September 2014 by McMahon Group

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 65, Number 9 • September 2014

Experts Cheer FDA Panel Vote on OIC Drug Safety

ENDOSCOPY SUITE

MI ‘signal’ seen with one drug, but not others

Solid Long-Term Outcomes Seen For ESD in Colorectal Cancer

BY KAREN BLUM xperts said they hoped a recent FDA advisory panel recommendation against requiring randomized controlled cardiovascular outcomes trials for new drugs to treat constipation associated with the use

see OIC, page 28

Group Forges Consensus on Early Rectal Cancer BY VICTORIA STERN

ver the past 15 years, the treatment of rectal cancer has improved significantly with the emergence of new surgical techniques and technologies and as physicians have gained a greater understanding of disease pathology.

BY CAROLINE HELWICK CHICAGO—For the management of colorectal neoplasms, endoscopic submucosal dissection (ESD) yields high en bloc resection rates, which enhances the histologic evaluation and the potential for completely eliminating the tumor. However, ESD remains technically challenging. Japanese researchers pioneered ESD, and they

are now providing evidence of its long-term efficacy and safety. Two such studies were presented at Digestive Disease Week (DDW) 2014. “ESD provided excellent long-term outcomes for patients with large colorectal neoplasms treated in the Japanese Multicenter Cohort Study,” said Kinichi Hotta, MD, of Shizuoka Cancer Center, who presented four-year follow-up data from the 10-center study (abstract 834). see ESD, page 17

see Rectal Cancer, page 24

I N S I D E

Finding Keys to Recovery After Colorectal Surgery

EXPERTS’ PICKS The Best of Digestive Disease Week (DDW): Part 3 Experts share their favorite abstracts from DDW 2014 ...................................................................page 36

BY VICTORIA STERN

he goal of any perioperative protocol is to improve patient outcomes after surgery. In colorectal surgery, however, there is minimal evidence to support traditional perioperative practices, such as bowel preparation and fasting before surgery. Vijay Yajnik, MD, PhD

see Recovery, page 21 PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Ultra-Slim Configuration Advances Upper Endoscopy And Colonoscopy Faculty Sunguk Jang, MD Staff, Division of Gastroenterology Section of Therapeutic Endoscopy Cleveland Clinic Foundation Cleveland, Ohio

Jason B. Samarasena, MD Director, Advanced Endoscopic Imaging H.H. Chao Comprehensive Digestive Disease Center Assistant Clinical Professor of Medicine University of California, Irvine Orange, California

Introduction

Ultra-Slim Configuration Advances Upper Endoscopy and Colonoscopy See page 6

Upper endoscopy and colonoscopy permit the direct evaluation of the mucosal surface of the gastrointestinal (GI) tract and the effective treatment of many conditions that were previously only treated by surgery.1 However, patient discomfort and longer procedure duration can increase the probability for complications and make it less likely that the procedure’s goals will be met. Additionally, the formation of loops during the procedure, redundant colons, difficult or complex flexures, and the presence of strictures are all factors associated with increased patient discomfort.2 Innovations in endoscopy equipment hold the potential to improve the experience for the patient and physician, and to extend what is clinically feasible using an endoscopic approach. A new generation of ultra-slim endoscopes from the Olympus EVIS EXERA III platform advances visualization, scope maneuverability, and workflow. The new instruments are appropriate for any patient, but may especially benefit patients with altered anatomy, diverticular disease, or strictures.

Common Procedures, Common Challenges In esophagogastroduodenoscopy (EGD), reducing endoscope diameter addresses 2 specific needs. First, strictures or lesions may prevent the endoscope from reaching the intended location.3 Second, transnasal EGD (TN-EGD) requires a scope with a diameter less than 6 mm.4 Therefore, reducing scope diameter may influence utility, and in some conditions equipment traits can make the difference between a successful procedure and failure to obtain a specimen or relieve a stricture.5 In the United States, EGD is typically performed by mouth in patients under conscious or moderate sedation. However, slimmer scopes may reduce or eliminate the need for anesthesia during procedures. Direct comparison of unsedated

TN-EGD and unsedated or sedated transoral EGD (TO-EGD) demonstrated a lower rate of gag reflex and smaller changes in arterial oxygen saturation and pulse rate in patients who underwent TN-EGD.6 Overall, TN-EGD is a more comfortable and tolerable procedure for the patient and may result in a safer and more useful examination.4,7 Additionally, unsedated upper endoscopy reduces sedation costs and can increase patient satisfaction. Colonoscopy also presents challenges related to equipment size and capability. In many cases, obtaining a complete colonoscopy, extending to the cecum, may be difficult. Altered anatomy as a result of colorectal cancer, diverticula, prior surgery, or inflammatory bowel disease is associated with incomplete procedures.3,5 Strictures, lesions, and inflamed tissue create narrowing and may prevent passage of a standard-sized endoscope.3 In situations where conventional colonoscopes are too large, some endoscopists use pediatric instruments or other endoscopes, although these instruments may be too short or floppy to reach the cecum.5,8 In addition to anatomic impediments, endoscope looping may occur during colonoscopy.5,8 Looping deforms the wall of the colon, causing pain to the patient, and can result in loss of control of the endoscope and perforation of the colon.5 The primary challenge of colonoscopy derives from the necessity of pushing the endoscope through the colon, which is too flaccid to resist or redirect the force.9 Carefully chosen scope maneuvers, including pulling back as needed and reducing bends in the scope as they occur, decrease colon stretching and reduce procedural pain. However, endoscopists are often unaware of loops forming and subsequent perforation of the colon. Direct visualization of the endoscope during the procedure improves loop detection and resolution.5

Advances in Scope Technology The newest-generation colonoscope (PCF-PH190L/I) and upper endoscope (GIF-XP190N) employ innovations in 3 areas: physical dimensions, angulation range and bending design, and optical system (Table).10,11 The slim diameter of the colonoscope (9.5 mm) makes insertion easier under all conditions, but is especially valuable for difficult cases of stricture or lumen narrowing. The ultra-slim gastroscope is suitable for TN-EGD, with a distal end outer diameter of 5.4 mm and an insertion tube diameter of 5.8 mm (Figure 1).4,11 In addition, this is the first ultra-slim gastroscope with electrosurgery compatibility from Olympus. 11 The colonoscope and gastroscope have working channels of 3.2 and 2.2 mm, respectively.10,11 Therefore, although the scopes are

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

ultra-slim, they have ample working channels, allowing for increased suction volume and a greater variety of device selection. The optical system of the Olympus UltraSlim EVIS EXERA III scopes has 3 new features that enhance performance: 2 light guides that increase brightness and reduce device-use shadows, increased viewing angle (140 degrees for both the gastroscope and ultra-slim colonoscope), and narrow band imaging (NBI) capability.10-12 NBI uses wavelengths in the blue-green range to visualize tissue and enhance mucosal and vascular pattern observation.13 The EVIS EXERA III colonoscope features 2 distinct insertion tube technologies that together constitute Olympus’ proprietary Responsive Insertion Technology: High Force Transmission and Passive Bending (Figure 2).12 Physicians move endoscopes through the colon by pushing, pulling, and applying torques. High Force Transmission transfers physician-applied forces in a 1:1 ratio with a minimum loss of force. High Force Transmission is beneficial in situations where the colon has many bends or where loops have formed in the endoscope, and allows operators to use less force, reducing physician effort and stress.14 Physician fatigue has been identified as a potentially significant variable in adenoma detection.15 Additionally, Passive Bending helps move scopes through flexures more easily. The Passive Bending segment is located behind the tip and active bending segment of the instrument. When the scope contacts the colon wall, the Passive Bending

segment senses the change in pressure and bends in the direction of the lumen, creating a gentle curve that allows the scope to slide forward around flexures. ScopeGuide reveals endoscope position in real time and alongside the endoscopic view on the same monitor.16 The real-time image of the insertion tube shows the location and shape of the instrument. Loops can be identified as they form, and a hand coil allows the precise location of the scope to be identified for applying hand pressure accurately and effectively.17 ScopeGuide can be enabled with the PCF-PH190L/I colonoscope through the use of the MAJ-1878 ScopeGuide probe passed through the instrument channel.

Keys to Success in the Clinic Ultra-Slim Advantages in Upper Endoscopy Sedation requirements are typically reduced when using the slimmer scope for TN-EGD instead of TO-EGD, benefiting the patient and reducing the likelihood of complications.4 Reduced use of anesthesia also may shorten the procedure time.4 Kadayifci and colleagues performed a prospective, randomized clinical study in 100 patients scheduled for upper endoscopy to investigate the potential of minimal sedation in this procedure.7 All patients had undergone an unsedated TO-EGD within the past 12 months. Half of these patients underwent unsedated TO-EGD using a traditional endoscope and the other half underwent

Table. Features of Olympus Ultra-Slim EVIS EXERA III Colonoscope And Upper Endoscope Colonovideoscope (PCF-PH190L/I)

Gastrointestinal Videoscope (GIF-XP190N)

Physical dimensions, mm Distal end outer diameter Insertion tube outer diameter Working length Channel inner diameter

Feature

9.7 9.5 1,680 3.2

5.4 5.8 1,100 2.2

Optical system Narrow band imaging Enhanced image quality Field of view, degrees Brightness

Yes Yes 140 2 light guide lenses

Angulation range, bending section, degrees Up Down Right Left

180 180 160 160

210 90 100 100

Adapted from references 11 and 12.

Manoop S. Bhutani, MD

EDUCATIONAL REVIEW The Changing HCV Landscape: Update on Diagnosis and Treatment

The Changing HCV Landscape: Update on Diagnosis and Treatment SONAL KUMAR, MD, MPH Assistant Professor of Medicine Weill Medical College of Cornell University New York, New York

IRA M. JACOBSON, MD Chief of the Division of Gastroenterology and Hepatology Vincent Astor Distinguished Professor of Medicine Weill Medical College of Cornell University New York, New York

PRINTER-FRIENDLY VERSION A AVAILABLE AT GASTROENDONEWS.COM

EDUCATIONAL REVIEW Ulcerative Colitis: Diagnosis and Treatment

Ulcerative Colitis: Diagnosis and Treatment ELLEN J. SCHERL, MD Director, Jill Roberts Center for Inflammatory Bowel Diseasea Attending Physiciana Professor of Clinical Medicineb Jill Roberts Professor of Inflammatory Bowel Diseaseb Adjunct Professor of Medicinec

he greatest challenge for clinicians who treat patients with inflammatory p y bowel disease (IBD) is to move from symptom-oriented

(sstep-up) strategies toward prevention-oriented

BRIAN P. BOSWORTH, MD

(e early intervention) strategies aimed at tight

Director, Gastroenterology Fellowship Programa,b Associate Attending Physiciana Associate Professor of Medicineb Anne and Ken Estabrook Clinical Scholar in Gastroenterologyb

of the natural history of IBD. This

VINITA E. JACOB, MD Director Interdisciplinary Education, Jill Roberts Center for IBDa Assistant Attending Physiciana Assistant Professor of Medicineb

in nflammation control and alteration re eview focuses on a personalized approach to the treatment of patients with ulcerative co olitis (UC).

ADAM F. STEINLAUF, MD

See insert at end of issue

ith more than 170 million people worldwide infected with the hepatitis C virus (HCV), the burden of the

disease is indisputably significant.1-4 In 2010, there

were an estimated 2.7 to 3.9 million cases of chronic HCV in the United States alone, with up to 75% of individuals unaware of their diagnosis.5 Due to the high prevalence and underdiagnosis of disease, the Centers for Disease Control and Prevention in 2012 and the U.S. Preventative Services Task Force in 2013 modified their guidelines to recommend a one-time screening of adults born between 1945 and 1965.5 I NDEPENDENTLY DEVELOPED BY MCMAHON PUBLISHING

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

See insert at end of issue

Director of Strategic Planning and Growth, Jill Roberts Center for IBDa Assistant Attending Physiciana Assistant Professor of Medicineb a

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

Dr. Bosworth has served as a consultant to and speaker for Salix. Dr. Scherl has served as a consultant or advisory board member for AbbVie, Crohn’s and Colitis Foundation of America (CCFA), GIHealth Foundation, Janssen, Prometheus, Protagonist Therapeutics, Salix, Takeda Pharmaceuticals, and UCB. Drs. Scherl, Bosworth, Jacob, and Steinlauf have received grant or research support from Abbott (AbbVie), AstraZeneca, CCFA, Elan, Janssen Research & Development, Millennium Pharmaceuticals, National Institutes of Health, New York Crohn’s Foundation, Mesoblast (formerly Osiris Therapeutics), Pfizer, Prometheus Laboratories, UCB, UCSF–CCFA Clinical Research Alliance. She also has received honoraria from the GIHealth Foundation and Janssen.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G G A S T R O E N T E R O L O G Y & E N D O S C O P Y N E W S • S E P T E M B E R 2 0 1 4

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Drug for Celiac Disease Eases Symptoms in Multicenter Trial But some experts question size of benefit BY TED BOSWORTH CHICAGO—A novel agent called larazotide acetate for the treatment of celiac disease significantly reduced symptoms in a large double-blind, placebo-controlled trial. The drug’s mechanism of action is to prevent gluten uptake by

closing tight junctions in the gastrointestinal (GI) tract. “This is the first large randomized and blinded trial to associate a therapeutic agent with significant symptom reduction in celiac disease,” said Joseph A. Murray, MD, of the Division of Gastroenterology and Hepatology at Mayo Clinic, in Rochester, Minn. The

tolerability of the drug was “comparable to placebo,” said Dr. Murray, who presented the data at Digestive Disease Week 2014 (abstract 929f ). Larazotide acts by altering paracellular permeability in the GI tract to inhibit transport of gluten peptides into the lamina propria. By closing tight junctions in the intestinal epithelium, immunogenic

peptides are prevented from initiating a cycle of events that includes cytokinemediated inflammation. The therapy is not expected to replace gluten-free diets, but to act as an adjunct because of the frequency with which patients experience symptoms despite avoiding gluten. The trial included 342 patients at 74 sites in North America randomized to receive 0.5, 1 or 2 mg of larazotide (Alba Therapeutics) or placebo taken three times daily. The design included a fourweek placebo run-in, 12 weeks on the assigned therapy and a four-week placebo run-out. The primary outcome was a significant reduction when compared with placebo of diarrhea, indigestion and abdominal pain as measured on the Celiac Disease Gastrointestinal Symptom Rating Scale (CeD GSRS). Larazotide acetate increased the proportion of patients who reported no or very few symptoms by 31% (P=0.034), P yet only the 0.5-mg dose was effective, according to the researchers. Fulfilling the primary end point, symptom reductions see Larazotide, page 4

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Larazotide

Heard Here First

continued from page 3

See page 12

Physicians

need not perform

endoscopic screening for

esophageal cancer in low-risk patients, because their risk of being sued for malpractice for

a delay in

diagnosis is low.

on larazotide acetate were significant in an intention-to-treat analysis (P=0.022). P The clinical value of the agent was supported by a prespecified per-protocol analysis, which demonstrated an even more significant treatment effect (P=0.007). P Why the higher doses produced no benefit is unclear, the investigators said, but improvement with the 0.5-mg dose was observed for several additional end points, including reductions in headache and tiredness (P=0.01). P Patients taking larazotide also experienced a 26% reduction (P=0.017) P in the number of days with severe celiac symptoms compared with those taking placebo. Based on these results, larazotide acetate 0.5 mg “has the potential to become the first pharmacologic therapy for celiac disease,” Dr. Murray said. “Treatments are needed because inadvertent exposure to glutens and nonadherence to glutenfree diets are common with more than 70% of individuals with celiac disease reporting continued symptoms despite the dietary restrictions.” Dr. Murray said the drug, if approved, would not be a panacea, but rather an

option to improve signs and symptom control along with current dietary strategies. Daniel Leffler, MD, director of research at the Celiac Center of Beth Israel Deaconess Medical Center, in Boston, called the new findings “exciting results.” Dr. Leffler predicted the drug likely would be useful in routine care if further studies result in regulatory approval. “The magnitude of improvement in GI symptoms is in line with what we see for other effective treatments of GI diseases such as Helicobacter pylorii eradication in patients with dyspepsia,” Dr. Leffler said. “In addition, the significant improvement in non-GI symptoms is intriguing, especially given what looks like a very good safety profile.” ■ Dr. Murray has financial relationships with Alvine, AMAG, Bioline Rx, Enterohealth, Enteromedics, Flamentera, GlaxoSmithKline, Iralnd, Ironwood Pharmaceuticals, Torax Medical and Vysera. Dr. Leffler reported no relevant financial conflicts of interest. Funding for the study was provided by Alba Therapeutics.

Vol. 65, No. 9 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

September 2014

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Remifentanil an Option for Conscious Sedation But risk for respiratory effects warrants closely controlled setting BY MICHAEL VLESSIDES

n increasing number of procedures either do not require general anesthesia or are performed in patients too fragile to tolerate it, opening the door to increased use of conscious sedation, particularly with a fast-onset/fast-offset drug. An observational study by a team of French investigators has concluded that target-controlled infusion with remifentanil is appropriate for conscious sedation, even in fragile patients or for long-duration procedures. They noted, however, that a risk for respiratory depression suggests that the approach be used only in a controlled environment with continuous monitoring.

Each patient received a target-controlled infusion of remifentanil, with an initial target of 2 ng/mL. “We increased the target if the patient complained of pain or was agitated,” Dr. Billard said. “We decreased the target if we observed low respiratory rate, hypoxemia, bradycardia or hypotension.” Assisted ventilation, atropine, ephedrine and propofol

were all kept at hand if adjusting the target did not allow the procedure to be completed. As Dr. Billard reported at the 2013 annual meeting of the American Society of Anesthesiologists (abstract 2127), procedures were successfully completed with remifentanil in 86 patients. Four patients required a bolus of propofol to

see Conscious, page 8

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‘Remifentanil is really suitable for this kind of conscious sedation in fragile patients.’ —Valerie Billard, MD

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EUS “Conscious sedation using remifentanil makes sense in cases of narrow therapeutic window, especially when administered as a target-controlled infusion,” said Valerie Billard, MD, professor of anesthesiology at Institut Gustave Roussy, in Villejuif. The trial included 91 patients, all of whom required conscious sedation with spontaneous ventilation for procedures including hepatic embolization or chemoembolization, gastrointestinal endoscopy and skin surgery. The average duration of sedation was 69±53 minutes, and 13 cases lasted longer than 120 minutes.

quell agitation; one was converted to general anesthesia. “Respiratory depression is a main concern,” Dr. Billard noted, “and 37% of patients had at least one episode of respiratory rate below eight [breaths] per minute. But most of the time it was of very brief duration, and could be reversed

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THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Introduction Upper endoscopy and colonoscopy permit the direct evaluation of the mucosal surface of the gastrointestinal (GI) tract and the effective treatment of many conditions that were previously only treated by surgery.1 However, patient discomfort and longer procedure duration can increase the probability for complications and make it less likely that the procedure’s goals will be met. Additionally, the formation of loops during the procedure, redundant colons, difficult or complex flexures, and the presence of strictures are all factors associated with increased patient discomfort.2 Innovations in endoscopy equipment hold the potential to improve the experience for the patient and physician, and to extend what is clinically feasible using an endoscopic approach. A new generation of ultra-slim endoscopes from the Olympus EVIS EXERA III platform advances visualization, scope maneuverability, and workflow. The new instruments are appropriate for any patient, but may especially benefit patients with altered anatomy, diverticular disease, or strictures.

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Table. Features of Olympus Ultra-Slim EVIS EXERA III Colonoscope And Upper Endoscope Feature

Colonovideoscope (PCF-PH190L/I)

Gastrointestinal Videoscope (GIF-XP190N)

Physical dimensions, mm Distal end outer diameter Insertion tube outer diameter Working length Channel inner diameter

9.7 9.5 1,680 3.2

5.4 5.8 1,100 2.2

Optical system Narrow band imaging Enhanced image quality Field of view, degrees Brightness

Yes Yes 140 2 light guide lenses

Angulation range, bending section, degrees Up Down Right Left

180 180 160 160

210 90 100 100

Adapted from references 11 and 12.

Supported by

lesions.18 All 105 patients included in the study underwent TN-EGD and were examined using WLE, NBI, and Lugol staining. Results showed that NBI had almost 100% detection of squamous cell carcinoma and noninvasive high-grade intraepithelial neoplasia. However, WLE only detected 66.7% of squamous cell carcinomas. The investigators concluded that the use of NBI in TNEGD is useful for differentiating between inflammatory lesions and the early stage of esophageal cancer.18

Advantages in Colonoscopy

Figure 1. Olympus GIF-XP190N EVIS EXERA III gastrointestinal videoscope. Image courtesy of Olympus.

Studies have demonstrated the advantages of using advanced technology scopes in colonoscopy as well. For instance, Rastogi and colleagues investigated cecal intubation times with the use of scopes incorporating both Passive Bending and High Force Transmission technologies.19 Using a post hoc analysis of 2 prospective trials including 1,077 patients, the investigators found that mean cecal intubation times were significantly shorter when using instruments with Passive Bending and High Force Transmission technologies than without (P=0.005). The investigators suggest that by reducing intubation times, clinician fatigue and patient discomfort also may be reduced during the insertion phase of colonoscopy.19

Conclusion

➞

Figure 2. Responsive Insertion Technology of the EVIS EXERA III colonoscope. (A) Passive Bending redistributes pressure when the scope meets resistance so that the insertion tube automatically bends to adjust to the acute curves of the colon. (B) High Force Transmission transfers rotational torque down the length of the insertion tube, allowing the scope to react more sensitively to physician handling. Images courtesy of Olympus.

Clear observation of the GI tract is an absolute requirement for disease surveillance and treatment; innovations in endoscopy equipment aid physicians in providing optimal care to patients with minimal patient discomfort. The optical system of EVIS EXERA III provides greater brightness, increased viewing angle, and push-button availability of NBI. The slimmer profile of both gastroscope and colonoscope, combined with an ample working channel, supports TN-EGD for upper endoscopy patients and permits mobility around strictures and inflamed areas of the GI tract. Electrosurgery functionality supports therapy. Finally, the greater ease of use of the instruments, due to proprietary Responsive Insertion Technology, aids insertion and completion of procedures and protects physicians with high-volume practices. Added value is derived from the possibility of reduced use of anesthesia during procedures, which may lower the risk for complications, reduce sedation costs, and improve patient satisfaction.20,21

References 1. American Society for Gastrointestinal Endoscopy Standards Practice Committee, Early DS, Ben-Menachem T, et al. Appropriate use of GI endoscopy. Gastrointest Endosc. 2012;75(6):1127-1131. 2. Brooker JC, Saunders BP, Shah SG, et al. A new variable stiffness colonoscope makes colonoscopy easier: a randomized controlled trial. Gut. 2000;46(6):801-805.

3. Loffeld RJ, van der Putten AB. The completion rate of colonoscopy in normal daily practice: factors associated with failure. Digestion. 2009;80(4):267-270. 4. Atar M, Kadayifci A. Transnasal endoscopy: Technical considerations, advantages and limitations. World J Gastrointest Endosc. 2014;6(2):41-48. 5. Waye JD. Difficult colonoscopy. Gastroenterol Hepatol. 2013;9(10):676-678. 6. Tsuboi M, Arai M, Maruoka D, et al. Utility of unsedated transnasal endoscopy for pharyngeal observation during esophagogastroduodenoscopy. A prospective study to assess cardiopulmonary function. Scand J Gastroenterol. 2013;48(7):884-889. 7. Kadayifci A, Atar M, Parlar S, et al. Transnasal endoscopy is preferred by transoral endoscopy experienced patients. J Gastrointestin Liver Dis. 2014;23(1):27-31. 8. Witte TN, Enns R. The difficult colonoscopy. Can J Gastroenterol. 2007;21(8):487-490. 9. Loeve AJ, Fockens P, Breedveld P. Mechanical analysis of insertion problems and pain during colonoscopy: why highly skill-dependent colonoscopy routines are necessary in the first place ... and how they may be avoided. Can J Gastroenterol. 2013;27(5):293-302. 10. Olympus. EVIS EXERA III colonovideoscope PCFPH190L/I. 2012. 11. Olympus. EVIS EXERA III gastrointestinal videoscope GIF-XP190N. 2012. 12. Olympus. 190-series colonoscopes, EVIS EXERA III. 2014. 13. Valdastri P, Simi M, Webster RJ, 3rd. Advanced technologies for gastrointestinal endoscopy. Annu Rev Biomed Eng. 2012;14(1):397-429. 14. Olympus. Evis Exera III Video. http://link.videoplatform.limelight.com/media/?mediaId=6f2f7ba9feec 40a8b1e69ea6927f349c&width=480&height=321& playerForm=463201359c694be2ae93af3071ff9273. Accessed July 23, 2014. 15. Lee TJ, Rees CJ, Blanks RG, et al. Colonoscopic factors associated with adenoma detection in a national colorectal cancer screening program. Endoscopy. 2014;46(3):203-211. 16. Ellul P, Fogden E, Simpson C, et al. Colonic tumour localization using an endoscope positioning device. Eur J Gastroenterol Hepatol. 2011;23(6):488-491. 17. Ambardar S, Arnell TD, Whelan RL, et al. A preliminary prospective study of the usefulness of a magnetic endoscope locating device during colonoscopy. Surg Endosc. 2005;19(7):897-901. 18. Kawai T, Takagi Y, Yamamoto K, et al. Narrow-band imaging on screening of esophageal lesions using an ultrathin transnasal endoscopy. J Gastroenterol Hepatol. 2012;27(suppl 3):34-39. 19. Rastogi A, Kaltenbach T, Soetikno R, et al. Cecal intubation times with colonoscopes incorporating passive bending and high-force transmission technology: a multicenter randomized controlled trial. Presented at the American College of Gastroenterology Annual Scientific Meeting; October 11-16, 2013. 20. Petrini JL, Egan JV, Hahn WV. Unsedated colonoscopy: patient characteristics and satisfaction in a community-based endoscopy unit. Gastrointest Endosc. 2009;69(3 Pt 1):567-572. 21. Mannath J, Subramanian V, Hawkey CJ, et al. Narrow band imaging for characterization of high grade dysplasia and specialized intestinal metaplasia in Barrett’s esophagus: a meta-analysis. Endoscopy. 2010;42(5):351-359.

OAIGI0814REP13519

Furthermore, Kawai and colleagues used an ultra-slim transnasal scope to compare the diagnostic performance of conventional white light endoscopy (WLE) with NBI in the detection of esophageal

Disclosures: Dr. Jang reported no conflicts of interest. Dr. Samarasena reported that he has served as a consultant for Pentax Medical Company and received honoraria from Covidien, Ltd. and Mauna Kea Technologies, S.A.

BB1416

unsedated TN-EGD using an ultra-slim scope. The investigators found that 82% of patients reported the TN-EGD procedure to be much more tolerable than their previous TO-EGD endoscopy.7

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

COMMENTARY

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

The Prime Directive BY STEVEN S. KRON, MD

s anyone with a computer knows, before downloading a new program, you must indicate agreement with the Terms of Service (TOS), a tedious multipage scroll. By checking a box at the bottom of the page, you acknowledge that you have read and accept the TOS. Those crafted by the really expensive lawyers have two check boxes—the first

indicating that you agree with and accept the TOS, the other that you indeed have read the words to which you assent. Yeah right! Does anyone without a certifiable DSM-5 [Diagnostic and Statistical Manual] l disorder go through the ponderous legalese before checking off the box that says he or she has done so? Furthermore, have there ever been negative consequences to such gross dishonesty? I doubt it.

Which brings us to the written consent form that I’m confident we all obtain before administering anesthesia. Naturally, obtaining consent and obtaining a consent form are different animals entirely. Although few if any anesthesia lawsuits hinge exclusively on the lack of a consent form, the absence of one may hurt a defendant accused of other misbehavior. Should a lawsuit arise for an unrelated cause, those smart, really expensive lawyers certainly will use a poorly written

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Dr. Kron is an anesthesiologist in Hartford, Conn.

consent to raise doubts about the anesthesiologist’s professionalism or concern for the patient. The anesthesia consent form has come a long way since my residency. Back then, it simply did not exist. Of course, we discussed anesthesia with patients during the preoperative visit. But because the surgical consent included a line that anesthesia would be administered, a separate written consent for the receipt of anesthesia was deemed unnecessary. The surgeon or anesthesiologist pretty much dictated the type of anesthesia, so the conversation tended to be one-sided. Entering private practice, I soon learned that patients’ desires mattered. If my plan conflicted with their preconception, I would need to convince them of the benefits of my approach. Yet I did not need their signature. After a decade or so, in response to some outside review, we decided to add a line signed by the anesthesiologist testifying to the fact that he or she discussed anesthesia, possible complications and alternatives with the

Conscious continued from page 5

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by verbal command, light stimulation or by decreasing the target.” Two patients required brief assisted ventilation; SpO2 in one patient dropped below 90%. No patient required atropine or ephedrine. “Remifentanil is really suitable for this kind of conscious sedation in fragile patients,” Dr. Billard said. “Failure of sedation remains possible, however, and respiratory depression is not rare and suggests that this technique should be limited to a controlled environment.” Evan D. Kharasch, MD, PhD, the Russell D. and Mary B. Shelden Professor of Anesthesiology at Washington University in St. Louis, said the study identified the growing demand for conscious sedation and the desire for drugs with rapid onset and offset, which is most commonly achieved with

COMMENTARY

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

sick of words.’ —Eliza Doolittle in My Fair Lady

patient. There was still no requirement for the patient to sign. The next incarnation added a requirement for the patient’s signature. This was a bit of an adjustment for those of us who were not sure how to discuss complications. Conventional medicolegal wisdom says that you need to mention common but minor and rare but catastrophic ones. So, do you tell them that they may get a little sore throat, a bit of nausea and oh, by the way, you might die (please sign at the X)? Our most recent consent form is by far the most thorough I have ever seen and has been made the standard for all the members of the mega–hospital conglomerate to which we belong. It is similar to but even more complete than the form on the website of the American Society of Anesthesiologists and covers every possible issue that could arise. Of the hundreds of patients I have asked to sign this document, none—not one—has hesitated. Unfortunately, the problem I have consistently encountered is, despite a willingness to sign, their near 100% unwillingness to read that to which they are attesting! Some of the reluctance is no doubt due to the same lack of interest I have for reading the TOS discussed above: an

have signed multiple forms—consents, releases of information, HIPAA forms and assignments of benefits and are, like Eliza Doolittle, just so sick of words. In my dealings with genuinely sick patients having major procedures, I have found that they and their families generally do seem to appreciate the potential hazards of anesthesia and a signature at the bottom of the page is a true acknowledgment of that.

