July 2014

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 65, Number 7 • July 2014

Candidates for Celiac Disease Detection Go Unscreened

BY TED BOSWORTH Chicago—Fewer than half of people who should be screened for celiac disease according to current guidelines are being evaluated for the condition, new data suggest.

Given the limited prevalence of celiac disease, population-based screening is impractical, but patients with see Celiac, page 36

EXPERT ROUNDTABLE

Alcohol-Related Liver Dam Damage

BY BRIGID DUFFY Alcoohol abuse accounted for an estimaated 88,000 deaths in the United States each year between 2006 and 2010.. And the bar tab was steep: $224 billion in n economic costs in 2006 alone, see Alcohol, page 24

Time To Reconsider Cold Sn Hot snare bessts cold for intermediate-sized flat or sessile polyps in Korean study

BY CAROLINE HELWIICK When it comes to polypectomy, more should like it hot.

That’s the conclusion of a new studyy by Korean researchers wh ho found that hot snare polyp pectomy (HSP) proved better than the cold snare method when removing flat or sessile intermediate-sized polyps.

“Hot snare polypectomy was superior to cold snare polypectomy [CSP] in the complete resection rate of 5- to 9-mm–sizzed colorectal polyps, without resulting in additionall complications,” said HyunSoo Kim, MD, profeessor of internal medicine at Yonsei University Wonju j College C ll off Medicine, M di i who h presented the findings at Digestive Disease Week 2014. “Hot snare polypectomy should be considered as the first-line therapy for 5- to 9-mm–sized sessile or flat colorectal polyps.”

Kenneth McQuaid, MD, professor of medicine at the University of California, San Francisco, who comoderated the session at which the study was presented, said the results will make him rethink CSP. “I h have to say, the h fi findings di give i me pause as I think hi k about my own practice, because in the last few years we have moved pretty aggressively to CSP in this size range,” he told Gastroenterology & Endoscopy News. see Snare, page 48

I N S I D E

Study Links Heavy Use of Antibiotics To Ri T Risk k ffor Colorectal Cancer

EXPERTS’ PICKS The Best of Digestive Disease Week (DDW): Part 1 Experts share their favorite abstracts from the 2014 DDW meeting .............................................................................................. page 10

BY KATE O’ROURKE Chicago—The use of certain antibiotics is associated with an increased risk for colorectal cancer, according to a case–control study involving roughly 100,000 patients.

Antibiotics may reduce overall bacterial diversity, which can Prateek Sharma, MD

see Antibiotics, page 45

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

Introduction

Improving Quality Outcomes: Assessing Factors Related to Failed Colonoscopy See page 22

Among clinicians performing colonoscopy for colorectal cancer (CRC) screening, failure to complete the procedure remains a significant concern.1 Large-scale reviews have shown rates of incomplete colonoscopy— defined as the inability to achieve cecal intubation and mucosal visualization effectively1,2—between 10% and 20%,1 well over targets recommended by the US Multi-Society Task Force on Colorectal Cancer.3 Thus, it is important for clinicians to understand the numerous modifiable physician- and patientrelated factors that can lead to colonoscopy failure in order to reduce its incidence and provide patients with improved outcomes.

Multiple Factors Related to Incomplete Colonoscopy Because effective colonoscopy depends on several events occurring successfully before and during the procedure,4 the reasons for incomplete colonoscopy can vary. Sidhu et al audited all colonoscopies performed between April 2005 and 2010 at the Royal Liverpool University.5 Of 8,910 colonoscopies, 693 were incomplete (7.8%; 58% women; mean age, 61 years). Reasons for incomplete colonoscopy included inadequate bowel preparation (24.8%), patient discomfort (22.2%), obstruction (17.2%), presence of diverticular disease (4.3%), adverse events (0.4%), and other (3.2%) or unrecorded (16.9%) causes.5

Bowel Preparation As illustrated by the aforementioned study, insufficient bowel prep remains a major contributor to incomplete colonoscopy.6 According to a consensus document from 3 leading gastrointestinal societies on bowel preparation for colonoscopy, inadequate bowel preparation can result in failed detection of prevalent neoplastic lesions and has been linked to an increased risk for procedural complications.6 Various studies and reviews have attempted to identify predictors of poor colonoscopy preparation6-8 and have found that inadequate bowel preparation is more

22

common in patients with the following characteristics: non–English-speaking, Medicaid insurance, single and/or inpatient status, polypharmacy, obesity, increased age, male gender, and comorbidities such as diabetes mellitus, stroke, dementia, and Parkinson’s disease.6-8 Additionally, procedure-related factors, such as poor adherence to preparation instructions,6 erroneous timing of bowel purgative administration,8 and longer appointment wait times for colonoscopy,7 were associated with poor bowel preparation. Nevertheless, Hassan et al found that awareness of these and other predictors of inadequate bowel preparation can be used to facilitate effective, targeted bowel preparation improvement programs in order to reduce the risk for incomplete colonoscopy.7

Disease-Related Factors A “difficult” colonoscopy, where reaching the cecum is challenging or not possible, may be related to anatomic and/or diseaserelated factors.9 The most common patientrelated causes of difficult colonoscopy are endoscope loops or angulation in the colon, limiting effective advancement of the colonoscope. Similarly, diverticular disease may increase the inability to achieve an adequate preparation, possibly due to stool retention in diverticula and/or myochosis which can limit insufflation, making it more

challenging to confidently visualize the colonic lumen (Figure).9

Technical Performance Loops and angulations also can test the experience and skill of the endoscopist to navigate the colon successfully.9 The overall technical skill of the endoscopist, which is dependent on manual dexterity and cumulative experience, is a major determinant of colonoscopy success. Not surprisingly, Shah et al reported that endoscopists who performed a higher volume of colonoscopies experienced fewer incomplete procedures, whereas endoscopists in the lowest volume quintile had incomplete colonoscopy rates of nearly 29%.2 Interestingly, the same study demonstrated that rates of incomplete colonoscopy were higher in office settings, although the authors concluded this finding might be explained by increased patient discomfort due to reduced levels of sedation used in this setting.2 Other studies have reviewed timing aspects related to endoscopist performance.

Sanaka et al found that even after accounting for bowel preparation, incomplete colonoscopies were more common when performed in the afternoon.10 The potential for variation in colonoscopy performance has been judged to be an important issue that led to the recommendation by national

Difficult colonoscopy

Redundant colon

Shortening basic skills

Overtubes

Variable stiffness colonoscope

Pediatric colonoscope

Upper endoscope

Double balloon enteroscope

Figure. Approach strategy in the difficult colon.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Cap-assisted colonoscopy

EDUCATIONAL REVIEW

Endoscopic Eradication Therapy for

The consequences of incomplete colonoscopy are potentially profound and widespread. For patients undergoing diagnostic colonoscopy, who have an increased risk for organic gastrointestinal disease, uncertainty and delay in diagnosis can be extremely stressful. Furthermore, some patients who experience unsuccessful colonoscopy might not be willing to undergo a repeat attempt at the procedure. For these patients, failure to detect advanced adenomas or early CRC could lead to poor outcomes and significant risk for morbidity and mortality. Even in patients who do undergo subsequent colonoscopy, a second procedure involves re-exposure to the risk for procedure-related adverse events.

For clinicians, the effects of incomplete colonoscopy can mirror those for patients.

Unsuccessful colonoscopy is essentially as costly as well as time- and resource-consuming (ie, patient and physician time, staff and office time, equipment and drug availability) as successful colonoscopy without the same benefits generated by a successful procedure, such as accurate diagnosis, treatment, and primary and secondary prevention of colon cancer.2 Additionally, as colonoscopy quality measurement becomes more compulsory for practices,11 incomplete colonoscopy could adversely affect practice quality benchmarking.

SHREYAS SALIGRAM, MD, MRCPa,b PRASHANTH VENNALAGANTI, MDa PRATEEK SHARMA, MDa,b a

In this evolving era of value-based care, considerable uncertainty exists as to whether payors will continue to reimburse health care providers for unsuccessful colonoscopies, particularly if the cause of procedural failure is deemed to be preventable.6 As reimbursement often is based on the depth of cecal intubation, incomplete colonoscopy may affect how procedures are billed and coded; incorrect billing and coding could result in an audit of an office’s billing practices.2 Also, if incomplete colonoscopies are not reimbursed, the payment responsibility for the original procedure and subsequent procedures may transfer to the patient.7 Therefore, there is a financial incentive for clinicians to perform complete, high-quality colonoscopy as often as possible.2,6

Endoscopic Eradication Therapy for Barrett’s Esophagus

Ignore patient Internet communities at your peril ......... page 20

Barrett’s Esophagus

Effect on Patients and Practice

Costs

Difficult sigmoid Water immersion method

Adapted from reference 9.

agencies for continuous colonoscopy quality improvement monitoring and initiatives to ensure that clinicians who perform colonoscopy remain educated about optimal preparation and procedural techniques.3

Brian E. Lacy, PhD, MD

PRINTER-FRIENDLY VERSION AVAILA A BLE AT GASTROENDONEWS.COM

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Improving Quality Outcomes: Assessing Factors Related to Failed Colonoscopy

Randy S. Longman, MD, PhD

Department of Veterans Affairs Medical Center Kansas City, Kansas b University of Kansas School of Medicine Kansas City, Kansas

Dr. Sharma has received grant support from Barrx Medical, CDX Labs, Cook Medical, Ninepoint Medical, and Olympus Inc. Drs. Saligram and Vennalaganti reported no relevant conflicts of interest.

B

arrett’s esophagus (BE) is the precursor lesion to esophageal adenocarcinoma, which if diagnosed at an invasive stage is

associated with significant morbidity and mortality. Surgery was the mainstay

of treatment for patients with high-grade dysplasia (HGD) and adenocarcinoma associated with BE. However, surgery in itself carries significant morbidity.

There e has been tremendous progress in the minimally inv vasive treatment of BE in the past decade.

See supplement

The premise to be aggressive in treating dysplastic BE an nd early stage of adenocarcino oma is to prevent progression to a an advanced stage cancer. Most interv ventional endoscopists are comfortable e treating dysplasia and intramucosal esoph hageal cancer, although recently there have been emerging data on the treatment of early submucosal cancer in BE. This article reviews the different modes of and strategies for endoscopic treatment of BE with emphasis on newer techniques.

eventually to esophageal adenoca are cinoma.7 Patients with HGD have the highest tendency to progress to esophageal adenocarcinoma.

Therefore, endoscopic eradication therapy is increasingly used to treat HGD and early esophageal adenocarcinoma to decrease th he progression to invasive disease. D Data from the US National Cancer In nstitute show a 6-fold increase in the incidence id off esophageal h l adenocarcinoma in 2001; the disease now is considered the fastest rising cancer in the United States.8

Introduction Barrett’s esophagus is defined as displacement of squamocolumnar junction by intestinal metaplasia (IM; goblet cells) proximal to the gastroesophageal junction.

The overall population prevalence is estimated at 1.6%1 with an annual incidence of 62 per 100,000.2 In patients with BE, the annual incidence of esophageal adenocarcinoma is reported between 0.12% and 0.5%.3-6 Intestinal metaplasia can have a histologic transformation from no dysplasia to low-grade dysplasia (LGD), HGD, and

Rationale for Endoscopic Eradication Barrett’s esophagus has the potential to transform itself into esophageal adenocarcinoma by genetic alteration of IM, where there is unregulated cell growth due to inactivation of tumor suppressor genes and activation of oncogenes. This genetic activity causes a morphologic change in the lining of the epithelium of the esophagus called dysplasia (cytologic atypia, architectural complexity due to nuclear pleomorphism and

G A S T R O E N T E R O LO GY & E N D O S CO P Y N E WS • J U LY 2 0 1 4

1

Colonoscopy add-on reaps big gains in detection ........ page 38 Standard of care: Don’t try this at home ......................... page 51

3

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

‘Good Vibrations’ Might Ease Constipation

BY CAROLINE HELWICK CHICAGO—A remotely activated vibrating capsule can relieve chronic constipation and might be a good alternative for patients reluctant to try the latest pharmacologic treatments for the condition, Israeli researchers have found.

