(5728):1635-1638.

27. Macpherson AJ, Harris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol. 2004;4:478-485. 28. McDermott AJ, Huffnagle GB. The microbiome and regulation of mucosal immunity. Immunology. 2014;142(1):24-31. 29. Collins J, Borojevic R, Verdu EF, et al. Intestinal microbiota influence the early postnatal development of the enteric nervous system. Neurogastroenterol Motil. 2014;26(1):98-107. 30. Schwiertz A, Taras D, Schäfer K, et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity. 2010;18(1):190-195. 31. Macfarlane GT, Macfarlane S. Bacteria, colonic fermentation, and gastrointestinal health. J AOAC Int. 2012;95(1):50-60. 32. Quigley EMM. Gut bacteria in health and disease. Gastroenterol Hepatol. 2013;9(9):560-569. 33. Sudo N, Chida Y, Aiba Y, et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol Rev. 2004;558(Pt 1):263-275. 34. Frank DN, Robertson CE, Hamm CM. Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm Bowel Dis. 2011;17(1):179-184. 35. 35. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146(6):1489-99. 36. Joossens M, Huys G, Cnockaert M, et al. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut. 2011;60(5):631-637. 37. Mukhopadhya I, Hansen R, El-Omar EM, et al. IBD-what role do Proteobacteria play? Nat Rev Gastroenterol Hepatol. 2012;9(4):219-230. 38. Martinez-Medina M, Aldeguer X, Lopez-Siles M. Molecular diversity of Escherichia coli in the human gut: new ecological evidence supporting the role of adherentinvasive E. coli (AIEC) in Crohn’s disease. Inflamm Bowel Dis. 2009;15(6):872-882. 39. Manichanh C, Rigottier-Gois L, Bonnaud E, et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut. 2006;55(2):205-211.

19. Lagier JC, Million M, Hugon P, et al. Human gut microbiota: repertoire and variations. Front Cell Infect Microbiol. 2012;2:136.

40. Duboc H, Rajca S, Rainteau D, et al. Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut. 2013;62(4):531-539.

20. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559-563.

41. Irrazabal T, Belcheva A, Girardin SE, et al. The multifaceted role of the intestinal microbiota in colon cancer. Mol Cell. 2014;54(2):309-320.

G AST R O E N D O N E WS .CO M

42. Chen W, Liu F, Ling Z, et al. Human intestinal lumen and mucosaassociated microbiota in patients with colorectal cancer. PLoS One. 2012;7(6):e39743. 43. Scanlan PD, Shanahan F, Clune Y, et al. Culture-independent analysis of the gut microbiota in colorectal cancer and polyposis. Environ Microbiol. 2008;10(3):789-798. 44. Ahn J, Sinha R, Pei Z, et al. Human gut microbiome and risk for colorectal cancer. J Natl Cancer Inst. 2013;105(24):1907-11. 45. Kostic AD, Chun E, Robertson L, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumorimmune microenvironment. Cell Host Microbe. 2013;14(2):207-215. 46. Huycke MM, Moore D, Joyce W, et al. Extracellular superoxide production by Enterococcus faecalis requires demethylmenaquinone and is attenuated by functional terminal quinol oxidases. Mol Microbiol 2001;42(3):729-740. 47. Macfarlane S, Steed H, Macfarlane GT. Intestinal bacteria and inflammatory bowel disease. Crit Rev Clin Lab Sci. 2009;46(1):25-54. 48. Lochhead P, El-Omar EM. Helicobacter pylori infection and gastric cancer. Best Pract Res Clin Gastroenterol. 2007;21(2):281-97. 49. Cryan JF, O’Mahony SM. The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil. 2011;23(3):187-92. 50. Pimentel MF, Giamarellos-Bourboulis EJ, Pyleris E. The first large scale deep sequencing of the duodenal microbiome in irritable bowel syndrome reveals striking differences compared to healthy controls. Gastroenterology. 2013;144:S59. 51. Carroll IM, Ringel-Kulka T, Keku TO, et al. Molecular analysis of the luminal- and mucosal-associated intestinal microbiota in diarrheapredominant irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2011;301(5):G799-G807. 52. Jeffery IB, O’Toole PW, Ohman L, et al. An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut. 2012;61(7):997-1006. 53. Brenner DM, Moeller MJ, Chey WD, Schoenfeld PS. The utility of probiotics in the treatment of irritable bowel syndrome: a systematic review. Am J Gastroenterol. 2009;104(4):1033-1049. 54. Halmos EP, Christophersen CT, Bird AR, et al. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2014;64(1):93-100. 55. Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiota-liver axis in hepatic disease. Hepatology. 2014;59(1):328-339.

56. Shanab AA, Scully P, Crosbie O, et al. Small intestinal bacterial overgrowth in nonalcoholic steatohepatitis: association with tolllike receptor 4 expression and plasma levels of interleukin 8. Dig Dis Sci. 2011;56(5):1524-1534. 57. Mutlu EA, Gillevet PM, Rangwala H, et al. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol. 2012;302(9):G966-G978. 58. Le Roy T, Llopis M, Lepage P, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut. 2013;62(12):1787-1794. 59. Bajaj JS, Ridlon JM, Hylemon PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 2012;302(1):G168-G175. 60. Qin N, Yang F, Li A, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature. 2014;513(7516):59-64. 61. Schippa S, Lebba V, Barbato M, et al. A distinctive “microbial signature” in celiac disease pediatric patients. BMC Microbiol. 2010;10:175. 62. Borody TJ, Brandt LJ, Paramsothy S. Therapeutic faecal microbiota transplantation: current status and future developments. Curr Opin Gastroenterol. 2013;30(1):97-105. 63. Wu T, Zhang Z, Liu B, et al. Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study. BMC Genomics. 2013;14:669. 64. Farrell JJ, Zhang L, Zhou H, et al. Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut. 2012;61(4):582-588. 65. Petrof EO, Khoruts A. From stool transplants to next-generation microbiota therapeutics. Gastroenterology. 2014;146(6):1573-1582. 66. Grehan MJ, Borody TJ, Leis SM, et al. Durable alteration of the colonic microbiota by the administration of donor fecal flora. J Clin Gastroenterol. 2010;44(8):551-561. 67. Damman CJ, Miller SI, Surawicz CM, et al. The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation? Am J Gastroenterol. 2012;107(10):1452-1459. 68. Kruis W, Fric P, Pokrotnieks J, et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut. 2004;53(11):1617-1623. 69. Murphy EF, Cotter PD, Hogan A, et al. Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut. 2013;62(2):220-226.

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • A P R I L 2 0 1 5

Read the No. 1 publication in the

gastroenterology market,

anywhere, anytime!

Explore gastroendonews.com at your convenience, from your iPad, personal computer or smartphone.

gastroendonews.com Read all the articles from each monthâ&#x20AC;&#x2122;s issue online. Search the archive for articles from past issues that you may have missed. Post a comment about an article for your colleagues to see. Share articles you read online with your colleagues via email, Facebook, Twitter and other popular social networking sites. Follow our Twitter feed and keep up with us between monthly issues. View our Digital Edition, which includes articles in the same layout as our print edition.