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sedative-hypnotics such as propofol and benzodiazepines. “While remifentanil did achieve sedation, there was also a high incidence of respiratory depression, which, while generally brief and treated with patient stimulation or changing infusion rates, required ventilatory assistance in a few patients, while others needed propofol for agitation or conversion to general anesthesia,” Dr. Kharasch said. “As the authors identified, failure of sedation was a real possibility, a controlled environment is critical and skilled practitioners are needed in attendance at all times. “Thus,” Dr. Kharasch added, “the technique of using [remifentanil] only for conscious sedation would appear to need improvement prior to widespread and safe implementation.” ■

Ironically, it is the healthier and particularly the morbidly obese patients with sleep apnea who are having moderate sedation for minor procedures, such as endoscopies, who seem less willing to understand risk. Explaining to these folks that propofol is a great drug that will quickly sedate them and allow for a rapid and nausea-free emergence, but may cause apnea or an obstructed airway, can be tricky. It also violates the prime directive: Don’t scare the customer. ■

New York Society for Gastrointestinal Endoscopy

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understanding that these are lawyer-generated documents designed to, as more than one patient has accurately put it, “cover your ass”! My response is to agree, again offer to tell them the risks, and if and when they refuse, make a few lawyer jokes and off to sleep. Often, there is the complaint that the document is too long and wordy and written in an illegibly small font. Perhaps most important, by the time they have gotten to me, they

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REGISTER ONLINE AT WWW.NYSGE.ORG • CONTACT US AT INFO@NYSGE.ORG NURSING ACCREDITATION STATEMENT This educational activity has been submitted to the Society of Gastroenterology Nurses and Associates, Inc. for approval. The Society of Gastroenterology Nurses and Associates, Inc. is accredited as an approver of continuing CREDIT DESIGNATION STATEMENT Albert Einstein College of Medicine of Yeshiva University designates this live activity nursing education by the American Nurses Credentialing TM M for a maximum of 15.0 AMA PRA Category 1 Creditss . Physicians should claim only the credit commensurate with Center’s Commission on Accreditation. the extent of their participation in the activity. 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 through the joint sponsorship of Albert Einstein College of Medicine of Yeshiva University and the New York Society for Gastrointestinal Endoscopy. Albert Einstein College of Medicine of Yeshiva University is accredited by the ACCME to provide continuing medical education for physicians.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

40 Years in a Changing Field An interview with Jerome Siegel, MD, winner of the 2014 Rudolf V. Schindler Award BY BRIGID DUFFY

n May 4, 2014, Jerome Siegel, MD, received the Rudolf V. Schindler Award at the American Society for Gastrointestinal Endoscopy’s (ASGE) Crystal Awards in Chicago. The award is ASGE’s highest honor, given to a member whose accomplishments in endoscopic research, teaching and service to ASGE exemplifies the standards and traditions of Rudolf Schindler, MD, founder of the American Gastroscopic Club, the forerunner of ASGE. Dr. Siegel has witnessed and participated in the meteoric advances in gastrointestinal (GI) endoscopy from the primary stages of examining most of the GI tract to treating most of the disease affecting that system as alternatives to surgery, and he is a leader in the field of endoscopic retrograde cholangiopancreatography (ERCP) for the management and treatment of pancreaticobiliary diseases. He is a master of the American College of Gastroenterology, a fellow Master Endoscopist of the ASGE, a fellow of the American Gastroenterological Association and a fellow of many other U.S. and international organizations. Gastroenterology & Endoscopy Newss recently had the pleasure of talking with Dr. Siegel as he reflected on 40 years of changes in endoscopy, the global reach of the gastroenterology community and emerging therapeutic capabilities.

s a doctor who has been part of ASGE for many decades, what does the Rudolf V. Schindler Award mean to you?

It’s an honor that is very meaningful to me. My residency in gastroenterology was at Columbia Presbyterian Medical Center [in New York City], where I had two mentors who influenced me tremendously: Charles Flood and Henry Colcher. Flood was part of the first group to be certified in gastroenterology in 1949 when it became a specialty, and he was one of the founding members of the organization that became the ASGE. And Colcher, who was also very active within the group, invented the flexible endoscope, which was nothing more than a flexible fiberglass chain of tiny lenses in a hose. They both became president of the ASGE; they both received the Schindler Award; and they both had some experience working with Dr. Schindler. So it was very sentimental and symbolic to me that my former mentors were all recipients.

he process of taking a new technology from one area and adapting it to fit another was very similar to how D Dr. Schindler worked, wasn’tt it?

It is exactly what Dr. Schindler was doing. He was always briinging new technology to the field, and d he h was one of the first to realize that a lot of what we were doing could be done endoscopically. He would even draw his own pictures after endoscopic procedures because there was no photography. Other surgeons and other jealous competitors criticized him, but eventually some of his advancements became the standard of care. It’s funny, in the early days when I was reporting some of the work that I was doing nationally, some of the members of the audience would get up and ask, “How can you do that?” But many of those things—ERCP for patients with cholangitis, for example—became the standard of care. Things are always evolving.

they had the foresight to advance into therapeutic endoscopy. Their restrictions aren’t as great as what we have in the United States, and they don’t face the issue of malpractice as much as we do, so they had the freedom to innovate, and we learned from their innovation. When we saw what they were doing, we thought, “we’ll try to advance ourselves a little more safely for the patients.” n addition to teaching in Vietnam, you’re also a clinical professor at Albert Einstein College of Medicine. How does teaching affect your understanding of the field?

It’s truly a wonderful exchange. Every day, we’re working shoulder to shouls you mentioned, you der with students. Didactically, it’s nice completed a fellowship when someone is right there working in gastroenterology and liver with you, one-on-one. And when we diseases in London. Through the do live courses, it’s a treat, but challengou’ve been instrumental in ASGE’s Ambassador Program, ing to teach, particularly when you have pancreaticobiliary disease you teach a seminar at the Hue people looking over your shoulder. You treatment, which is arguably one Medical School in Vietnam, and really need to be extra cautious because of the more complex areas to treat the most important thing is always treatwithin gastroenterology. What drew you have spoken at countless international meetings. How ing the patient. you to this area? important is it to connect with And the important thing with the Again, it was my background with Col- gastroenterologists who practice Vietnam ambassador trips is being able to cher and Flood. After my fellowship in outside of the United States? bring different specialties to poorer provgastroenterology and liver diseases at the inces. There are a number of accidents Royal Free Hospital, University of LonIt’s really important. Cooperation with bicycles and motorbikes in that area, don, England, they wanted me to partici- between international gastroenterologists and they’re still in great need of advanced pate in their endoscopy program in New and American gastroenterologists is very endoscopic training and resources. The York. In order to get Vietnamese physicians’ to that level I had to enthusiasm for acquirbe accomplished in ‘Cooperation between international gastroenterologists ing advanced endoupper endoscopy and and American gastroenterologists is very friendly, and we scopic techniques was colonoscopy, which remarkable considering was a great challenge. share a unique brotherhood.’ the limited exposure There are many more they receive during their risks involved in ERCP than in other friendly, and we share a unique broth- training and in daily practice. As we were parts of the field, and a lot of people didn’t erhood. More than 50% of the student leaving, we witnessed some of our stuwant to take that risk, but many of our body of ASGE is from foreign countries. dents teach other doctors on the premfellows enjoyed the challenge. Then we In the beginning, the influence of other ises, so we know that they were confident applied what we learned to other areas— doctors—primarily Asians, Germans to spread the training that they had problems in the esophagus, mucosal and the Dutch—was very instrumental received from us. resection, all parts of the luminal GI tract. to American gastroenterologists because see Siegel, page 12

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Malpractice Claims s Rare for Undetected Esopha Esophageal Cancer Surveys of gastroenterologists suggest that fear of litigation may drive endoscopic screening for esophageal cancer in low-risk CHICAGO—Malpractice claims for delay in the patients, and this type of defensive medidiagnosis of esophageal cancer in patients at cine may contribute to rising health care low risk for the disease are uncommon, and the costs, according to the investigators. They rate of payment for such claims is even lower, said such costs could be avoided by adherMichigan researchers have found. ing to recommended guidelines in lowIn a study covering more than 100,000 insurrisk patients because the data suggest an ance claims, only 62 over an 11-year period extremely small risk of being sued for delay alleged a delay in diagnosis of an esophageal in diagnosis of esophageal cancer. Accordmalignancy, and only four of 19 claims in which ing to Dr. Adams, prior studies indicate no alarm symptoms had been alleged were paid. that previous screening was performed in The researchers said performing endoscopy in only 15% of the approximately 8,000 new low-risk patients with gastroesophageal reflux esophageal adenocarcinoma cases diagnosed ‘Physicians need not perform endoscopic screening for disease for the purpose of avoiding malpractice in the United States each year. esophageal cancer in low-risk patients because their risk of claims does not appear to be justified. Lyndon V. Hernandez, MD, chairman of “The incidence of malpractice claims against the editorial review board for Gastrointestibeing sued for malpractice for a delay in diagnosis is low.’ physicians for failure to screen for esophageal nal Endoscopy, and clinical associate profes—Lyndon V. Hernandez, MD cancer appears to be very low,” said Megan A. sor at the Medical College of Wisconsin, in Adams, MD, JD, a fellow in the Division of Gastroen- Of the 278,220 claims during that period, only 761 Milwaukee, said he agreed with the conclusion of the terology at the University of Michigan Health System, (0.027%) involved upper endoscopy. Of these, only 17 new study. in Ann Arbor. She performed this work in collabora- (2.2%) alleged inadequate indication for the procedure. “Physicians need not perform endoscopic screening tion with Joel H. Rubenstein, MD, MSc, an assistant Slightly less than half were paid. For malpractice claims for esophageal cancer in low-risk patients, because their professor in the division. The researchers reported their related to delay in diagnosis of cancer, the analyses had to risk of being sued for malpractice for a delay in diagnofindings at the 2014 Digestive Disease Week (abstract be confined to claims made from 2002 to 2012 because sis is low,” said Dr. Hernandez, who led a recent study Mo1087). earlier claims did not include presenting symptoms. Of on malpractice claims in endoscopy (World J Gastrointest Drs. Adams and Rubenstein hypothesized that the endoscopy claims in this period, 122 (0.1%) involved Endoscc 2013;5:169-173). incidence of claims alleging a delay in the diagnosis of esophageal malignancies, of which 62 (50.8%) alleged a Although the PIAA database does not have the detail esophageal cancer is lower than the incidence of claims delay in diagnosis. Of the 19 claims involving patients to permit variables to be cross-referenced “at a granular for complications from an endoscopy performed for an without alarm symptoms, only four (21.1%) were paid. level,” preventing strong conclusions, Dr. Hernandez inadequate indication. To test that theory, they used a The incidence of malpractice claims for failure to said adhering to guideline definitions of risk is likely malpractice database maintained by PIAA, an insurance screen for esophageal cancer appeared to be “of a simi- to be a sufficient measure to minimize likelihood of a trade association representing medical professional lia- lar magnitude as the incidence of claims alleging com- malpractice claim. ■ bility insurance companies that collectively insure more plications from [upper endoscopies] with questionable than two-thirds of physicians in private practice. indication,” but “the latter are more likely to result in Drs. Adams, Rubenstein and Hernandez reported no The data initially spanned the years 1985 to 2012. payment,” the investigators reported. relevant financial conflicts of interest. BY TED BOSWORTH

Siegel continued from page 10

ou’ve been a vital member of the field for many decades and you’ve basically seen endoscopy evolve from its inception into what it is today. What are some changes that we can anticipate in the near future?

Newer diagnostic and therapeutic capabilities are evolving every day. Endoscope manufacturers have upgraded their systems to provide a 180-degree field of view with NPI and zoom qualities that enhance our yield. And the Fuse system, or “full-spectrum endoscopy,” provides a 330-degree field of view for colonoscopes and a 245-degree field of view for upper endoscopes. Such developments enable endoscopists to appreciate more significant findings and miss fewer lesions. Capsule endoscopy will advance to a “controller system,” one in which biopsies might be available when a distant lesion is found. Just as ERCP, colonoscopy and

polypectomy and PEG [percutaneous procedure of choice for evaluating and centers of excellence, where multidisciendoscopic gastrostomy] procedures draining pseudocysts. plinary specialties are available, including emerged as our first therapeutic proceEUS has supplanted the radiologic state-of-the-art interventional radiology, dures, endoscopists had to adapt to these concept of rendezvous—it can do it all. surgery and critical care units. newer techniques or elect to refer patients Importantly, these techniques are not for Other procedures evolving and in requiring such techniques elsewhere. the faint of heart, and special training use include confocal microscopy and its From the time some of us entered is needed to become proficient in these derivatives, endoscopic suturing devices, the field, endoscopy has changed dra- areas. My recommendation for training at endoscopic bariatric procedures, endomatically, and many of us have become this point in time is that fellows spend an scopic gastroduodenostomy and jejuendoscopic surgeons, noenterostomy. I encourage as opposed to “surgical fellows to become proficient endoscopists” who perin many of these techniques, ‘From the time some of us entered the form laparoscopy, etc., especially removing larger field, endoscopy has changed dramatically, performing such techcolon or intestinal polyps, as niques as endoscopic the field is changing from and many of us have become endoscopic mucosal resection and screening procedures, which surgeons—as opposed to “surgical endoscopic surgical may be performed by nurse dissection. practitioners or other trained endoscopists” who perform laparoscopy, etc.’ Endoscopic ultrasound health care providers, leav(EUS) has evolved to ing the complex procedures to replace other diagnostic tests and has additional year in an advanced program. trained endoscopists. Thus is the everbecome a therapeutic modality. It not I share this philosophy with other leaders changing field of endoscopy that I have only helps clinicians perform fine-needle in the field of interventional endoscopy: been privileged to witness, participate in and core biopsies, but it has become the These procedures should be performed in and contribute to. ■

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

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Water Exchange Eases Pain of Colonoscope Insertion BY CAROLINE HELWICK CHICAGO— —Water exchange during colonoscopy is the least painful method for colonoscope insertion, recent studies have found. Several trials have shown that use of water to facilitate insertion of the colonoscope and carbon dioxide (CO2) insufflation are associated with less pain than air insufflation. Evidence also indicates that waterassisted and water exchange colonoscopy are valuable aids for improving

patient comfort during colonoscopy, colonoscopy esspepe cially for patients who elect not to have sedation for the examination. The findings from two studies presen nted at Digestive Disease Week (DDW) 2014 support the application of this techniqque, said Colleen M. Schmitt, MD, presid dent of the American Society for Gastrointeestinal Endoscopy and a practitioner with the Galen Group in Chattanooga, Tenn. “As we seek to enhance our existing toolkit in identifying ways to improve the quality of the examination for our patients, I look forward to future studies to help define the effectiveness of this technique in the larger clinical arena,” Dr. Schmitt said. “Unsedated colonoscopy is feasible but may be painful. Sedation increases costs, complications, and may be

Table 1. P Procedural d lO Outcomes t off C Colonoscopy l M Methods th d Outcome

CO2 (N=239)

Water Exchange (N=234)

P Value

Sedation/analgesia on demand

0.95

Intention to treat cecal intubation rate

92%

84%

0.01

Overall cecal intubation rate 92%

97%

0.02

Cecal intubation time, min (median)

<0.001

Total procedure time, min (median)

<0.001

External abdominal pressure

51%

38%

0.003

Post-procedural involuntary leakage

0.24

CO2, carbon dioxide

Table 2. Patients Reporting No Pain During Colonoscopy Pain During Colonoscopy, % Water Exchange 13

Water Immersion 7

Air Insufflation 6

Discomfort Only During Colonoscopy, % Water Exchange 40

Water Immersion 38

Air Insufflation 23

Request for Sedation, % Water Exchange 13

Water Immersion 14

Air Insufflation 30

impractical for patients patients,” said Kjetil GarGarrborg, MD, of Sorlandet Hospitall HF in Kristiansand, Norway, who led d on one of the studies (abstract 838). In the multicenter rando domized trial, Dr. Garborg directly compar ared waterassisted colonoscopy (water exchange) ex and CO2 insufflation with rega gard to procedural pain during unsedated co colonoscopy. The hypothesis was that wate ater exchange would reduce pain by 50% over er CO2 insufflation.

Water Exchange or CO2 The procedures were performed by six endoscopists who were experienced with unsedated colonoscopy. All the endoscopists participated in supervised hands-on training to learn the water exchange technique. Their cecal intubation rate was at least 90% in the last 30 cases before the study began.

Water exchange W h involved i l d simultaneous i l infusion and suction of water to identify the lumen during insertion, with the CO2 pump turned off during insertion and on during withdrawal. The study enrolled consecutive patients, aged 50 to 80 years, undergoing primary unsedated colonoscopy chiefly for screening. The researchers excluded patients who demanded sedation before the procedure and those with colonic resections, but sedation and analgesia were available during colonoscopy as needed. Patients were blinded to group allocation. The primary end point was the proportion of patients who reported “moderate” or “severe” pain on a four-point Likert scale (“no” and “slight” pain were the remaining points) to a blinded research assistant before leaving the endoscopy center. Patients also were asked to score pain on a scale from 0 to 10 in each colonic segment during insertion of the colonoscope. Secondary end points included maximum and mean pain scores on the numeric rating scale NRS11; cecal intubation rate; and detection rates of polyps, adenomas and sessile serrated adenomas.

Reduction in Pain In all, 473 patients were randomized; 90% were undergoing colonoscopy for screening. Baseline characteristics

w e r e ba nced balan betw etw ween the ar aarms. Sedation was as use sed in 6% off paattients. The he occurrenc nce of modera erate ate or se severe pain, the study’s pri primary ary end point, int did not differ significantly: 21% di in the water exchange group and 27% in the CO2 group (P=0.15). P However, significantly fewer patients in the water exchange group reported

procedural d l pain i at discharge: di h 44% versus 31% (P=0.003). P Mean pain scores during insertion were higher among patients who received insufflation with CO2, both for maximum (P<0.01) and overall pain (P<0.01). The differences were most pronounced in men (P=0.02), P but were not significantly greater in women. By colonic segment, the differences were observed in the sigmoid and transverse colon, and at the hepatic flexure (P<0.05 for all). “The sigmoid was the most painful, and this pain was significantly reduced with water exchange,” Dr. Garborg said. The tradeoff for slightly less pain, however, was a significantly longer procedural time with water exchange, and somewhat prolonged cecal intubation, although the overall rate of cecal intubation was higher with water exchange (Table). The rate of polyp detection was significantly higher in the water exchange group than in the CO2 insufflation group (63% vs. 47%; P<0.001), but there were no differences in the detection of adenomas, sessile serrated adenomas and advanced adenomas, nor in the number of adenomas detected per procedure. Dr. Garborg concluded that water exchange reduced procedural pain compared with CO2 insufflation, “but to a lesser degree than hypothesized.” see WATER page 14

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

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Transoral Fundoplication Effective For GERD Poorly Controlled With PPIs TED BOSWORTH CHICAGO—One year after treatment, transoral fundoplication appears to provide superior relief of regurgitation and atypical symptoms associated with persistent reflux compared with high-dose drug therapy, new research shows. The 12-month crossover study found that patients with chronic gastroesophageal reflux disease (GERD) were far more likely to be free of symptoms if they underwent transoral fundoplication with the EsophyX2 device (EndoGastric Solutions) than if they remained on high doses of proton pump inhibitors (PPIs). By the end of 12 months, 77% had achieved global elimination of regurgitation and atypical symptoms, and 82% were off PPIs. At a six-month interval, before a control group on high-dose PPIs was allowed to cross over to fundoplication, only 5% reported global elimination of symptoms. Based on these results, “transoral fundoplication is capable of dramatically eliminating GERD symptoms in appropriately selected patients with incomplete symptom control on high doses of PPIs,” said Karim S. Trad, MD, of the George Washington University School of Medicine and Health Sciences, in Washington, D.C. Dr. Trad, who presented the results at the 2014 Digestive Disease Week (DDW), emphasized that the relatively long-term results suggest that the benefit of GERD repair with this device is durable (abstract 724). A variety of devices for improving the barrier function of the lower esophageal sphincter have been developed over the past 40 years. Success has been uneven, however, particularly with long-term follow-up. The potential advantage of a transoral device approach over laparoscopic surgery is more rapid recovery and reduced risk for complications from anesthesia or infection. The EsophyX2 is equipped with a cartridge to deploy fasteners, and therefore is sutureless. The new study, conducted at seven centers in the United States, included patients with persistent symptoms on high-dose PPIs, a hiatal hernia of 2 cm or smaller, and increased esophageal acid exposure. Patients were randomized to transoral fundoplication or highdose PPI therapy in a 2-to-1 ratio. With three patients lost to follow-up, there were 39 evaluable patients in the fundoplication group and 21 patients who were treated

Image is provided here exclusively for promotion, editorial and academic use and/or media coverage of EndoGastric Solutions and its product, the EsophyX® Device for treatment of GERD to produce a TIF® (Transoral Incisionless Fundoplication). This notification serves as an authorization for publications to make duplicate copies of the available high-resolution scans for these uses only. ©2014 EndoGastric Solutions, Inc.

initially with PPIs. At six months, all of those assigned to PPIs elected to cross over to transoral fundoplication. Of the 19 fundoplication patients with esophagitis at study entry, all were healed at the end of 12 months. Of the control group, 38% had healed on PPIs at six months, and 75% were healed six months after crossing over to fundoplication. At the start of the study, almost 75% of patients complained of regurgitation while on PPIs (and 90% when off PPIs). At the end of 12 months, only 10% of those randomized to fundoplication had complaints of regurgitation when off PPIs. At entry, the prevalence of such atypical symptoms as hoarseness, throat clearing and cough ranged from less than 60% to nearly 80% in the absence of PPIs. At 12 months, none of these symptoms was observed in more than 10% of patients off PPIs. Although the device is attractive for patients who are not responding to PPIs, who wish to reduce reliance on daily medical therapy, or who are concerned about the potential side effects of PPIs such as impaired nutrient absorption, evidence of efficacy is encouraging. It is even more encouraging in a population with atypical symptoms, because they

have long been challenging to treat and typically respond poorly to PPIs. For a chronic disease like GERD, documentation of benefit over even longer periods of follow-up will provide additional reassurance. Lars Lundell, MD, professor of surgery at Karolinska Institutet, in Stockholm, called the data “promising.” Previous studies of GERD, including many trials he has led, suggest that five-year data are required to confirm a durable response from surgical therapies, Dr. Lundell said. Still, he characterized the new study as “well designed,” and said the findings support including transoral fundoplication in the mix of therapeutic alternatives in GERD. “In my opinion, these observations are pivotal, and would form a robust platform and background for a shift in the current and future therapeutic algorithms for chronic GERD,” Dr. Lundell said. He indicated that the extended follow-up will better show where it fits in the context of other options. ■ Dr. Trad disclosed a financial relationship with EndoGastricSolutions, which sponsored the study. Dr. Lundell reported no relevant financial conflicts of interest.

Water continued from page 13

Water Exchange an ‘Easier’ Procedure Also at DDW, Italian researchers reported their findings from a randomized controlled trial of air insufflation, water immersion and water exchange that reached a similar conclusion (abstract 295). “Water exchange was significantly less painful and makes for an easier procedure,” said Sergio Cadoni, MD, of the S. Barbara Hospital in Iglesias, Italy, who led the study. “More of the water exchange group completed the colonoscopy without sedation, had zero pain or reported only discomfort.”

The study compared water immersion (water removal during withdrawal; n=197), water exchange (water removal during insertion; n=186) and air insufflation (n=193). Approximately 50% of the patients in the trial were undergoing colonoscopy for screening; the remainder had clinical indications for the procedure. Patients reported maximum pain scores on a visual analog scale (VAS; 0-10) to an unblinded observer; patients with a VAS score of 2 or greater could receive on-demand sedation (2-5 mg of IV midazolam). “During the procedure, pain was checked at frequent, irregular intervals by nurses to avoid bias by the colonoscopist,” Dr, Cadoni added.

For validation, recollected maximum pain was reported at discharge to a blinded observer, and this report was compared with pain reported during insertion. Patients who had water exchange reported the lowest mean maximum pain scores during the examination: 2.5, versus 3.5 for water immersion and 4.1 for air insufflation. The differences were marked between water exchange and air insufflation (P<0.0005) and water exchange versus water immersion (P<0.0006), according to the researchers. Similarly, maximum pain score recollected at discharge was lowest for water exchange: 1.3, versus 1.8 for water immersion (P=0.022) P and 1.9 for air

insufflation (P=0.014). P Secondary outcomes—proportion of patients completing without sedation, less need for abdominal compression or loop reduction, and willingness to repeat the procedure—favored both water-assisted colonoscopy methods, with some preference for water exchange, Dr. Cadoni reported (Table 2). More than 95% of the water-assisted groups were willing to repeat the examination, versus 77% of the air insufflation group (P<0.0005). ■ Dr. Garborg received grant and/or research support from Olympus Norway. Drs. Cadoni and Schmitt reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Transnasal End doscopy To Go? Mobile unit offers screeening for Barrett’s esophagus CHICAGO—Food trucks are all the raage. So why not appeal to the anatomy a little higher up in the gastrointestinal tract? New studies suggest that transn nasal endoscopy (TNE) could become more acceptablle as a screening tool for Barrett’s esophagus (BE), thankks to recent technological advances that have improved d the portability of the procedure. One study looked at the feasibilitty of screening with TNE in a van set up as a mobile research unit. Another, using th he same patient data, demonstrated that substantial rates of BE can be identifieed in patients with obesity whether or noot they complain of symptoms of gastroesophageal reflux (GERD). TNE, which can be performed without sedation, is already widespread, but renewed interest in this techniquee as a screening tool is being driven by the development of smaller units with disp posable sheaths. The sheaths, which prevent contact beetween the scope and the patient to circumvent the need d for scope sterilization, greatly facilitate portable units. Both new studies were presented by investigators at Mayo Clinic, in Rochester, Minn., at Digestive Disease Week 2014 (DDW). Prasad G. Iyer, MD, a consultant in the Barrett’s Esophagus Unit in the Division of Gastroenterology and Hepatology at Mayo, led the work. Study participants were recruited from a sample of residents 50 years of age or older from Olmsted County, the home of the Mayo Clinic, who completed a questionnaire on gastrointestinal (GI) symptoms. Of an initial cohort of 459 patients, 209 agreed to undergo screening for BE. The patients were randomized to conventional sedated endoscopy, unsedated TNE performed in a clinic setting and unsedated TNE performed in a mobile unit. In a feasibility study (abstract 160), the primary outcome was participation, said Sarmed S. Sami, MD, of Mayo’s Division of Gastroenterology and Hepatology and the Nottingham Digestive Diseases NIHR Biomedical Research Unit, in the United Kingdom. Rates of participation did not differ significantly among the three groups, ranging from about 41% to 48%. Independent of endoscopy type, the presence of frequent GERD symptoms was associated with a threefold increase in screening participation.

Although Altho gh the q quality alit of the endoscopic eexamination amination was judged to be similar in the three groups, biopsy rates were 80% for TNE compared with 100% for sedated endoscopy. According to the researchers, some patients could not tolerate the TNE with a biopsy channel, thus explaining the lower biopsy rates in the TNE group. Unsedated TNE was associated with shorter procedure times. Patients who underwent sedated endoscopy reported less discomfort, but unsedated TNE was generally well tolerated, and approximately 80% of patients who underwent the procedure said they would be willing to do so again in the future. Although the results of this study suggest that outpatient TNE, including mobile, “may be a feasible alternative to sedated endoscopy” for BE screening, the second study elaborated why easier, more cost-effective screening tools are needed (abstract 105). In this evaluation of the same population, presented by Nicholas R. Crews, MD, a fellow in Mayo’s Division of Gastroenterology and Hepatology, the prevalence of BE in the 33% of patients with GER symptoms on questionnaires was compared with the 67% without GER symptoms. The BE prevalence was 8.7% for those with GER versus 7.9% for those without, a difference that did not reach statistical significance. In these subgroups, the mean length of the BE segment also did not differ.

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Regardless of GER, GER those with ith BE were ere more likely likel to be men, to exhibit central obesity and to consume more than two alcoholic beverages per day. “This directly challenges the established GER-based screening paradigm for BE and provides strong rationale for using central obesity in Caucasian males, with or without GER, as a criterion for screening,” Dr. Crews said. Joel Richter, MD, director of the Division of Digestive Diseases and Nutrition at the University of South Florida, in Tampa, said TNE “may be the best screening tool for asymptomatic patients who are well educated and informed.” However, Dr. Richter said, “in the real world, most patients prefer to be put to sleep.” Dr. Richter also noted that optimal biopsies, which are more consistently obtained with a conventional scope, are required for patients with BE. “Maybe when reimbursement becomes higher for transnasal endoscopy than for standard endoscopy with propofol sedation, transnasal endoscopy will be better utilized,” Dr. Richter observed. Without this incentive, he predicted that the current “dope-and-scope” approach will prevail at most centers. ■ Drs. Iyer has a financial relationship with Takeda Pharmaceuticals. Drs. Sami, Crews and Richter reported no relevant financial conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

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ESD continued from page 1

Table 1. Long-Term Outcomes for ESD in Colorectal Cancer

ESD has become important in the treatment of large colorectal neoplasms, Dr. Hotta said. “ESD can resect colorectal neoplasms that are difficult for conventional endoscopic mucosal resection [EMR] methods,” he said. Although good short-term outcomes have been established, data on the long-term outcomes after such treatment have been lacking, he noted.

‘ESD can resect colorectal neoplasms

Cohort

3-Year RFS, %

3-Year OS, %

5-Year RFS, %

5-Year OS, %

Group A (curative)

100

96.8

Group B (non-curative, surgery)

96.2

Group C (non-curative, no surgery)

97.9

100

89.5

100

OS, overall survival; RFS, recurrence-free survival

that are difficult for conventional endoscopic mucosal resection [EMR] methods.’ —Kinichi Hotta, MD At DDW, he reported long-term outcomes from a cohort of patients who underwent colorectal ESD between 1998 and 2008 and were classified into the following three groups (Table 1): curative resection (group A), noncurative resection with additional surgery (group B) and noncurative resection without additional surgery (group C). The criteria for curative resection included the following: adenoma/intramucosal adenocarcinoma/submucosal invasive adenocarcinoma less than 1,000 mcm; no poorly or mucinous differentiated adenocarcinoma; no lymphovascular permeation; negative vertical margins; and negative or indistinct horizontal margins. Patients were followed annually by colonoscopy, with computed tomographic (CT) imaging and tumor marker tests in noncurative patients. The investigators determined the three- and five-year disease-specific recurrence-free and overall survival rates. Intramucosal local recurrences, which were controlled by endoscopic treatments only, were excluded from recurrent events. Median follow-up was 44 to 62 months.