“This is an example of thinking outside the box. It’s an innovative idea,” said Yishai Ron, MD, director of

neurogastroenterology and motility at Tel Aviv Sourasky Medical Center. “You swallow this capsule. It’s not absorbed. It does not cause side effects, unlike all the medications currently used for treating constipation.”

But Nicholas J. Talley, MD, PhD, professor of medicine at the University of Newcastle, in Australia, said it’s not clear why the capsule might help relieve constipation and urged caution without more data.

“How this would work, I don’t know, and I’m not sure the investigators know either. That’s part of the problem,” Dr. Talley said. “They say it is mimicking peristalsis, but to be honest, we have no idea.”

Dr. Ron, who presented a poster on the technology at Digestive Disease Week 2014 (abstract Sa2023), said that although drugs are the mainstay treatment for constipation, about half of patients who use those agents are unsatisfied with their treatment. Lack of effectiveness is the

primary reason, but patients also complain of side effects, such as diarrhea and cramping, and are concerned about the long-term safety of the regimens. A nonpharmacologic alternative therefore would be welcome, he said.

Dr. Ron said the vibrating capsule might be a good option for patients who fail to respond to laxatives before they start on more expensive medications. The cost of the device has not been set, but he predicted the capsule will not be more expensive than the newest medications.

The capsule, which is similar in size to the video capsule (PillCam, Given Imaging), houses a tiny receiver and vibrating mechanism and is activated by an external transmitter six to eight hours after ingestion. When activated, the device generates three pulses per minute in the colon. “We wanted to imitate the internal pacemaker of the large bowel, but we can change the parameters. It’s very smart, it’s very flexible,” Dr. Ron said.

Rise in Bowel Movements The study of the vibrating capsule involved 28 patients with chronic idiopathic constipation or constipationpredominant irritable bowel syndrome, who had failed pharmacologic treatment.

Most were women, and their median age was 47 years (range, 19-70). All patients discontinued laxatives for two weeks before enrolling in the trial, for which they swallowed two capsules per week for two weeks and recorded their bowel movements and symptoms. The study was completed by 26 of the 28 patients.

During the treatment phase, the patients reported a significant increase in the number of bowel movements over the two-week run-in phase of the openlabel study. The average number of bowel movements increased from about two per week at baseline to almost four by the end of the study (P<0.0001). Three patients required rescue medication more than once during the run-in and study periods.

Two patients reported adverse events: One complained of abdominal pain, diarrhea and flatulence; the other reported feeling muscle twitches in the abdominal wall.

Dr. Ron said that although patients were not formally followed after the study, many are his own patients and he has observed that, for reasons that remain unclear, some no longer need medication for constipation.

He acknowledged that while the clinical results are favorable, the results must be confirmed. Vibrant Medical, the company in the United Kingdom that makes the device and supported the study, is planning a multinational, randomized and placebo-controlled trial that will aim to enroll approximately 80 patients.

■

4

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Heard Here

First

See page 48

Gallstone

disease

was once considered been a

Follow us on Twitter

CORRECTION:

An article on page 1 of the May 2014 issue about

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hepatocellular carcinoma contained an erroneous quotation from Hashem

gastroendonews

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El-Serag, MD. The quotation should have read:

noticeable change in

demographics. No of women

“This information has important implications

longer is this a disease

in their 40s

for what will happen after

who have

the HepC epidemic is over,” Dr. El-Serag noted.

had multiple childbirths.

“The risk for HCC is unlikely to return to baseline.”

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Reduce Costs With Selective Pre-Op Testing NYC panel highlights waste in system ASA re released its list of indications for preoperative tessts, a surgeon from Texas wrote in a peerrevieweed journal that the recommendations lacked clarity,, were not specific to ambulatory surgery and were n not based on well-designed studies (Adv Surg 2013;4 47:81-98).

Panelist Tomas Heimann, MD, chief of surgery at James J. Peters VA Medical Center, in New York City, and professor of surgery at Mount Sinai, said the problem is not that preoperative testing is useless, but rather that the wrong tests are often performed.

“Our system is flawed because if a patient has an operation at Montefiore [in New York City] and is now at Mount Sinai with a complication, that information isn’t always provided,” Dr. Heimann said. “We’re doing a lot of tests now that have some usefulness, but a lot of them aren’t really making any difference. If you’re about to operate on a patient to remove his gallbladder, these routine tests aren’t going to help you. It’s critical that we’re doing tests of clinical benefit.” ■

BY PAUL BUFANO Routine preanesthetic tests cost more than $60 billion every year, but far fewer than 1% reveal pertinent abnormalities relating to the anesthetic or the surgery, according to a 1989 study published in the Canadian Journal of Anesthesia (1989;36:S13-S19).

For that reason, national guidelines recommend minimizing preoperative testing in low-risk, stable patients undergoing nonemergent surgery. The American Society of Anesthesiologists (ASA) released a guideline in 2012 that advised against routine testing, such as labs, chest x-rays and electrocardiograms (EKG). But the ASA suggested a tailored approach for anything with a high risk.

Yet testing remains a common practice. Roughly half of low-risk patients still undergo unnecessary preoperative testing, accoording to two recent studies (Ann ( Surgg 2012;256:518-5228; Anesth Analgg 2011;112:207-212).

An interdisciplinary panel of physicians from m around New York City met recently to discuss the appropriate use of pre-op testing at the New York Acaademy of Medicine. The session, “Why Bother! The Com mprehensive Pre-Op Panel,” was organized after the American Board of Internal Medicine (ABIM) Foundatiion listed preoperative testing in patients undergoing rou utine surgery as one of five medical services of questionaable value.

Preoperative testing has been an accepted d part of medicine for more than 150 years since the English physician John Snow wrote about the benefit of examining his patient before administering chloroform. In the 1990s, however, doctors began to ask if these tests made any difference in outcome, and the answer was “we always did it that way,” said Elizabeth Frost, MD, clinical professor of anesthesiology at the Icahn School of Medicine at Mount Sinai, in New York City, who appeared on the panel.

“I’ve heard surgeons say that their administrator orders the tests, that the patient expects to give blood and be tested, that anesthesia will cancel the case if there are no tests, that there’s a legal liability without testing and that they have to support the hospital and labs,” Dr. Frost said.

Dr. Frost is the creator of the PreAnesthetic Assessment, a series of continuing medical education articles (published in Anesthesiology Newss and online).

The ABIM Foundation’s “Choosing Wisely” campaign, an initiative to reduce the overuse of tests and procedures, created a guideline to help clinicians better understand and deal with the controversial medical services. The framework consists of four points: evidence of harm or little benefit, frequent misuse in practice, that it be measurable and that it be under provider control.

Preoperative testing certainly is measurable and under provider control, but many physicians are unconvinced about the other two aspects, said panelist Deborah Korenstein, MD, editor of ACP Smart Medicine, a publication of the American College of Physicians.

“There is strong evidence that pre-op testing does not change outcomes or surgery cancellation rates for

A Sysstem for Reducing Need dless Testing patients undergoing minor procedures like cataract surgery,” Dr. Korenstein told attendees. “Studies have looked for harms that were a direct result of the tests, like bleeding and nerve damage from blood draws; and although they are rare, they are not nonexistent.”

These tests also can have non-physical consequences, such as false-positive results that trigger patient anxiety and even surgical delays, she continued.

So what do all these tests cost? A chest x-ray is $128, EKG is $216, CBC is $156, electrolytes is $626, urinalysis is $85 and a stress test is $2,300, for a grand total of $3,511, according to prices from Dr. Frost’s bill at White Plains Hospital in 2012 and the cost of a stress test at Mount Sinai.

“Pre-op lab and EKG testing should clearly be driven by history, physical and surgical risk only,” said Dr. Frost, a member of the editorial board of Anesthesiology News.

“You should do a test only if it can correctly identify abnormalities, if it can change the diagnosis, or if it’s going to change the management plan or outcome. Such tests are very expensive, can cause delays and can come with unforeseen complications.”

Dr. Frost researched policies around the world and found that several other countries shared her views. Germany and Thailand are using preoperative guidelines that reduce unnecessary testing; the United Kingdom believes that there is no evidence of clinical benefit and cost-effectiveness of routine testing; and Canada supports pregnancy tests but discourages nearly all the rest.

Yet the United States has no consensus. After the

The rad diology department at Weill Cornell Medical Center, in New York City, implemented a clinical decision support system that has improved health care by influencing physician choices.

The system was embedded into the department’s electronic ordering system several years ago to assist with real-time decisions. After a specific image or procedure is entered into the machine, a menu will appear and ask for more information.

The system then scores the request based on previously applied criteria, and either approves it or suggests another course that is more appropriate.

There are some guidelines that indicate when a physician should do a specific test, but the problem is what they are and how to remember them all in the moment, said Keith Hentel, MD, executive vice chairman and associate professor of radiology at Weill Cornell.

“With the evidence that we’ve incorporated into our clinical practice, it’s now clear that the pre-op chest x-ray is an avoidable test,” Dr. Hentel said. “Clinical decision support is one mechanism that can be used to reduce imaging, and it could be easily applied to other fields. I would encourage individual practices to get started reducing unnecessary testing and then make their results known, because big changes are being made to health care.”

—P.B.

IN THE TREATMENT OF CHRONIC HEPATITIS B (CHB) IN ADULTS WITH COMPENSATED LIVER DISEASE

TAKE A CLOSER LOOK AT LAMIVUDINE (LAM) RESISTANCE MORE THAN NEARLY Not an actual patient, but is representative of a real patient type. Models are used for illustrative purposes only.

50% 70% 70% 2%

of Americans living with CHB are Asian and Pacific Islanders1

of Asian Americans were born or have parents born in countries where CHB is common1

of patients receiving lamivudine develop resistance at 5 years2

of patients in the United States use lamivudine; up to 88% in Asia3

Indication and Usage VIREAD® (tenofovir disoproxil fumarate) is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older.

The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: s The indication in adults is based on data from treatment of subjects who were nucleoside–treatment-naïve and treatment-experienced with documented resistance to lamivudine. Subjects were adults with HBeAgpositive and HBeAg-negative chronic hepatitis B with compensated liver disease s VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease s The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efficacy

Important Safety Information BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS s Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases cases, have been reported with the use of nucleoside analogs, analogs including VIREAD, in combination with other antiretrovirals s Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted

Warnings and Precautions s New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of VIREAD. In all patients, assess estimated creatinine clearance (CrCl) prior to initiating and during therapy. In patients at risk for renal dysfunction, including those

who previously experienced renal events while receiving adefovir dipivoxil, additionally monitor serum phosphorus, urine glucose, and urine protein. In patients with CrCl <50 mL/min, adjustt dosing interval and closely monitor renal function. Avoid concurrent or recent use with a nephrotoxic agent.

Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after initiation of high dose or multiple NSAIDs in HIV-infected patients with risk factors for renal dysfunction; consider alternatives to NSAIDs in these patients. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function s Coadministration with other products: – Do not use in combination with other products containing tenofovir disoproxil fumarate – Do not administer in combination with adefovir dipivoxil s Patients coinfected with HIV-1 and HBV: Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen. HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD s Bone effects: Decreases in bone mineral density (BMD) and mineralization defects, including osteomalacia, have been seen in patients treated with VIREAD. C VIREAD Consider id assessmentt off BMD in i adult d lt andd pediatric di t i patients ti t who h have h a history of pathologic bone fracture or other risk factors for bone loss. In a clinical trial conducted in pediatric subjects 12 to <18 years of age with chronic hepatitis B, total body BMD gain was less in VIREAD-treated subjects as compared to the control group. In patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms, hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered

Adverse Reactions s In HBV-infected subjects with compensated liver disease: Most common adverse reaction (all grades) was nausea (9%). Other treatmentemergent adverse reactions reported in >5% of patients treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash

TAKE A CLOSER LOOK AT VIREAD LAM-resistant VIREAD patients (Study 121) achieving viral suppression (HBV DNA <400 copies/mL) at 96 weeks of treatment 4,5 VIREAD

100 90

89%

(n=126)

Patients (%)

80 70 60 50 40

s As a secondary endpoint, no HBV resistance (0%) was detected at 96 weeks in CHB patients with LAM resistance4

30 20 10 0

Study 121 was a randomized, double-blind, active-controlled 96-week trial evaluating the safety and efficacy of VIREAD (n=141) compared to an unapproved antiviral regimen (n=139) in subjects with CHB, persistent viremia (HBV DNA ≥1000 IU/mL), and genotypic evidence of LAM resistance. The primary endpoint in Study 121 was HBV DNA <400 copies/mL (69 IU/mL) at Week 96.4,5

0

4

8

12 16

24

32

40

48

60

72

Important Safety Information (cont’d) s In HBV-infected subjects with decompensated liver disease: Most common adverse reactions (all grades) reported in ≥10% of patients treated with VIREAD were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%)

Drug Interactions s Didanosine: Coadministration increases didanosine concentrations.

Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy). Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with VIREAD and in patients weighing <60kg, the didanosine dose should be reduced to 200 mg once daily when coadministered with VIREAD s HIV-1 protease inhibitors: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations; use atazanavir given with ritonavir. Coadministration of VIREAD with atazanavir and ritonavir, darunavir and ritonavir, or lopinavir/ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity s Drugs affecting renal function: Coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir

Dosage and Administration s Recommended dose, in adults and pediatric patients ≥12 years of age (≥35 kg), for the treatment of chronic hepatitis B: one 300 mg tablet, once daily, taken orally, without regard to food s In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown

84

96 Weeks

s Safety and efficacy in pediatric patients <12 years of age or weighing <35kg with chronic hepatitis B have not been established s The dosing interval of VIREAD should be adjusted (using recommendations in the table below) and renal function closely monitored in patients with baseline creatinine clearance <50 mL/min Dosage Adjustment for Patients with Altered Creatinine Clearance Creatinine clearance (mL/min)a ≥50 Recommended 300 mg dosing interval

Every 24 hours

30-49

Every 48 hours

10-29

Every 72 to 96 hours

Hemodialysis patients Every 7 days or after a total of approximately 12 hours of dialysisb

a

Calculated using ideal (lean) body weight.

Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration.

VIREAD should be administered following completion of dialysis.

b

s The pharmacokinetics of tenofovir have not been evaluated in nonhemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients s No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50-80 mL/min). Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in these patients s No data are available to make dose recommendations in pediatric patients with renal impairment

Please see Brief Summary of full Prescribing Information, including BOXED WARNING, on the adjacent pages.

References: 1. CDC Web site. CDC Features-August 2011: Chronic hepatitis B and Asian & Pacific Islanders. Centers for Disease Control and Prevention. http://www.cdc.gov/Features/ChronicHepatitisB/. Accessed June 26, 2013. 2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. J Hepatol.l 2012;57:167-185. 3. Data on file, Gilead Sciences, Inc. Gilead HBV LAM assessment, IMS MIDAS data. May 2013. 4. Data on file, Gilead Sciences, Inc. 0121 CSR. 5. VIREAD Prescribing Information, Foster City, CA: Gilead Sciences, Inc.; October 2013.

VIREAD® (tenofovir disoproxil fumarate) tablets Brief summary of full Prescribing Information. Please see full Prescribing Information including Boxed WARNING. Rx only WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS @ Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals (See Warnings and Precautions) @ Severe acute exacerbations of hepatitis have been reported in HBVinfected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted (See Warnings and Precautions) INDICATIONS AND USAGE: VIREAD is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: J The indication in adults is based on safety and efficacy data from treatment of subjects who were nucleoside-treatment-naïve and subjects who were treatment-experienced with documented resistance to lamivudine. Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease (See Adverse Reactions) J VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease (See Adverse Reactions) J The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efficacy DOSAGE AND ADMINISTRATION: For the treatment of chronic hepatitis B the recommended dose, in adults and pediatric patients ≥12 years of age (≥35 kg), is one 300 mg tablet, once daily, taken orally, without regard to food. In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. Safety and efficacy in pediatric patients <12 years of age with chronic hepatitis B weighing <35 kg have not been established. Dose Adjustment for Renal Impairment in Adults: Significantly increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment. Therefore, the dosing interval of VIREAD tablets 300 mg should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease (ESRD) requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients (See Warnings and Precautions). No dose adjustment of VIREAD tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose and urine protein should be performed in patients with mild renal impairment (See Warnings and Precautions).

Dosage Adjustment for Adult Patients with Altered Creatinine Clearance

Recommended 300 mg dosing interval

Creatinine clearance (mL/min)a ≥50 30-49 10-29

Hemodialysis patients

Every 24 Every 48 Every 72 to hours hours 96 hours

Every 7 days or after a total of approximately 12 hours of dialysisb

a. Calculated using ideal (lean) body weight. b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis.

The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients. No data are available to make dose recommendations in pediatric patients with renal impairment.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS: Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors.

Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be

suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Exacerbation of Hepatitis after Discontinuation of Treatment: Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. New Onset or Worsening Renal Impairment: Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD (See Adverse Reactions). It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of VIREAD, and periodically during VIREAD therapy. Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 mL/min (See Dosage and Administration). No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity. VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs (NSAIDs)) (See Drug Interactions). Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy.

Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. Coadministration with Other Products: VIREAD should not be used in combination with the fixeddose combination products ATRIPLA®, COMPLERA®, STRIBILD® or TRUVADA® since tenofovir disoproxil fumarate is a component of these products. VIREAD should not be administered in combination with adefovir dipivoxil (See Drug Interactions).

Patients Coinfected with HIV-1 and HBV: Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen. HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD. Bone Effects Bone Mineral Density:: In clinical trials in HIV-1 infected adults, VIREAD was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving VIREAD (See Adverse Reactions).

Clinical trials evaluating VIREAD in pediatric and adolescent subjects were conducted.

Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the VIREAD-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected (See Adverse Reactions).

The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

Mineralization Defects:: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of VIREAD (See Adverse Reactions). Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF (See Warnings and Precautions).

ADVERSE REACTIONS: Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease: Treatment-Emergent Adverse Reactions:: In controlled clinical trials in subjects with chronic hepatitis B (0102 and 0103), more subjects treated with VIREAD during the 48-week double-blind period experienced nausea: 9% with VIREAD versus 2% with adefovir dipivoxil. Other treatmentemergent adverse reactions reported in >5% of subjects treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash. No significant change in the tolerability profile was observed with continued treatment with VIREAD for up to 240 weeks.

Laboratory Abnormalities:: in Studies 0102 and 0103 (0–48 Weeks) laboratory

Brief Summary (cont’d) abnormalities (Grades 3–4) reported in ≥1% of subjects treated with Viread (n=426) and adefovir dipivoxil (n=215), respectively, were: any ≥Grade 3 laboratory abnormality (19%, 13%); creatine kinase (M: >990 U/L; F: >845 U/L) (2%, 3%); serum amylase (>175 U/L) (4%, 1%); glycosuria (≥3+) (3%, <1%); AST (M: >180 U/L; F: >170 U/L) (4%, 4%); and ALT (M: >215 U/L; F: >170 U/L) (10%, 6%). Laboratory abnormalities (Grades 3–4) were similar in subjects continuing VIREAD treatment for up to 240 weeks in these trials.

The overall incidence of on-treatment ALT flares (defined as serum ALT >2 × baseline and >10 × ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and adefovir dipivoxil (2%). ALT flares generally occurred within the first 4-8 weeks of treatment and were accompanied by decreases in HBV DNA levels.

No subject had evidence of decompensation. ALT flares typically resolved within 4-8 weeks without changes in study medication. The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with VIREAD were consistent with those observed in other hepatitis B clinical trials in adults. Clinical Trial in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease:: In a small randomized, double-blind, active-controlled trial (0108), subjects with CHB and decompensated liver disease received treatment with VIREAD or other antiviral drugs for up to 48 weeks. Among the 45 subjects receiving VIREAD, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus <2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score ≥10 and MELD score ≥14 at entry) developed renal failure. Because both VIREAD and decompensated liver disease may have an impact on renal function, the contribution of VIREAD to renal impairment in this population is difficult to ascertain. One of 45 subjects experienced an ontreatment hepatic flare during the 48 week trial.

Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B: Assessment of adverse reactions is based on one randomized study (0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with VIREAD (N = 52) or placebo (N = 54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults.

In this study, both the VIREAD and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population. The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively).

Three subjects in the VIREAD group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72. At baseline, mean BMD Z-scores in subjects randomized to VIREAD were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body. In subjects receiving VIREAD for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo. As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected (See Warnings and Precautions).

Postmarketing Experience: The following adverse reactions have been identified during postapproval use of VIREAD. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: allergic reaction, including angioedema, lactic acidosis, hypokalemia, hypophosphatemia, dyspnea, pancreatitis, increased amylase, abdominal pain, hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT), rash, rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria, asthenia. The following adverse reactions listed above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

DRUG INTERACTIONS: Didanosine: Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.

When administered with VIREAD, Cmaxx and AUC of didanosine increased significantly.

The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving VIREAD with didanosine 400 mg daily. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with VIREAD. In patients weighing <60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with VIREAD. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). For additional information on coadministration of VIREAD and didanosine, please refer to the full Prescribing Information for didanosine.

HIV-1 Protease Inhibitors: VIREAD decreases the AUC and Cmin of atazanavir. Viread should not be coadministered with atazanavir without ritonavir. Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters. When tenofovir disoproxil fumarate is co-administered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving VIREAD concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions.

Drugs Affecting Renal Function: Since tenofovir is primarily eliminated by the kidneys, coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs (See Warnings and Precautions). In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with adefovir dipivoxil.

USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B:: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, VIREAD should be used during pregnancy only if clearly needed. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to VIREAD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. Animal Data: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIREAD. Geriatric Use: Clinical studies of VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Patients with Impaired Renal Function: It is recommended that the dosing interval for VIREAD be modified in patients with estimated creatinine clearance <50 mL/min or in patients with ESRD who require dialysis (See Dosage and Administration).

For detailed information, please see full Prescribing Information. To learn more call 1-800-GILEAD-5 (1-800-445-3235) or visit www.VIREAD.com.

COMPLERA, EMTRIVA, GSI, HEPSERA, STRIBILD, TRUVADA, and VIREAD are trademarks or registered trademarks of Gilead Sciences, Inc., or its related companies.

ATRIPLA is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.

©2013 Gilead Sciences, Inc. All rights reserved. VIRP0103 12/13

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DDW 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Experts’ Picks

The Best of Digestive Disease Week 2014: Part 1 COMPILED AND WRITTEN BY DAVID WILD

In the first of a three-part series, our roster of experts highlights what they thought were some of the most important studies presented at Digestive Disease Week 2014.