Table 2. Independent Predictors of En Bloc Resection Failure or Perforation (Multivariate Analysis) Factor

Description

Odds Ratio

P Value

Endoscopist

Less experienced vs. experienced

2.10

0.004

Location

Right side vs. rectum Left side vs. rectum

3.21 3.03

0.0005 0.0005

Macroscopic type

Protruding vs. LST-G

3.58

0.001

On semilunar fold

Present vs. absent

2.14

0.005

Recurrences Rare to None

Fold convergence

Present vs. absent

4.37

0.0004

The study included 844 patients who had 577 colorectal cancers (including 168 submucosal invasive cancers) and 267 colorectal adenomas. These included 738 in group A, 55 in group B and 51 in group C. Mean lesion size was 33.9 mm. Recurrences were exceedingly rare. In group A, only one of 738 patients (0.13%) had a recurrence (distant metastasis) and died, Dr. Hotta reported. In group B, two of 55 patients (3.6%) had recurrences, both distant metastases, and one died. In group C, three of 51 patients (5.9%) had a recurrence, one of which was a distant metastasis and two were localized, but no patient died. Deaths from other causes numbered 70 in group A, none in group B and one in group C. “Salvage treatments were possible for almost all recurrences in the noncurative resection groups; however, additional surgery might be required to suppress recurrence,” Dr. Hotta added.

Scope operability

Poor vs. good

3.50

0.0005

Factors Predicting Failure of En Bloc Resection or Perforation Also from the Shizuoka Cancer Center was a largescale analysis of ESD for colorectal neoplasms (abstract 835). Presented by Kenichiro Imai, MD, the study

LST-G, laterally spreading tumor-granular

identified preoperative indicators of failure of en bloc resection—single-piece removal with macroscopically free lateral margins—or perforation (endoscopic diagnosis of presence of free air). The analysis was based on 673 patients with 716 intraepithelial neoplasms, who underwent ESD between 2002 and 2013. Preoperative characteristics for determining odds ratios included sex, age, tumor size and location, macroscopic type, preoperative tumor depth, presence of fold convergence, location on semilunar fold, scope operability and endoscopist’s experience with ESD (more than 40 cases were considered “experienced”).

Procedural Outcomes The median tumor size was 30 mm (range, 5-130), and 92 (13%) lesions were larger than 50 mm. The median procedure time was 62 minutes (range, 8 to 600 minutes). En bloc resection was possible in 90% of all cases;

5.5% required piecemeal resections and 4.5% of the procedures were not completed. Perforations occurred in 6.6%, Dr. Imai reported. Pathologic examination revealed that 251 (35%) tumors were adenomas and 465 (65%) were carcinomas. Of the 465 carcinomas, 341 were intramucosal lesions, 54 were slightly invasive submucosal cancers (<1 mm) and 70 were deeply invasive submucosal cancers (≥1 mm). “We noted that the presence of fold convergence, poor scope operability, protruding morphology, rightand left-sided colon location, presence of a deep semilunar fold and an endoscopist less experienced in ESD for colorectal neoplasms were independent predictors for en bloc resection failure or perforation,” Dr. Imai said (Table 2). Dr. Imai noted that lesions larger than 50 mm can sometimes, but not always, be difficult to resect by ESD. “Difficult large lesions include other ‘difficult’ factors,” see ESD, page 18

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

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ESD continued from page 17

such as deep semilunar folds and poor scope operability, he said (Figure). In the absence of other difficult factors, large lesions can be resected easily, en bloc, without perforation, in about two hours, he said. “The preoperative indicators we identified for en bloc

‘Devoting two hours to getting one polyp out may not be something that most gastroenterologists or colorectal surgeons are willing to do, without a

Fold convergence

On the semilunar fold

Protruding type

Colonic lesions

Poor scope operability

Less experienced endoscopiset

better understanding of the oncologic safety of the procedure.’ —Najjia Mahmoud, MD resection failure or perforation in ESDs for colorectal neoplasms may be useful for developing preoperative assessments of technical difficulty,” Dr. Imai said. “This could enable the accurate stratification of lesions according to operator skill.” “ESD has become a feasible technique for the expert hand, but there may be some hurdles for colonic ESD in the United States,” said Naohisa Yahagi, MD, PhD, of the Cancer Center at Keio University, in Tokyo, where seminal work on the technique has been performed. ESD is time-consuming and technically demanding, and poses a higher risk for complications if not performed by an experienced endoscopist, Dr. Yahagi said. The “ideal lesion for beginners” may be flat rectal lesions that are smaller than 3 cm [30 mm] without scar, and located for good maneuverability, he said. But before tackling these lesions, Dr. Yahagi suggested that endoscopists train sufficiently on animal models, then move to gastric lesions, then to squamous cell carcinoma of the esophagus or Barrett’s before attempting ESD in the colon or rectum.

U.S. Perspective “It is clear that if there were better techniques for endoluminal treatment, many patients could avoid surgery for benign lesions. But it should be recognized that colorectal ESD is an advanced technique that requires significant operator experience, not only in performing the dissection itself, but also in carefully evaluating the characteristics of the lesion to assess risk for a more advanced neoplasm,” said George J. Chang, MD, chief of colon and rectal surgery and director of clinical operations for the Minimally Invasive and New Technologies in Oncologic Surgery Program at the University of Texas MD Anderson Cancer Center, in Houston. “This is done to avoid a nontherapeutic ESD and, even more importantly, a nontherapeutic ESD that is associated with a complication, such as perforation at the site of the tumor,” Dr. Chang said. “In the studies reported at DDW, the operators were highly experienced and most of the lesions were intramucosal or earlier, where excellent outcomes would be expected with complete endoscopic therapy,” Dr. Chang added. “Careful provider and patient selection are keys to success with this technique, along with dedicated pathologic evaluation to clearly assess for highrisk histologic findings and the depth of invasion within the submucosa, particularly for sessile lesions.”

Figure. Identified predictors.

Although ESD is “a great advance” for some patients and often a preferred alternative to surgery, Dr. Chang said, endoscopists in the United States who have reported success with ESD have received dedicated training, often with their counterparts in Japan. “ESD is not for the casual endoscopist; rather, referral to endoscopists who have the interest, expertise and volume for performing ESD for complex lesions should be strongly encouraged,” he cautioned. Najjia Mahmoud, MD, chief of the Division of Colon and Rectal Surgery at the University of Pennsylvania, in Philadelphia, said EMRs are an important part of her center’s treatment armamentarium for large colon polyps. As a surgeon, Dr. Mahmoud said she routinely refers patients to interventional gastroenterologists within their hospital-based endoscopy unit, which her center views as a safer site for such procedures than ambulatory surgery centers. Endoscopic resection, when it can be done safely, allows for a faster recovery, “but you have to think about what you are endoscopically resecting,” Dr. Mahmoud said. The aggressiveness with which Japanese clinicians approach endoscopic removal of lesions distinguishes them from the typical practice in the United States, she said. “ESD is different from what we feel comfortable doing here, where we are more averse to risk,” Dr. Mahmoud said. “First, when you do ESD, you do not obtain nodal data. If you have a benign polyp, there is no risk, but if you have an invasive cancer, even if it is early stage, there is always the risk for nodal disease. Data from the National Cancer Institute indicate a 10% nodal spread

for stage I colon cancer,” she said. There is also the potential to disrupt the tumor and disseminate malignant cells, and imaging of these lesions in the colon is not reliable, she added. “You cannot be sure from a CT scan that a lesion is only invading into the submucosa, and therefore is appropriate for endoscopic resection.” Essentially, she said, ESD of invasive disease does not, in all cases, necessarily “adhere to oncologic principles of not violating the tumor and of removing the tumor with negative margins. Traditionally, in the United States, clinicians have been less willing to take these chances.” The fact that ESD is a lengthy procedure also does not sit well with most U.S. operators, she said. “Devoting two hours to getting one polyp out may not be something that most gastroenterologists or colorectal surgeons are willing to do, without a better understanding of the oncologic safety of the procedure,” she maintained. In short, the uptake of EMR among specialized gastroenterologists has been good, “but for the most part, this has been confined to resections in patients with large benign polyps in whom piecemeal removal will not be prejudicial to the outcome,” she said. “Endoscopic removal of invasive cancers as the definitive procedure is far less routine.” ■ Drs. Hotta, Imai, Yahagi, Chang and Mahmoud reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Inverse Relationship Between Adenomas Detected And Later Cancer FROM THE NEW ENGLAND JOURNAL OF MEDICINE

he adenoma detection rate (ADR) has been proposed as a physician quality benchmark, with recommended rates of 15% or more for women and 25% or more for men undergoing

colonoscopy. A new study published in The New England Journal of Medicine (2014;370:1298-1306) indicates that, perhaps, those recommended rates should be higher. During the study, researchers from Kaiser Permanente Northern California gathered data from more than 314,000 colonoscopies performed between 1998

and 2010. The data were eligible for inclusion in the study if the physician had performed more than 300 procedures. Patients with less than six months of follow-up data were not included. If colorectal cancer (CRC) was detected within six months of the baseline colonoscopy, it was determined to be diagnostic and removed from final analysis.

The study’s lead author, Douglas A. Corley, MD, PhD, and his coinvestigators found more than 264,000 colonoscopies performed by 136 gastroenterologists that were eligible for analysis. Of these, 712 cases of interval colorectal adenocarcinoma were identified, of which 255 were advanced-stage cancer. There were 147 deaths from these interval CRCs. The investigators found that the median interval between the colonoscopy and subsequent cancer diagnosis was 39 months.

When the ADR was modeled as a continuous variable, each 1% increase in detection predicted a 3% decrease in interval cancer risk.

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ADRs for physicians ranged from 7.4% to 52.5% (9.7%-60.5% for men and 3.9%-45.9% for women). The risks for development of CRC according to quintiles of ADRs, from lowest to highest, were 9.8, 8.6, 8.0, 7.0 and 4.8 cases per 10,000 person-years of follow-up. The risk for receiving a diagnosis of an interval cancer was 0.52 (95% confidence interval [CI], 0.39-0.69) for patients of physicians in the highest quintile compared with those of physicians in the lowest quintile. Dr. Corley and his co-investigators found that when the ADR was modeled as a continuous variable, each 1% increase in detection predicted a 3% decrease in interval cancer risk. “As we continue to build evidence that colonoscopy with polypectomy reduces CRC incidence, and even more importantly, reduces mortality from CRC, the focus will turn to ways to enhance the effectiveness of the procedure,” said Peter P. Stanich, MD, assistant professor at The Ohio State University, in Columbus. Dr. Stanich said the study was posied to be a landmark as this shift occurs. “The finidings are summarized in a simple, eye-opening statistic: Every 1% increase in adenoma detection is aassociated with a 3% decrease in the risk for interval colon cancer. This is convincing evidence that adequate adenoma detection and removal is a key variable in the effectiveness of colonoscopy as a cancer prevention tool.” ■

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Recovery continued from page 1

In the mid-1990s, this gap in understanding prompted a group of surgeons, led by Henrik Kehlet, MD, PhD, from Copenhagen, to begin implementing early recovery efforts. Following Dr. Kehlet’s work, a multinational group of surgeons and anesthesiologists began collaborating as the Enhanced Recovery After Surgery (ERAS) research group. The aim of ERAS is to systematically study patients’ physiologic responses to surgery and develop a multifaceted, evidence-based approach to patient care in colorectal surgery and other disciplines. At the 22nd International Congress of the European Association for Endoscopic Surgery (EAES), Nader Francis, MBChB, PhD, and colleagues presented an up-to-date review of ERAS in colorectal surgery, pinpointing factors that may allow surgeons to enhance and ultimately predict patient outcomes (abstract O074). “There are many features that impact patient outcomes, and we don’t necessarily know which are the most relevant to recovery,” said Dr. Francis, consultant colorectal surgeon at Yeovil District Hospital, in Somerset, England. “Our ongoing research is working to uncover the key factors in perioperative care.” Although no standard ERAS protocol yet exists in colorectal surgery, most include formal patient education, eliminating bowel preparation and allowing clear fluids up to three hours before surgery. Intraoperatively, studies show that laparoscopic surgery, goal-directed fluid management, less operative time and reduced blood loss aid patient recovery ( S 2014;18:265-272). Postoperatively, (JSLS the use of thoracic epidural analgesia, avoidance of nasogastric tubes, and early feeding, mobilization, discontinuation of IV fluid and removal of urethral catheters are important features as well (Ann ( Surg 2000;232:51-57).

Despite the lack of consensus, a growing body of research shows that employing ERAS principles reduces hospital length of stay and complications in colorectal surgery ((Ann Surgg 2000;232:51-57; Br J Surg 2006;93:800-809; Anesth Analg 2014;118:1052-1061). For instance, in a 2014 study comparing outcomes in a traditional care (99 patients) and ERAS group (142 patients), Julie Thacker, MD, and her colleagues at Duke University Medical Center, in Durham, N.C., found that patients following an enhanced recovery protocol had a significantly shorter length of stay (five vs. seven days; P<0.001), fewer urinary tract infections (13% vs. 24%; P P=0.03), reductions in duration of ileus and lower readmission rates (9.8% vs. 20.2%; P=0.02). P The Duke enhanced recovery protocol was also associated with lower medical costs, about $2,000 per patient or a 10% decrease in the costs of traditional care. “This reduction in cost is a huge bonus

for patients and the health system,” said Dr. Thacker, assistant professor in the Department of Surgery. “It could save hundreds of thousands of dollars a year and would require minimal to no extra costs for hospitals to realize.” But, given the abundance of perioperative factors being studied and the complexity of different health systems, ERAS can be difficult to implement. In a 2012 study (Colorectal Diss 14:e727-e734), Dr. Francis and his colleagues retrospectively analyzed outcomes of 385 patients who underwent elective laparoscopic or open colorectal resection at Yeovil District Hospital between 2002 and 2009, and found that 31% of patients stayed more than one week (delayed discharge), and 41% deviated from the ERAS protocol. The authors concluded that failing to comply with ERAS one day after surgery was strongly associated with delayed discharge. In a recent analysis, Dr. Francis and his colleagues tried to determine what

‘[An enhanced recovery protocol] could save hundreds of thousands of dollars a year and would require minimal to no extra costs for hospitals to realize.’ —Julie Thacker, MD

factors cause patients to deviate from an enhanced recovery protocol. After prospectively collecting data from 178 patients who had undergone open or laparoscopic colorectal surgery between January 2006 and December 2009, the surgeons found that of the 32% of patients who deviated from the program, the most common reasons cited were failure to mobilize after surgery (80.7%), continued use of IV fluids beyond 24 hours (59.7%), failure to resume an oral diet (45.6%) and inadequate pain control (10.5%). The adoption of ERAS across Europe and the United States has also seen varied success. In the United Kingdom, hospitals are encouraged to adopt enhanced recovery for colorectal surgery, and their payment schemes are tied to protocol compliance. “Over the last 10 years, we’ve seen an amazing spread of ERAS,” Dr. Francis said. “The program now exists in every hospital in England.” But looking beyond the United Kingdom to the rest of Europe and the United States, ERAS is not taking hold as quickly. “National mandates, transparent audits and government-funded implementation efforts in the U.K. create a very different picture than surgeon and anesthesiologist-driven work in the U.S.,” Dr. Thacker said. “Trying to change a little bit about everything included in perioperative care in the U.S. is extraordinarily challenging.” Part of the difficulty is that each hospital in the United States has different capabilities and guidelines, which means the challenges to implementing an enhanced recovery protocol will vary by hospital, Dr. Thacker noted. Despite these complex barriers, Dr. Thacker has started to garner support from surgical societies throughout the United States. “The more interest we get at the society and health system level, the easier it will be to improve perioperative care.” ■

Gastrectomy for Chronic Leak After Lap Sleeve Gastrectomy BY MAYANK ROY, MD

lmino Ramos, MD, from Brazil, discussed the management of leak after laparoscopic sleeve gastrectomy (LSG) at the 2014 Surgery of the Foregut Symposium, in Coral Gables, Fla. Laparoscopic sleeve gastrectomy has increased exponentially over the past decade. Chronic leak after LSG remains a challenging complication to manage for most bariatric surgeons. Dr. Ramos discussed the management of chronic leak and shared some of his experiences with performing gastrectomy for resistant cases. Sleeve gastrectomy creates a perfect storm for

development of a fistula at the angle of His. Physiologic obstruction due to the pylorus and mechanical obstruction from the “L” shape of the sleeve causes increased pressure inside the sleeve. The negative pressure inside the thorax compounds this process. Complete resection of the angle of His is desirable to achieve maximum weight loss. However, this might cause a leak due to the loss of blood supply in the surrounding area, leading to ischemic changes. Initial management of leak at the angle of His remains nasoenteral feeding and drainage. Stent placement by endoscopy is one of the conventional methods used for fistula treatment. However, the anatomic position of the angle of His poses a challenge. Endoscopy has also been used for fibrin glue, mesh placement or clips.

Some surgeons have proposed conversion of the sleeve into a Roux-en-Y gastric bypass. Dr. Ramos discussed his experience with performing laparoscopic total gastrectomy for resistant cases of leak in 12 patients who already had at least one attempt with conventional treatment. Dr. Ramos concluded that, in his experience, laparoscopic total gastrectomy could be the only alternative in some cases of resistant leak and can be performed safely. These patients should wait at least three months and should initially undergo conventional methods of leak management. Surgeons should consider this procedure only after they have acquired substantial experience in bariatric and minimally invasive surgery procedures. ■

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Adjuvant Chemo Still Underused in Late Colon Cancer BY KATE O’ROURKE CHICAGO—Roughly one-third of patients with stage III colon cancer may not be receiving the recommended adjuvant chemotherapy, according to a study presented at the 2014 annual meeting of the American Society of Clinical Oncology. The data suggest that age and insurance status were among the factors that influenced physicians to forgo the potentially

life-prolonging therapy (abstract 3576). “This is the largest, most recent study to determine the use of chemotherapy in stage III colon cancer. Older age was the biggest factor. People who were above the age of 60 years were less likely to receive chemotherapy,” said the study’s lead author Vijaya Bhatt, MBBS, a hematology-oncology fellow at University of Nebraska Medical Center, in Omaha. In 1990, the National Institutes of Health (NIH) Consensus Conference

recommended that patients with stage III colon cancer receive adjuvant chemotherapy, based on clinical trials demonstrating that it improved survival in patients who were given a 5-fluorouracil–based regimen. Since then, investigators have determined that this practice has not been adopted completely. A study by Milburn et al, for example, found that use of adjuvant chemotherapy in stage III colon cancer patients increased from 39% in 1991 to 64% in 2002 ((JAMA

2005;294:2703-2711), thus falling short of the NIH recommendation that all such patients be given the treatment. The new study looks at more recent data that show that although use of adjuvant chemotherapy has continued to rise, it still does not reach all patients. Dr. Bhatt and her colleagues identified roughly 200,000 patients diagnosed with stage III colon cancer between 2000 and 2011 through the National Cancer Database, which contains information on approximately 70% of all new cancer diagnoses in the United States. They found that the use of chemotherapy increased over time, from 59% between 2000 and 2002, to 62% between 2003 and 2006, and 64% between 2007 and 2011. Provision of chemotherapy was most influenced by patient age, gender and insurance status (Table). Chemotherapy use was lowest for patients with Medicare (52%), followed by Medicaid (70%), no insurance (73%) and private insurance (77%). Dr. Bhatt said age alone was not a valid

Table. Factors Associated With Adjuvant Chemotherapy for Colon Cancer Demographics

Patients Given Chemotherapy, %a

Age, y <60 ≥60

82 55

Gender Male Female

65 60

Race/Ethnicity White African American Hispanic

61 65 66

Insurance status Private Uninsured Medicaid Medicare

77 73 70 52

Annual household income, $ <28,000 28,000-49,000 >49,000 a

P<0.0001 for all comparisons.

59 62 63

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

CDC Sees Gains, Losses in Effort Against Foodborne Infections BY GEN STAFF

early 70% of strains of Salmonella Typhi were resistant to quinolones in 2012, according to a new report on foodborne pathogens from the Centers for Disease Control and Prevention (CDC). The report found that the prevalence of multidrug resistant (MDR) Salmonella fell between 2003 and 2012, and that germs that resist cephalosporins and fluoroquinolones remain uncommon. However, the incidence of quinolone-resistant

reason to skip chemotherapy for patients with colorectal cancer. A recent analysis of four large data sets of patients older than 75 years with stage III disease showed that adjuvant chemotherapy reduced the risk for death by as much as 40% (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.53-0.68) ((J Clin Oncoll 2012;30:26242634). Patients were treated with various combinations of fluorouracil, leucovorin, capecitabine and oxaliplatin. In an earlier study of pooled trial data by Sargent et al, adjuvant therapy with fluorouracil plus leucovorin or levamisole reduced patients’ risk for death by 24% (HR, 0.76; 95% CI, 0.680.85), and patients were just as likely to receive benefit from treatment if they were older than 70 than if they were in three other age groups (≤50, 51-60, or 61-70) (N Engl J Med 2001;345:1091-1097).

Standard of Care Not Met Al Benson III, MD, professor of medicine and associate director for clinical investigations at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center, in Chicago, said the study was “important” and continues to demonstrate that a standard-of-care treatment is not being administered to a large enough percentage of patients. “Treatment guidelines should be followed based on evidence,” Dr. Benson said. “Even for patients with comorbidities, guidelines, such as those from the NCCN [National Comprehensive Cancer Network], include treatment approaches for patients who might be considered for less intensive therapy.” He recommended that strategies be employed to ensure that all patients are informed about the reported benefits of adjuvant chemotherapy in colon cancer and provided access to this standard of care. For example, for patients with limited or no insurance, it is important to involve social workers to assist them with accessing appropriate care. ■ Drs. Bhatt and Benson reported no relevant financial conflicts of interest.

S. Typhi —which causes typhoid fever— surged 68% over the study period, according to the CDC report. “Our latest data show some progress in reducing resistance among some germs that make people sick but unfortunately we’re also seeing greater resistance in some pathogens, like certain types of Salmonella,” said Robert Tauxe, MD, MPH, deputy director of the CDC’s Division of Foodborne, Waterborne, and Environmental Diseases, in a statement.

“Infections with antibiotic-resistant germs are often more severe. These data will help doctors prescribe treatments that work and to help CDC and our public health partners identify and stop outbreaks caused by resistant germs faster and protect people’s health.” The report also found that ciprofloxacin-resistant Campylobacterr held steady at 25% of isolates in 2012, unchanged from 2005 when the FDA barred the use of enrofloxacin (Baytril, Bayer) in poultry

over fears that resistance to the animal antibiotic could lead to resistance to Cipro. Antibiotic-resistant foodborne pathogens cause some 430,000 cases of illness per year in the United States, health officials estimate. Of those, 100,000 are attributable to MDR Salmonella. President Obama’s 2015 budget includes money for CDC to improve its ability to detect and track MDR Salmonella—including a a 20-fold increase in testing over the agency’s current capacity. ■

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Rectal Cancer continued from page 1

Despite such improvements, considerable variation exists in how experts manage early rectal cancer. That is why Mario Morino, MD, chair and director of Digestive and Minimal Invasive Surgery at University of Turin School of Medicine, in Italy, and president of the European Association for Endoscopic Surgery (EAES), organized an international, multidisciplinary panel at the 2014 EAES meeting in Paris to

help unify and optimize the treatment of early rectal cancer. After combing through the literature, the panel members presented the best recommendations for the perioperative care of early rectal cancer based on the existing evidence. “This consensus congress was a very positive experience on an important topic that needs robust guidelines,” said Regina Beets-Tan, MD, PhD,

professor in the Department of Radiology at Maastricht University Medical & Oncology Center, in The Netherlands. Yves Panis, MD, head of the Department of Colorectal Surgery at Beaujon Hospital, in Paris, agreed. “It was a strong panel of surgeons, gastroenterologists, radiologists and pathologists who worked well together to answer all questions related to the treatment of early rectal cancer and to create the consensus guidelines,” he said.

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However, Dr. Panis noted that for many statements, the level of evidence was low because few, if any, prospective randomized controlled studies exist. “Thus, a consensus was often based on literature reviews, retrospective studies and personal experience.” When defining an optimal effective preoperative workup, Dr. Beets-Tan reported that every patient should have a physical examination, a test for carcinoembryonic antigen levels, a digital rectal examination that may include a rigid proctoscopy and a total colonoscopy (level 2, grade B, consensus 100%). Dr. Beets-Tan also found strong evidence in favor of endoscopic ultrasound for staging small rectal tumors (T1) and magnetic resonance imaging (MRI) for staging T2 or large tumors (level 2, grade B, consensus 100%). “The imaging guidelines are strongly evidence-based for local tumor staging,” Dr. Beets-Tan said. But, she added, further work is required to detect lymph node metastases, and she is currently conducting a multicenter study in The Netherlands to validate the use of dynamic contrast-enhanced MRI. The panel then focused on delineating the best method for treating early rectal cancer. “To me, the most important elements of the guidelines are defining the limits of local incision and choosing the best technique for patients,” Dr. Panis said. To this end, the panel said that local excision is most effective for treating T1

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

When determining when a more radical approach is warranted, Tonia Young-Fadok, MD, professor of surgery and chair of the Division of Colon and Rectal Surgery at Mayo Clinic College of Medicine, in Phoenix, reported the panel’s conclusion that complete resection of the rectum using total mesorectal excision, or TME, should be performed when biopsy and imaging indicate that local excision is inadequate or when

local excision shows the lesion is more advanced than expected (level 2a, grade B, consensus 90.9%). Another reason to opt for a more invasive approach is patient preference. In terms of the patients’ quality of life after surgery, the evidence strongly points to laparoscopic over open surgery in most cases, considering the advantages of shorter length of stay and postoperative complications (level

1a, grade A, consensus 100%). Commenting on what the future holds, Dr. Panis said, “We will continue to review and revise the guidelines, but today the idea is to publish these recommendations quickly to help unite the treatment protocols for early rectal cancer worldwide.” The full consensus guidelines will be published within the year in Surgical Endoscopy. ■

“This consensus congress

presents

was a very positive experience on an important topic that needs robust guidelines,” —Regina Beets-Tan, MD, PhD

N0 lesions with favorable clinical and pathologic features (level 4, grade C, consensus 100%). For lesions with less favorable clinical and pathologic features, the panel advocated neoadjuvant therapy followed by local excision to preserve the rectum (level 2b, grade B, consensus 90.9%). When performing a local excision, Dr. Panis advised endoscopic submucosal dissection (ESD) or transanal endoscopic microsurgery (TEM) (level 4, grade C, consensus 90.9%). When comparing the efficacy of ESD and TEM, however, the evidence did not clearly favor one technique over the other: In a recent meta-analysis, experts found that TEM provided better R0 resection rates (88.5% vs. 74.6%; P<0.001) but worse recurrence rates (5.2% vs. 2.6%; P<0.001) (Surg Endoscc 2014;28:427-438). “Choosing the best technique for the patient is a critical element of care, and we need to adapt to each patient’s individual needs to achieve this goal,” Dr. Panis said. “Ultimately, the goal is to preserve the rectum in early rectal cancer.” For patients with T1-2 N0 rectal cancer who are considered high risk for surgery, the panel recommended using neoadjuvant chemoradiation therapy followed by TEM (level 2b, grade B, consensus 90.9%). The panel cautioned, however, that until further evidence emerges, low-risk patients should only undergo this procedure within a clinical trial setting.

Brooks D. Cash, MD, AGAF, FACG, FASGE Professor of Medicine College of Medicine University of South Alabama a Mobile, Alabama

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Higher Bar Set for Trials in Advanced Colorectal Cancer BY CHRISTINA FRANGOU CHICAGO—Patients with KRAS S wild-type metastatic colorectal cancer (mCRC) receiving first-line treatment with a chemotherapy backbone plus bevacizumab or cetuximab survived for a median of 29 months, the longest median survival time reported in a major trial of these severely ill patients. Importantly, survival times were the same, whether patients received the anti–vascular endothelial growth factor bevacizumab (Avastin, Genentech) or the anti– epidermal growth factor receptor (EGFR) cetuximab (Erbitux, Bristol-Myers Squibb), or whether they received FOLFOX or FOLFIRI, results from the longawaited Phase III CALGB/SWOG 80405 trial showed. “What this tells us is that either FOLFIRI [folinic acid, fluorouracil and irinotecan] or FOLFOX [folinic acid, 5-fluorouracil and oxaliplatin] with either bevacizumab or cetuximab are perfectly reasonable options,” said Alan P. Venook, MD, the Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California, San Francisco.

The results, presented at the 2014 annual meeting of the American Society of Clinical Oncology (abstract LBA3) as well as at the European Society for Medical Oncology (ESMO) 16th World Congress on Gastrointestinal Cancer, were achieved across a broad clinical trials network, suggesting that the results apply in a variety

Model Questions Cost-Effectiveness Of Avastin for Metastatic Colorectal Caancer CHICAGO—The addition of bevacizumab to chemotherapy as a first- or second-line treatment for metastatic colorectal cancer is not cost-effective, according to an analysis presented at ASCO. However, new data from the CALGB/SWOG 80405 trial showing improved survival with bevacizumab could change that. The incremental cost-effectiveness ratio (ICER) for bevacizumab (Avastin, Genentech) as a first-line treatment was assessed at $240,814 for each quality-adjusted lifeyear (QALY), based on a Markov model. The rate was even higher when bevacizumab was included as part of a second-line therapy, at $363,066. That puts bevacizumab far beyond the typical cutoff for what is considered a costeffective therapy. Typically, policymakers are willing to pay $100,000 to $150,000 per QALY. Anything beyond that is not considered cost-effective, said the investigators, led by Daniel A. Goldstein, MD, a hematology and medical oncology fellow at Emory University, in Atlanta. Dr. Goldstein said bevacizumab could become cost-effective if an effective biomarker were found to select patients most likely to benefit. “However, so far, this search has been elusive.” A spokesperson for Genentech said the company is examining a broad range of different types of biomarkers across more than

five cancer types to identify a way to predict which patients may benefit most from bevacizumab treatments. “We are committed to determining if some patients derive a great benefit from Avastin,” said Holli Dickson, Genentech’s senior manager of corporate relations. Sandra Wong, MD, assistant professor of surgical oncology at the University of Michigan, in Ann Arbor, and a member of ASCO’s comparative effectiveness research task force, noted that based on the costs used in the analysis (in 2013 U.S. dollars), “there is no cost-effectiveness in what we’re seeing here.” However, Dr. Wong said recent data from CALGB/SWOG 80405 showing median survival of more than 29 months could affect the ICER for bevacizumab (see story on this page). The improved survival could lead to higher QALYs for patients on this therapy, thereby lowering ICERs. ICERs are rarely taken into account when cancer therapies are recommended, Dr. Wong noted. “In truth, ICERs and willingness-to-pay thresholds aren’t enforced when clinicians, especially clinicians in the United States, make decisions. However, payors could start using these data to inform coverage decisions and that would be how appropriate value-based limits are put into place.” —C.F. Drs. Goldstein and Wong reported no relevant financial conflicts of interest.

of practice settings, Dr. Venook said. They show that “patients with KRAS S wild-type colorectal cancer have choices,” he said. “First-line therapy should reflect the patient’s preference or concern for potential side effects.” The study, which began in 2004 after the two biologics were approved in this setting, included 1,420 patients with mCRC assigned to chemotherapy with FOLFOX (73.4%) or FOLFIRI (26.6%), given at the choice of the investigator, and then randomly assigned to also receive cetuximab (400 mg/m2 loading dose, then 250 mg/m2 once a week), bevacizumab (5 mg/kg twice a week) or both. The combination arm was later discontinued. Once KRAS S mutation testing became available, the study was amended to include only the 1,137 patients with KRAS S wild-type tumors. Median follow-up was 24 months. There were no significant differences in either overall survival (OS) or progression-free survival (PFS) between the treatment groups. OS and PFS were 29 and 10.8 months, respectively, in the bevacizumab plus chemotherapy group and 29.9 and 10.4 months, respectively, in the cetuximab plus chemotherapy group. The trial showed no new adverse events for any of the therapies. The most frequent toxicities associated with bevacizumab included hypertension (7%) and gastrointestinal events (2%). For cetuximab, adverse events included acne-like rash (7%) and diarrhea (11%). In one of the most notable findings, 10.9% of patients were disease-free after surgery and therapy. Median OS of these patients now exceeds 5.5 years. “There is a subset of patients with metastatic CRC who will do exceedingly well,” which is an important take-home message from the study, said Dr. Venook. “There may be some temptation to top-line this as a negative trial [because] the two arms are the same,” said Clifford A. Hudis, MD, the outgoing ASCO president and a medical oncologist at Memorial Sloan-Kettering Cancer Center, in New York City, during a press conference. “But the really important thing is that this sets an entirely new high standard and a new high bar for clinical trials in advanced CRC.” Some oncologists who heard the study results being presented said they would base their decisions about which drug regimen to use on patient preference and the side-effect profile of the agents. “It’s good to have two different choices, two different options,” said Marwan Fakih, MD, professor of medical oncology see Bar, page 33

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

OIC continued from page 1

‘Whether the [cardiovascular] signal is true or

of opioids would unblock the field for more such medications. Opioid-induced constipation (OIC) “is a real problem,” said Eugene Viscusi, MD, professor of anesthesiology and director of acute pain management at Thomas Jefferson University, in Philadelphia. Additional drugs in development “are at a critical point that if the FDA required long-term studies, the market would be very limited.” Many physicians are unaware that these drugs are available, while others have been concerned about cardiovascular risk, said Dr. Viscusi, who noted he has frequently prescribed the two FDAapproved peripherally acting µ-opioid receptor antagonists (PAMORAs), methylnaltrexone bromide (Relistor, Salix) and alvimopan (Entereg, Cubist), with good results. The advisory committee’s conclusion “was the outcome I was hoping for,” he said. “There’s not really enough evidence that these longterm safety trials would be required. I’m now optimistic that additional drugs will become available for a very unmet need in the chronic pain community.”

not, it is a signal about a major complication for

Divided Panel In a close decision following a lengthy meeting in June, 12 of the 24 panelists on the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee voted against requiring cardiovascular outcomes trials; seven recommended the agency require trials for all PAMORAs and five recommended the agency require trials for alvimopan and similar biologics. The group largely agreed that cardiovascular studies can be conducted as postmarketing surveillance, with the exception of alvimopan, and they should last at least a year to sufficiently assess long-term outcomes. Both alvimopan and methylnaltrexone bromide are approved only for specific situations. Alvimopan is restricted to hospitalized patients with postoperative ileus and capped at 15 doses, and only hospitals that register in the Entereg Access Support and Education (E.A.S.E.) program may offer the drug. Methylnaltrexone bromide is approved for short-term treatment in patients with advanced illness receiving palliative care. Alvimopan’s restrictions stem from data resulting from one clinical trial by former manufacturer GlaxoSmithKline, which hinted at an increased risk for myocardial infarction (MI) associated with the medication. In that study, from the mid-2000s, seven patients taking alvimopan experienced MIs, compared with none taking placebo.

an elective medication, and therefore it must be studied carefully. I do trust that the FDA will come to a fair, equitable decision to this dilemma.’ —Mitchell Cappell, MD, PhD

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

“Whether the [cardiovascular] signal is true or not, it is a signal about a major complication for an elective medication, and therefore, it must be studied carefully,” said Mitchell Cappell, MD, PhD, section head of gastroenterology and hepatology at William Beaumont Hospital, in Royal Oak, Mich. “I do trust that the FDA will come to a fair, equitable decision to this dilemma.” During the meeting, committee members heard from pharmaceutical

companies Cubist, Salix, AstraZeneca/ Nektar (manufacturer of naloxegol/ Movantik, which is under review for FDA approval), Theravance (manufacturer of investigational PAMORA axelopran), Develco Pharma Schweiz (manufacturer of naloxone, approved for opioid overdose) and several physician consultants paid by the manufacturers. Manufacturers presented clinical trial data about their respective medications. Only alvimopan was shown to have any

link to MI, and only in one trial testing the medication for long-term use. Cubist is not pursuing long-term use of the drug. Bill McCarberg, MD, a consultant and president-elect of the American Academy of Pain Medicine, noted that although opioids are “lifesavers,” OIC is prevalent and laxatives often are not effective. William Mezzanotte, MD, MPH, vice president for global medicines

development at AstraZeneca, said the imbalance in MI seen with alvimopan has not been observed in any other trial of alvimopan, in trials of other PAMORAs or in the literature. “PAMORAS that demonstrate a favorable risk–benefit profile in Phase III studies can be safely approved for the treatment of chronic OIC in patients with noncancer pain without the need for cardiovascular outcomes trials,” Dr. Mezzanotte said. see OIC, page 30

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

OIC continued from page 29

For several hours, panelists debated whether the presented data suggested the presence of a cardiovascular safety signal associated with the drugs, whether the signal related to just alvimopan versus all PAMORAs and if the signal had a plausible biological explanation. Overall, the committee felt there was a signal, although moderate at most, from alvimopan and that there was insufficient information to

determine the presence or absence of a class effect. Dr. Cappell, who voted in favor of outcomes trials, said at the meeting that his decision would depend on cost. Randomized controlled trials can be “overly aggressive,” he noted, so he advocated for postmarketing observational studies. However, Milton Packer, MD, professor and chair of clinical sciences at the University of Texas Southwestern

Medical Center, in Dallas, said trials are always feasible. An estimated 116 million Americans are in chronic pain, he said. Of those 116 million, 16% take opioids—and many of them wind up constipated and in need of treatment. “We routinely ask sponsors for cardiovascular outcomes trials when the consequences are a lot smaller than this one,” Cappell said. Sonia Hernández-Díaz, MD, DrPH,

director of the pharmacoepidemiology program at the Harvard School of Public Health, in Boston, questioned whether the panel would have been convened at all if it had not been for the results of one single, unreplicated GlaxoSmithKline trial. There is no word yet on when the FDA will make its decision. “We cannot comment on future rulemaking,” said spokesman Jeff Ventura. ■

with the best-read gastroenterology publication.

♦ ♦ ♦ ♦ ♦ Based on data from Kantar Media, June 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Survival Benefit From Panitumumab in Wild-Type KRAS mCRC FROM ANNALS OF ONCOLOGY

atients with wild-type ( WT) KRAS S metastatic colorectal cancer (mCRC) had extended progressionfree survival (PFS) following a regimen of panitumumab (Vectibix, Amgen) plus FOLFOX4 (i.e., leucovorin, fluorouracil and oxaliplatin) compared with those treated with FOLFOX4 alone. Objective response rates were

higher, and a trend toward improved overall survival (OS) was noted. Finalized data collected 30 months after the enrollment of the last patient in PRIME (Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy) were analyzed, with results published in Annals of Oncology (2014 Apr 8. [Epub ahead of print]. In this international, multisite Phase III study, 1,183 patients with previously

untreated mCRC were randomized to receive panitumumab plus FOLFOX4 (arm 1) or FOLFOX4 alone (arm 2). Preliminary results led to the further investigation of patients based on KRAS status. Jean-Yves Douillard, MD, PhD, and his co-investigators confirmed that mCRC patients with mutated (MT) KRAS S mCRC had better results when treated with FOLFOX4 without the addition of panitumumab. Patients with WT KRAS S mCRC

had improved PFS and OS in arm 1 compared with those treated in arm 2. In these patients, median PFS was 10 months (95% confidence interval [CI], 9.3-11.4 months) in arm 1 versus 8.6 months (95% CI, 7.5-9.5 months) in arm 2; the hazard ratio (HR) was 0.80 (95% CI, 0.67-0.95; P=0.01). Median OS was 23.9 months (95% CI, 20.327.7 months) in arm 1 versus 19.7 months (95% CI, 17.6-22.7 months) see KRAS, page 32

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

Guidance Equivocal On HCV Screening Of Baby Boomers

Despite Above Average Income, Gastros Report Job Dissatisfaction BY VICTORIA STERN

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

Gastroenterologists are the fourth most highly compensated physicians compared with doctors in 24 other medical specialties, according to an online survey conducted by Medscape in February 2013. Average annual income for gastroenterologists was up 13% in 2012 compared with 2011, coming in at $342,000. The three specialties that beat out gastroenterology in average yearly compensation were orthopedists at $405,000, cardiologists at $357,000 and radiologists at $349,000 (see Figure 1, page 28). But despite robust earnings, less than half (48%) of the gastroenterologists surveyed said they felt fairly compensated, the same percentage as that of physicians of all specialties who said they felt fairly compensated. The findings were based on responses collected in a third-party online survey of 21,878 U.S. physicians, 2% of whom were gastroenterologists. Most gastroenterologists who responded were men (84%) and board certified (96%), and 62% were aged 45 years or older.

see NAFLD, page 14

see Income, page 28

BY CHRISTINA FRANGOU Hepatologists have added their voices to the debate over screening for hepatitis C virus (HCV) infection and are urging the U.S. Preventive Services Task Force (USPSTF) to upgrade its current recommendation see HCV Screening, page 18

NAFLD Threatening Public Health BY KATE O’ROURKE

I N S I D E

Cost Sharing for Polyp Removal During Colonoscopy Waived for Some Patients

H E PAT O L O G Y

I N

FOCUS

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

BY MONICA J. SMITH

tor

Ma Vis it y DD 19-2 us W bo 1, 20 oth 13 15 31

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

Patients with private insurance will no longer be responsible for any cost sharing in the event that a polyp is removed during a screening colonoscopy, according to a recent clarification, issued by the federal government, on preventive screening benefits under the Affordable Care Act (ACA). “This is very good news,” said Durado Brooks, MD, MPH, direcof Prostate and Colorectal Cancers at the American Cancer Society in

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

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

CLINICAL REVIEW see insert between pages 20 and 21

Ulcerative Colitis: Treatment Strategies By Ellen J. Scherl, MD, Arun Swaminath, MD, Brian Bosworth, MD, and Vinita Jacob, MD

PRODUCT ANNOUNCEMENT

Ulcerative Colitis: Optimizing Mesalamine Strategies ELLEN J. SCHERL, MD Director, Jill Roberts Center for Inflammatory Bowel Diseasea Jill Roberts Center for Inflammatory Bowel Disease Director of Researchb Jill Roberts Associate Professor of Inflammatory Bowel Diseaseb Associate Professor of Clinical Medicineb Adjunct Associate Professor of Medicinec

see page 63 for product information

he e greatest ch hallenge for clinicians who

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

ARUN SWAMINATH, MD

at tight inflammation control and alteration of the natural

Assistant Attending Physiciana Assistant Professor of Clinical Medicinec

history of IBD. This review focuses on a personalized

BRIAN BOSWORTH, MD

acid (5-ASA) agents.

approach to the treatment of IBD using 5-aminosalicylic

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

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

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

Challenging the Traditional IBD Diagnosis Traditionally, IBD has been divided into 2 distinct entities: ulcerative colitis (UC) and Crohn’s disease (CD). A nuanced view presents IBD as an immunoinflammatory spectrum of chronic and recurring diseases of the intestines defined by individual molecular signatures. This newly gained perspective holds the promise of moving treatment in a more proactive, personalized direction, toward targeting molecules and risk assessment, rather than treating symptoms of the disease. One of the major questions facing clinicians is whether IBD is a single entity or a spectrum of multiple disorders. This distinction becomes particularly difficult to make when attempting to

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

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

KRAS continued from page 31

in arm 2; HR was 0.88 (95% CI, 0.731.06; P=0.17). The updated final analysis of median OS confirmed these numbers. Results for patients with MT KRAS mCRC favored the administration of FOLFOX 4 alone. In the final analysis of these patients, median OS was 15.5 months (95% CI, 13.1-17.6 months) in arm 1 and 19.2 months (95% CI, 16.221.5 months) in arm 2; HR was 1.16

Patients with wild type KRAS metastatic colorectal cancer experienced extended progression-free survival when they received panitumumab plus FOLFOX4.

(95% CI, 0.94-1.41; P=0.16). Quality-of-life surveys revealed no statistically significant or clinically meaningful

difference between the two study arms. Adverse events were consistent with earlier reports: Patients treated with panitumumab

reported higher rates of skin toxicity, diarrhea and hypokalemia. Patients with WT KRAS S mCRC who reported grades 2 to 4 skin toxicities (rash, acneiform dermatitis, pruritus, dry skin, skin fissures or erythema) had longer PFS and OS as well as overall response rates, suggesting development of skin toxicity is an early clinical indicator of the panitumumab regimen’s efficacy. ■

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

may give the patient the likelihood of surviving about 30 months. However, there is no clear winner in terms of [OS].”

Bar continued from page 27

and director of gastrointestinal medical oncology at City of Hope Comprehensive Cancer Center, in Duarte, Calif. Commenting on the data presented at the ESMO Congress in a press release, Dirk Arnold, MD, director of the Department of Medical Oncology at the Tumour Biology Centre, in Freiburg, Germany, said, “We now know that using any monoclonal antibody with any standard chemotherapy in first-line treatment

Data Are ‘Tip of the Iceberg’ Questions remain, and there are still important subgroup analyses that need to be conducted, particularly those looking at additional RAS S mutations. These analyses may help identify patients who will benefit most from particular combinations of therapies. One of the questions raised at the meeting was why this study differed

from the FIRE-3 trial of FOLFIRI combined with cetuximab or bevacizumab, presented last year. Response rates were similar for both groups in the FIRE-3 trial, but OS was three months longer in patients who received FOLFIRI plus cetuximab. “What’s important from [the Phase III CALGB/SWOG 80405 trial] is there will be more to learn from this study than what’s been presented,” Dr. Fakih said. The data are “just the tip of the iceberg. Maybe there are clinical biomarkers or molecular biomarkers

that will define a percentage of patients who are superior responders with one regimen versus the other. Is one regimen associated with a higher rate of resection of metastatic disease? These are important questions to move the field forward. We’re all awaiting these data but it’s going to be a while. These things will trickle forward over the next year or so.” ■ Dr. Venook reported financial relationships with Bristol-Myers Squibb, Genentech and Roche, and Dr. Fakih with Genentech.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Immune Response to Major GI Surgery, Blood Transfusions Mapped Mortality affected; findings offer possibility of risk stratification BY JAMES PRUDDEN STOCKHOLM—Major gastrointestinal (GI) surgery promotes a specific gene expression pattern that upregulates the anti-inflammatory cytokine interleukin

(IL)-10 while depressing proinflammatory immune pathways. Blood transfusions likely exacerbate this immune response, which also is associated with an increase in infectious complications. The finding raises the possibility that risk stratification for postoperative

complications might use immunologic factors for prediction. Immune response to a major physiologic insult includes an early proinflammatory phase, known as the systemic inflammatory response syndrome, which is then followed by an anti-inflammatory phase,

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

known as the compensatory anti-inflammatory response syndrome (N Engl J Med 2003;348:138-150). Noting that the evidence supporting these two phases is scant and that more recent data have questioned its accuracy—especially in patients with severe sepsis or blunt trauma (Nat Rev Immunoll 2013;13:862-874)—a group of investigators from Barts and The London School of Medicine and Dentistry as well as Bloomsbury Institute of Intensive Care Medicine at University College, London, undertook an analysis of gene expression in patients having major GI surgery.

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

—

36th Anniversary — 2014 2014

Table. Patient Demographics

Age (y)

66 (range, 59-75)

64 (5671)

0.19

Male, %

1.0

Diabetes, %

0.80

Current smokers, % Smoking history, % Cancer diagnosis, % Preoperative immunosupppression, % Duration of operation, min

0.64

0.34

0.10

1.0

243 (range, 176-313)) 18

195 0.06 (142295)) 32 0.13

Endoscopic surgery, %

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.

77 Planned post-op ICU admission, % 30 ASA grade 3 or 4, % By Surgical Specialty, n

P Value

levels were lower in those receiving blood transfusions in the first 24 hours postoperatively. Foxp3, IL-23, RORg and TNFα/IL-10 mRNA levels were also lower at 48 hours postoperatively. IL-27 mRNA levels were unaffected by blood transfusion. The authors, who presented their results at Euroanaesthesia 2014 (abstracts 1AP4-2 and 6AP2-1), found that mortality was associated with higher IL-10 mRNA levels at 48 hours, lower levels of IL-23 mRNA at 24 and 48 hours, and lower levels of RORg mRNA at 48 hours.

Infection Free (n=75; 63%)

19 7 8

They also surmised that the transfusions themselves might contribute to immunosuppression in these surgical patients. Blood was collected preoperatively and at 24 and 48 hours postoperatively. Messenger RNA (mRNA) was extracted and mediators descriptive of specified T-cell pathways were quantified by polymerase chain reaction. The analysis of blood transfusion and immune pathways revealed a distinctive gene expression pattern. Foxp3, IL-12, IL-23, GATA3, RORg and tumor necrosis factor (TNF)α/IL-10 mRNA

Infection (n=44; 37%)

All patients were aged over 45 years and were examined daily for the presence of infection (Table). Packed red blood cell (PRBC) transfusions were used because, unlike the effect of whole blood transfusions on postoperative infections, the immunologic consequence of leukocyte-depleted, PRBC transfusions is not well defined. The investigators, whose principal author was Paraskevi Fragkou, MBBS, hypothesized that major GI surgery will provoke an early postoperative immunosuppressive pattern of gene expression that will increase susceptibility to infectious complications.

0.22

1.0

General

–

Upper GI

–

Colorectal

–

HPB

–

HPB + colorectal General + colorectal Intraoperative blood transfusion

–

0.84

0.17

Blood transfu- 23 sion in the last 24 h, % 1 In-hospital death, %

0.02

1.0

HPB, hepatopancreatobiliary

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They concluded that patients receiving blood transfusions were more likely to develop infectious complications and pneumonia, and were more likely to die in hospital. They found that blood transfusions during and after major GI surgery were “associated with a distinctive gene expression pattern that includes a dramatic upregulation of the anti-inflammatory cytokine IL-10.” ■

DDW 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Experts’ Picks:

The Best of Digestive Disease Week 20 COMPILED AND WRITTEN BY DAVID WILD

In the final installment of our three-part series highlighting some of the most im mportant studies presented at Digestive Disease Week 2014, two experts discuss key abstracts covering topics from infliximab dosing in ulcerative colitis patients to biomarke ers for survival in patients with pancreatic cancer.

Vijay Yajnik, MD, PhD Co-director Massachusetts General Hospital Crohn’s and Colitis Center Assistant Professor of Medicine Harvard Medical School, Boston

Serum CRP is a Better Early Marker for Re sponse to Infliximab Induction Ther apy Than Fecal Calprotectin in Pa tients With Moderate-to-Severe Ul cerative Colitis (Brandse JF, et al) Dutch investigators set out to determine the accuracy of serum C-reactive protein (CRP), serum albumin and fecal calprotectin—all of which are biomarkers of inflammation—in predicting successful response to infliximab (IFX) therapy in patients with ulcerative colitis (UC). The study included 15 patients with UC about to start IFX treatment who underwent measurement of serum CRP, albumin and fecal calprotectin during the six-week induction period. The biomarkers were measured frequently during the first three weeks and then once at weeks 4 and 6. The researchers documented clinical and endoscopic response using the Clinical Colitis Activity Index and a colonoscopy conducted six to eight weeks after initiation of treatment. Patients were considered unresponsive to treatment if they required dose increases during induction or underwent colectomy within three months of the induction period. Five patients had left-sided colitis, 10 had pancolitis and seven received combination treatment with an immunosuppressive agent. At baseline, serum CRP was a median 36 mg/L, albumin was a median 38 g/L and fecal calprotectin was a median 1,800 mcg/g of feces. The researchers found responders had median serum CRP levels of 3.8 mg/L

212.

four days after the first infusion of IFX compared with 59 mg/L for those who did not respond to the six-week IFX induction treatment (P=0.01). CRP above 25 mg/L at the four-day point was the most sensitive and specific cutoff for predicting response to induction treatment, they reported. At seven days, CRP levels were associated with post-induction response, they found. Specifically, median CRP at seven days was 1.6 mg/L among those with endoscopic healing after the six-week induction period compared with 15.3 mg/L among those without endoscopic healing (P=0.06). P Analyses showed individuals with CRP above 5 mg/L were 23 times more likely than those with CRP no more than 5 mg/L to have endoscopic response at six weeks, although this was not statistically significant (95% confidence interval, 0.99-556; P=0.02). Serum albumin and fecal calprotectin were not as useful as CRP in predicting clinical and endoscopic response, the researchers reported.

clinically useeful: It indicates the presence of inflammattion and can help guide both the overall neeed for treatment and, as this study shows, IFX-specific drug dosing. It also is easy to measure and most institutions can testt for it. Prospective Therapeutic Drug Monitoring to Optimizing Infliximab (IFX) Maintenance Therapy in Patients With Inflammatory Bowel Disease (IB BD) (Vaughn BP, et al) Some pattients receiving IFX experience gradual loss of response to treatment resulting from m the formation of antibodies to IFX (A ATI)—leading to recurrence of disease or antibody-mediated side effects. Although ough trough concentrations of serum IFX between 5 and 10 mcg/mL are associated with improved outcomes, clinicians typically test IFX trough concentrations and ATI levels only after loss of response. In this study, researchers from Beth Israel Deaconess Medical Center, in Boston, and the University of California,

209.

Short of a colonoscopy, most clinicians depended on patients’ symptoms and laboratory findings to get a sense of the extent of active inflammation. Now, biomarkers like CRP can be used to noninvasively measure inflammation. —Vijay Yajnik, MD, PhD

Dr. Yajnik: Short of conducting a colonoscopy, most clinicians have had to depend on patients’ symptom reports and laboratory findings of albumin and hemoglobin to get a sense of the extent of active inflammation. Now, however, biomarkers like CRP can be used to measure inflammation in a noninvasive manner. This study adds to the utility of the CRP test because it shows that levels of CRP also correlated with induction treatment efficacy. So, the test is very

San Diego, in La Jolla, studied the impact of prospective testing of serum trough concentrations of IFX as a way of guiding drug dosing and thus preventing loss of response to the therapy. They enrolled 48 patients with IBD to undergo at least one prospective measurement of serum trough concentration of IFX, at the end of the six-week IFX induction phase. Forty of these patients had at least one more measurement conducted after six to 12 months and the researchers adjusted IFX doses if necessary, aiming

for an IFX serum target trough concentration of 5 to 10 mcg/mL. The investigators examined the therapeutic impact of prospective measurement on the course of treatment among 78 IFX recipients who had achieved clinical remission but did not have IFX trough concentrations measured prospectively. The two groups were similar demographically. According to the study, 12 patients had undetectable IFX serum trough concentrations and nine others had subtherapeutic concentrations, prompting the researchers to adjust IFX dosing accordingly. When the investigators analyzed the therapeutic course of IFX use in these patients, they found five (10.4%) and 24 (30.7%) of the prospectively monitored and nonmonitored groups, respectively, discontinued IFX during follow-up (P=0.009). P Reasons for treatment discontinuation in the 24 nonmonitored patients included ongoing IBD symptoms (15), acute infusion reactions (6), reasons unrelated to treatment (2) and pneumonia (1). In the five patients who were prospectively monitored, reasons for IFX discontinuation included druginduced lupus (1), emergent psoriasis (1), high antibody concentrations in one delayed infusion reaction (1) and reasons unrelated to treatment (1). see Best of DDW, page 38

Lowest volume of active prep solution— only 10 oz.

Superior

cleansing *

…that

patients preferred †

in clinical trials

*Demonstrated non-inferiority with both split-dose and day-before regimens, evaluated in randomized trials using the validated Aronchick scale. Superior cleansing efficacy of split-dose regimen demonstrated vs day-before regimen comparator (84% vs 74%, respectively, achieving “excellent or good” visualization). The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efficacy endpoint was the proportion of patients with successful colon cleansing defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists. [Prepopik: n=256/304; comparator: n=221/297].1-3 SUPERIOR CLEANSING

PATIENT PREFERENCE

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

reported in clinical trials†1-3

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

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

Colon segment

Prepopik

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

Overall

84%

74%

(n=256/304)

Ascending Mid (Transverse and Descending)

Rectosigmoid

90%

(n=272/304)

92%

(n=221/297)

79%

10%

86%

(n=255/297)

92%

87%

Completed preparation

DIFFERENCE

(n=234/297)

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

Patient perspective

(n=259/297)

Prepopik

99%

(n=304/305)

96%

Would ask for the prep again in the future

(n=290/302)

Was very easy or easy to take

(n=270/302)

89%

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

91%

(n=267/292)

55%

(n=162/296)

29%

(n=86/296)

SPLIT-DOSE OR DAY-BEFORE REGIMEN4

INDICATION AND IMPORTANT SAFETY INFORMATION Prepopik ® for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. • Prepopik is contraindicated in the following conditions: patients with severely reduced renal function, gastrointestinal obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should be advised on the importance of adequate hydration, and post-colonoscopy lab tests should be considered if a patient develops significant vomiting or signs of dehydration after taking Prepopik • Patients with electrolyte abnormalities should have them corrected before treatment. Use caution when prescribing for patients who are at risk for seizures, or arrhythmias, including those patients with a history of prolonged QT, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy. Caution should also be used in patients with impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function, electrolyte imbalance and/or water retention • Oral medication administered within one hour of the start of administration of Prepopik solution may be flushed from the GI tract and the medication may not be absorbed. Prior or concomitant use of antibiotics with Prepopik may reduce its efficacy. Tetracycline and fluoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of Prepopik to avoid chelation with magnesium. Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of additional stimulant laxatives with Prepopik may increase this risk • Prepopik should not be used if gastrointestinal obstruction or perforation is suspected. Prepopik is not for direct ingestion. Each packet must be dissolved in 5 ounces of cold water and administered at separate times, in addition to additional clear fluids, according to the dosing regimen. In randomized, multicenter, controlled clinical trials, nausea, headache, and vomiting were the most common treatment-emergent adverse reactions (>1%) following Prepopik administration

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

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

‡

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

Visit prepopik.com/testimonials to hear what patients and healthcare professionals have to say about Prepopik! References: 1. Rex DK, Katz PO, Bertiger G, et al. Split-dose administration of a dual-action, low-volume bowel cleanser for colonoscopy: the SEE CLEAR I study [published online ahead of print]. Gastrointest Endosc. 2013. http://dx.doi.org/10.1016/j.gie.2013.02.024. 2. Data on ﬁle. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA. 3. Katz PO, Rex DK, Epstein M, et al. A dual-action, low-volume bowel cleanser administered the day before colonoscopy: results from the SEE CLEAR II study. Am J Gastroenterol. 2013;108:401-409. http//dx.doi. org/10.1038/ajg.2012.441. 4. Prepopik® Prescribing Information, July 2012. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA. PREPOPIK® is a registered trademark of Ferring B.V. © 2013 Ferring B.V. All rights reserved. PK/1219/2013/US(1)

DDW 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Best of DDW continued from page 36

‘At the moment, we tend to believe that pathologists

Dr. Yajnik: Vaughn et al hypothesized that higher IFX serum trough concentrations might directly correlate with outcomes, and these data support that theory. If clinicians monitored IBD patients’ IFX serum trough concentrations proactively, their response to treatment would be much more durable, as these results suggested. Currently, however, clinicians are looking

tend to overcall the dysplastic potential of lesions when they diagnose lesions as indefinite for dysplasia. However, these data show that, indeed, a very high rate of this subgroup of lesions progresses to CRC.’ —Vijay Yajnik, MD, PhD

at IFX levels reactively, only after a loss of response or presentation in the clinic

Aspiration Patients with impaired gag reÀex and patients prone to regurgitation or aspiration should be observed during the administration of PREPOPIK. Use with caution in these patients. Not for Direct Ingestion Each packet must be dissolved in 5 ounces of cold water and administered at separate times according to the dosing regimen. The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information. ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances. INDICATIONS AND USAGE PREPOPIK® (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, CONTRAINDICATIONS adverse reaction rates observed in the clinical trials of a drug cannot PREPOPIK is contraindicated in the following conditions: be directly compared to rates in clinical trials of another drug and may • Patients with severely reduced renal function (creatinine clearance not reÀect the rates observed in practice. less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium and vomiting were the most common adverse reactions (>1%) • Gastrointestinal obstruction or ileus following PREPOPIK administration. The patients were not blinded to • Bowel perforation the study drug. Since abdominal bloating, distension, pain/cramping, • Toxic colitis or toxic megacolon and watery diarrhea are known to occur in response to colon cleansing • Gastric retention preparations, these effects were documented as adverse events in • An allergy to any of the ingredients in PREPOPIK the clinical trials only if they required medical intervention (such as a change in study drug or led to study discontinuation, therapeutic or WARNINGS AND PRECAUTIONS diagnostic procedures, met the criteria for a serious adverse event), Serious Fluid and Serum Chemistry Abnormalities or showed clinically signi¿cant worsening during the study that was Advise patients to hydrate adequately before, during, and after the not in the frame of the usual clinical course, as determined by the use of PREPOPIK. Use caution in patients with congestive heart investigator. failure when replacing Àuids. If a patient develops signi¿cant vomiting PREPOPIK was compared for colon cleansing effectiveness with or signs of dehydration including signs of orthostatic hypotension a preparation containing two liters (2L) of polyethylene glycol plus after taking PREPOPIK, consider performing post-colonoscopy electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets, all lab tests (electrolytes, creatinine, and BUN) and treat accordingly. administered the day before the procedure. Table 1 displays the most Approximately 20% of patients in both arms (PREPOPIK, 2L of PEG common adverse reactions in Study 1 and Study 2 for the PREPOPIK + E plus two x 5-mg bisacodyl tablets) of clinical trials of PREPOPIK Split-Dose and Day-Before dosing regimens, respectively, each as had orthostatic changes (changes in blood pressure and/or heart rate) compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were documented out to seven days post colonoscopy. Table 1: Treatment-Emergent Adverse Reactions observed in at Fluid and electrolyte disturbances can lead to serious adverse events Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** and electrolyte abnormalities should be corrected before treatment with PREPOPIK. In addition, use caution when prescribing PREPOPIK Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen for patients who have conditions or who are using medications that Reaction increase the risk for Àuid and electrolyte disturbances or that may PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* increase the risk of adverse events of seizure, arrhythmia, and renal with 2 x (N=296) with 2 x 5-mg (N=305) impairment. n (% = n/N) 5-mg n (% = n/N) bisacodyl Seizures There have been reports of generalized tonic-clonic seizures with the use of bowel preparation products in patients with no prior history of seizures. The seizure cases were associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. The neurologic abnormalities resolved with correction of Àuid and electrolyte abnormalities. Use caution when prescribing PREPOPIK for patients with a history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with known or suspected hyponatremia. Use in Patients with Renal Impairment As in other magnesium containing bowel preparations, use caution when prescribing PREPOPIK for patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or non-steroidal anti-inÀammatory drugs). These patients may be at increased risk for renal injury. Advise these patients of the importance of adequate hydration before during and after the use of PREPOPIK. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur.