Prateek Sharma, MD Professor of Medicine University of Kansas Medical School Kansas City

sophageal Brush Biopsy with ComputerAssisted Tissue Analysis Increases Detection of Barrett’s Esophagus and Dysplasia in a MultiSite Community-Based Setting (Gross SA, et al; abstract 371)

E

Researchers examined the accuracy of two-brush Wide Area Transepithelial Sampling with three-dimensional analysis (WATS3D) as an adjunct to traditional forceps biopsy in the diagnosis of Barrett’s esophagus (BE) and esophageal dysplasia and neoplasia. WATS3D allows clinicians to collect samples from a wider area of the suspicious esophageal tissue than with forceps biopsy. Collected samples then undergo 3D computerassisted analysis, and the most abnormal cells are isolated and subsequently examined by a pathologist.

The new study included data from 2,559 patients, most of whom had gastroesophageal reflux disease (GERD).

The patients had been treated by one of 28 gastroenterologists at several community clinics. Patients underwent upper endoscopy and had tissue samples removed using both WATS3D and four-quadrant forceps biopsies, with samples removed no more than every 2 cm throughout the suspected BE segment using the conventional approach. Patients were an average of 55 years old, and 80% had suspected BE segments of less than 3 cm long.

According to the researchers, traditional forceps biopsies diagnosed 377 cases (15.1%) of BE and identified 17 cases (4.51%) of esophageal dysplasia. WATS3D detected an additional 258 cases (25.4% overall), translating to a 68.4% increase in the diagnostic yield above that of forceps biopsies. WATS3D also detected 10 additional cases of dysplasia and one case of neoplasia, increasing the diagnostic yield for dysplasia and neoplasia by 64.7%.

Dr. Sharma: Right now, for surveillance of Barrett’s esophagus, the standard approach is to conduct four-quadrant biopsies, removing tissue every 2 cm throughout the suspected Barrett’s segment. This approach samples less than 10% of the Barrett’s segment. Brush biopsy is an interesting concept that has been tried in the past. It is simple to

perform; it can be passed through the channel of the endoscope; and if you move the brush around the suspected segment, you can theoretically sample a larger p surface area than with forceps biopsy.

Studies using previous-generation brush cytology have not shown an improved diagnostic accuracy in Barrett’s esophagus [Kumaravel A, et al. Endoscopy 2010;42:800-805]. However, with the augmented WATS approach, besides the fact that you can sample a larger surface area, the use of an abrasive brush can pick up tissue and epithelial cells, and the 3D computeraided algorithm selects the most abnormal cells to present to a pathologist. old SNARE Versus Hot SNARE Polypectomy for the Complete Resection of 5-9 mm Sized Colorectal Polyps; a Randomized Controlled Trial (Kim HS, et al; abstract 373)

C

‘Brush biopsy is an interesting concept that has been tried in the past. It is simple to perform; it can be passed through the channel of the endoscope; and if you move the brush around the suspected segment, you can theoretically sample a larger surface area than with forceps biopsy.’

—Prateek Sharma, MD

This prospective trial compared cold snare polypectomy (CSP) and hot snare polypectomy (HSP) for the removal of flat or sessile colorectal polyps between 5 and 9 mm in diameter. Researchers randomized 203 patients with these types of polyps to undergo polypectomy with one of the techniques, yielding a total of 213 excised polyps that were a mean 6.4 mm in size. Following polypectomy, researchers conducted forceps biopsy of adjacent tissue and identified any residual polyp tissue. They also compared the extent of bleeding in the two snare approaches.

The investigators found that HSP completely removed 92.2% of polyps, compared with a 79.1% complete resection rate for CSP (P=0.012).

P Multivariate analyses revealed that CSP increased the risk for incomplete resection by nearly three times (odds ratio [OR], 2.935;

95% confiden nce interval [CI], 1.2208-7.130; P=0.017). Serraated polyps P also were more likely to be incompletely reesected, the investigators found (OR, 5.348; 95% CI, 2.31812.336; P<0 0.001).

Neither approaach was associated with h significant bleeding.

Dr. Sharma: When faced with small colon polyps between 5 and 9 mm, clinicians use either hot or cold snare. Some clinicians prefer cold snare, since it avoids any minor complications associated with the use of cautery and electric current necessary for hot snare. To date, however, research has not yielded definitive findings on whether these two techniques are comparable when it comes to removal of colon polyps.

In this randomized controlled trial, Korean investigators demonstrated that hot snare polypectomy completely resected significantly more polyps than cold snare. The findings suggest that the preferred approach for polypectomy of colon polyps should be to use hot snare, unless there are contraindications to employing this method.

See article on page 1 for more. evised Classification of Low Grade Dysplasia (LGD) in Barrett’s Esophagus (BE): Time to Rethink the Role of LGD as a Risk Stratification Strategy in BE (Vennalaganti P, et al; abstract 856) Researchers at two tertiary referral centers in the United States studied the degree of interobserver agreement in the diagnosis of low-grade dysplasia (LGD) in patients with BE. They asked three experienced gastrointestinal pathologists to examine 79 slides from patients with BE who had varying degrees of dysplasia. Before evaluating the slides, the pathologists came to a consensus regarding the histopathologic criteria they would use for a diagnosis of LGD, LGD with predominant inflammatory features, LGD with predominant dysplastic features, high-grade dysplasia (HGD) and nondysplastic BE. The researchers rated the pathologists’ interobserver agreement using kappa values ranging from 0 to 1, where a value of 1 indicated perfect agreement and a value of 0 represented agreement due to chance. The pathologists also rated their confidence in each diagnosis.

The researchers found a moderate degree of interobserver agreement for all diagnoses, with a kappa score

R

see Best of DDW, page 12

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Best of DDW continued from page 10

of 0.44 (95% CI, 0.35-0.54). When they looked at individual diagnoses, the investigators found a kappa score of 0.030 for diagnoses of LGD with predominant inflammatory features (95% CI, –0.042 to 0.133) and 0.040 for diagnoses of LGD with predominant dysplastic features (95% CI, –0.159 to 0.108). They also found a kappa score of 0.44 for HGD diagnoses (95% CI, 0.28-0.61), 0.20 for LGD (95% CI, 0.04-0.42) and 0.24 for diagnoses of nondysplastic BE (95% CI, –0.08 to 0.56). Interobserver agreement was higher when pathologists were more confident of their diagnoses, the investigators reported.

Dr. Sharma: As we’re not able to define LGD appropriately, making a clinical judgment on how to treat LGD remains a dilemma. Previous studies have shown that even in the hands of experienced pathologists, interobserver agreement in diagnosing LGD is low, with a kappa value as low as 0.2. The variability in diagnoses—and by default, in progression rates—has led to differing opinions regarding the clinical management of Barrett’s esophagus patients with LGD. Some researchers cite a low risk for progression to cancer and recommend following these patients through surveillance programs, while other investigators advocate for endoscopic ablation of LGD, since they see a higher rate of progression from LGD to cancer [see for example, Gastroenterology l 2011;141:1179-1186].

In this study, investigators enrolled a group of expert gastrointestinal pathologists and asked them to define and refine their LGD diagnostic criteria. Because one factor that makes diagnosing LGD difficult is the presence of inflammatory cells, the pathologists subdivided LGD into predominantly inflammatory or predominantly dysplastic features. Despite this subclassification, these expert pathologists had a low rate of agreement, with a poor kappa value that ranged from 0.1 to 0.2.

Dr. Sharma reported receiving grant support from Cook Medical, Olympus Inc., and NinePoint Medical Inc.

Randy S. Longman, MD, PhD Assistant attending physician at NewYork-Presbyterian Hospital Assistant professor of medicine at Weill Cornell Medical College New York City

he Treatment-Naïve Microbiome in EarlyOnset Crohn’s Disease (Gevers D, et al; abstract 5095)

T

Researchers at 28 centers in the United States and Canada collected mucosal tissue samples from 447 children, aged 3 to 17 years, with new-onset Crohn’s disease (CD) who had not yet received treatment. They also collected similar samples from 221 matched controls without inflammatory conditions.

Using gene sequencing technologies, the researchers analyzed the microbial populations in the samples. They

found both increased and decreased population sizes of a variety of bacteria in children with CD. Enterobacteriaceae, Pasteurellaceae, Veillonellaceae and Fusobacteriaceae were in greater abundance, and Erysipelotrichales, Bacteroidales and Clostridiales were less prevalent. The researchers also found that these trends in microbial populations were more pronounced in patients with previous exposure to antibiotics.

‘As we’re not able to define LGD appropriately, making a clinical judgment on how to treat LGD remains a dilemma.’

—Prateek Sharma, MD

Dr. Longman: Distinct alterations in the intestinal microbiota have long been associated with IBD [inflammatory bowel disease]—and in particular with Crohn’s disease—but the role of these microbiota in the emergence of disease remains unclear. Several notable studies have used high-throughput sequencing technology to define key changes in the intestinal microbiota, but the majority of these studies have included patients with varying duration of disease who were exposed to a variety of therapeutic regimens [see for example, Frank D, et al. PNAS 2007;104:13780-13785; Qin J, et al. Nature 2010;464:59-65].

This pioneering work by Gevers et al examined the microbiome of patients with new-onset, treatment-naive Crohn’s disease and revealed several new microbial biomarkers of treatment-naive Crohn’s disease, suggesting that identifying specific mucosal-associated microbiota may be useful diagnostically. Moreover, the amplification of ‘dysbiosis’ observed in patients exposed to antibiotics reflects the association between disease onset and antibiotic exposure that we see clinically.

Randomized, Placebo Controlled Trial of Fecal Microbiota Therapy in Active Ulcerative Colitis (Moayyedi P, et al; abstract 5220) Researchers enrolled 63 patients with active ulcerative colitis (UC) to participate in this randomized, placebo-controlled trial of fecal microbiota therapy (FMT). Inclusion criteria were a Mayo score of 4 or higher and an endoscopic Mayo score of at least 1; a negative Clostridium difficile test; stable disease; and no use of antibiotics within 30 days of study entry. Patients in the FMT and placebo groups had similar clinical characteristics: 45% had pancolitis, 42% were receiving corticosteroids during the study, 19% were receiving immunosuppressive agents and 9% were undergoing treatment with biologics.

Both FMT and placebo were administered by a 50 mL enema once weekly for six weeks. Patients underwent flexible sigmoidoscopy at baseline and one week after the end of treatment, and were assessed for endoscopic inflammation and improvements as well as overall clinical remission, which the researchers

A

defined as a Mayo score of 2 or lower and an endoscopic score of 0.

The researchers presented data from 53 of the patients at DDW, including 27 who were randomized to receive FMT and 26 who were given placebo treatment. The findings showed that four FMT recipients (15%) and two placebo controls (8%) achieved clinical remission.

In the FMT group, seven patients (26%) experienced at least a 30% improvement in Mayo scores, compared with eight placebo controls (31%). Neither difference was statistically significant.

In addition, 16 FMT recipients who did not achieve clinical and endoscopic remission reported subjective improvements after treatment, and continued with six to 12 weeks of open-label FMT after the blinded phase. When analyses included these patients’ follow-up experience, clinical remission rates rose to nine patients (33%) in the FMT group (95% CI, 15%-51%; P not significant).

There were no major adverse events attributed to FMT, the investigators reported.

Dr. Longman: While the study by Gevers, et al. offers novel insights into the microbial landscape associated with Crohn’s disease onset, the ability to therapeutically modulate the intestinal microbiota and alter disease activity remains an elusive goal. Randomized controlled trials of probiotics in mild to moderate ulcerative colitis support the potential therapeutic efficacy of this strategy in the ulcerative colitis patient population (Sood A, et al, Clin Gastroenterol Hepatol 2009;7:1202-1209).

‘This pioneering work by Gevers et al examined the microbiome of patients with new-onset, treatment-naive Crohn’s disease and revealed several new microbial biomarkers of treatment-naive Crohn’s disease, suggesting that identifying specific mucosalassociated microbiota may be useful diagnostically.’

—Randy S. Longman, MD, PhD

However, the efficacy of FMT for treatment of inflammatory bowel disease has not been proven, despite the fact that FMT has gained significant popularity for its efficacy in preventing recurrent C. difficile infection and restoring luminal microbial diversity (van Nood E, et al. N Engl J Medd 2013;368:407-415).

In this study, the researchers provide the first randomized controlled trial to assess the efficacy of FMT in UC. While the study size is small and the results failed to meet the primary or secondary end points, these data are a critical step in evaluating the therapeutic potential of see Best of DDW, page 14

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)

14

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Best of DDW continued from page 12

microbial therapy. Factors such as longer duration of therapy, extent of disease and engraftment of donor microbiota may be critical in stratifying those that clinically respond.

L1A Modulates the Different Effect of IL-17 Blockade on Mucosal Inflammation (Wallace LK, et al; abstract 4730) Previous research has shown that

T

treatment with IL-17 blocking agents leads to improvement in some IBD patients and disease worsening in others.

Moreover, a variant of the TL1A gene predicts high levels of IL-17 expression and therefore a higher likelihood of treatment response with IL-17 blockade.

To confirm this relationship, researchers administered one of four types of mousederived cells to colitis-induced mice: wildtype (WT) cells, TL1A cells, IL-7A cells 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.

DRUG INTERACTIONS

intestinal inflammation.

Dr. Longman: Wallace, et al conducted a very elegantly designed study that follows on the heels of a post-hoc analysis of the secukinumab trial for Crohn’s disease by Hueber et al [Hueber W, et al. Gut 2012;61;1693-1700] which failed to meet its primary end point, and also revealed that several single nucleotide polymorphisms (SNPs), including TL1A/ TNFSF15, help robustly stratify clinical response to anti–IL-17A therapy.

Using mouse models of colitis, Wallace, et al showed a clear mechanistic role for IL-17A in TL1A-dependent colitis.

This work offers important insights into future diagnostic strategies that will make our therapeutic arsenal in IBD patients more precise and help us stratify patients, so that the right therapy is given to the right person.

Dr. Longman reported no relevant financial conflicts of interest.

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.

and TL1A cells encoded for a deficiency in IL-17A expression.

The investigators found that mice administered either the TL1A or IL-17A cells alone experienced a worsening of their colitis compared with mice transplanted with WT cells. Moreover, when the combined TL1A/IL-17A-deficient A cells were administered, colitis improved, confirming that IL-17A blockade in the presence of the TL1A gene reduces

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

Brian E. Lacy, PhD, MD Professor of Medicine Geisel School of Medicine Chief of the Section of Gastroenterology and Hepatology Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire

luxadoline for the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome: Results of 2 Randomized, Double-Blind, Placebo-Controlled Phase 3 Clinical Trials of Efficacy and Safety (Lembo AJ, et al; abstract 929d)

E

In two double-blinded Phase II trials, 2,428 patients with Rome III–defined diarrhea-predominant irritable bowel syndrome (IBS-D) were randomized to receive 26 weeks of either 75 or 100 mg eluxadoline, a locally active, mixed mu-opioid receptor agonist/delta-opioid receptor antagonist, or a placebo.

Two-thirds of study participants were women, and the mean age was 45 years.

Pooled findings showed that 12and 26-week rates of composite clinical response (≥30% improvement in abdominal pain for at least half of the study days and significantly improved

DDW 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

stool consistency) were greater in both treatment groups than in placebo controls: 26.2% and 26.7% for eluxadoline 75 mg; 27% and 31% for eluxadoline 100 mg; and 16.7% and 19.5% for placebo (P<0.001 for both eluxadoline doses vs. placebo).

‘Given the prevalence of IBS-D and the dearth of approved therapies, other

constipation or, much less commonly, ischemic colitis.

The study by Lembo and colleagues was designed to meet both FDA and EMA [European Medicines Agency] end points, and the results showed that the 100 mg dose of eluxadoline improved global symptoms of IBS-D, quality of life, and also individual symptoms of diarrhea and urgency, in both men and women. The overall therapeutic gain was approximately 10%, translating to a number-needed-to-treat of 10. Although the 75 mg dose yielded

similar efficacy results, these did not meet EMA end points in one of the two studies.

Although there was no difference in abdominal pain between placebo and eluxadoline at the 30% improvement level required by the FDA, it is worth noting that there were differences at higher levels of pain. This indicates that IBS-D patients with more severe pain are more likely to experience reductions in symptoms of pain than those with less severe abdominal pain.

Although the safety profile of

15

eluxadoline seems favorable, five patients developed pancreatitis during the study, which raises the possibility that eluxadoline could have led to sphincter of Oddi dysfunction.

Overall, these results are clinically important as no medication is approved for the treatment of IBS-D in men, and eluxadoline has the potential to improve symptoms without the risk for uncommon, but potentially serious, side effects of severe constipation or ischemic colitis that are sometimes seen with alosetron. see Best of DDW, page 16

therapeutic options are needed.’

—Brian E. Lacy, PhD, MD

Notably, non-pooled findings showed that the 26-week composite clinical response rate in the 75 mg eluxadoline group in one of the trials was not greater than that in controls (23.4% vs. 19%; P=0.112).

P At week 26, 36.8% and 23.9% of eluxadoline 100 mg and controls, respectively, experienced significant improvements in stool consistency (P<0.001), and 53.7% and 49.2%, respectively, reported adequate relief during half or more of the study period (P≤ P 0.011). A numerically, but not significantly, greater number of eluxadoline 100 mg recipients than controls had 30% or better improvement in abdominal pain during half or more of treatment days.

At week 26, more eluxadoline 100 mg patients reported significantly fewer daily bowel movements, more urgencyfree days, better IBS-D global symptoms and quality of life scores, than controls (P<0.05 for all measures vs. placebo).

Rates of clinical efficacy were similar among men and women who received treatment.

Common adverse events included constipation (7.4% and 8.3% for eluxadoline 75 and 100 mg, respectively, vs. 2.4% for placebo), nausea (7.8% and 7.3% vs.

4.8%) and abdominal pain (5.7% and 6.9% vs. 3.8%).

Dr. Lacy: Given the prevalence of IBS-D and the dearth of approved therapies, other therapeutic options are needed. At the moment, alosetron [Lotronex; Prometheus Therapeutics and Diagnostics] is the only approved treatment for IBSD, but it is approved only for women.

Prescribing of alosetron is also limited by the requirement for participation in a risk mitigation program because of an associated increased risk for significant

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PROMETHEUS, the Link Design, For the person in every patient, ANSER, and the ANSER design mark are trademarks or registered trademarks of Société des Produits Nestlé S.A. Vevey, Switzerland. ©2013 Société des Produits Nestlé S.A. Vevey, Switzerland. All rights reserved. ADA13044 08/13 A Nestlé Health Science Company Prometheus diagnostic services provide important information to aid in the diagnosis and management of certain diseases and conditions. How this information is used to guide patient care is the responsibility of the physician.

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DDW 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Best of DDW continued from page 15

fficacy and Safety of Linaclotide in Chronic Idiopathic Constipation Patients with Abdominal Bloating: Phase 3b Trial Results (Lacy BE, et al; abstract Sa2008) In this Phase 3b, double-blinded trial, 483 patients with chronic idiopathic constipation (CIC) and bloating as a prominent symptom were randomized to receive either 145 or 290 mcg of linaclotide or a placebo once daily for 12 weeks. Throughout the study, participants recorded the daily number of spontaneous bowel movements (SBMs) and complete SBMs as well as stool consistency, straining, bloating, discomfort, pain, cramping and fullness. At baseline, patients had a mean bloating score of 5 or greater on an 11-point scale.

At the end of 12 weeks, patients in the linaclotide 145 and 290 mcg groups experienced a mean reduction in bloating scores of 34.9% and 34.3%, respectively, compared with baseline. Patients receiving placebo reported a 22.7% mean reduction in bloating scores at the end of the trial (P<0.05).

A subanalysis showed that 40.5% and 43.4% of the low- and high-dose linaclotide groups, respectively, reported at least a 30% reduction on the bloating scale relative to baseline for at least six of the 12 weeks, compared with 29.2% of placebo patients (P<0.05). Moreover, significantly more patients who received linaclotide reported reduced bloating within one week of treatment, compared with the placebo group.

E

‘Although the precise mechanism by which linaclotide improves bloating is unknown, this may reflect a combination of improvements in visceral sensitivity and intestinal transit.’

—Brian E. Lacy, PhD, MD

During at least nine of the 12 weeks, 15.7% and 16.4% of patients given low- or high-dose linaclotide, respectively, reported at least three complete SBMs weekly along with at least one complete SBM weekly relative to baseline. In contrast, 7.6% of placebo recipients met these response criteria (P<0.05 for both treatment groups vs. placebo).

Safety results showed that the most common adverse event was diarrhea, which occurred in 5.9% and 16.9% of linaclotide 145 and 290 mcg recipients, respectively, and in 2.3% of placebo patients.

Dr. Lacy: At present, there is no FDA-approved treatment for abdominal bloating, which is a highly prevalent disorder and one that is commonly reported by patients with symptoms of CIC and IBS. The etiology of abdominal bloating is incompletely understood. It is multifactorial and it likely differs from patient to patient. Potential causes include visceral hypersensitivity, abnormal intestinal gas transit, impaired evacuation of rectal gas, excess

fermentation, an abnormal abdomino-diaphragmatic reflex and disorders related to the gut microbiota.

This novel study assessed multiple end points in patients with CIC and prominent abdominal bloating, in contrast to the two prior pivotal studies that more narrowly evaluated the efficacy and safety of linaclotide for the treatment of CIC and that led to its approval for the treatment of CIC (Lembo AJ, et al. N Engl J Med 2011;365:527-536). Similar to those studies, in this trial linaclotide led to significant improvements in multiple symptoms of constipation and, more importantly, both doses of linaclotide significantly improved symptoms of bloating, compared with placebo.

Although the precise mechanism by which linaclotide improves bloating is unknown, this may reflect a combination of improvements in visceral sensitivity and intestinal transit. ffects of Low-FODMAP and Gluten-Free Diets in Irritable Bowel Syndrome Patients.

A Double-Blind Randomized Controlled Clinical Study (Piacentino D, et al; abstract 374) Italian researchers randomized 20 patients with IBS to follow a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, another 20 individuals with IBS to follow a combined low-FODMAP/gluten-free diet, and an additional 20 patients with IBS to eat a normal diet, all for four weeks.

Patients rated symptoms of bloating, abdominal distension and abdominal pain throughout the study.

According to the investigators, patients in both dietary intervention groups experienced significant improvements in bloating, abdominal distension and pain relative to baseline. Patients following only the low-FODMAP diet reported slightly greater improvements in symptoms than the combined low-FODMAP/ gluten-free patients, although this was not statistically significant. Although there were “slight” improvements in IBS symptoms in the control group, these were not significant, the researchers found.

E

Dr. Lacy: Nearly two-thirds of IBS patients believe that diet plays some role in the generation of their symptoms. However, understanding the role of diet in IBS is complicated. Common symptoms of IBS, such as bloating, distension, cramps, spasms, abdominal pain and diarrhea, could easily represent a food intolerance such as lactose intolerance, or they could just as easily be a manifestation of altered gastrointestinal motility or sensation. As well, because dietary content changes from day to day and symptoms frequently reflect past meals rather than the most recently ingested meals, it is difficult to accurately relate specific symptoms to specific foods.

Nonetheless, both patients and clinicians have expressed significant interest in dietary interventions for the treatment of IBS, because dietary interventions are considered safe in the short term, and generally are reasonably inexpensive.