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

arrhythmias, and prolonged QT in the setting of Àuid and electrolyte abnormalities. This includes patients receiving drugs which may be associated with hypokalemia (such as diuretics or corticosteroids, or drugs where hypokalemia is a particular risk, such as cardiac glycosides) or hyponatremia. Use caution when PREPOPIK is used in patients on nonsteroidal anti-inÀammatory drugs (NSAIDS) or drugs known to induce Antidiuretic Hormone Secretion (SIADH), such as tricyclic antidepressants, selective serotonin re-uptake inhibitors, antipsychotic drugs and carbamazepine, as these drugs may increase the risk of water retention and/or electrolyte imbalance. Consider additional patient evaluations as appropriate. Potential for Altered Drug Absorption Oral medication administered within one hour of the start of administration of PREPOPIK solution may be Àushed from the GI tract and the medication may not be absorbed. Tetracycline and Àuoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of PREPOPIK to avoid chelation with magnesium. Antibiotics Prior or concomitant use of antibiotics with PREPOPIK may reduce ef¿ f cacy of PREPOPIK as conversion of sodium picosulfate to its active metabolite BHPM is mediated by colonic bacteria. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Reproduction studies with PREPOPIK have been performed in pregnant rats at oral doses up to 2000 mg/kg/day (about 1.2 times the recommended human dose based on the body surface area), and did not reveal any evidence of impaired fertility or harm to the fetus due to PREPOPIK. The reproduction study in rabbits was not adequate, as treatment-related mortalities were observed at all doses. A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses up to 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on the body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, PREPOPIK should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PREPOPIK is administered to a nursing woman. Pediatric Use The safety and effectiveness of PREPOPIK in pediatric patients has not been established.

Geriatric Use In controlled clinical trials of PREPOPIK, 215 of 1201 (18%) patients were 65 years of age or older. The overall incidence of treatmentemergent adverse events was similar among patients 65 years of age ( 3%) and patients <65 years of age ( 1%). Among all patients 65 years of age, the proportion of patients with successful colon cleansing Electrolyte abnormalities was greater in the PREPOPIK group (81.1%) than in the comparator In general, PREPOPIK was associated with numerically higher rates group (70.9%). of abnormal electrolyte shifts on the day of colonoscopy compared to the preparation containing 2L of PEG + E plus two x 5-mg bisacodyl Renal InsufÀ f ciency tablets. These shifts were transient in nature and numerically similar Patients with impaired renal function or patients taking concomitant between treatment arms at the Day 30 visit. medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor Postmarketing Experience blockers, or non-steroidal anti-inÀammatory drugs) may be at The following foreign spontaneous reports have been identi¿ed during increased risk for further renal injury. Advise these patients of the use of formulations similar to PREPOPIK. Because these events are importance of adequate hydration before during and after the use reported voluntarily from a population of uncertain size, it is not always of PREPOPIK. Consider performing baseline and post-colonoscopy possible to reliably estimate their frequency or establish a causal laboratory tests (electrolytes, creatinine, and BUN) in these patients. relationship to drug exposure. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur. The Allergic reactions signs and symptoms of hypermagnesemia may include, but are not Cases of hypersensitivity reactions including rash, urticaria, and limited to, diminished or absent deep tendon reÀexes, somnolence, purpura have been reported. hypocalcemia, hypotension, bradycardia, muscle, respiratory paralysis, complete heart block, and cardiac arrest. Electrolyte abnormalities There have been reports of hypokalemia, hyponatremia and OVERDOSAGE hypermagnesemia with the use of PREPOPIK for colon preparation The patient who has taken an overdose should be monitored carefully, prior to colonoscopy. and treated symptomatically for complications.

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

with symptoms that might be related to the formation of IFX antibodies.

DRUG INTERACTIONS

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

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

Although the study outlines what looks like a clinically useful approach, the high cost of testing IFX serum levels means few clinicians will follow the proactive monitoring approach. Long-Term Colonoscopic Surveillance for Ulcerative Colitis Reveals a Low Overall Rate of Cancer Progression and the Significant Risk of Cancer Following an “Indefinite for Dysplasia” Diagnosis (Choi CHR, et al) Investigators documented the longterm incidence of colorectal cancer (CRC) in 1,375 patients with extensive ulcerative colitis (UC) treated at a British medical center between 1971 and 2013. The researchers examined medical records, as well as surgical, endoscopic and histology reports for recorded instances of neoplastic or dysplastic colorectal lesions and CRC. Patients had undergone a cumulative 8,263 surveillance colonoscopies and a per-patient median of five colonoscopies. The median age was 30 years at onset of disease, and the median followup period was 10 years. According to the researchers, 318 patients (23.1%) were diagnosed with neoplastic lesions during the study period; 69 (5%) had CRC. Patients were a median of 55 years old at the time of CRC diagnosis and had UC for a median of 22 years at that time. The cumulative incidence of CRC according to UC duration was 0.2% after 10 years, 2.6% after 20 years, 7.3% after 30 years, 10.1% after 40 years and 13.1% after 50 years (some people in the surveillance study had disease before enrollment). Patients with high-grade dysplasia were most likely to develop CRC (8 of 27), followed by patients with indefinite dysplasia (12 of 49), low-grade dysplasia (19 of 131) and adenomas (3 of 79). The researchers found that 40 (58%) of those with CRC had cancer distal to the splenic flexure and 24 (35%) had CRC proximal to the splenic flexure; three patients had CRCs in both locations and the location of two patients’ CRCs was not known. Twenty-one patients with CRC (30%) had one or more additional dysplastic lesions.

670.

Dr. Yajnik: At the moment, we tend to believe that pathologists overcall the dysplastic potential of lesions when they diagnose lesions as indefinite for dysplasia. However, these data show that, indeed, a very high rate (24.4%) of this subgroup of lesions progresses to CRC. We need to take these lesions as seriously as we

DDW 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

do other types of dysplastic lesions. A diagnosis of indefinite dysplasia should be considered in the same way as a diagnosis of high-grade dysplasia. Dr. Yajnik reported no relevant financial conflicts of interest.

Manoop S. Bhutani, MD Professor of Medicine and Cancer Systems Imaging Director of Endoscopic Research and Development Department of Gastroenterology, Hepatology and Nutrition University of Texas MD Anderson Cancer Center, Houston

Biomarker Assessment From EUS-Guided Biopsy Predicts Survival Outcomes and Surgical Treatment in Pancreatic Carcinoma (Nguyen NQ, et al)

Sa1369.

Tissue expression of the proteins S100A2 and S100A4 predicts disease and surgical outcomes in patients with pancreatic carcinoma (see e.g., Biankin et al, Gastroenterology 2009;137:558568). Currently, only surgically resected specimens provide enough tissue to assess these biomarkers. In this study, Australian researchers from the Royal Adelaide Hospital, in Adelaide, and the Garvan Institute of Medical Research, in Darlinghurst, investigated whether pancreatic biopsy specimens collected during endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) using the thicker, 22-G ProCore needle (Cook Medical) can provide enough tissue to evaluate levels of S100A2/A4. The investigators examined prospectively collected data from 123 patients with pancreatic ductal adenocarcinoma who underwent surgery and had preoperative EUS-guided FNA using the ProCore. Patients were a mean age of 70 years, and 65 were men. Clinicians proceeded with pancreatectomy in 22% of patients (24) and decided to provide palliative care in the remaining patients. The researchers reported they were able to assess levels of S100A2/A4 in 91% of patients (112) preoperatively and found these proteins expressed in 51% (57) of these patients. In the pancreatectomy patients, who also had surgically resected specimens available for analysis, concordance between FNA- and

surgically obtained specimens was 89% in identifying and measuring S100A2/ A4 levels. In the overall patient population, those with S100A2/A4 survived a median 10 months after surgery, whereas those without the proteins survived a median 17 months after surgery (P=0.004). P In the subgroup of patients who underwent pancreatectomy, median survival was 17 months after surgery when S100A2/A4 was present compared with 32 months

when the proteins were not expressed in tissue (P=0.04). P Statistical analyses showed that survival did not differ significantly if patients underwent pancreatectomy or palliative care when they had S100A2/A4 proteins present (median 17 vs. 10 months, respectively; P=0.42). P Dr. Bhutani: With the explosion of genomics, proteomics and the use of various molecular

markers on cancer tissue, personalized medicine is becoming a very important aspect of cancer care. The approach is already being applied for many cancers—melanoma, for example—and is resulting in dramatically improved treatment responses and individualized treatment plans that are based on each cancer patient’s personalized molecular and genetic profile. These treatment plans take into account the patient’s prognosis see Best of DDW, page 40

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

www.CMEZone.com

Release Date: February 10, 2014

Expiration Date: February 10, 2015

Chair

Statement of Need

Intended Audience

William D. Chey, MD

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

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

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

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

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

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

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

Estimated Time for Completion 1 hour

Course Format Monograph

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

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

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

Jointly sponsored by AKH Inc. and Applied Clinical Education

Supported via an educational grant from Procter & Gamble

Distributed via CMEZone and Gastroenterology and Endoscopy News

DDW 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Best of DDW continued from page 39

as well as information on which treatments the individual is likely or unlikely to respond to. As this study suggests, EUS-guided FNA and core biopsies of the pancreas will likely be very important for developing and applying tumor-specific targeted therapies in individual patients, bringing the personalized medicine approach to this patient population.

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Comparison of Histological Characteristics of the Gastric Wall Muscularis Propria in Gastroparetic Patients by Endoscopic Ultrasound (EUS) Fine-Needle Aspiration (FNA) Technique Versus Full-Thickness Surgical Biopsy (Othman MO, et al; Figure) Structural changes of the gastric wall in patients with gastroparesis currently are assessed using surgical full-thickness biopsies. In this prospective, nonrandomized feasibility study, researchers examined whether such alterations can be evaluated using EUS and EUS-guided FNA. The researchers were from Texas Tech University Health Sciences Center at El Paso. Gastric wall measurements using specimens obtained by EUS-guided FNA of the muscularis propria in the gastric body and antrum were compared with findings from full-thickness biopsies removed surgically during placement of a neurostimulator. Participants included nine women with gastroparesis, of whom six had diabetes-related gastroparesis and one had idiopathic illness. Surgical and biopsy specimens were evaluated for tissue morphology, loss of interstitial cells of Cajal (ICC), enteric neurons and fibrosis. (The researchers presented only ICC findings.) The study found that EUS-guided core biopsies provided sufficient tissue for histologic assessment of ICC in eight patients (88%), and there was strong agreement on the extent of ICC loss when the surgical and biopsy specimens were analyzed (ρ=0.73). EUS-guided FNA was associated with mild bruising and localized formation of hematomas. Dr. Bhutani: In gastroparetic patients, staining for loss of ICC, inflammatory changes and neuronal loss in the myenteric plexus generally requires surgical full-thickness resection of the muscularis propria. These findings suggest that EUS-guided core biopsy could replace surgical biopsy of the muscularis propria in these patients because it is much less invasive, safer

Figure. C-kit staining of endoscopic ultrasound stomach wall biopsy highlights normal interstitial cells of Cajal in the gastric antrum muscularis propria of a gastroparetic patient. and less expensive. Because of its advantages, it also could be applied much more widely, with the potential for a much better understanding of the pathophysiology of these patients and development of targeted therapies for gastroparesis. Development of a Device for Facilitating the Detection of Target Specimens From EUS-FNA Samples in Pancreatic Tumors (Matsumoto K, et al) Fine gauge needles are recommended for endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) of pancreatic tumors because they are associated with fewer complications. However, given the miniscule size of specimens collected with fine needles, it can be difficult to determine whether there is enough tissue in the biopsied specimen to conduct laboratory analyses. To address this clinical challenge, researchers developed a target sample check illuminator (TSCI), which uses a specific wavelength of light for real-time identification of tissue specimen inside an FNA biopsy. The researchers, from Tottori University School of Medicine and Tottori University Hospital, both in Yonago, Japan,

832.

tested the accuracy of the TSCI in 142 pancreatic samples collected through EUS-guided FNA in 58 patients with suspected pancreatic tumors. They conducted FNA using a 22-G needle in 26 patients, a 25-G needle in 31 patients and a 19-G needle in one individual. They also sent samples for cytopathologic analysis.

sample has been obtained for cytologic examination; sometimes only blood elements can be visualized. The problem becomes even more complicated if there is no onsite cytopathologist to examine the specimen. Even in the presence of an onsite cytopathologist, EUS-guided core biopsies that are sent for histopathology in formalin are not,

If evaluated by other centers, TSCI appears to be very helpful in overcoming problems inherent in today’s cytologic sampling.

TSCI accurately identified tissue specimen 93.7% of the time (133), they found. Approximately 91% (53) of the 58 patients who were identified by TSCI as having adequate tissue samples did not require repeat FNA. Dr. Bhutani: EUS-guided FNA pancreatic samples are frequently contaminated with blood, which makes it difficult to determine whether an adequate

and cannot be, pathologically evaluated before being sent out. With any of these scenarios, if there is inadequate specimen, patients may be required to return for a repeat EUSguided FNA. If the TSCI is validated by other centers, it could be very helpful in overcoming these problems. ■ Dr. Bhutani has received financial support from Cook Medical to travel to medical meetings and has received a research grant from Boston Scientific.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Physician Stresses Simulation To Avert Harm to Real Patients Physicians should be selected on skills outside of cognition BY CHRISTINA FRANGOU SALT LAKE CITY— —As a young combat pilot in the Israeli Air Force, Amitai Ziv, MD, practiced on a simulator for every nightmare scenario his trainers could come up with: ejecting from airplanes, landing planes overcome with flames, managing all sorts of equipment malfunctions. When he started medical school after leaving the air force, he was astonished that medical trainees honed their skills not on simulators, but on real patients. “We expect both health care and aviation to have very low tolerance for errors. But in health care, we are very much behind aviation in that respect,” Dr. Ziv said in a lecture at the 2014 Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) meeting. “Our health care training, despite the simulation movement, is still by and large the old model: See one, teach one, do one, kill one. … The patients are the ones who pay the price,” said Dr. Ziv, chair of medical education at the Sackler School of Medicine of Tel Aviv University. As deputy director of Sheba Medical Center, he is responsible for patient safety, risk management and medical education. A pediatrician, Dr. Ziv has spent the past 20 years trying to adapt the lessons of flight simulation training to the field of medical training. According to his bio, this idea came to him in medical school when a fellow student committed suicide hours after failing a test. The future Dr. Ziv decided then that the testing system, both to get into medical school and to become a licensed physician, was inadequate. It focused purely on a student’s cognition. The system failed to assess the human being. Driven by this realization, Dr. Ziv completed his MD dissertation on peer evaluation. Later, he worked with the Educational Commission for Foreign Medical Graduates on a simulation-based program that certifies foreign immigrant doctors applying to work in the United States. In 2001, Dr. Ziv returned to Israel and founded the Israel Center for Medical Simulation (MSR), now “arguably one of the most effective and influential simulation centers in the world,” said Gerald Fried, MD, immediate past president of SAGES and chair of surgery at McGill University, in Montreal, Canada. Housed in a virtual hospital on the massive Chaim Sheba Medical Center campus just outside Tel Aviv, MSR is home to more than 100 different kinds of simulators and employs more than 150 professional actors for its courses. The nonprofit center, which operates on a fee-for-service model, trains more than 10,000 health professionals in more than 60 courses annually. Almost all health care practitioners in Israel have undergone some training at MSR. The student body ranges from medical school applicants to hospital CEOs. Among the trainees are pharmacists who learn communication skills that can help with angry patients and reduce errors; surgeons who rehearse complex procedures in a high-tech operating room simulator; and surgical residents who practice on virtual-reality simulators. MSR instructors watch everything through one-way mirrors and conduct extensive aviation-style debriefs. Even the country’s medical clowns refine their skills through courses at MSR.

Trainees perform a simulated case at the Israel Center for Medical Simulation.

MSR trains health care workers for run-of-the-mill scenarios but also for the catastrophic “unimaginable” ones. Israel is known for its extensive mass casualty preparedness; much of that training is conducted at MSR. The training extends also to Palestinians; MSR uses simulation to provide trauma training for Palestinian physicians and paramedics through an affiliation with Physicians for Human Rights. MSR’s simulation model can be used around the world to improve safety and medical training, Dr. Fried said. “This can reshape the way medical care is delivered around the world.”

The center is founded on the principle that simulation-based medical training and assessment can revolutionize the safety culture in medicine. For too long, medicine has accepted suboptimal levels of safety, Dr. Ziv said. He likes to compare medicine to aviation. If the deaths attributed to medical errors are put into aviation terms, they amount to four Boeing 747 crashes daily, Dr. Ziv said, citing a recent controversial study in the Journal of Patient Safety (2013;9:122-128). Medical errors disproportionately affect women, children and older patients, he added. “This is not something intentional, but these are groups, perhaps, that we do not communicate as effectively with.” Simulation, which ranges from expensive hightech simulators to low-tech role-playing with actors, see Simulation, page 43

Amitai Ziv, MD, believes personality traits should count more when evaluating medical students and physicians.

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

provides an environment for people to learn by hands-on practice but without putting patients’ lives at risk, Dr. Ziv said. “This is a very powerful way of teaching.” Dr. Ziv pointed to data collected by the American nonprofit behavioral psychology center, the National Training Laboratory, which showed that learners who are taught by hands-on practice retain around 75% of information. In contrast, students remember about 5% of what they hear in lectures, 10% of what they read and 30% of what they see. A key advantage of simulation is that it can teach skills needed in emergency situations, the medical equivalents of trying to land a plane with a fire in the cockpit, Dr. Ziv said. These are low-frequency but high-stakes scenarios.

‘We will have to change course. We have some barriers

for medicine”—to measure candidates’ judgment and decision-making skills. Candidates complete a series of behavioral stations, including encounters with simulated patients and group tasks, an autobiographical questionnaire, and a judgment and decision-making questionnaire. They are evaluated on interpersonal communication skills, ability to handle stress, initiative and responsibility, and self-awareness. This program resulted in a change of about 20% in the cohort of accepted students compared with previous admission

criteria (Med Educ 2008;42:991-998). The investigators found very low correlation between the candidates’ MOR scores and cognitive scores. “MOR conveys the importance of maintaining humanistic characteristics in the medical profession to students and faculty staff,” Dr. Ziv noted. He would like to see similarly thorough assessments of physicians throughout their career. Physicians should be evaluated on all aspects of the care they provide, from their ability to deal with high-stress situations to their operative skill, he said.

“Surgeons can be operating with Parkinson’s and nobody can ground that surgeon. That’s true today around the world and it is not right.” Dr. Ziv hoped that simulation-based medical education will spark a revolution in medicine. “We will have to change course. We have some barriers but they are not as high as we think. The end of it, there’s the humility message that if we meet our errors in the simulation environment, we will be better off in the real world,” he said. ■

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but they are not as high as we think. The end of it, there’s the humility message that gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

if we meet our errors in the

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HEPATOLOGY

simulation environment, we will be better off in the real world.’ —Amitai Ziv, MD

Fecal Transplants for IBD Show Mixed Results in Trials

F O C U S

I N

Probiotics Could Prevent Hepatic Encephalopathy

BY DAVID WILD

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

see Probiotics, page 11

Studies Challenge Conventional Wisdom In Biliary Stent Cost

MSR runs programs to teach trainees and practicing physicians how to respond in so-called “nightmare scenarios.” There is even a module known as the “nightmare course,” a mandatory five-day program for Israeli interns about to begin their first hospital rotations. They are challenged with a series of stressful situations such as finding themselves in an elevator alone at night with a patient who stops breathing. “Or it could be the nightmare on the emotional front: telling a family that we have erred and we gave their father the wrong blood, that we are responsible for the loss of a loved one,” Dr. Ziv said. “It’s through this kind of proactive learning, rather than [a] reactive one with our apprentice one, [that] we can enact nightmares.” Dr. Ziv asserted that medical errors occur because of malfunctions built into the health care system from the moment applicants are evaluated as candidates for medical school. At most medical schools, the application committee considers grades and extracurricular activities, but places little emphasis on personality traits. But medical schools need to consider personality traits, Dr. Ziv said. And so, MSR, together with Israeli medical schools and Israel’s National Institute for Testing and Evaluation, developed an assessment program—known as MOR, a Hebrew acronym for “selection

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

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

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

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see Fecal, page 19

I N S I D E EXPERTS’ PICKS

Inside Ins ide the Electronic Health Record

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

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

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PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

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

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

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

NEIL GUPTA, MD

PRATEEK SHARMA, MD

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

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

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

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

olorectal

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

cancer

(CRC) is the second leading cause of

cancer-related in

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world.1

Screening colonoscopy and polypectomy have become widely accepted as the most st effective available methods for for early detection and prevention of

See page 20

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

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

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

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

INDICATION SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) as a component of a combination antiviral treatment regimen. • SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection Prescribing Considerations: • Monotherapy of SOVALDI is not recommended. • Treatment regimen and duration are dependent on both viral genotype and patient population. • Treatment response varies based on baseline host and viral factors.

SOVALDI REGIMENS WERE STUDIED ACROSS MANY TYPES OF HCV-INFECTED SUBJECTS Treatment-naïve and -experienced subjects1 • Treatment-naïve GT 1, 4, 5 and 6 subjects achieved an overall SVR12 of 90% (N=327), with GT 1 subjects achieving an SVR12 of 89% (n=292) and GT 4 subjects achieving an SVR12 of 96% (n=28), with SOVALDI + peginterferon (Peg-IFN) alfa + ribavirin (RBV) for 12 weeks in NEUTRINO1,a • Treatment-experienced GT 1 patients can be treated with SOVALDI + Peg-IFN + RBV for 12 weeks, with an estimated SVR of 71%1,b • An all-oral regimen of SOVALDI + RBV for 12 weeks (GT 2) and 24 weeks (GT 3) demonstrated efficacy in treatment-naïve and treatment-experienced subjects1

Subjects with traditionally lower rates of response to treatment2 • SOVALDI delivered high SVR rates in GT 1, 4, 5 and 6 subjects with compensated cirrhosis (80%; n=54) and without cirrhosis (92%; n=273)1 • SVR12 was comparable in subjects with HCV GT 1a and 1b, IL28B C/C and non-C/C alleles, high and low baseline viral load and in Black and non-Black subjects1,3,4

HCV/HIV-1 co-infected subjects1 • SOVALDI is indicated for the treatment of HCV in HCV/HIV-1 co-infected patients. Treatment regimens recommended for co-infected patients are the same as those for HCV mono-infected patients1

NEUTRINO—GT 1 and 4 treatment-naïve adult subjects1 An open-label, single-arm trial evaluating 12 weeks of treatment with SOVALDI in combination with peginterferon (Peg-IFN) alfa 2a and ribavirin (RBV) in treatment-naïve subjects (N=327) with genotype 1, 4, 5 or 6 HCV infection, compared to a pre-specified historical control. a In each of the phase 3 studies, sustained virologic response (SVR) was the primary endpoint, which was defined as HCV RNA <25 IU/mL at 12 weeks after the end of treatment.1 Achieving SVR is considered a virologic cure.2 b The response rate in treatment-naïve subjects with difficult-to-treat factors in NEUTRINO (n=52) may approximate the response rate in patients who previously failed pegylated interferon and ribavirin therapy. (Difficult-to-treat factors include GT 1 subjects with IL28B non-C/C alleles, HCV RNA >800,000 IU/mL and Metavir F3/F4 fibrosis.)1

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS • SOVALDI combination treatment with ribavirin or with peginterferon alfa plus ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risk for birth defects and fetal death associated with ribavirin. Contraindications to peginterferon alfa and ribavirin also apply to SOVALDI combination treatment. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.

WARNINGS AND PRECAUTIONS • Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners must use 2 forms of non-hormonal contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the prescribing information for ribavirin.

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

sovaldi.com/hcp

ADDITIONAL SUBJECTS STUDIED WITH SOVALDI REGIMENS IFN-unable subjects1 • SOVALDI + RBV was evaluated in GT 2 and GT 3 subjects who were IFN-intolerant, -unwilling, or -ineligible1 • An IFN-free regimen of SOVALDI + RBV is the recommended regimen for GT 2 and 3 patients and can be considered as a therapeutic option for GT 1 patients who are ineligible to receive an interferonbased regimen. Treatment decision should be guided by an assessment of the potential beneﬁts and risks for the individual patient1

Patients with HCC awaiting liver transplant1 • SOVALDI + RBV is the ﬁrst approved, all-oral regimen for HCV-infected subjects with HCC meeting the Milan criteria who are awaiting liver transplantation. Recommended treatment duration is up to 48 weeks or until the time of transplantation, whichever comes ﬁrst, to prevent post-transplant HCV reinfection1 • The safety and efficacy of SOVALDI have not been established in post-liver transplant patients1

IMPORTANT SAFETY INFORMATION (CONTINUED) WARNINGS AND PRECAUTIONS (CONTINUED) • Use with Potent P-gp Inducers: Rifampin and St. John’s wort should not be used with SOVALDI as they may signiﬁcantly decrease sofosbuvir plasma concentration, reducing its therapeutic effect.

ADVERSE REACTIONS Most common (≥20%, all grades) adverse reactions for: • SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia, and anemia • SOVALDI + ribavirin combination therapy were fatigue and headache

DRUG INTERACTIONS • In addition to rifampin and St. John’s wort, coadministration of SOVALDI is not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of sofosbuvir, reducing its therapeutic effect.

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

Use with Potent P-gp Inducers: Drugs that are potent P-gp inducers in the intestine (e.g., rifampin, St. John’s wort) may significantly decrease sofosbuvir plasma concentration leading to reduced Brief summary of full Prescribing Information. Please see full Prescribing Information. therapeutic effect of SOVALDI. Rifampin and St. John’s wort should not be used with SOVALDI. Rx Only. ADVERSE REACTIONS: Adverse Reactions from Clinical Trials Experience: SOVALDI should be

SOVALDI® (sofosbuvir)

INDICATIONS AND USAGE: SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) as a component of a combination antiviral treatment regimen. • SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection Prescribing considerations: • Monotherapy of SOVALDI is not recommended • Treatment regimen and duration are dependent on both viral genotype and patient population • Treatment response varies based on baseline host and viral factors DOSAGE AND ADMINISTRATION: Adult Dosage: one 400 mg tablet, taken orally, once daily with or without food. SOVALDI should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for treatment of CHC in adults.

administered with ribavirin or peginterferon alfa/ribavirin. Refer to the prescribing information of peginterferon alfa and ribavirin for a description of adverse reactions associated with their use. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety assessment of SOVALDI is based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including 650 subjects who received SOVALDI + ribavirin combination therapy for 12 weeks, 98 subjects who received SOVALDI + ribavirin combination therapy for 16 weeks, 250 subjects who received SOVALDI + ribavirin combination therapy for 24 weeks, 327 subjects who received SOVALDI + peginterferon alfa + ribavirin combination therapy for 12 weeks, 243 subjects who received peginterferon alfa + ribavirin for 24 weeks and 71 subjects who received placebo (PBO) for 12 weeks. The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving SOVALDI + ribavirin for 12 weeks, <1% for subjects receiving SOVALDI + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving SOVALDI + peginterferon alfa + ribavirin for 12 weeks. Treatment-emergent adverse events observed in ≥15% of subjects in clinical trials are provided in Table 1. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. The most common adverse events (≥ 20%) for SOVALDI + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥ 20%) for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.

Recommended dose and treatment duration for SOVALDI combination therapy for patients with: genotype 1 or 4 CHC is SOVALDI + peginterferon alfa + ribavirin for 12 weeks; genotype 2 CHC is SOVALDI + ribavirin for 12 weeks; and genotype 3 CHC is SOVALDI + ribavirin for 24 weeks. See peginterferon alfa prescribing information for dosing recommendation for patients with genotype 1 or 4 CHC. Dose of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). Daily dose of ribavirin is administered orally in two divided doses with food. Patients with renal impairment (CrCl ≤50 mL/min) require ribavirin dose reduction; refer to ribavirin prescribing information. Table 1 Treatment-Emergent Adverse Events (All Grades) Reported in ≥15% of Subjects in SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for Any Treatment Arm CHC patients with genotype 1 infection who are ineligible to receive an interferon-based regimen. Interferon-free Regimens Interferon-containing Regimens Treatment decision should be guided by assessment of potential benefits and risks for individual patient. SOVALDI + Patients with Hepatocellular p Carcinoma Awaitingg Liver Transplantation: p SOVALDI in combination Peg-IFN alfa + PBO SOVALDI + SOVALDI + Peg-IFN alfa with ribavirin is recommended for up to 48 weeks or until time of liver transplantation to prevent RBV Va 12 RBV Va RBV Va + RBVb post-transplant HCV reinfection. weeks 12 weeks 24 weeks 24 weeks 12 weeks Dose Modification: Dose reduction of SOVALDI is not recommended. Genotype yp 1 and 4: If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue peginterferon alfa and/or ribavirin dose. Genotype yp 2 and 3: If a patient has a serious adverse reaction potentially related to ribavirin, ribavirin dose should be modified or discontinued, if appropriate, until adverse reaction abates or decreases in severity. Ribavirin dose modification guideline for coadministration with SOVALDI: Reduce the ribavirin dose to 600 mg/daya in patients with no cardiac disease if hemoglobin is <10 g/dL and discontinue ribavirinb if it is <8.5 g/dL. Reduce the ribavirin dose to 600 mg/daya in patients with history of stable cardiac disease who have ≥2 g/dL decrease in hemoglobin during any 4 week treatment period and discontinue ribavirinb if it is <12 g/dL despite 4 weeks at reduced dose.a Daily dose of ribavirin is administered orally in two divided doses with food.b Once ribavirin has been withheld due to either laboratory abnormality or clinical manifestation, an attempt may be made to restart ribavirin at 600 mg daily and further increase dose to 800 mg daily. It is not recommended that ribavirin be increased to original assigned dose (1000 mg to 1200 mg daily). Discontinuation of Dosing: If other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should also be discontinued. Severe Renal Impairment and End Stage Renal Disease: No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite.