In the current trial, patients with all subtypes of Rome III–defined IBS randomized to a low-FODMAP diet, either with or without gluten, noted a significant improvement in symptoms of bloating, abdominal distention and abdominal pain. Interestingly, the low-FODMAP/gluten-free diet group did

‘This study adds to a growing body of literature showing that a low-FODMAP diet can improve symptoms of bloating, distention and pain in IBS patients. Given its safety and reasonable cost, this diet should be employed routinely in the clinic.’

—Brian E. Lacy, PhD, MD

not report improvements in gastrointestinal symptoms above and beyond those reported by the low-FODMAP/normal-gluten diet group.

This may have occurred for several reasons: One possibility is that because this study was limited to four weeks, it did not detect further improvements in symptoms with gluten exclusion that would have only occurred after two to three months of a gluten-free diet. Another possible explanation is that because a low-FODMAP diet already excludes wheat, a significant amount of gluten was already excluded. A third possibility is that dietary interventions may produce only a certain level of improvement and there may be a ceiling effect in terms of symptom improvement, and the use of a low-FODMAP diet, which excludes a large number of foods, may have induced the maximum improvement. Lastly, this was a small study, and a larger study focusing only on IBS-D patients could produce different results.

Overall, this study adds to a growing body of literature showing that a low-FODMAP diet can improve symptoms of bloating, distension and pain in IBS patients.

Given its safety and reasonable cost, this diet should be employed routinely in the clinic.

■ Dr. Lacy has served on the scientific advisory boards for Forest Pharmaceuticals, Furiex Pharmaceuticals, Ironwood Pharmaceuticals, Prometheus Labs and Takeda Pharmaceuticals.

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18

DDW 2014

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Prioritize Prevention To Control C. difficile

BY PAUL BUFANO There is more to Clostridium difficile than just nausea and diarrhea; it is a highly contagious bacterium linked to 14,000 deaths in the United States annually, according to the Centers for Disease Control and Prevention.

With C. difficilee now rivaling methicillin-resistant Staphylococcus aureuss as the most common bacteria to cause health care–associated infections (HAIs), a team of experts has issued updated practice guidelines that encourage hospitals and other acute care settings to implement and prioritize prevention efforts.

The recommendations, which are part of the “Compendium of Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals: 2014 Updates” (Infect Control Hosp Epidemiol 2014;35:455-459), advise creating a multidisciplinary strategy that enlists a broad scope of hospital personnel, including leadership, physicians, pharmacists, and lab and environmental services staff.

The recommendations cite a wide range of tools for controlling HAIs, including promoting appropriate antimicrobial use and stewardship programs, treating infected patients in isolated rooms with proper contact precautions, requiring physicians to wash their hands with soap and water before every patient interaction, cleaning patient rooms and surfaces touched by doctors and patients, and creating reporting and alert systems to document and provide immediate notification of newly diagnosed patients.

Aggressive implementation of these basic measures and improvement of antimicrobial prescribing could result in about a 30% reduction in C. difficilee cases (Br J Clin Pharmacoll 2014;77:896-903; J Hosp Infectt 2013;84:227-234), noted d Erik Dubberke, MD, MSPH, co-lead author of the practice guidelines and director of the Section of Transplant Infectious Diseases at the Washington University School of Medicine, in St. Louis.

“These decreases will occur primarily at the hospitals whose C. difficilee infection

(CDI) incidence is above the median,” Dr. Dubberke said. However, “more studies are needed to determine how to optimally reduce CDI incidence beyond this point, such as what to do with asymptomatic carriers and the potential impact of vaccines being developed.”

have the highest quality of data to support them” and have declined significantly in many hospitals, he noted (PLoS One 2014;9:e93898), “but there are no C. difficilee prevention [efforts] that have that level of evidence.”

The same is true for surveillance data

and then form a usable plan of action,” Dr. Potoski said. It thus “would be wise” for such institutions to base their CDI control efforts on the new guidelines, he said. “But sometimes it’s the simple things that are the most important. Look at hand hygiene, for example, because it can easily be tracked and implemented. And because it’s not exclusive to C. difficile, you’ll get a lot of bang for your buck.”

In one study, he noted, hand hygiene measures reduced the incidence of several HAIs from 4.8 to 3.3 per 1,000 patientdays (BMJ Qual Saff 2012;21:1019-1026).

Can Robots Prevent CDIs?

‘Medical institutions and hospital administrators have to be willing to spend a little more now [on C. dfficile prevention] to save down the road and help cut back on readmissions and avoidable care.’

—Brian Potoski, PharmD A Team Effort Due to a lack of definitive data, several additional strategies for reducing CDIs were not included in the new guidelines, the authors noted. These include using gowns and gloves by family members and other visitors, prescribing probiotics, using no-touch disinfection technology and restricting the use of gastric acid suppressants.

It is in part because of this lack of high-quality data on optimal prevention methods that rates of CDI have remained high for years, whereas other HAIs have declined, Dr. Dubberke said. “For instance, catheter-associated bloodstream infections

on C. difficile, Dr. Dubberke said. The National Healthcare Safety Network only started collecting data for CDIs a few years ago, he noted, and benchmark data on CDI incidence in the United States have not yet been published.

Because of these limitations, the updated HAI recommendations can serve as a roadmap for institutions that do not have an approach for addressing CDIs, commented Brian Potoski, PharmD, the associate director of the antibiotic management program at the University of Pittsburgh School of Pharmacy. “The resources aren’t there for some hospitals, so it can be difficult to collect all the data

Advances in medical technology also offer hope for improved CDI prevention, including robots designed to kill off and prevent the transmission of pathogens by emitting ultraviolet (UV) light in hospital rooms, Dr. Potoski said. The University of Pittsburgh Medical Center recently implemented such a device, but the frequency of where and when to use it optimally is still to be determined, he noted.

What hass been determined is the overall efficacy of the devices: one study showed that a mobile UV light unit significantly reduced C. difficilee spores on contaminated surfaces in patient rooms (Infect Control Hosp Epidemioll 2011;8:737-742).

Based on such data, “after a [UV-emitting robot] leaves an exposed area, you can be assured that the chance of transmission is significantly [reduced],” Dr. Potoski said.

“Hospital administrators have to be willing to spend a little more now [on such technology] to save down the road and help cut back on readmissions and avoidable care.”

The compendium on HAIs is a result of a collaboration led by the Society for Healthcare Epidemiology of America, the Infectious Diseases Society of America, the American Hospital Association, and the Joint Commission, among others.

■ Dr. Dubberke reported that he has conducted research and/or has consulted for Sanofi Pasteur, Merck, Cubist, Microdermis and Rebiotix. Dr. Potoski had no relevant financial conflicts of interest to disclose.

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Standard Colonoscope

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Limited 170° Field of View

only 7%3. Overall, Fuse enabled this international team of endoscopists to find 76% more polyps after SFV had been used.

How was this achieved? Traditional endoscopes provide endoscopists only a limited forward view (up to 170 degrees) causing them to potentially miss adenomas that hide behind folds.

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Fuse® Colonoscope

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Panoramic 330° Field of View

Adenoma Miss Rate Standard, Forward Viewing (SFV) Colonoscope

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Incremental polyp find rate with Fuse®

To schedule a Fuse experience, call your Endo oChoice sales representative, or the EndoChoice Headquarters, at 888.682.3636 x..5, or email fuse@endochoice.com.

EndoChoice.com/Fuse (1) Rex et al. Gastroenterology, 1997; (2) Siersema et al. World Journal of Gastroenterology, 2012; (3) Gralnek et al. The Lancet Oncology, 2014

20

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

As Patients Turn to Web Communities, Physicians Must Take Notice

BY MONICA J. SMITH BOSTON—Approximately 1.1 billion people have Facebook accounts, and the number of social media sites and users just keeps growing. Whether this trend forges relationships or increases isolation is an ongoing debate, but in the realm of medicine, social media that goes beyond the Yelp-like physician rating sites might enhance the patient experience and benefit physicians and their institutions as well, according to a group of experts who recently addressed the topic at a panel for gastroenterologists.

“As physicians, we can no longer ignore [social media]; we have to understand how patients are wanting to connect with us,” said M. Bridget Duffy, MD, chief medical officer at Vocera Communications, an information technology company that develops mobile communication devices and services for use in health care and other industries.

Dr. Duffy moderated a session on the emergence of social media in medicine at the 2014 GI Roundtable, a conference dedicated to exploring challenges and their solutions for gastroenterology and the field’s future (http://giroundtable.com).

“Historically, we’ve focused on the intervention, but patients want us to connect with them before they arrive at the clinic or hospital. They want us to understand their preferences; they want a personalized plan and a path to their well-being; and they want a connectivity after they leave,” said Dr. Duffy, who has spent the past 20 years researching ways to improve the patient, staff and physician experience.

Dr. Duffy leads the Experience Innovation Network, a group of health care organizations committed to accelerating innovation on patient and staff experience. In addition, Vocera partners with Rock Health, a start-up incubator in San Francisco that mentors and supports medical tech companies dedicated to that goal. Dr. Duffy and her team participate in this mentoring and support, and help connect the companies to providers to test and adopt their novel products and services.

“We need to find technologies and process improvements that create consistent, seamless experiences of care, and that empower and engage patients to be partners in their care,” she added.

Cancer Connect—A Platform for Patients Social media, by definition, refers to the virtual communities and networks in which people generate, distribute and discuss information. Charles Weaver, MD, an oncologist and founder of Cancer Connect—a popular cancer information website—predicts this is how patients will interact with each other from now on. “The question for all of us is how do we become a part of it?

How do we participate, and how do we use it to everyone’s best advantage?”

A pioneer of Internet-based patient education, Dr. Weaver got the idea to add a social media component to Cancer Connect after his elder son developed a rare sarcoma. Treatment required a long commute from their remote home in Sun Valley, Idaho, to the University of Utah Hospital. “I got to experience the fear, anxiety,

confusion and isolation that any parent or patient experiences when they’re diagnosed with a significant illness,” Dr. Weaver said.

Fast forward several years, and Dr. Weaver found his sons engaged on Facebook one afternoon when they should have been doing homework. He was on the verge of scolding them when the younger one said, “‘Think if there was a Facebook just for cancer patients. Wouldn’t it be neat if they could connect with each other? They wouldn’t have to go through what [my brother] went through in a small town,’” Dr. Weaver recalled.

His older son chimed in, “That would have been really helpful.” He had, in fact, already been using Facebook to locate and connect with other kids who had cancer.

The next day, Dr. Weaver called his programmers to discuss creating a Facebook-type of application just for cancer patients. Now, a little more than two years after Cancer Connect added its social media component, 52,000 people have registered to participate. Some 9,000 patients visit the physician-moderated virtual communities every month.

Users “are looking for validation of what their physician told them, for translations of what their physician said, and for support from others who have gone through their experience,” Dr. Weaver said. They “also told us that it was very important for them to give back.

In fact, the patients we surveyed rated that as the most important aspect.”

Private-Label Communities Cancer Connect’s social media platform is free and open to any patient who wants to join, but it also is used by practices as a virtual home base for their patients.

Dana-Farber Cancer Institute, Memorial Sloan-Kettering Cancer Center and Fred Hutchinson Cancer Research Center are just a few of the institutions that use Cancer Connect to supplement supportive care of their patients and patients’ families.

For such centers and practices, creating privatelabel communities has several advantages. On a practice’s website, Cancer Connect is part of the patients’ experience as it relates to that particular institution, an approach that may improve patient retention, increase patient referrals and enhance patient satisfaction, Dr. Weaver said.

The model works fairly simply. For example, from Dana-Farber’s home page, a click on “My Dana-Farber” brings the visitor to an invitation to join their online cancer community. “It explains the rules of the community and how you participate in it. From that point on, the patient never leaves the experience of your brand and what you’re providing,” Dr. Weaver said.

Once a patient becomes part of Dana-Farber’s online community, he or she can participate in both local and national conversations. They can choose to interact only with Dana-Farber patients, with patients from other centers using Cancer Connect, or both.

“The beauty of this is that for [cancers] that are common, you can build a community on your own website because you’ll have enough patients to benefit from the experience,” Dr. Weaver said. “With rare conditions, even a place like Dana-Farber won’t have a critical mass of patients who can support each other,

but by sharing the community with other large centers, you aggregate patients so they can get the support they need.”

This need, of course, varies from one patient to another. Some visit Cancer Connect communities looking for an answer to a specific question or problem, whereas others desire a stronger connection.

“The ones who want a deeper relationship tend to find others who are also looking for a deeper level,” Dr. Weaver said. “People initially join up because they want support and information. Those who stay want to share information and provide support, to give back,” he noted.

GI Connection, a New Kid on the Block When Klaus Mergener, MD, PhD, MBA, of Digestive Health Specialists in Tacoma, Wash., learned about Cancer Connect and its offshoot, The RA Connection (www.theraconnection.com), for people with rheumatoid arthritis, he quickly envisioned the utility of the concept for gastroenterology.

“We have a huge number of chronic diseases,” Dr. Mergener said, from irritable bowel syndrome to cirrhosis. “If we can get a few hundred [GI] patients to start talking and connecting about their illnesses, I think that might be very useful.”

He proposed the idea of a GI-specific platform to Dr. Weaver, and the two worked together to develop GI Connection, which is scheduled to go live this summer (www.thegiconnection.com). “GI and cancer have a couple of things in common,” Dr. Weaver said. “The most important is that both specialties deal with chronic conditions, and people with chronic conditions want to stay connected.

“Also, they are both subspecialties that get their patients from someplace else—you’re typically not diagnosed with cancer by an oncologist,” Dr. Weaver continued. “This gives the subspecialties an opportunity to create communities to aggregate around the experience at their center.”

21

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

QR codes. “Charles [Weaver] tells me that once you get up to 100 or 200 patients, involvement snowballs by word of mouth,” he said.

Crohnology

Aside from patients with chronic GI diseases, those worried about an upcoming procedure might take comfort in the support of others, too. “Connecting with someone who has had a colonoscopy or multiple colonoscopies and can tell you that it’s OK is very powerful,” Dr. Weaver said. “Sorry to say, but patients put a lot more value on one-to-one interactions with other patients than with health care providers.”

Before the launch of GI Connection, Dr. Mergener began raising awareness among practices that he hopes will be early adopters, mentioning the site to patients and increasing visibility with business cards and scannable

Older women who take proton pump inhibitors (PPIs) are at substantially increased risk for falls and broken bones, but a new study suggests that the drugs do not affect the skeleton. Instead, the study found that postmenopausal women who use the reflux medications may experience side effects, such as dizziness and instability, that make them unsteady on their feet.

Researchers in Australia looked at fracture and fall risks, as well as skeletal integrity, in postmenopausal women who had been taking PPIs for at least one year.

The drugs were associated with

As Sean Ahrens took the podium at the GI Roundtable to discuss Crohnology, the platform that he developed to capture the experiences of patients with inflammatory bowel disease (IBD), he acknowledged that physicians are his toughest audience.

“Partly, I think that’s because there is a wave, a front, of patients connecting back toward each other; the case I want to make to you is toward [the acquisition of ] medical knowledge,” Mr. Ahrens said. “We are moving from the era of traditional media, where people are receiving information, to one in which they are contributing to the knowledge source.”

Mr. Ahrens was 12 years old when he experienced the onset of Crohn’s disease. Now 28, he has gone through a host of different treatments, or as he thinks of them, experiments. “These include physicians prescribing different medications, and me doing things like changing my diet,” he said.

Mr. Ahrens began to develop Crohnology as a college student, but the concept for the site gelled a few years later during one of his more unusual self-experiments.

Remicade ( Janssen Biotech; infliximab) was no longer controlling his symptoms, but he feared making the leap to Humira (AbbVie; adalimumab). Under the supervision of a physician who thought the novel therapy probably wouldn’t hurt him, Mr. Ahrens started inoculating himself with a pig whipworm solution he’d ordered from a company in Germany.

“During this treatment, it occurred to me that the very least I could do, as a favor to humanity, was leave a paper trail so that others could learn from this experiment,” he said.

It became clear about two-thirds of the way through that the pig whipworm therapy wasn’t working, as Mr. Ahrens’ symptoms remained severe. For the sake of his health, he adopted a specific carbohydrate diet, although he knew that it would compromise the quality of the

roughly doubled risks for falls and fractures (P=0.006 and P=0.007, respectively).

Although PPIs did not affect bone structure, women on PPIs were significantly more likely to report a variety of falling-related measures. These included fear of falling both indoors and outdoors, dizziness and numb feet. They also scored worse than nonusers on the Timed Up and Go and Romberg’s tests, which assess steadiness and mobility.

“Similar to previous studies, we identified an increased fracture risk in subjects on long-term PPI therapy,” the authors, led by Richard

data. But the experience further supported his theory that patients are vast silos of information, and that there should be a system to capture those experiences and learn from them, instead of dismissing each patient’s experience as anecdotal.

In 2011, Rock Health selected Crohnology as part of its inaugural class of start-ups to nurture. The support solidified development of Crohnology’s website (www. crohnology.com) and mobile platform. To date, the network has about 5,500 patient contributors with irritable bowel disease, representing 70 different countries.

As for that physician audience? Reactions have been mixed. “On the whole, physicians like the concept of connecting patients and giving them emotional and social support,” Mr. Ahrens said. “But they’re also generally of the school of thought that medical knowledge needs to be very carefully collected and dispensed inside the physician system, through rigorous clinical trials.”

He views Crohnology as a model that can accrue useful knowledge without the staggering costs of clinical trials.

Catching Up to the Consumer Ironically, although the increasing presence of technology has been criticized for creating barriers between physicians and patients, in the right hands, social media technology may be a way to start tearing down those walls, Dr. Duffy said.

“I think there is a way that technologies can be humanizing if you pick the right ones,” she said. “That’s what patients are doing through sites like Cancer Connect and Crohnology, using technology to create human connections with others who have conditions like theirs.”

One of her concerns with these technological innovations, however, is that physicians, who historically have been a bit recalcitrant with social media in their profession, are falling behind what their patients want and need.

“Doctors on the delivery side have to figure out how to find those resources that help restore people to a full life versus just a great technical outcome,” Dr. Duffy said. “And we have to move faster to catch up with where consumers are going.”

■

L. Prince, MD, of the University of Western Australia, in Perth, wrote.

“This increase in fracture risk in elderly women, already at high risk of falling, appears to be mediated via increased falls risk and falling rather than impaired bone

structure, and should be carefully considered when prescribing longterm PPI therapy.”

The researchers reported their findings online May 13 in the Journal of Bone and Mineral Research.

— Adam Marcus

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Improving Quality Outcomes: Assessing Factors Related to Failed Colonoscopy Brooks D. Cash, MD, AGAF, FACG, FASGE Professor of Medicine College of Medicine University of South Alabama Mobile, Alabama

Introduction Among clinicians performing colonoscopy for colorectal cancer (CRC) screening, failure to complete the procedure remains a significant concern.1 Large-scale reviews have shown rates of incomplete colonoscopy— defined as the inability to achieve cecal intubation and mucosal visualization effectively1,2—between 10% and 20%,1 well over targets recommended by the US Multi-Society Task Force on Colorectal Cancer.3 Thus, it is important for clinicians to understand the numerous modifiable physician- and patientrelated factors that can lead to colonoscopy failure in order to reduce its incidence and provide patients with improved outcomes.

Multiple Factors Related to Incomplete Colonoscopy Because effective colonoscopy depends on several events occurring successfully before and during the procedure,4 the reasons for incomplete colonoscopy can vary. Sidhu et al audited all colonoscopies performed between April 2005 and 2010 at the Royal Liverpool University.5 Of 8,910 colonoscopies, 693 were incomplete (7.8%; 58% women; mean age, 61 years). Reasons for incomplete colonoscopy included inadequate bowel preparation (24.8%), patient discomfort (22.2%), obstruction (17.2%), presence of diverticular disease (4.3%), adverse events (0.4%), and other (3.2%) or unrecorded (16.9%) causes.5

Bowel Preparation As illustrated by the aforementioned study, insufficient bowel prep remains a major contributor to incomplete colonoscopy.6 According to a consensus document from 3 leading gastrointestinal societies on bowel preparation for colonoscopy, inadequate bowel preparation can result in failed detection of prevalent neoplastic lesions and has been linked to an increased risk for procedural complications.6 Various studies and reviews have attempted to identify predictors of poor colonoscopy preparation6-8 and have found that inadequate bowel preparation is more

22

common in patients with the following characteristics: non–English-speaking, Medicaid insurance, single and/or inpatient status, polypharmacy, obesity, increased age, male gender, and comorbidities such as diabetes mellitus, stroke, dementia, and Parkinson’s disease.6-8 Additionally, procedure-related factors, such as poor adherence to preparation instructions,6 erroneous timing of bowel purgative administration,8 and longer appointment wait times for colonoscopy,7 were associated with poor bowel preparation. Nevertheless, Hassan et al found that awareness of these and other predictors of inadequate bowel preparation can be used to facilitate effective, targeted bowel preparation improvement programs in order to reduce the risk for incomplete colonoscopy.7

Disease-Related Factors A “difficult” colonoscopy, where reaching the cecum is challenging or not possible, may be related to anatomic and/or diseaserelated factors.9 The most common patientrelated causes of difficult colonoscopy are endoscope loops or angulation in the colon, limiting effective advancement of the colonoscope. Similarly, diverticular disease may increase the inability to achieve an adequate preparation, possibly due to stool retention in diverticula and/or myochosis which can limit insufflation, making it more

challenging to confidently visualize the colonic lumen (Figure).9

Technical Performance Loops and angulations also can test the experience and skill of the endoscopist to navigate the colon successfully.9 The overall technical skill of the endoscopist, which is dependent on manual dexterity and cumulative experience, is a major determinant of colonoscopy success. Not surprisingly, Shah et al reported that endoscopists who performed a higher volume of colonoscopies experienced fewer incomplete procedures, whereas endoscopists in the lowest volume quintile had incomplete colonoscopy rates of nearly 29%.2 Interestingly, the same study demonstrated that rates of incomplete colonoscopy were higher in office settings, although the authors concluded this finding might be explained by increased patient discomfort due to reduced levels of sedation used in this setting.2 Other studies have reviewed timing aspects related to endoscopist performance.

Sanaka et al found that even after accounting for bowel preparation, incomplete colonoscopies were more common when performed in the afternoon.10 The potential for variation in colonoscopy performance has been judged to be an important issue that led to the recommendation by national

Difficult colonoscopy

Redundant colon

Overtubes

Variable stiffness colonoscope

Pediatric colonoscope

Upper endoscope

Double balloon enteroscope

Figure. Approach strategy in the difficult colon.

Adapted from reference 9.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Effect on Patients and Practice The consequences of incomplete colonoscopy are potentially profound and widespread. For patients undergoing diagnostic colonoscopy, who have an increased risk for organic gastrointestinal disease, uncertainty and delay in diagnosis can be extremely stressful. Furthermore, some patients who experience unsuccessful colonoscopy might not be willing to undergo a repeat attempt at the procedure. For these patients, failure to detect advanced adenomas or early CRC could lead to poor outcomes and significant risk for morbidity and mortality. Even in patients who do undergo subsequent colonoscopy, a second procedure involves re-exposure to the risk for procedure-related adverse events.