N=71

N=650

N=250

N=243

N=327

Fatigue

24%

38%

30%

55%

59%

Headache

20%

24%

30%

44%

36%

Nausea

18%

22%

13%

29%

34%

Insomnia

15%

16%

29%

25%

Pruritus

11%

27%

17%

Anemia

10%

12%

21%

Asthenia

21%

Rash

18%

Decreased Appetite

10%

18%

Chills

18%

17%

Influenza Like Illness

18%

16%

Pyrexia

14%

18%

Diarrhea

12%

17%

12%

Neutropenia

<1%

12%

17%

Myalgia

16%

14%

Irritability 1% 10% 10% 16% 13% CONTRAINDICATIONS: When SOVALDI is used in combination with ribavirin or peginterferon alfa/ a Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per ribavirin, contraindications applicable to those agents are applicable to combination therapies. Refer day if weighing ≥75 kg). to prescribing information of peginterferon alfa and ribavirin for a list of their contraindications. b Subjects received 800 mg ribavirin per day regardless of weight. SOVALDI combination treatment with ribavirin or peginterferon alfa/ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant With the exception of anemia and neutropenia, the majority of events presented in Table 1 occurred because of the risks for birth defects and fetal death associated with ribavirin. at severity of grade 1 in SOVALDI-containing regimens. WARNINGS AND PRECAUTIONS: Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin may cause birth defects Less Common Adverse Reactions Reported in Clinical Trials (<1%):: The following ADRs and/or death of the exposed fetus and animal studies have shown that interferons have abortifacient occurred in <1% of subjects receiving SOVALDI in a combination regimen in any one trial. These effects. Extreme care must be taken to avoid pregnancy in female patients and in female partners of events have been included because of their seriousness or assessment of potential causal male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test relationship. Hematologic Effects:: pancytopenia (particularly in subjects receiving concomitant has been obtained immediately prior to initiation of therapy. When SOVALDI is used in combination pegylated interferon). with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners Psychiatric Disorders:: severe depression (particularly in subjects with pre-existing history of must use two forms of effective contraception during treatment and for at least 6 months after psychiatric illness), including suicidal ideation and suicide. treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Laboratory Abnormalities: Changes in selected hematological parameters are described in Table 2. There are no data on the effectiveness of systemic hormonal contraceptives in women taking A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be SOVALDI, therefore, two non-hormonal methods of contraception should be used during treatment made due to differing trial designs. with SOVALDI and concomitant ribavirin. Refer also to the prescribing information for ribavirin.

Brief Summary (cont.) Table 2 Percentage of Subjects Reporting Selected Hematological Parameters Interferon-free Regimens

Interferon-containing Regimens

PBO 12 weeks

SOVALDI + RBV Va 12 weeks

SOVALDI + RBV Va 24 weeks

Peg-IFN + RBVb 24 weeks

SOVALDI + Peg-IFN + RBV Va 12 weeks

N=71

N=647

N=250

N=242

N=327

<10

14%

23%

<8.5

<1%

Hematological Parameters Hemoglobin (g/dL)

Neutrophils (x109/L) ≥0.5 - <0.75 <0.5

<1%

12%

15%

<1%

Platelets (x10 /L) ≥25 - <50 <25 a

Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing ≥75 kg). b Subjects received 800 mg ribavirin per day regardless of weight.

USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy g y Category g y X: Use with Ribavirin and/or Peginterferon g Alfa/Ribavirin: Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using two forms of effective contraception during treatment with ribavirin and for 6 months after treatment has concluded. There are no data on the effectiveness of systemic hormonal contraceptives in women taking SOVALDI. Therefore, two effective non-hormonal methods of contraception should be used during treatment with SOVALDI and concomitant ribavirin. In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling Ribavirin Pregnancy Registry at 1-800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263. Animal Data:: Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans. Pregnancy g y Category g y B: SOVALDI: There are no adequate and well-controlled studies with SOVALDI in pregnant women. Animal Data:: No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to the predominant circulating metabolite GS-331007 increased over the course of gestation from approximately 5 to 10-fold and 12 to 28-fold the exposure in humans at the recommended clinical dose, respectively.

Nursing Mothers: It is not known whether SOVALDI and its metabolites are present in human breast milk. The predominant circulating metabolite GS-331007 was the primary component observed in the milk of lactating rats, without effect on nursing pups. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing Bilirubin Elevations: Total bilirubin elevation of more than 2.5xULN was observed in none of the or discontinue treatment with ribavirin containing regimens, taking into account the importance of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of the therapy to the mother. See also the prescribing information for ribavirin. subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks and SOVALDI + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during the first 1 to 2 weeks of Pediatric Use: Safety and effectiveness of SOVALDI in children less than 18 years of age have not treatment and subsequently decreased and returned to baseline levels by post-treatment Week 4. been established. These bilirubin elevations were not associated with transaminase elevations. Geriatric Use: Clinical studies of SOVALDI included 90 subjects aged 65 and over. The response Creatine Kinase Elevations: Creatine kinase was assessed in the FISSION and NEUTRINO trials. rates observed for subjects over 65 years of age were similar to that of younger subjects across Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10xULN was observed treatment groups. No dose adjustment of SOVALDI is warranted in geriatric patients. in <1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + Renal Impairment: No dose adjustment of SOVALDI is required for patients with mild or moderate peginterferon alfa + ribavirin 12 weeks and SOVALDI + ribavirin 12 weeks groups, respectively. Lipase p Elevations: Isolated, asymptomatic lipase elevation of greater than 3xULN was observed renal impairment. The safety of SOVALDI has not been assessed in patients with severe renal 2 in <1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, impairment (eGFR <30 mL/min/1.73m ) or end stage renal disease (ESRD) requiring hemodialysis. Refer also to ribavirin prescribing information for patients with CrCl<50 mL/min. SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively.

Hepatic Impairment: No dose adjustment of SOVALDI is required for patients with mild, moderate DRUG INTERACTIONS: Potential for Drug Interactions: After oral administration of SOVALDI, or severe hepatic impairment (Child-Pugh Class A, B or C). Safety and efficacy of SOVALDI have sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts not been established in patients with decompensated cirrhosis. See peginterferon alfa prescribing for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir information for contraindication in hepatic decompensation. accounts for approximately 4% of drug related material. In clinical pharmacology studies, both Patients with HCV/HIV-1 Co-infection: The safety and efficacy of SOVALDI was assessed in 223 sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses. Sofosbuvir is HCV/HIV-1 co-infected subjects. See Dosage and Administration for dosing recommendations in a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS 331007 HCV/HIV-1 co-infected patients. The safety profile in HCV/HIV-1 co-infected subjects was similar to is not. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John’s wort) may that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of SOVALDI and in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the thus should not be used with SOVALDI. Coadministration of SOVALDI with drugs that inhibit P-gp subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV concentration; accordingly, SOVALDI may be coadministered with P-gp and/or BCRP inhibitors. mono-infected subjects receiving SOVALDI + ribavirin in Phase 3 trials. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to Patients with Hepatocellular Carcinoma (HCC) Awaiting Liver Transplantation: SOVALDI increase exposures of drugs that are substrates of these transporters. The intracellular metabolic was studied in HCV-infected subjects with HCC prior to undergoing liver transplantation in an activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase open label clinical trial evaluating the safety and efficacy of SOVALDI and ribavirin administered and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs. pre-transplant to prevent post-transplant HCV reinfection. See Dosage and Administration for dosing Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended recommendations in patients with HCC awaiting liver transplantation.The safety profile of SOVALDI Based on Drug Interaction Studies or Predicted Interaction: Drug interaction information for and ribavirin in HCV-infected subjects prior to liver transplantation was comparable to that observed SOVALDI with potential concomitant drugs is summarized as follows and the list is not inclusive. The in subjects treated with SOVALDI and ribavirin in Phase 3 clinical trials. drug interactions described are based on potential drug interactions that may occur with SOVALDI. Post-Liver Transplant Patients: The safety and efficacy of SOVALDI have not been established in Anticonvulsants: Coadministration of SOVALDI with carbamazepine, phenytoin, phenobarbital, post-liver transplant patients. oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Such coadministration is not recommended. Antimycobacterials: CHC Patients with Genotype 5 or 6 HCV Infection: Available data on subjects with genotype 5 or Coadministration of SOVALDI with rifabutin or rifapentine is expected to decrease the concentration 6 HCV infection are insufficient for dosing recommendations. of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Such coadministration is not ® recommended. SOVALDI should not be used with rifampin, a potent intestinal P-gp. Herbal References: 1. SOVALDI (sofosbuvir). US Prescribing Information. Gilead Sciences, Inc. Foster City, CA. December 2013. 2. US Department of Health and Human Services, Center for Drug Evaluation and Research. Draft Guidance for Industry. Supplements: SOVALDI should not be used with St. John’s wort (Hypericum perforatum), a potent Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment. http://www.fda.gov/downloads/ intestinal P-gp inducer. HIV Protease Inhibitors: Coadministration of SOVALDI with tipranavir/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf. Published October 2013. Accessed May ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic 6, 2014. 3. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, et al. Sofosbuvir for previously untreated chronic hepatitis C effect of SOVALDI. Coadministration is not recommended. infection. N Engl J Med. d 2013;368(20):1878-1887. 4. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, et al. Sofosbuvir Drugs without Clinically Significant Interactions with SOVALDI: In addition to the drugs listed above, the interaction between SOVALDI and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

for previously untreated chronic hepatitis C infection. N Engl J Med. d 2013;368(20)[suppl]. SOVALDI, the SOVALDI Logo, GILEAD and the GILEAD Logo are trademarks of Gilead Sciences, Inc., or its related companies. ©2014 Gilead Sciences, Inc. All rights reserved. SVDP0115 07/14

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

History of Lap Colectomy: An Approach Still Awaiting iting Widespread Use BY VICTORIA STERN

n October 1990, an elderly woman came to see Dennis Fowler, MD. She had several critical issues, including severe lung disease and a tumor resting in the middle of her sigmoid colon. Dr. Fowler, an assistant clinical professor of surgery at the University of Missouri, Kansas City School of Medicine at the time, sat with his patient and her son, discussing treatment options. Dr. Fowler was reluctant to perform surgery because of the woman’s obstructive lung disease. The patient, however, kept insisting that she would rather die from an operation than leave the cancer inside her. Dr. Fowler told her about a new technique that he and several colleagues had been investigating over the summer. It involved taking out a section of the colon laparoscopically. He had trialed the technique in the pig lab, but the procedure had never, to his knowledge, been attempted in a human patient. “After numerous discussions, the patient said she wanted this new procedure,” Dr. Fowler said. On Oct. 19, after receiving three prototypes of a laparoscopic intestinal stapler from U.S. Surgical, Dr. Fowler performed the first laparoscopic sigmoid colectomy. He used one stapler to ligate the mesentery and two to transect the colon intraperitoneally. He then created a small muscle-splitting incision in the left lower quadrant of the abdomen to remove the specimen and completed the anastomosis intracorporeally with a circular stapler. Dr. Fowler was astonished by the patient’s progress. “Her recovery was amazing considering that she had such serious obstructive lung disease,” Dr. Fowler recalled. “I realized there might be a real benefit to having colon surgery performed laparoscopically.”

Laparoscopic Colectomy Beginnings As laparoscopic cholecystectomy gained popularity in the late 1980s, physicians started looking for the next home run for minimally invasive surgery (MIS). “The way we started was very innocent,” said Miamibased general surgeon Moises Jacobs, MD, recalling his first laparoscopic colectomy case in June 1990. The patient had a particularly “floppy colon,” Dr. Jacobs recalled, and consequently he could mobilize everything using one small incision. Dr. Jacobs and colleagues Harold Goldstein, MD, and Juan Carlos Verdeja, MD, placed four trocars in the abdominal cavity and, using cautery, mobilized the white line of Toldt and the hepatic flexure. Through a small incision in the right lower quadrant, they exteriorized the colon, completing the first laparoscopic-assisted right hemicolectomy. The woman went home four days after surgery. “We knew there must be something to this new technique,” Dr. Jacobs said. Dr. Jacobs’ foray into laparoscopy began with cholecystectomy. In December 1989, he and his colleagues began performing laparoscopic cholecystectomies using a two-handed approach. “We were doing two-handed surgery from the very beginning, and as a result, it was easier for us to transition into more complex surgeries,” Dr. Jacobs said.

‘I didn’t just jump off a cliff without a parachute. I took the idea to the lab, worked out issues, bounced ideas off colleagues, and consequently have had minimal problems.’ —Morris Franklin, MD

When Dr. Jacobs became interested in applying laparoscopic techniques to colon surgery, he worked intensively in the pig lab to hone his skills until completing his first laparoscopic colectomy in June 1990. After this success, Dr. Jacobs began investigating a variety of techniques for laparoscopic colon surgery with colleagues, including Dr. Verdeja and colorectal surgeon Gustavo Plasencia, MD ((Arch Surg 1994;129:206-212; Dis Colon Rectum 1994;37:829-833). “These surgeons knew this was going to be the next big deal,” said Morris Franklin, MD, director of the Texas Endosurgery Institute. “They made significant contributions early on when it really counted.” Halfway across the country in San Antonio, Dr. Franklin was also exploring laparoscopic surgery. In 1988, Dr. Franklin, alongside urologist William Schuessler, MD, and gynecologist Thierry Vancaillie, MD, started investigating laparoscopic pelvic lymph node dissection for prostate cancer, a demanding procedure they eventually mastered and began teaching to urologists worldwide. Dr. Franklin saw laparoscopic cholecystectomy as a better teaching tool for laparoscopy. He and Dr. Schuessler began performing up to 15 cholecystectomies a day. They also received institutional review board approval from their hospital to explore new, more advanced laparoscopic techniques, and completed the first distal prostatectomy, splenectomy and one of the first hiatal hernia repairs. Dr. Franklin soon developed an interest in colon surgery. He and his colleagues spent every weekend for 18 months in the pig lab and any additional free moments developing their skills. In August 1990, Dr. Franklin performed his first laparoscopic colectomy. Several months later, in April 1991, he did the first completely laparoscopic right hemicolectomy.

“I tried to do it right,” Dr. Franklin said. “I didn’t just jump off a cliff without a parachute. I took the idea to the lab, worked out issues, bounced ideas off colleagues, and consequently have had minimal problems.” Richard Whelan, MD, recalls Dr. Franklin’s unique abilities. “Dr. Franklin set the bar in the early days and he still does today,” said Dr. Whelan, professor of surgery and chief of surgical oncology at St. Luke’sRoosevelt Hospital, in New York City. “His skill set is hard to match.” Perhaps the first person to perform a laparoscopic colectomy was a gynecologist named David Redwine, MD, in the late 1980s, Dr. Franklin noted. Several other general surgeons ventured into laparoscopic colon surgery early as well. In 1990, Garth Ballantyne, MD, started visiting U.S. Surgical on Tuesday afternoons to practice laparoscopic colectomies on pigs with fellow surgeon Patrick Leahy, MD. In late 1990, Dr. Leahy resected a proximal rectal cancer laparoscopically with the EndoGIA (U.S. Surgical) and in February 1991, Dr. Ballantyne did his first laparoscopic colectomy at Yale University. Another general surgeon, Joseph Uddo, MD, performed an entirely laparoscopic right hemicolectomy in July 1991.

Technique Spreads Dr. Fowler presented on his first laparoscopic sigmoid resection at the Society of American Gastrointestinal and Endoscopic Surgeons meeting in April 1991 (Surg Laparosc Endoscc 1991;1:183-188). “I had an overwhelming response from people all over the world,” Dr. Fowler said. “Not many surgeons knew what had been done, and were eager to engage in training programs to learn the procedure.” see Colectomy, page 50

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

Colectomy continued from page 49

As with laparoscopic cholecystectomy, interest in laparoscopic colectomy prompted surgeons to initiate weekend training courses. By November 1991, Dr. Ballantyne had organized courses for U.S. Surgical. Around that time, Ethicon had arranged laparoscopic colectomy workshops, run by Steven Wexner, MD, of Cleveland Clinic, in Weston, Fla. The industry competitors invited many of the same faculty to their courses, and this core group of surgeons soon branched off into U.S. Surgical and Ethicon camps. Several industry leaders, namely Lee Cohen, head of laparoscopic marketing and technology at U.S. Surgical, in Norwalk, Conn., and Nicholas Valeriani, president of Ethicon Endo-Surgery for many years, supported and pushed the advancement of laparoscopic technology and education. “I often referred to Ms. Cohen as the queen of laparoscopy,” Dr. Ballantyne recalled. On the global front, Dr. Franklin traveled to Australia, New Zealand and South America in the early 1990s to introduce laparoscopic colectomy to surgeons. Drs. Jacobs and Plasencia also

taught some of the first international courses in laparoscopic colectomy. “International surgeons, such as [Australians] Russell Stitz, MD, and Leslie Nathanson, MD, who went back home after these courses, are now leaders in laparoscopic colorectal surgery,” said Dr. Franklin. Even with training, however, many surgeons struggled to learn the new techniques. Dr. Ballantyne recalled surgeons’ ambivalence about laparoscopic colectomy. “When we surveyed the attendees [of the U.S. Surgical course], many said, ‘Thanks for a great course, Garth, but you’ve convinced me that laparoscopic colectomy is too hard to do and I’ll never do one.’” Laparoscopic colectomy is not as easy as laparoscopic cholecystectomy largely because it involves navigating at least two, and often all four, quadrants of the abdomen. “The majority of surgeons didn’t want to learn laparoscopic colectomy because it was much harder than open surgery,” Dr. Whelan said. Laparoscopic colectomy was also different from laparoscopic cholecystectomy because patients didn’t demand that their colectomy be completed laparoscopically. “Surgeons, even now, don’t

‘I had an overwhelming response from people all over the world. Not many surgeons knew what had been done, and were eager to engage in training programs to learn the procedure.’ —Dennis Fowler, MD

as often feel pressure from patients to do their colectomy laparoscopically,” Dr. Fowler said. Dr. Jacobs noted that the low volume of laparoscopic colectomy cases by general surgeons in the United States made it harder for surgeons to gain experience. “I think the low volume of cases slowed down the adoption of laparoscopic colectomy,” he said. But what almost halted its evolution was the concern over tumor recurrence.

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In 1994, worries about the safety of the procedure emerged. A study by Berends et al in The Lancett reported that three of 14 patients (21%) undergoing laparoscopic colectomy had tumor recurrence at the trocar wound sites (1994;344:58). Subsequent data have shown unambiguously that when the procedure is performed correctly, there is no increase in tumor recurrence at the incision. “A surgeon can prevent a portsite recurrence simply by doing good, clean surgery,” said Dr. Franklin, who found that the quality of surgical technique directly influenced the incidence of port-site recurrences (Surg Endosc 2001;15:121-125). “After 3,500 cases, I haven’t had a single tumor implant at the trocar site.” But even the suggestion that tumors implanted in laparoscopic incisions more often than in open incisions led some major academic institutions and colorectal societies to limit or even ban laparoscopic colectomies. “At Columbia University, senior surgeons stopped us from doing laparoscopic surgery, and colorectal societies were against laparoscopy because of the lack of data,” said Dr. Whelan. “In addition, many older surgeons felt threatened and didn’t want to see any laparoscopic surgery.” Surgeons who continued to perform

laparoscopic colectomies experienced considerable backlash from the surgical community. “Several of us were threatened by colleagues,” Dr. Fowler said. “Sometimes action was taken against us to reduce our privileges or turn patients against us.” The resistance to laparoscopic colectomy reveals a lot about human nature, Dr. Jacobs said. “Some surgeons [who performed open surgery] didn’t want to lose patients and money to this new technique.” It took 10 years before a definitive randomized controlled trial (RCT) created a large-scale shift in people’s thinking about laparoscopic colectomy (N Engl J Medd 2004;350:2050-2059). The COST (Clinical Outcomes of Surgical Therapy) trial, which began in 1994, involved 48 institutions and 872 patients with colon cancer randomly assigned to open or laparoscopic-assisted colectomy. Recurrence rates in surgical wounds were less than 1% in both groups, and the overall survival rate at three years was almost identical. Before the study was ultimately published in 2004, a group of laparoscopic surgeons worked diligently to verify the safety of laparoscopic colectomy. “Despite the resistance, we persisted,” Dr. Jacobs said. “My colleagues and I had been doing laparoscopic colectomy for four years already and didn’t have any bad results.” In 1991, Dr. Jacobs and his colleagues completed a series of 20 laparoscopicassisted colon resections (Surg Laparosc Endoscc 1991;1:144-150), and independently, Dr. Franklin and his colleagues performed 51 laparoscopic colectomies ((Ann Surgg 1992;216:703-707). Both studies showed the technique was safe. Several years later, Dr. Franklin published a five-year prospective randomized trial comparing open and laparoscopic approaches to colon cancer, and found

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2014

the laparoscopic procedure offered similar oncologic resections and better recovery than open surgery (Dis Colon Rectum 1996;39:S35-S46). In 1996, James Fleshman, MD, Anthony Senagore, MD, and Heidi Nelson, MD, reported retrospective data from the COST study, showing the same 1% rate of tumor recurrence at the wound sites in laparoscopic and open colectomy (Dis Colon Rectum 1996;39:S53-S58). In 1998, Jeffrey Milsom, MD, from Cornell University, in Ithaca, N.Y., performed a prospective RCT comparing laparoscopic and open techniques in 109 patients undergoing bowel resection for colorectal cancers or polyps. Dr. Milsom showed an advantage in the laparoscopic group in terms of recovery time and return to bowel function, and found no port-site cancer recurrences in the laparoscopic group ((J Am Coll Surg 1998;187:46-54). That same year, Antonio M. de Lacy, MD, from Barcelona, Spain, also published a prospective randomized trial comparing laparoscopic-assisted and open colectomy for colon cancer, revealing similar results, and in 2002, published a follow-up showing a slight survival benefit in the laparoscopic group (Surg Endoscc 1998;12:1039-1042; Lancet 2002;359:2224-2229). These studies not only confirmed that laparoscopic colectomy was as effective as open for curing cancer, but that laparoscopic colectomy conferred greater benefits to patients, including better cosmesis, fewer wound infections, less inflammatory response, decreased postoperative pain and quicker return to normal activities. “The only reason laparoscopic colectomy was eventually accepted was because of these trials,” Dr. Whelan said.

Current Landscape Despite compelling evidence of a benefit, many surgeons still do not offer laparoscopic colectomy to patients. According to Drs. Whelan and Franklin, less than 30% of all colectomies are performed laparoscopically. Over the next decade, as more surgical residents are trained in MIS techniques, laparoscopic colectomy may become more standard. “Surgical residents are being exposed to laparoscopic colectomy, so the hope is that much of the future of resectional colorectal surgery will be minimally invasive,” Dr. Fowler said. Still, making laparoscopic methods more widespread continues to be a challenge. Hand-assisted laparoscopic surgery (HALS), developed by Drs. Ballantyne and Leahy in 1993, represented one of the first attempts to bridge the gap between open and laparoscopic techniques. With

HALS, surgeons make a slightly larger incision compared with laparoscopic surgery, but studies show that patients experience many of the same benefits (Dis Colon Rectum 2008;51:818-826). “HALS is an enabling technology for colorectal surgery,” Ms. Cohen said. “The procedure becomes much easier to perform when surgeons can insert their hand in the belly to feel the anatomy and tumor site, just like they do in an open case.” Surgical robotics is another MISenabling technology. The da Vinci

Robot, for instance, is designed to restore sensory perception and give surgeons more intuitive control of their instruments. However, according to Dr. Wexner, the expense of the technology has limited its widespread use, and studies have consistently failed to show that the robot is superior to laparoscopy despite significantly more time and expense. “I think many surgeons are struggling with these laparoscopic techniques, which is why they use tools such as HALS and robotics,” Dr. Franklin said. “However,

I don’t think these tools are the answer. Mastering difficult laparoscopic techniques is about constant exposure, hard work and revision. I continue to modify my technique even today.” Reflecting on the past 25 years of surgery, Dr. Jacobs recalls how laparoscopy gave him a new perspective on his profession. “I never wanted to be the first at anything, but the benefits of laparoscopy became obvious when we saw how we helped patients,” he said. “It was truly exciting to be part of a change that revolutionized surgery.” ■

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SONAL KUMAR, MD, MPH

IRA M. JACOBSON, MD

Assistant Professor of Medicine Weill Medical College of Cornell University New York, New York

Chief of the Division of Gastroenterology and Hepatology Vincent Astor Distinguished Professor of Medicine Weill Medical College of Cornell University New York, New York

Dr. Kumar has served as an advisor to Gilead. Dr. Jacobson has received grant or research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, Janssen, Merck, Novartis, and Vertex. He has served on the speakersâ&#x20AC;&#x2122; bureaus of Bristol-Myers Squibb, Genentech, Gilead, Vertex, and Janssen. He has been a consultant or advisor to AbbVie, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, Idenix, Janssen, Merck, and Vertex.

ith more than 170 million people worldwide infected with the hepatitis C virus (HCV), the burden of the

disease is indisputably significant.1-4 In 2010, there

were an estimated 2.7 to 3.9 million cases of chronic HCV in the United States alone, with up to 75% of individuals unaware of their diagnosis.5 Due to the high prevalence and underdiagnosis of disease, the Centers for Disease Control and Prevention in 2012 and the U.S. Preventive Services Task Force in 2013 modified their guidelines to recommend a one-time screening of adults born between 1945 and 1965.5 IN D E PE N D ENTLY D EVELOP ED BY MCM A HON PU B LI SHI NG

G ASTROEN TER OLOGY & EN DOSCOPY NE WS â&#x20AC;˘ SE PT E MBE R 2014

The goal of identifying undiagnosed adults is to eradicate the virus and avoid the development of cirrhosis and its life-threatening complications. Pegylated interferon (PegIFN) and ribavirin (RBV) have served as the foundations of HCV therapy for years but are accompanied by suboptimal rates of sustained virologic response (SVR) and significant adverse events (AEs). The lack of ideal treatment options was the impetus for further study of HCV and the development of novel therapies.

Hitting the Target (Molecule) Stages of the HCV life cycle have become targets of newer direct-acting antivirals (DAAs) that target several molecules required for HCV infection, such as the NS3/4a protease, NS5B RNA-dependent RNA polymerase, or the NS5A protein.6,7 The NS3/4A serine protease is a noncovalent heterodimer with a catalytic subunit (the NS3 N terminal) and an activating cofactor (NS4A protein), which plays an important role in viral replication through cleavage of 4 sites of the HCV polyprotein.8 The HCV NS5A phosphoprotein is also essential for viral RNA synthesis and virion assembly and secretion. The exact mechanism of action of NS5A inhibitors is unknown, but one route is through inhibition of hyperphosphorylation, which has an essential role in replication.9 The NS5B polymerase is another enzyme involved in viral replication. Inhibitors of this enzyme are classified as either nucleoside/nucleotide or non-nucleoside

Table 1. HCV Infection (Antibody Positive Only or RNA Positive) 2011 Site

Site Population

Rate per 100,000

Colorado

2,901

5,116,796

56.7

New Mexico

3,188

2,082,224

153.1

San Francisco

1,944

812,826

239.2

Minnesota

1,925

5,344,861

36.0

New York state

7,047

11,220,287

62.8

Oregon

5,464

3,871,859

141.1

Connecticut

2,898

3,580,709

80.9

New York City

8,749

8,244,910

106.1

Total

33,919

40,274,472

84.7

Source: Centers ffor or Disease Co Control ontrol and Prevention

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

inhibitors. Non-nucleoside/nucleotide inhibitors bind to sites away from the active site of the polymerase and cause conformational changes in the protein. Nucleoside/nucleotide analogs mimic the natural substrate of the NS5B protein, leading to RNA chain termination.10 In 2011, the protease inhibitors (PIs) telaprevir (Incivek, Vertex) and boceprevir (Victrelis, Merck) became the first approved DAAs to be combined with PegIFN/RBV for the treatment of genotype 1 (G1) HCV. The regimens significantly increased SVR rates, serving as a major advance in the treatment of HCV and opening the door for DAA therapy. However, the incremental adverse reactions were significant, and the regimen was not well tolerated by many patients.11-13 More recently, the FDA approved sofosbuvir (SOF; Sovaldi, Gilead), an NS5B nucleotide polymerase inhibitor, and simeprevir (Olysio, Janssen), a second-wave PI, used with PegIFN/RBV. Simeprevir was studied extensively with PegIFN/RBV before its approval. The QUEST-1 and QUEST-2 studies randomized G1, treatment-naive patients to receive simeprevir combined with PegIFN/RBV for 24 or 48 weeks based on response-guided therapy. In QUEST-1, the overall SVR at 12 weeks (SVR12) after therapy with simeprevir was 80% versus 50% in controls; 85% were able to shorten therapy to 24 weeks and 91% of these patients achieved SVR.14 In QUEST-2, therapy was shortened in 91% of patients, of whom 86% achieved SVR12 after treatment.15 The PROMISE trial had a similar study design except study patients had relapsed after prior IFN-based therapy.16 Results also were similar, reporting SVR rates of 80%. All of these studies showed lower SVR rates in patients with advanced fibrosis and in patients with IL28B non-CC genotype. Adverse events associated with simeprevir included hyperbilirubinemia related to interactions with transporters but no actual hepatotoxicity; a slight increase in photosensitivity; and in one study, mild pruritus. No additional hemoglobin decline was noted. Based on these studies, the FDA approved simeprevir for use in G1 patients, as a regimen consisting of 12 weeks of triple therapy and 12 to 36 weeks of PegIFN/RBV for treatment-naive or relapsed patients and prior nonresponders, respectively, with or without cirrhosis. Response-guided therapy is not a component of the approved regimen but parameters of viral response must be met at 4 weeks (HCV RNA <25 IU/mL) for treatment to continue. Sofosbuvir also has been studied comprehensively, leading to its approval nearly contemporaneously with simeprevir. The Phase II trials initially demonstrated promising results in G1 patients treated with PegIFN/ RBV and SOF with SVR rates of 87% to 92%,17,18 which led to the Phase III NEUTRINO study of 12 weeks with the same regimen in patients with HCV genotypes 1, 4, 5, or 6.19 Most of the study population consisted of G1 patients, who overall achieved 89% SVR. The study also included a significant number of patients with compensated cirrhosis, with an SVR of 80% in patients

with cirrhosis compared with 92% without cirrhosis. No incremental AEs were ascribed to SOF compared with those historically attributed to PegIFN/RBV alone, and only 2% of patients discontinued treatment due to AEs. The shortened treatment duration, higher success rate, and superior tolerability compared with the previous standard of care with PIs took IFN-based therapy to a new plateau, the utility of which has only been limited by the even greater paradigm shift to IFN-free regimens.

New Backbones of Therapy The high barrier to resistance imposed on viral replication by nucleotide polymerase inhibitors, related to the highly conserved structure of the polymeraseâ&#x20AC;&#x2122;s active binding site, makes potent nucleotide analogs like SOF highly attractive as a backbone of regimens consisting of DAA agents. One of the first trials demonstrating success with SOF and RBV was the ELECTRON trial, revealing SVR in 84% of 25 treatment-naive patients. Subsequent studies with the same drugs given for 12 to 24 weeks yielded SVR12 rates of 52% to 68% after therapy.20,21 Although promising, this regimen was unsuccessful in the few study patients with cirrhosis, as well in null responders in a separate arm, with only a 10% SVR (1 out of 10),22 signaling an inability of the regimen to overcome undefined factors linking IFN nonresponsiveness to impaired clearance of virus with SOF as the sole active agent in 12 weeks. The PHOTON study was the only Phase III study of this regimen in treatment-naive, mainly non-cirrhotic G1 patients, which resulted in 76% SVR in patients with HIV-HCV coinfection.23 This accounts for the stipulation in the US labeling that SOF and RBV for 24 weeks could be an option for IFN-ineligible patients with G1 infection. Other regimens of DAAs combined with a nucleoside polymerase inhibitor have shown additional advances in oral treatment relative to the regimen of SOF and RBV alone. For example, the potent pangenotypic activity of the NS5A inhibitor daclatasvir complements the broad genotypic activity and high barrier to resistance of SOF.24 This was demonstrated in a Phase II trial in which non-cirrhotic treatment-naive patients and patients who had previously failed treatment with a PI received daclatasvir and SOF, with or without RBV.25 Treatmentnaive patients were treated for 12 or 24 weeks, and the previously treated patients were treated for 24 weeks. Collectively, there was a 98% SVR12 after therapy, with all 3 treatment failures being due to loss to followup. Two had documented SVR24 after treatment. No patient had virologic breakthrough during treatment, and rates of virologic response were similar across subgroups, including genotype subtypes, IL28B genotype, race, RBV treatment, and PI resistance. Ledipasvir (LDV) is another NS5A inhibitor that has yielded similar results in combination with SOF and RBV. In additional arms of the ELECTRON trial, treatment-naive patients and previous null responders,

which included those who failed prior treatment with PIs, had an SVR of 100%.26 The Phase II LONESTAR study substantiated these results with SVR rates of 95% to 100% in both treatment-naive patients and those who had previously failed treatment with a PI, including cirrhotics and prior nonresponders.27 Notably, similarly high rates of SVR were seen in treatment arms with only 8 weeks of therapy, raising the possibility of even shorter regimens. More recent Phase III studies involving 1,952 patients treated with LDV/SOF have focused on optimizing duration, need for RBV, and treatment in subpopulations. ION-1 randomized patients to receive the fixed-dose LVD/SOF for 12 or 24 weeks. All treatment arms had 97% to 99% SVR12 after treatment.28 Even in patients with cirrhosis, SVR was 94% to 100%. ION-2 used the same regimen in patients who had previously failed IFN-based treatment with or without a PI. Again SVR rates were high; 96% and 94% with and without RBV, respectively, in the 12-week treatment arm and 99% in both 24-week arms.29 Baseline PI resistance did not affect treatment outcome, but prior treatment failures with cirrhosis had a higher rate of relapse, resulting in SVR of 82% to 86%. Still with such high overall SVR12 and the results of the LONESTAR trail, the ION-3 trial evaluated 8 weeks of treatment in treatment-naive, non-cirrhotic patients. There was no difference based on the use of RBV (SVR 93%-94%) in the 8-week arm and SVR was 95% in the 12-week arm.30 Although the frequency of relapse in patients treated for 8 weeks was somewhat higher, these findings introduced the possibility of highly successful treatment with an 8-week regimen. Patients with characteristics historically associated with poorer response, including cirrhosis, G1a subtype, non-CC IL28B allele, and race, all still had SVR rates higher than 90%. Mild AEs were common, including fatigue and insomnia, and were incrementally observed in treatment arms containing RBV. Anemia generally was only seen in RBV recipients. Given that RBV did not improve efficacy, collectively, the data from these trials support the absence of RBV from this regimen. Of note, deepsequencing analyses revealed that most of the patients who failed to have SVR in these studies had NS5A-resistant variants, some at baseline. Conversely, however, the SVR rates in patients with baseline NS5A-resistant variants were very high.

Interferon-Free Regimens The FDA has not approved simeprevir and SOF for use in combination, but this regimen has been studied as part of Phase II trials. Its success has motivated clinicians to treat selected G1 patients with an IFN-free regimen. Moreover, the new online guidance from the American Association for the Study of Liver Diseases/ Infectious Diseases Society of America has recommended the regimen in IFN-ineligible treatment-naive patients, as well as treatment-experienced patients, whether IFN eligible or not, as long as they have not previously received a PI. The COSMOS trial evaluated

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS â&#x20AC;˘ S E P T E M B E R 2 0 1 4

the 2 drugs, with or without RBV for 12 or 24 weeks in G1 patients. There were 2 cohorts, the first of which enrolled previous null responders with METAVIR F0-F2 fibrosis.31 In this group, SVR12 post-therapy ranged between 79% and 93% by intent-to-treat analysis with 4 patients with nonvirologic failure clustered in the group receiving 24 weeks of therapy, including RBV. The second cohort included treatment-naive and prior null responders (without prior PI exposure) with METAVIR F3-F4 fibrosis.32 Overall SVR12 ranged from 93% to 100%; 3 patients who relapsed were in the 12-week arm. Of the 6 patients who relapsed in the entire study, 4 had G1a with the Q80K polymorphism, leaving open the possibility of a small effect of this polymorphism but with insufficient numbers to definitively address the issue until the completion of ongoing Phase III trials. Although regimens without a nucleotide polymerase inhibitor lack a single class that has the high barrier to resistance of a nucleotide polymerase inhibitor, potent combinations of other classes cumulatively impose the high barrier to resistance needed to attain SVR rates similar to those seen with the nucleotides. One emerging regimen is the combination of the PIs ABT-450/r boosted with low-dose ritonavir and ombitasvir (ABT257, NS5A inhibitor), coformulated in a single-daily pill, with twice-daily ABT-333 (non-nucleoside NS5B inhibitor) and RBV. This regimen was studied initially in the AVIATOR trial for 12 weeks, yielding SVR rates in non-cirrhotic, treatment-naive patients and prior null responders of 96% and 93%, respectively.33 With these SVR rates comparing favorably with those obtained with 24 weeks of therapy or with regimens containing 3 of the 4 components previously outlined, the “3D plus RBV” regimen was chosen as the foundation of a robust Phase III program. SAPPHIRE-1 studied the 3D plus RBV regimen for 12 weeks in non-cirrhotic, treatment-naive patients.34 Of the 473 patients, 96% achieved SVR12 after therapy, 95% in G1a, and 98% in G1b, with no difference in outcome due to baseline characteristics including HCV RNA, gender, race, age, fibrosis, and IL28B genotype. In SAPPHIRE-2, the same regimen was evaluated in treatment-experienced patients, with the same overall SVR12 rate of 96% (96% and 97% in genotypes 1a and 1b, respectively).35 TURQUOISE-II included both treatment-naive and treatment-experienced patients with compensated cirrhosis.36 SVR12 after therapy was 92% in patients treated for 12 weeks and 96% in those treated for 24 weeks. With subgroup analysis, it became evident that G1a null responders were the treatment population that drove the difference in SVR based on treatment duration. SVR12 post-therapy was achieved in 93% of the group that was treated for 24 weeks but only 80% in those who were treated for 12 weeks, suggesting a continued effect of prior IFN response, as well as a difference between G1a and G1b patients. SAPPHIRE-1 and SAPPHIRE-2 were both placebo-controlled trials allowing for a true assessment of safety and tolerability of the regimen. Patients receiving active treatment experienced more AEs, although

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

the overall rate of such events was high even among patients who received placebo (88%-91% in treatment arms compared with 73%-83% with placebo). Adverse events were generally mild but included fatigue, headache, nausea, and pruritus. Elevations in alanine transaminase, through which most patients were able to continue treatment, occurred in about 1% of patients. No patient discontinued treatment as a result of laboratory abnormalities. Some patients required a lower dose of RBV, however, the outcome of treatment was not affected. Baseline resistance data were unavailable, however, most patients who failed treatment had 2 or 3 class drug-resistant variants after treatment. Additional studies include PEARL-4 in G1a treatment-naive patients without cirrhosis who received the 3D regimen for 12 weeks, with or without RBV. In this group, RBV did appear to have an added benefit, with SVR12 after treatment of 97% compared with 90% without RBV.37 RBV appears to have no effect with G1b infection as demonstrated in the PEARL-2 and PEARL-3 studies in treatment-experienced and treatment-naive patients, respectively (all without cirrhosis).37,38 In PEARL-2, 97% of patients achieved SVR with RBV and 100% achieved SVR without RBV. In PEARL-3, SVR was 99% in both groups. Other non-nucleotide–containing regimens being studied include daclatasivir combined with the PI asunaprevir and BMS-791325, a non-nucleoside inhibitor. This treatment was evaluated in 166 treatment-naive G1 patients for 12 weeks.39 There was 3% viral breakthrough, all in G1a, and 3.6% viral relapse, also restricted to G1a, resulting in an overall SVR of 92%. This regimen also was well-tolerated, with treatment discontinuation as a result of AEs of only 1.2%. The HALLMARK study looked at asunaprevir and daclatasvir in G1b patients. Patients received 24 weeks of treatment and the study included cirrhotics. SVR ranged from 80% to 90% based on prior treatment history, with the highest SVR rates in treatment-naive patients.49

Efficacy Across Genotypes? The effectiveness of HCV treatment varies with nature of the infection. Genotype 2 and 3 HCV had been more successfully treated with IFN and RBV, with SVR rates of 70% to 85%, compared with the lower rates in G1 infection.41 Some of the newer DAAs have demonstrated efficacy across genotypes, allowing for IFN-free regimens to be formulated in this population as well. With 100% SVR in G2 and G3 patients treated for 12 weeks with SOF and RBV as part of the original arms of the ELECTRON trial,22 Phase III studies sought to corroborate the results. The FISSION trial compared 12 weeks of SOF and RBV with the standard of care.19 The trial demonstrated that G2 and G3 patients could no longer be grouped together appropriately, as 97% of G2 patients achieved SVR compared with only 56% of G3 patients (78% and 63%, respectively, in the standard-of-care arm). Cirrhosis was a strong predictor of poor outcome in G3 patients, with SVRs of 61% without and 34% with

Table 2. Interpretation of Results of Tests for HCV Infection and Further Actions Test Outcome

Interpretation

Further Action

HCV antibody nonreactive

No HCV antibody detected

Sample can be reported as nonreactive for HCV antibody. No further action required. If recent HCV exposure in person tested is suspected, test for HCV RNAa

HCV antibody reactive

Presumptive HCV infection

A repeatedly reactive result is consistent with current HCV infection, or past HCV infection that has resolved, or biologic false positivity for HCV antibody. Test for HCV RNA to identify current infection.

HCV antibody reactive, HCV RNA detected

Current HCV infection

Provide person tested with appropriate counseling and link person tested to medical care and treatmentb

HCV antibody reactive, HCV RNA not detected

No current HCV infection

No further action required in most cases. If distinction between true positivity and biologic false positivity for HCV antibody is desired, and if sample is repeatedly reactive in the initial test, test with another HCV antibody assay. In certain situationsc follow up with HCV RNA testing and appropriate counseling.

HCV, hepatitis C virus a

If HCV RNA testing is not feasible and person tested is not immunocompromised, do follow-up testing for HCV antibody to demonstrate seroconversion. If the person tested is immunocompromised, consider testing for HCV RNA.

It is recommended before initiating antiviral therapy to retest for HCV RNA in a subsequent blood sample to confirm HCV RNA positivity.

If the person tested is suspected of having HCV exposure within the past 6 months, or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen.

Source: Centers for Disease Control and Preventio Prevention on

cirrhosis. Similar outcomes were seen with the POSITRON trial, which studied the SOF and RBV regimen for 12 weeks in G2 and G3 patients who were IFN intolerant to the drugs, or ineligible or unwilling to take them.42 SVR in G2 was 93% in G2 and 61% in G3. Cirrhosis again predicted poorer outcome, with SVR of 94% in G2 and 21% in G3. The FUSION trial evaluated the effect of extending treatment to 16 weeks instead of 12 for patients who had failed prior therapy.42 SVR increased from 86% to 94% with longer treatment in G2 patients, and from 30% to 62% in G3 patients. The additional benefit was seen in cirrhotic patients as well, with SVR increased to 78% from 60% with the additional 4 weeks of treatment in G2 and 61% from 19% in G3. However, the number of G2 patients with cirrhosis was too small to draw meaningful comparisons. In the VALENCE trial, G2 treatment-naive patients treated for 12 weeks had 97% to 100% SVR, as did 78%

of G2 treatment-experienced patients with cirrhosis, and 94% of G2 treatment-experienced patients without cirrhosis.43 Treatment was extended to 24 weeks in G3 treatment-naive patients, with 95% of patients without cirrhosis achieving SVR compared with 92% in the cirrhotic population. Those who had failed prior therapy had SVR rates of 87% in the non-cirrhotic population and 62% in patients with cirrhosis. These results led to the approval of SOF and RBV for 24 weeks in G3 and 12 weeks in G2 patients. With still suboptimal results, especially in G3 patients, LONESTAR-2 evaluated the addition of PegIFN to the regimen for treatment-experienced G2 and G3 patients with or without compensated cirrhosis.44 G2 patients had an overall SVR of 96%. G3 patients, including both cirrhotics and non-cirrhotics, had an SVR of 83%, supporting the concept of an ongoing role of PegIFN at least in treatment-experienced cirrhotic patients. Recent data also show that among patients with G3

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who had failed a 12- to 16-week regimen of SOF and RBV, a 12-week retreatment regimen of PegIFN/RBV and SOF can act as a salvage regimen, even in patients with cirrhosis, with higher SVR rates than patients retreated with 24 weeks of SOF and RBV alone.45 Collectively, analysis from the NEUTRINO, FUSION, FISSION, POSITRON, and VALENCE trials has shown that no single AE led to discontinuation in more than 1 patient receiving SOF and RBV, and anemia was the only AE leading to discontinuation of treatment in more than 1 patient receiving IFN, RBV, and SOF.46 However, the use of IFN likely will be unnecessary in the future, as regimens combining SOF with other DAAs, including pan-genotypic NS5A inhibitors, currently in development appear to have high rates of SVR.47 Although limited data exist on treatment in other genotypes, the NEUTRINO trial did include G4, G5, and G6 patients, all of whom had more than 95% SVR, most notably 27 of 28 (96%) G4 patients.19 A small study of G4 Egyptian patients in the United States provided data for the use of SOF and RBV only. In treatment-naive patients, the highest rate of SVR24 was 100%, compared with SVR12 of 79%. In treatment-experienced patients, SVR was 59% with 12 weeks and 87% with 24 weeks of treatment.48 The combination of ABT-450/ritonavir and ombitasvir also was studied in G4 patients in the PEARL-1 trial.49 Treatment-naive patients received the combination, with or without RBV, for 12 weeks. The RBV-free arm had SVR of 91%, and 100% in the RBV-containing arm. In this study, the 2-drug regimen with RBV added was given to 49 treatment-experienced patients, all of whom achieved SVR.

The Most Difficult Patient The treatment of HCV historically has been the most difficult in patients who need it most urgently, especially those with decompensated cirrhosis. In addition to success rates being dismal, treatment regimens, particularly those containing IFN and RBV, have been intolerable for most of these patients. A safe, well-tolerated oral DAA regimen would be ground-breaking for this population. The initial report of SOF and RBV in patients on the transplant list showed that longer duration of undetectable HCV RNA before transplant (>30 days) predicted prevention, although this study included only patients listed because of hepatocellular carcinoma who were otherwise well compensated.50 An arm of the ELECTRON-2 trial administered LVD/SOF for 12 weeks in patients with decompensated cirrhosis. Of the 20 patients, 13 achieved SVR (65%). Seven of the 13 relapsed.51 Ongoing studies are evaluating additional regimens in the decompensated population. Sofosbuvir also has been studied as a regimen for recurrent HCV in patients who have undergone liver transplantation. As part of a compassionate-use program, 104 patients with severe recurrent hepatitis or fibrosing cholestatic hepatitis were treated with SOF and RBV for 24 to 48 weeks.52

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Physicians could add PegIFN at their discretion, which was done in about 25% of patients. Of the patients for whom there are data, 62% achieved SVR. Most patients also had improved liver function tests and clinical outcomes with treatment, including resolution of ascites, even in the absence of SVR. The 3D/RBV regimen also has been studied in the post-transplant population.53 Thirty-four patients received the regimen for 24 weeks. Data so far have shown a 96% (25 of 26) SVR, although patients with more aggressive liver disease were excluded. Importantly, there were no major interactions or apparent effects of immunosuppression, no organ rejections, and no serious AEs associated with the regimen.

Conclusion With the global burden of HCV, the need for effective, well-tolerated treatment regimens is essential. Elucidation of the HCV life cycle has allowed for newer drugs to be developed, overcoming some of the major disadvantages of prior standard of care with IFN-based therapy. The DAAs are anticipated to completely replace IFN as the foundation of HCV treatment. Among the major advantages of these oral regimens beyond their increased efficacy has been their relatively clean safety profile. Although AEs are common, they generally are mild, including headache, fatigue, and insomnia, and trivial relative to that of telaprevir and boceprevir.46 The low rate of discontinuation in all the trials further attests to the tolerance of the regimens, even in those containing RBV. In addition, the once-daily dosing and limited drug窶電rug interactions has minimized the AEs of treatment for most patients. As newer medications and regimens get approved, the next dilemma will be to determine the ideal combination of medications and treatment duration for each patient. Ideally, predictors of response to treatment would aid in the decision making, but none has consistently been identified. Although one study has suggested that early viral kinetics may identify those with a higher risk for relapse,21 such predictive value has not been gleaned from the Phase III databases. Importantly, these new regimens also have been able to overcome baseline factors previously associated with poorer outcomes including G1a subtype, race, non-CC IL28B allele, and prior treatment history. Although treatment-failure rates now appear to be minimal and routes to treatment failure have all but eliminated nonresponse and viral breakthrough, some patients will relapse. SOF has been associated in vitro with a S282T T signature mutation, but it is replicatively unfit54 and rarely found in samples from SOF-treated relapsers, providing a foundation for retreatment with a SOF-containing regimen in these failures. Now that the fundamental paradigm shift toward IFN-free regimens is imminent, further research will be needed to identify effective salvage therapies for patients who have failed both nucleotide-containing and nucleotide-free combination regimens.

20. Lalezari JP, Nelson DR, Hyland RH, et al. Once daily sofosbuvir plus ribavirin for 12 and 24 weeks in treatment-naive patients with HCV infection: the QUANTUM study. J Hepatol. 2013;58(1):S346.

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Lavanchy D. The global burden of hepatitis C. Liver Int. 2009;29(suppl 1):74-81.

21. Osinusi A, Meissner EG, Lee YJ, et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA. 2013;310(8):804-811.

2. Hajarizadeh B, Grebely J, Dore GJ. Epidemiology and natural history of HCV infection. Nat Rev Gastroenterol Hepatol. 2013;10(9):553-562. 3. Global surveillance and control of hepatitis C. J Viral Hepatol. 1999;6(1):35-47. 4. Afdhal NH. The natural history of hepatitis C. Semin Liver Dis. 2004;24(suppl 2):3-8. 5. CDC. New CDC Vital Signs: Hepatitis C testing. http://www.cdc. gov/media/dpk/2013/dpk-vs-hepatitisC_testing.html. Accessed July 29, 2014. 6. Poenisch M, Bartenschlager R. New insights into structure and replication of the hepatitis C virus and clinical implications. Semin Liver Dis. 2010;30(4):333-347.

23. Sulkowski MS, Rodriguez-Torres M, Lalezari J, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). Hepatology. 2013;58:313–314A. 24. Guedj J, Dahari H, Rong L, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci USA. 2013;110(10):3991-3996. 25. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370(3):211-221.

7. Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med. 2013;19(7):837-849. 8. Tan S-L. Hepatitis C Viruses: Genomes and Molecular Biology. Indianapolis, IN: Lilly Research Laboratories; 2006. 9. Pawlotsky JM. NS5A inhibitors in the treatment of hepatitis C. J Hepatol. 2013;59(2):375-382. 10. Koch U, Narjes F. Recent progress in the development of inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. Curr Top Med Chem. 2007;7(13):1302-1329. 11. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360(18):1827-1838. 12. Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;376(9742):705-716. 13. Hézode C, Fontaine H, Dorival C, et al. Triple therapy in treatmentexperienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) NCT01514890. J Hepatol. 2013;59(3):434-441. 14. Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2014;384:1-311. 15. Manns M, Marcellin P, Poordad F, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2014;384:1-13. 16. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial. Gastroenterology. 2014;146(7):1669-1679. 17. Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013;381(9883):2100-2107. 18. Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2013;13(5):401-408. 19. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887.

22. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368(1):34-44.

26. Gane EJ, Stedman CA, Hyland RH, et al. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. J Hepatol. 2013;58:S6–S7. 27. Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatmentnaive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet. 2014;383(9916):515-523. 28. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014:140411220115009. 29. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1483-1493. 30. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888. 31. Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: the COSMOS study. Hepatology. 2013;58:LB3. 32. Lawitz EJ, Ghalib R, Rodriguez-Torres M, et al. Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype 1 prior nullresponder/treatment-naive patients (COSMOS study): primary endpoint (SVR12) results in patients with Metavir F3-4 (cohort 2). Paper presented at: International Liver Congress 2014; April 2014; London. 33. Kowdley KV, Lawitz E, Poordad F, et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med. 2014;370(3):222-232. 34. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(20):1594-1603. 35. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(20):1604-1614. 36. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370(20):1973-1982. 37. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370(20):1983-1992. 38. Andreone P, Colombo MG, Enejosa J V, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced

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patients with HCV genotype 1b infection. Gastroenterology. 2014;147(2):359-365.

sofosbuvir + GS-5816 for 12 weeks in treatment naive patients with genotype 1-6 HCV infection. J Hepatol. 2014;60:S46.

39. Everson GT, Sims KD, Rodriguez-Torres M, et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology. 2014;146(2):420-429.

48. Ruane PJ, Ain D, Meshrekey R, et al. Sofosbuvir plus ribavirin, an interferon-free regimen, in the treatment of treatment-naive and treatment-experienced patients with chronic genotype 4 HCV infection. J Hepatol. 2014;60:S503-S504.

40. Manns M, Pol S, Jacobson IM, et al. All-oral dual therapy with daclatasvir and asunaprevir in patients with HCV genotype 1b infection: Phase 3 HALLMARK-DUAL study results. J Hepatol. 2014;60:O166.

49. Hezode C, Marcellin P, Pol S, et al. Results from the phase 2 PearlI study: Interferon-free regimens of Abt-450/R + Abt-267 with or without ribavirin in patients with HCV genotype 4 Infection. J Hepatol. 2014;60:S24.

41. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335-1374.

50. Curry MP, Forns X, Chung R, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology. 2013;58:314-315A.

42. Jacobson IM, Gordon SC, Kowdley K V, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877.

51. Gane EJ, Hyland RH, An D, et al. Sofosbuvir/ledipasvir fixed dose combination is safe and effective in difficult-to-treat populations including genotype-3 patients, decompensated genotype-1 patients, and genotype-1 patients with prior sofosbuvir treatment experience. J Hepatol. 2014;60:S3-S4.

43. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014;370(21):1993-2001. 44. Lawitz E, Poordad F, Brainard D, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 study. Paper presented at: AASLD: The Liver Meeting; November 2013; Washington DC. Abstract LB-4. 45. Esteban R, Nyberg L, Lalezari J, et al. Successful retreatment with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected patients who failed prior sofosbuvir plus ribavirin therapy. J Hepatol. 2014;60:S4-S5. 46. Gordon SC, Towner W, Aggarwal A, et al. Integrated safety analysis of sofosbuvir-based HCV treatment regimens from phase 3 studies. Gastroenterology. 2014;146:S921. 47. Everson GT, Tran TT, Towner WJ, et al. Safety and efficacy of treatment with the interferon-free, ribavirin-free combination of

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52. Forns X, Prieto M, Charlton M, et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C including fibrosing cholestatic hepatitis following liver transplantation. J Hepatol. 2014;60:S26. 53. Kwo P, Mantry P, Coakley E, et al. Results of the phase 2 study M12999: Interferon-free regimen of Abt-450/R/Abt-267 + Abt-333 + ribavirin in liver transplant recipients with recurrent HCV genotype 1 infection. Paper presented at: International Liver Congress 2014; April 2014; London. 54. Mariño Z, van Bömmel F, Forns X, et al. New concepts of sofosbuvir-based treatment regimens in patients with hepatitis C. Gut. 2014;63(2):207-215. 55. Osinusi A, Marti M, Townsend K, et al. Retreatment of relapsers to sofosbuvir/ribavirin with sofosbuvir/ledipasvir: complete and rapid virologic suppression by week 4. J Hepatol. 2014;60:S5–S6.

PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

he greatest challenge for clinicians who treat patients with inflammatory p y bowel disease (IBD) is to move from symptom-oriented

(sstep-up) strategies toward prevention-oriented

BRIAN P. BOSWORTH, MD

(e early intervention) strategies aimed at tight

Director, Gastroenterology Fellowship Programa,b Associate Attending Physiciana Associate Professor of Medicineb Anne and Ken Estabrook Clinical Scholar in Gastroenterologyb

in nflammation control and alteration of the natural history of IBD. This re eview focuses on a personalized approach to the treatment of

VINITA E. JACOB, MD Director Interdisciplinary Education, Jill Roberts Center for IBDa Assistant Attending Physiciana Assistant Professor of Medicineb

patients with ulcerative co olitis (UC).

ADAM F. STEINLAUF, MD Director of Strategic Planning and Growth, Jill Roberts Center for IBDa Assistant Attending Physiciana Assistant Professor of Medicineb a

NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York, New York b Weill Cornell Medical College, New York, New York c Columbia University College of Physicians and Surgeons, New York, New York Dr. Bosworth has served as a consultant to and speaker for Salix. Dr. Scherl has served as a consultant or advisory board member for AbbVie, Crohn’s and Colitis Foundation of America (CCFA), GIHealth Foundation, Janssen, Prometheus, Protagonist Therapeutics, Salix, Takeda Pharmaceuticals, and UCB. Drs. Scherl, Bosworth, Jacob, and Steinlauf have received grant or research support from Abbott (AbbVie), AstraZeneca, CCFA, Elan, Janssen Research & Development, Millennium Pharmaceuticals, National Institutes of Health, New York Crohn’s Foundation, Mesoblast (formerly Osiris Therapeutics), Pfizer, Prometheus Laboratories, UCB, UCSF–CCFA Clinical Research Alliance. She also has received honoraria from the GIHealth Foundation and Janssen.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G G A S T R O E N T E R O L O G Y & E N D O S C O P Y N E W S • S E P T E M B E R 2 0 1 4

Challenging the Traditional IBD Diagnosis

Molecular Classification of IBD

Traditionally, IBD has been divided into 2 distinct entities: UC and Crohn’s disease (CD). A nuanced view presents IBD as an immuno-inflammatory spectrum of chronic and recurring diseases of the intestines defined by individual molecular signatures. This newly gained perspective holds the promise of moving treatment in a more proactive, personalized direction, toward targeting molecules and risk assessment, rather than limiting treatment to symptoms alone. One of the major questions facing clinicians is whether IBD is a single entity or a spectrum of multiple disorders. This distinction becomes particularly difficult to make when attempting to classify CD. Three distinct manifestations of CD have been described—inflammatory, fistulizing, and fibrostenotic.1-3 However, Crohn’s colitis has not been well defined in the literature.4 Some patients present with CD-like features—such as UC with rectal sparing or UC with nonepithelial granulomas. Other manifestations of the heterogeneity of colitis are a superficial mucosal CD involving left-sided refractory colitis with rectal involvement (which may actually represent a type of mixed collagenous colitis or vascular collagen disorder still undefined), rectal disease with cecal patch, and a form of UC with post-treatment alterations.4 The many forms of UC (eg, ulcerative proctitis, leftsided colitis, universal colitis) led Brooke5 to suggest that, rather than a single disease entity, UC represents a pathologic state with many etiologies. Indeterminate colitis (IC) might represent part of an immunologic continuum, rather than a well-defined clinical subset of UC and CD.6,7 IBD is a dysregulated immune response to luminal microbial antigens. Serologic markers may provide a window for observing an abnormal antibody–antigen response and may help identify patients at risk for rapid progression of disease who may benefit from early intervention.8 Molecular diagnostics, such as antibody serology, biomarkers, and genotyping hold the promise of enhancing the understanding of IC and stratifying patients with IBD on the basis of immunophenotypes and immunogenotypes.9 Differential diagnosis is increasingly recognized as important in distinguishing active inflammation from medication–pseudo-refractory IBD—which may include infections (eg, Clostridium difficile, cytomegalovirus), overlap with irritable bowel syndrome, celiac disease, lactose and/or fructose intolerance, dietary indiscretion, bile acid diarrhea, and obstructive stricturing or fistulizing CD requiring surgery—and in stratifying optimal therapeutic response to biologics and immunosuppressives.10 In selected patients with moderate to severe active IBD, early intervention with effective therapy is associated with significant improvement in mucosal healing and reduction in the progression of disease.11-13

IBD nomenclature does not accurately reflect the complexity of clinical phenotype. Although the role of serum antibody markers remains controversial, using a combination of markers enhances accuracy and specificity in classifying IBD-related aberrant immunophenotypes. The emerging role of molecular diagnostics is vital in characterizing the immunologic heterogeneity of IBD and will be a bridge linking clinical immunophenotypes with genotypes.14,15 More than 163 genes associated with IBD have been identified using genome-wide association studies (GWAS), but account for only 25% of the heritability.16 At present, common gene variants identified by GWAS will be too insensitive and nonspecific to predict disease in unaffected patients. New genes continue to highlight host microbial interactions,17-22 and serologic markers indicate dysregulated antibody–antigen immune responses. Differentiation between types of IBD becomes important in stratifying therapeutic strategies. Poor therapeutic response is an indication for surgery in nearly one-third of patients with UC and approximately 50% to 70% of patients with CD. Patients with refractory left-sided colitis or IC may benefit from serologic testing, in addition to documentation of clubbing and oral aphthae.15 Serologic signatures have proven helpful in patient stratification. The incorporation of validated biomarkers, such as fecal calprotectin, which has been shown to correlate with endoscopic disease severity in both CD and UC,23,24 into clinical decision making also may help identify patients with active disease. Serologic diagnostic and biomarker testing provides a molecular snapshot of patients with IBD. New markers and prospective trials are required to correlate immunologic, molecular, and clinical patterns of IBD, and will advance the risk assessment of patients, the selection of prevention-oriented therapies, and the science of IBD.

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Epidemiology and IBD Subtypes Epidemiologic data on IBD are fractionated into the pigeonholes of separate diagnoses, with an incidence of 7 to 9 per 100,000 and a prevalence of 200 to 250 per 100,000 for UC; the incidence and prevalence of CD are 6 to 8 per 100,000 and 130 to 200 per 100,000, respectively.25-27 Although there are patients who fall more clearly into one category than another, the concept of IC is poorly defined and therapeutic guidelines are lacking. The majority of patients with IBD have moderate disease. Three-fourths of patients have active UC,28 and two-thirds of patients with CD have moderate to severe disease that requires alternatives to treatment with mesalamine therapies.29

Treatment Options for UC Treatment goals for patients with IBD are universal: induce remission as quickly as possible, maintain remission as long as possible, facilitate mucosal healing, improve quality of life, minimize toxicity, and minimize cost. For patients with UC, oral and rectal 5-aminosalicylic acid (5-ASA) agents (including free 5-ASA and 5-ASA prodrugs), corticosteroids (IV [eg, hydrocortisone] or oral [eg, prednisone, methylprednisolone]), immunomodulators (eg, azathioprine [AZA], 6-mercaptopurine [6-MP]), and cyclosporine are used to induce remission. Uceris is a new, daily-dose, extended-release formulation of budesonide for inducing remission of UC. For maintenance of remission of UC, 5-ASAs and 6-MP or AZA may be used. In addition, the anti-tumor necrosis factor (TNF) agents infliximab, adalimumab, and most recently golimumab30,31 as well as anti-integrin vedolizumab,32 are approved for the reduction of signs and symptoms, induction of clinical remission and mucosal healing, and elimination of corticosteroid use in patients with moderately to severely active UC who have had an inadequate response to conventional therapies.33 Probiotics and novel antibiotics (eg, rifaximin) have the potential to revolutionize the treatment of patients with IBD.34,35 For example, anti-inflammatory interleukin (IL)-10 levels have been associated with Bifidobacterium infantis.36 A greater understanding of gut microecology and the gut microbiome is emerging and further clinical trials are underway.37 Treatment with Trichuris suis is used to treat both UC and CD, and studies of this therapy in patients with UC are ongoing.38,39 Colitis-associated arthritis40 responds best to sulfasalazine and this may be related to the antibiotic properties of sulfapyridine rather than the anti-inflammatory properties of 5-ASA.41,42

5-ASA: First-Line Therapy MECHANISMS

ACTION

The specific goals of 5-ASA therapy are to quickly induce complete remission, facilitate mucosal healing, and minimize steroid use and toxicity. The effectiveness of the compound is related to its mucosal concentration,43 and systemic dosages remain low after administration of oral sulfasalazine and rectal 5-ASA.44 The putative anti-inflammatory actions of 5-ASA include modulation of inflammatory cytokine production, decreased transcriptional activity of nuclear factor-kappa B (NF-κB) by modulating RelA/ p65 phosphorylation, and inhibition of the biosynthesis of prostaglandins and leukotrienes.45 One proposed mechanism of action of 5-ASA is the inhibition of the cyclooxygenase (COX) and 5-lipoxygenase pathways of arachidonic acid metabolism,

resulting in a decrease of proinflammatory prostaglandins and leukotrienes.46 The role of the COX pathway and prostaglandin biosynthesis in IBD remains to be elucidated. Attention has shifted from the arachidonic acid cascade to NF-κB. The discovery of the role of nucleotide-binding oligomerization domain 2 in the activation of NF-κB emphasizes the importance of NF-κB in the inflammatory signaling cascade and its interaction with luminal bacterial antigens and genetic susceptibility. In vitro studies demonstrate that sulfasalazine inhibits NF-κB, which provides evidence in support of the direct biologic efficacy of 5-ASA. Recently, it has been postulated that 5-ASA leads to peroxisome proliferator–activated receptor-gamma (PPAR-γ) γ transcription and protein expression.47 The PPARs are members of the nuclear receptor superfamily. They are activated by fatty acids and are involved in the complex interplay of metabolic and nutritional signals leading to transcriptional responses. They are expressed in high levels in the colonic epithelium and their ligands are involved in regulation of inflammation. A randomized placebo-controlled trial of rosiglitazone (a PPAR-γγ ligand) demonstrated efficacy in treating mild to moderate UC.48 However, despite these numerous experimental studies, the mechanism of action of 5-ASA remains elusive. Clinicians should question whether the site of 5-ASA release is a determinant in optimizing and individualizing therapy. Two therapeutic strategies expose jousting views: One is that all 5-ASA preparations are equivalent and that dose escalation leads to optimization; the other is that differences in the mode of 5-ASA delivery translate into differences in clinical efficacy. Often overlooked is the distribution of UC—more than 50% of patients have left-sided disease (Figure)49—as well as the variability in colonic pH. Colonic pH may be lower in patients with UC than in those without IBD; thus, employing 5-ASA formulations that release at a lower pH (eg, granulated mesalamine [Apriso, Salix Pharmaceuticals]) may improve drug delivery to the colon while avoiding release in the small intestine.50 Both mesalamine (free, unconjugated 5-ASA) and mesalamine prodrugs (azo-bonded 5-ASA) have similar modes of action. Sulfasalazine, the archetypal azo-bonded 5-ASA designer drug, is engineered to release free 5-ASA in the colon, protecting it from proximal absorption.41,42 Intolerance and hypersensitivity to the sulfapyridine moiety limit the dose of sulfasalazine and have led to the development of new 5-ASA–containing analogs. The newer topical and oral 5-ASA agents are delivered to different anatomic sites, ideally corresponding to the distribution of active disease (Table).51-59 Although these agents are less toxic than sulfapyridine, mesalamine allergies

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Figure 1. Disease distribution of ulcerative colitis at presentation to the physicianâ&#x20AC;&#x2122;s office. Based on reference 49.

(eg, high fevers, allergic pneumonitis) and intolerance (eg, worsening IBD symptoms) may occur and discontinuation of 5-ASA therapy my be required. Interstitial nephritis has been reported with the 5-ASA moiety alone60 and mandates periodic renal function monitoring.

TREATMENT

Until the introduction of balsalazide, all of the newer 5-ASA agents had been shown to induce and maintain remission of UC nearly as well as sulfasalazine and usually as well as one another. The advantage of some of the newer 5-ASA preparations is that patients can tolerate higher doses. Recently, novel dual-delivery systems (delayed- and extended-release) allow for effective dose de-escalation, with lower doses of active 5-ASA delivered to the site of active colitis.55-57 In the first head-to-head trial comparing an equimolar dose of balsalazide (6.75 g) with pH-dependent mesalamine (2.4 g), balsalazide showed superior efficacy in patients with new-onset left-sided UC (62% vs 37%) and shorter time to response (10 vs 25 days); response rates also were higher in patients with right-sided UC, although the difference was less significant compared with patients with left-sided disease.61 A stratification study confirmed that among patients with new-onset

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left-sided UC, more than 60% of those treated with balsalazide were in remission at 1 month compared with 40% of those treated with pH-dependent mesalamine.62 Patients with right-sided UC who were treated with balsalazide also had less rectal bleeding, better sigmoidoscopic-evident healing, and improved stool frequency. A twice-daily balsalazide dosing regimen (3 1.1-g tablets, twice daily, for a total of 6.6 g/d) is well tolerated and effective in relieving signs and symptoms of mild to moderate UC.58,59 This regimen reduces pill burden and should improve adherence and convenience for patients. Levine et al63 conducted a randomized, doubleblind study comparing 2 doses of balsalazide (6.75 and 2.25 g) and mesalamine (2.4 g) in patients with active, mild to moderate UC. At week 8, rates of remission were similar for all 3 treatment groups, as were safety profiles. The primary difference between balsalazide (6.75 g) and mesalamine appeared to be the time to symptom resolution (10 vs 25 days, respectively). Kornbluth et al64 compared the colonic mucosal concentration of 5-ASA in patients treated with a mean of 6.75 g per day of balsalazide with those treated with a mean of 3.74 g per day of pH 7.0â&#x20AC;&#x201C;dependent mesalamine and demonstrated that patients who received balsalazide had significantly higher mean mucosal concentrations of 5-ASA than patients who received mesalamine. Because of the predominance of left-sided disease, the combination of oral and topical aminosalicylates is critical in inducing and maintaining remission. Safdi et al65 elegantly demonstrated that although topical mesalamine was more effective than oral in patients with left-sided UC, the combination of 2.4 g of oral mesalamine and mesalamine enemas produced earlier and more complete cessation of rectal bleeding. For maintenance of remission, Dâ&#x20AC;&#x2122;Albasio et al66 found that a combination of 1.6 g of oral mesalamine with twice-weekly mesalamine enemas produced higher rates of remission compared with oral therapy alone (61% vs 31%, respectively). Topical mesalamine (enema and suppository formulations), used as infrequently as twice per week, is effective in maintaining remission in patients with distal colitis. A systematic review compared the efficacy of combined oral and topical 5-ASA with oral therapy alone and found a significant increase in remission rates in mild to moderate UC with combined therapy, and intermittent topical therapy was superior to oral therapy in maintaining remission in quiescent UC.67 Biddle et al68 established that 75% of patients (9 of 12) randomized to receive mesalamine enemas remained in remission at 1 year compared with 85% of patients (11 of 13) on placebo who had relapsed by week 16. Similarly, mesalamine suppositories were associated with long-term remission in patients with ulcerative proctitis; at 12 and 24 months, 86% and 89% of patients on placebo had relapsed compared with 32%

Table. Mechanisms of Release of 5-ASAâ&#x20AC;&#x201C;Containing Drugs Type of 5-ASA

Mechanism of Action

Advantage

Indication

Time-released, moisturedependent ethylcelluloseencapsulated mesalamine travels in solution and allows free 5-ASA mesalamine to diffuse out of the ethylcellulose beads and begin releasing in the upper intestines and continue throughout the small and large intestines.

Independent of pH or bacteria; mucosal delivery of mesalamine is less affected by rapid intestinal transit time (ie, diarrhea).45

Free 5-ASA (mesalamine) is indicated in patients with proximal disease activity, severe diarrhea, strictures (1-mm ethylcellulose microspheres offer advantages), pouch-itis (the constant, moisture-dependent release may provide advantages), and postoperative anastomosis.

The pH-dependent mesalamine preparations are coated with an acrylate resin and are released at variable pH levels, between 6.0 and 7.0 in the distal ileum and colon. (The pH in the ileum and ascending colon is 7.0.)

Free 5-ASA (mesalamine) dosage can be maximized to 4.8-6 g daily, equivalent to a triple dose of sulfasalazine (12 g) with significantly less toxicity. Lialda is a 1.2-g tablet that is a high-dose, delayed-release, pH-dependent mesalamine formulation.46-48 Once-daily dosage is between 2.4 and 4.8 g (2-4 tablets). Apriso once-daily 1.5-g granulated delayed- and extendedrelease mesal-amine (four 0.375-g capsules) travels in solution.49-51

A pH-dependent delivery system is indicated in ileocolonic disease.

In these azo-bonded 5-ASA forms, the molecule reaches the colon primarily intact and the azo bond is cleaved by colonic-bacterial azo-reductase, thereby releasing free, unconjugated 5-ASA (mesalamine). A highdose, 1.1-g balsalazide tablet allows for lower pill burden and twice-daily dosing.52,53

This formulation is indicated for patients with universal and distal colitis.

Advantages of topical preparations include direct exposure to diseased mucosa.

These agents are indicated for patients with left-sided colitis and proctitis.

Diffusion-dependent Mesalamine, controlledrelease (Pentasa, Shire)

pH-dependent Mesalamine, delayedrelease, pH 7.0 (Asacol, Asacol HD, Delzicol; Actavis) MMX mesalamine, pH 7.0 (Lialda, Shire) Mesalamine, delayedrelease, pH >6.0 (Eudragit-L, Evonik) Mesalamine delayedand extended-release, pH 6.0 (polymer core of slow-release mesalamine; Apriso, Salix)

Colonic floraâ&#x20AC;&#x201C;dependent, azo-bonded Sulfasalazine (Azulfidine, Pfizer) Sulfasalazine, delayedrelease (Azulfidine EN-Tabs, Pfizer) Balsalazide disodium (Colazal, Giazo; Salix) Olsalazine sodium (Dipentum, Pfizer)

There are currently 3 variations of colonicreleasing, azo-bonded 5-ASA drugs: 1. Sulfasalazine consists of 5-ASA bonded to sulfapyridine; 2. Balsalazide links an inert polymer of 4-aminobenzoyl-B-alanine to 5-ASA; 3. Olsalazine consists of 2 molecules of 5-ASA linked to each other.

Topical/rectal formulations Mesalamine suppository Rectal preparations include (Canasa, Actavis) 5-ASA suspensions (4-g mesalamine enema and 500-mg mesalamine supMesalamine enema pository) that are instilled (Rowasa, Meda directly into the rectum. Pharmaceuticals) 5-ASA, 5-aminosalicylic acid; MMX, Multi Matrix System

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and 46% of patients treated with mesalamine suppositories, respectively.69 A meta-analysis established that in patients with left-sided UC and ulcerative proctitis, topical mesalamine showed greater efficacy and fewer side effects than oral therapies and topical steroids.70 Campieri et al71 also demonstrated that mesalamine suppositories were effective in inducing remission in patients with ulcerative proctitis (distal colitis up to 20 cm). In that study, 74% of patients who received mesalamine suppositories (1.5 g) achieved clinical remission at week 4 compared with 39% of patients who received placebo. The pH-sensitive 5-ASAs were evaluated in a placebocontrolled trial in patients with active mild to moderate UC.72 In contrast to a 71% maintenance of remission rate, complete remission was induced in 24% of patients on mesalamine 4.8 g, 9% of patients on mesalamine 1.6 g, and 5% of patients on placebo.73 Partial response was achieved in 50% of patients in the high-dose mesalamine group compared with 18% in the low-dose group and 13% in the placebo group.72 The ASCEND (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA) II trial found 4.8 g of delayed-release mesalamine (Asacol) to be superior to 2.4 g in patients with moderate UC, with response rates of 72% and 59%, respectively; remission rates were similar in both groups at 24%.74 ASCEND I and II were the first head-to-head—although non–placebo-controlled—comparisons of 2.4 versus 4.8 g of Asacol in patients with mild to moderate UC. In ASCEND III, the response rate at 6 weeks was 70% for patients taking 4.8 g of Asacol (6 tablets, 800 mg each) compared with 66% for those taking 2.4 g of Asacol (6 tablets, 400 mg each).75 Delzicol, released in early 2013, is a new delayed-release capsule formulation of mesalamine that has been shown to be equivalent to Asacol delayed-release tablets.76 It is available as a 400-mg delayed-release capsule. The prescribing information indicates that patients should take 800 mg, 3 times per day, for a total of 2.4 g per day for the treatment of mildly to moderately active UC. For maintenance of remission, patients should take 1.6 g daily, in divided doses. The medication should be taken at least 1 hour before or 2 hours after a meal. The dosing for Delzicol could be problematic in clinical practice. For example, patients may find it difficult to take the drug 3 times a day when it is supposed to be ingested 1 hour before or 2 hours after a meal. Because medication compliance is an extremely important issue in treating patients with UC, this may present a significant challenge to long-term compliance. A high-strength pH–dependent formulation of 5-ASA—MMX mesalamine (Lialda, Shire), taken once or twice daily, has been well tolerated and has induced remission in patients with mild to moderate UC. The formulation is a 1.2-g tablet and has been evaluated for

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twice-daily (one 1.2-g tablet, twice daily; 2.4 g/d) and once-daily (four 1.2-g tablets, once daily; 4.8 g/d) administration.52-54,77 Lichtenstein et al52 showed that after 8 weeks of treatment, rates of clinical and endoscopic remission were significantly higher for patients taking MMX mesalamine compared with patients taking placebo (34.1% and 29.2% for 2.4 g/d and 4.8 g/d, respectively, vs 12.9% for placebo; P<0.01). Increasing the dose to 4.8 g per day for an additional 8 weeks resulted in clinical and endoscopic remission and symptom resolution for nearly 60% of patients in a median time of 15 days.53 In a separate study by Kamm et al, once- or twice-daily MMX mesalamine resulted in maintenance of clinical and endoscopic remission.54 A granulated pH 6.0 delayed- and extended-release formulation of 5-ASA (Apriso) with a polymer matrix core has been approved by the FDA for the maintenance of remission at 1.5 g per day. Lichtenstein et al78 demonstrated maintenance of remission in nearly 79% of patients who switched from different 5-ASA formulations compared with almost 60% who maintained remission on placebo. In a European dose-ranging study that evaluated this pH 6.0–releasing granulated formulation of 5-ASA in patients with mildly to moderately active UC, remission rates were 66% for patients taking 3 g per day (1 g, 3 times daily), 50% for those taking 1.5 g per day (0.5 g, 3 times daily), and 55% in those taking 4.5 g per day (1.5 g, 3 times daily).55 Although the study had no placebo arm, clinical remission rates in all 3 treatment groups were high. With the exception of endoscopic improvement, which was better in the 3-g per day group than in the 1.5-g per day group, no significant differences among the 3 groups were observed. These findings suggest that the novel delivery mechanism of granulated mesalamine may lead to release of active drug at the site of active disease allowing for effective dose de-escalation. In another study, 2 doses of mesalamine granules— a 3-g dose given once daily and a 1-g dose given 3 times per day—were similarly safe and effective in producing clinical and endoscopic remission in patients with mildly to moderately active UC.56 This provides evidence that decreasing the dosing frequency may improve adherence to medication while maintaining efficacy. Once-daily, 1.5-g granulated mesalamine delayed-release (Eudragit-L, Evonik; dissolving at pH >6.0) and extended-release (polymer matrix core, containing slowly eluting mesalamine) have been shown to maintain remission in nearly 80% of patients who switched from different 5-ASA formulations compared with almost 60% who maintained remission on placebo.57 Dose de-escalation with granulated mesalamine 1.5 g per day may improve long-term adherence to medication and remission. Mesalamine granules also have demonstrated higher rates of induction of

remission of UC compared with budesonide (54.9% vs 39.5%).73 And in a comparison of MMX mesalamine and Asacol (Warner Chilcott), patients with UC who took MMX mesalamine maintained remission longer than those on Asacol.80 A recent meta-analysis confirmed the benefit of 5-ASA for inducing and maintaining remission in UC.81 The optimal dose appeared to be 2.4 g per day, with no apparent benefit from increasing the dose. Similarly, the optimum dose to prevent relapse was 2.0 to 2.4 g per day. These recommended doses are expressed in mesalamine or equivalent. Initial mesalamine dosing strategies followed the divided dosing paradigm used with sulfasalazine, which was developed to minimize sulfapyridinerelated adverse events (AEs). Several studies have assessed the safety and efficacy of once-daily mesalamine administration. The PODIUM (Pentasa Once Daily In Ulcerative colitis for Maintenance of remission) trial assessed the use of pH-sensitive mesalamine (Pentasa, Shire) 2 g per day taken as a single daily dose versus 2 divided doses over 1 year in left-sided UC.82 For once-daily dosing and divided dosing, remission rates were 69% versus 61%, respectively, and mucosal healing rates were 84% versus 78.6%, respectively, and there was no difference in AEs. The QDIEM (QD Dosing Investigation for Efficacy in UC Maintenance) study, a large, randomized controlled trial conducted by Sandborn et al,83 assessed Asacol 1.6 and 2.4 g per day in once- or twice-daily divided doses for maintenance of remission in 1,023 patients with mild to moderate UC in clinical remission. More than 90% of patients in both dosage groups at 6 months, and 85.4% at 12 months, remained in remission without differences in AEs or treatment withdrawal rates. An active-control randomized trial of 824 patients with UC in clinical remission by D’Haens et al84 demonstrated noninferiority of MMX mesalamine 2.4 g once daily compared with pHsensitive mesalamine 0.8 g twice daily. The aforementioned studies were not placebo-controlled but did demonstrate similar efficacy and safety profiles for the assessed end points. Furthermore, a meta-analysis of 10 randomized controlled trials in UC demonstrated no difference in the rates of maintenance of remission in patients with quiescent UC treated with once-daily mesalamine and also showed a mild but significant benefit in induction of remission in patients with mildly active UC, with improved adherence and a similar AE profile.85 A recent cost–benefit analysis suggested that inflammation-targeted treatment using 5-ASA therapy for patients with stool samples positive for inflammation may cost less than continuous treatment for all UC patients.86 Further studies correlating tight inflammation control and inflammatory biomarker monitoring are warranted.

MESALAMINE THERAPY DURING PREGNANCY In pregnant patients, 5-ASA and its metabolite, acetyl-5-ASA clearly cross the placenta and thus are found in both maternal and fetal plasma in women on mesalamine therapy.87 Currently, per FDA recommendations, all mesalamine therapies, except for olsalazine and Asacol/Asacol HD, are considered pregnancy safety classification B. In 2010, Asacol and Asacol HD were switched to a classification of C for safety in pregnancy by the FDA. Prior studies of mesalamine performed during organogenesis in rats and rabbits at oral doses up to 480 mg/kg per day showed no evidence of fetal malformations. These doses represented approximately 1.6 and 3.2 times the recommended human dose (based on body surface area). The class transition was based on more recent animal studies showing that the inert ingredient of Asacol’s enteric coating, dibutyl phthalate (DBP), is associated with adverse reproductive aberrations when given in very high doses.88 The maximum daily human intake of DBP is about 48 g. Published reports in rats exposed to DBP in utero at doses 17 times the human dose showed reproductive anomalies in male offspring, specifically an injury to androgenic-dependent development. Even higher doses of DBP, approximately 84 times the human dose, resulted in worse outcomes for these male rat offspring, including cryptorchidism, hypospadias, atrophy or agenesis of sex accessory organs, reduced daily sperm production, and permanent retention of nipples. The female offspring appeared to remain unaffected by these same doses. Exposure to DBP at doses equivalent to 106 times the human dose resulted in increased incidences of cleft palate and skeletal abnormalities in both female and male offspring. It is important to note that the dosage of Asacol/ Asacol HD appears to be the critical component in causing these adverse pregnancy outcomes in rats. Before this pregnancy reclassification of Asacol, gastroenterologists had been using this particular mesalamine preparation in varying doses (the maximum dose being 4.8 g daily) for the past decade in pregnant women with IBD without any AEs observed in the mothers or offspring. It appears that Asacol and Asacol HD can be used during pregnancy when administered in the appropriate doses as suggested by studies in human patients and the vast clinical experience of many IBD specialists. The PIANO registry is a prospective cohort of pregnant women with IBD that has enrolled nearly 1,300 patients to date.89,90 The analysis of the effect of mesalamine on pregnancy outcomes is pending. Early results have confirmed data from earlier studies that suggest no increase in congenital malformations in children born to mothers exposed to immunosuppressants or

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anti-TNF drugs compared with mothers who were not exposed to either group of medications. Notably, there was an increase in the number of infections in infants born to mothers exposed to the combination of thiopurines and anti-TNF agents during pregnancy, which merits closer investigation. Developmental milestones were similar among all exposure groups and will be followed in children up to age 4 years.

OPTIMIZING ORAL 5-ASAS Although there are no prospective studies evaluating combinations of oral 5-ASA drugs, combination therapy may be considered in patients who fail to respond to mesalamine monotherapy or 5-ASA prodrug monotherapy. 5-ASA nonresponders may benefit from a combination of pH-dependent polymer-coated mesalamine, moisture-dependent mesalamine, and azo-bonded 5-ASA preparations (eg, sulfasalazine, olsalazine, balsalazide). A flexible dosing schedule in which the patient actively modifies the combination therapy based on clinical response may shorten the duration to response. Lastly, a flexible dosing schedule that combines oral and topical 5-ASA agents is an effective therapeutic strategy that should not be overlooked. With the variety of 5-ASA preparations available, optimization of 5-ASA therapy may be viewed as a dynamic process rather than a static one. In a patient not responding to an initial 5-ASA therapeutic choice, dosage may be optimized (ie, escalated, deescalated), and oral preparations may be combined with each other, as well as with topical agents, in an attempt to optimize delivery of 5-ASA to the site of active disease.

NOVEL STEROID OPTIONS

FOR

Uceris, a new once-daily, extended-release formulation of budesonide–MMX Multi Matrix System (MMX) is effective for inducing remission in adults with mild to moderate UC and is associated with significantly fewer systemic AEs than conventional corticosteroids. The role of Uceris in maintaining remission in patients with UC needs to be further evaluated with prospective studies. Comparison of mesalamine and budesonide for both induction and maintenance of UC remains to be established.91-93

Biologic Therapeutic Options ANTI-TNFS There is increasing evidence that infliximab is useful for induction of remission in patients with UC who are steroid-refractory or steroid-dependent despite adequate doses of thiopurine, or who are intolerant of these medications. In ACT (Active Ulcerative Colitis Trials) 1 and 2, researchers evaluated the efficacy

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of infliximab in patients with severe UC.94 Patients with moderate to severe disease were randomized to receive IV infliximab (5 or 10 mg/kg) at weeks 0, 2, and 6, and every 8 weeks thereafter, or placebo. In these trials, 64% to 69% of patients who received infliximab 5 mg/kg exhibited a clinical response at week 8 compared with 29% to 37% of patients who received placebo. Infliximab also improved mucosal healing: Mucosal healing occurred in nearly twice as many patients in the infliximab treatment groups in ACT 1 and 2 at week 8 (62% and 60%, respectively) and week 30 (50% and 46%, respectively) as in the placebo groups at week 8 (34% and 31%, respectively) and week 30 (25% and 30%, respectively). Infliximab also demonstrated early and lasting steroid dose reduction: Patients in ACT 1 had a 75% reduction in their median daily dose of steroids from baseline. Also, nearly 3 times as many patients receiving infliximab 5 mg/kg achieved remission without steroids at week 54 compared with patients who received placebo (26% [18 of 70] vs 9% [7 of 79]; P=0.006). Adalimumab and golimumab are effective in patients with UC.30,31,95-97 Adalimumab at doses of 80 and 160 mg has been shown to induce clinical remission in 17% of patients with UC compared with 9% of those receiving placebo, respectively, at week 8. The same percentages maintained remission at week 52. Mucosal healing was achieved in 25% of patients taking adalimumab compared with 15% of patients on placebo. Golimumab 100 and 200 mg in patients with moderate to severe UC led to induction of clinical remission in 18% compared with 6% in a placebo group. At week 54, 25% of those receiving 100 mg of golimumab achieved clinical remission compared with 15% receiving placebo; and 42% achieved mucosal healing compared with 27% of patients in the placebo arm.

ANTI-INTEGRINS Vedolizumab is a systemically administered, gut selective antibody that blocks α4β7 integrin and inhibits its interaction with mucosal addressin cell adhesion molecule-1. Vedolizumab blocks gut lymphocyte recruitment, without interfering with the central nervous system. A randomized, placebo-controlled trial demonstrated that vedolizumab 300 mg (administered at weeks 0 and 2, and then beginning at week 6, every 4 or 8 weeks) was effective in induction and maintenance of remission in patients with moderate to severe UC.32

Combining Steroids, Immune Suppression, and Biologics The American College of Gastroenterology guidelines recommend 5-ASA as first-line therapy for maintenance of remission in patients with UC.98 Among the goals of therapy are the induction and maintenance

of remission of UC, and a reduction in the need for long-term corticosteroid use. Steroids are generally reserved for patients who are refractory to 5-ASAs, or for patients with severe UC with systemic illness. AZA and 6-MP are effective for patients who do not respond to steroids and continue to have moderate disease, and who are not acutely ill enough to require IV therapy. Treatment with IV cyclosporine or colectomy is indicated for patients with severe disease who fail to show significant improvement with 5-ASA, steroids, AZA, or 6-MP, including IV steroids, within 3 to 5 days.99,100 The ACT trials support a role for anti-TNF therapies in the reduction of steroid use and maintenance of remission in patients with UC.94 Approximately 22% of patients who received steroids at baseline had discontinued steroid use by week 30 in both ACT trials, or by week 54 in ACT 1. When infliximab was administered every 8 weeks, response and remission were maintained at week 30 (53% and 32%, respectively), and at week 54 (45% and 42%, respectively) in patients who had an initial response or remission at week 8 (after 3 infusions of infliximab 5 or 10 mg/kg at weeks 0, 2, and 6). Along with eliminating the use of steroids and induction of mucosal healing, increasing evidence shows that anti-TNF agents, specifically infliximab, are effective for induction and maintenance of remission in UC. The use of infliximab is expected to facilitate the widespread use of steroid-sparing therapy for patients with UC, thereby reducing the use of ineffective therapies and improving the quality of care.

Mucosal Healing Patients with longstanding UC are at increased risk for developing colorectal cancer (CRC). Mucosal healing as well as adherence to therapy has been associated with lower dysplasia and CRC. A recent nationwide study obtaining data from the Veterans Health Administration database included patients who had a total colectomy for CRC or dysplasisa in the setting of UC and had complete surgical pathology available for review. This study showed that adherence to screening guidelines resulted in detection of CRC at an earlier stage.101

Personalizing IBD Therapies In selected patients with moderate to severe UC, an earlier aggressive treatment approach is indicated.13,102 Some patients with mild to moderate disease may benefit from a decrease in medication dosage, adherence to therapeutic regimens, and in some cases, a reevaluation of the diagnosis. Identification of immunologically vulnerable patients through the use of emerging serologic markers, biomarkers, and genotyping may allow for individualized treatment that improves outcomes. A greater understanding of the human genome is

redefining the science of individuality. Less than 0.1% of our DNA is responsible for IBD susceptibility and therapeutic response.103-106 We are at the threshold for genotyping patients and bacteria, which will lead to a greater understanding of the pathobiology of IBD and its treatment.107 Until genomics can be applied to individualized medicine, predicting IBD progression may be achieved through risk assessment, emerging biomarkers, and optimizing mesalamine and biologic (anti-TNF and anti-Integrin) therapeutic strategies. In selected patients with moderate to severe UC, early intervention with immunosuppressive or biologic therapies— and limited use of steroids including Uceris92—may slow the progression of IBD, and treatment may move from a symptom-oriented, step-up strategy to a prevention-oriented, early intervention approach.

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