For clinicians, the effects of incomplete colonoscopy can mirror those for patients.

Unsuccessful colonoscopy is essentially as costly as well as time- and resource-consuming (ie, patient and physician time, staff and office time, equipment and drug availability) as successful colonoscopy without the same benefits generated by a successful procedure, such as accurate diagnosis, treatment, and primary and secondary prevention of colon cancer.2 Additionally, as colonoscopy quality measurement becomes more compulsory for practices,11 incomplete colonoscopy could adversely affect practice quality benchmarking.

Costs

Difficult sigmoid Water immersion method

Shortening basic skills

agencies for continuous colonoscopy quality improvement monitoring and initiatives to ensure that clinicians who perform colonoscopy remain educated about optimal preparation and procedural techniques.3

Cap-assisted colonoscopy

In this evolving era of value-based care, considerable uncertainty exists as to whether payors will continue to reimburse health care providers for unsuccessful colonoscopies, particularly if the cause of procedural failure is deemed to be preventable.6 As reimbursement often is based on the depth of cecal intubation, incomplete colonoscopy may affect how procedures are billed and coded; incorrect billing and coding could result in an audit of an office’s billing practices.2 Also, if incomplete colonoscopies are not reimbursed, the payment responsibility for the original procedure and subsequent procedures may transfer to the patient.7 Therefore, there is a financial incentive for clinicians to perform complete, high-quality colonoscopy as often as possible.2,6

Supported by

Multiple factors contribute to the small but significant risk for colonoscopy failure, which can have a disproportionate effect on patient outcomes and health care costs. It is incumbent on endoscopists to identify systematic reasons for colonoscopy failure within their individual practices and to address these obstacles in a proactive manner to improve patient outcomes and quality indicators, reduce costs, and maintain reimbursements.

References 1. Mitchell RM, McCallion K, Gardiner KR, et al. Successful colonoscopy; completion rates and reasons for incompletion. Ulster Med J. 2002;71(1):34-37.

2. Shah HA, Paszat LF, Saskin R, et al. Factors associated with incomplete colonoscopy: a population-based study. Gastroenterology. 2007;132(7):2297-2303.

3. Rex DK, Bond JH, Winawer S, et al; U.S. Multi-Society Task Force on Colorectal Cancer. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol.

2002;97(6):1296-1308.

4. Rex DK, Petrini JL, Baron TH, et al; ASGE/ACG Taskforce on Quality in Endoscopy. Quality indicators for colonoscopy. Am J Gastroenterol.

2006;101(4):873-885.

5. Sidhu S, Geraghty J, Karpha I, et al. Outcomes following an initial unsuccessful colonoscopy: a 5-year complete audit of teaching hospital colonoscopy practice. Presented at 2011 British Society of Gastroenterology Annual General Meeting; March 14-17, 2011; Birmingham, United Kingdom.

6. Wexner SD, Beck DE, Baron TH, et al; American Society of Colon and Rectal Surgeons; American Society for Gastrointestinal Endoscopy; Society of American Gastrointestinal and Endoscopic Surgeons. A consensus document on bowel preparation before colonoscopy: prepared by a task force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Gastrointest Endosc. 2006;63(7):894-909.

7. Hassan C, Fuccio L, Bruno M, et al. A predictive model identifies patients most likely to have inadequate bowel preparation for colonoscopy. Clin Gastroenterol Hepatol. 2012;10(5):501-506.

8. Nguyen DL, Wieland M. Risk factors predictive of poor quality preparation during average risk colonoscopy screening: the importance of health literacy. J Gastrointestin Liver Dis. 2010;19(4):369-372.

9. Jung Y, Lee SH. How do I overcome difficulties in insertion? Clin Endosc. 2012;45(3):278-281.

10. Sanaka MR, Shah N, Mullen KD, et al. Afternoon colonoscopies have higher failure rates than morning colonoscopies. Am J Gastroenterol.

2006;101(12):2726-2730.

11. Rathgaber SW, Wick TM. Colonoscopy completion and complication rates in a community gastroenterology practice. Gastrointest Endosc.

2006;64(4):556-562.

Disclosures Dr. Cash reported that he is a consultant for and has received speaker fees from Forest, Ironwood, Salix, and Takeda, and is a consultant for Prometheus.

Sample Case Study: A 64-Year-Old Man Presenting for Polyp Surveillance 10 Years After Screening Colonoscopy

A

patient with a history of an 8-mm sessile adenoma in the ascending colon identified on index colonoscopy 10 years ago presents for surveillance colonoscopy. Diffuse diverticulosis also was identified during the index examination. The patient’s only gastrointestinal complaint was 10 years of chronic constipation (infrequency, straining, and a sense of incomplete evacuation). He denied abdominal pain or hematochezia, and stated that he maintained a high-fiber diet. His medical history was notable for non–insulin-dependent diabetes mellitus, osteoarthritis, and benign prostatic hyperplasia. He was taking metformin 2,550 mg daily, lubiprostone 24 mcg twice daily, psyllium 2 tbs daily, and ibuprofen 800 mg as needed. He had no history of abdominal surgery. His physical examination was unremarkable and recent laboratory values were within normal limits.

The patient was instructed to consume 4 L of polyethylene glycol electrolyte lavage solution the night before the colonoscopy. He arrived for his colonoscopy at the appointed time. When asked about his experience with the preparation, the patient said that he was unable to complete the entire preparation due to nausea and that it “didn’t seem to take.” Upon intubation, liquid and semi-solid stool that obscured the colonic mucosa was encountered. Aggressive irrigation permitted better visualization of the distal colon, but the colonoscope suction channel repeatedly clogged with effluent and more solid stool was encountered proximally, prohibiting safe advancement of the colonoscope beyond the sigmoid colon. The bowel preparation was deemed “inadequate” and the procedure was aborted.

The patient was instructed on various methods to improve the preparation for a repeat colonoscopy, including using a lower volume and split-dose regimen.

The patient was given an early morning appointment for a repeat attempt at screening colonoscopy in 1 month. For the repeat colonoscopy, his preparation involved using a low-volume sodium sulfate–based preparation in a split-dose fashion, with the second dose consumed 5 hours before the scheduled appointment. He arrived at the appointed time, and reported being able to follow the instructions and complete the preparation. The second preparation was deemed “excellent,” and two 10-mm tubular adenomas were identified and successfully removed from the ascending and transverse colon.

Discussion Diagnostic accuracy and therapeutic safety of colonoscopy depends, in part, on the quality of the colonic cleansing or preparation. The ideal preparation for colonoscopy should reliably empty the colon of all fecal material in a rapid fashion with no gross or histologic alteration of the colonic mucosa, and should not cause any patient discomfort or shifts in fluids or electrolytes.

The preparation should be convenient, tolerable, and inexpensive. It is important for patients to be educated and engaged in the preparation process. Patient counseling along with written instructions that are simple and easy to follow should be provided. Use of visual aids and effective education may significantly improve the quality of preparation.1,2 Additional modifications may be required in special populations, such as diabetic patients, individuals with chronic constipation, or patients with a history of poor bowel preparation.

Although the individual components of bowel preparations vary widely, dietary restrictions and cathartics are the standard combination for colonoscopy preparation. A second dosage of bowel preparation administered the same day as the colonoscopy (so-called “split-dose”) has been shown to increase the adenoma detection rate and improve preparation tolerability.3,4 When using a split-dose preparation, the standard dosage of a bowel preparation is split between the day before and the morning of the procedure. The second dose must be given early enough for the patient to take the full dosage, have the desired response, and travel to the procedure location, typically 3 to 4 hours before the colonoscopy.5,6 Bowel preparations are inadequate in up to 25% of patients and can result in missed lesions and increased procedural time.7 Patients with inadequate preparation usually require a repeat examination with a more thorough attempt at colonic cleansing.

In practice, there are highly variable recommendations regarding timing of follow-up colonoscopy. A recent study suggested that patients who were instructed to repeat colonoscopy the following day were 4 times more likely to adhere to recommendations than patients who were instructed to return after longer intervals.8 It is generally recommended that patients with inadequate bowel preparations be offered repeat colonoscopy examinations within 1 year.9

Disclaimer The cited case study is hypothetical, illustrative only, and not based on an existing patient. The purpose of the case is to explicate clinical aspects that might be encountered.

References 1. Tae JW, Lee JC, Hong SJ, et al. Impact of patient education with cartoon visual aids on the quality of bowel preparation for colonoscopy. Gastrointest Endosc.

2012;76(4):804-811.

2. Liu X, Luo H, Zhang L, et al. Telephone-based re-education on the day before colonoscopy improves the quality of bowel preparation and the polyp detection rate: a prospective, colonoscopist-blinded, randomised, controlled study.

Gut. 2014;63(1):125-130.

3. Gurudu SR, Ramirez FC, Harrison ME, et al. Increased adenoma detection rate with system-wide implementation of a split-dose preparation for colonoscopy.

Gastrointest Endosc. 2012;76(3):603-608.

4. Kilgore TW, Abdinoor AA, Szary NM, et al. Bowel preparation with split-dose polyethylene glycol before colonoscopy: a meta-analysis of randomized controlled trials. Gastrointest Endosc. 2011;73(6):1240-1245.

5. Bryant RV, Schoeman SN, Schoeman MN. Shorter preparation to procedure interval for colonoscopy improves quality of bowel cleansing. Intern Med J. 2013;43(2):162-168.

6. Seo EH, Kim TO, Park MJ, et al. Optimal preparation-to-colonoscopy interval in split-dose PEG bowel preparation determines satisfactory bowel preparation quality: an observational prospective study. Gastrointest Endosc.

2012;75(3):583-590.

7. Froehlich F, Wietlisbach V, Gonvers JJ, et al. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest Endosc.

2005;61(3):378-384.

8. Chokshi RV, Hovis CE, Colditz GA, et al. Physician recommendations and patient adherence after inadequate bowel preparation on screening colonoscopy.

Dig Dis Sci. 2013;58(8):2151-2155.

9. Lieberman DA, Rex DK, Winawer SJ, et al; United States Multi-Society Task Force on Colorectal Cancer. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2012;143(3):844-857.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

23

BB1410

Conclusion

EXPERT ROUNDTABLE

24

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Alcohol continued from page 1

Vijay Shah, MD

Raymond Chung, MD

Sumeet Asrani, MD

Chair of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota

Associate Professor of Medicine Harvard Medical School Director of Hepatology Massachusetts General Hospital Boston

Liver Consultants of Dallas Dallas

Kris Kowdley, MD

Suthat Liangpunsakul, MD, MPH

Director, and Director of Research Liver Center of Excellence Digestive Disease Institute Virginia Mason Medical Center Seattle

A Associate Professor of Gastroenterology and Hepatology Hep IIndiana University School of Medicine IIndianapolis

according to a Jan. 10, 2014, report from the Centers for Disease Control and Prevention (CDC).

Yet despite these sobering statistics, the CDC found that only one in six adults, including binge drinkers, reported ever discussing alcohol consumption with a health professional. In light of this reported lack of communication between health professionals and their patients, Gastroenterology & Endoscopy Newss asked a team of hepatologists and gastroenterologists to share their experiences in treating alcohol-related liver damage.

The roundtable includes Vijay Shah, MD, chair of gastroenterology and hepatology at Mayo Clinic, in Rochester, Minn.; Raymond Chung, MD, associate professor in the Department of Medicine at Harvard Medical School and director of hepatology at Massachusetts General Hospital, in Boston; Suthat Liangpunsakul, MD, MPH, associate professor of gastroenterology and hepatology at Indiana University School of Medicine, in Indianapolis; Sumeet Asrani, MD, of Liver Consultants of Dallas; and Kris Kowdley, MD, director of research and director of the Liver Center of Excellence at the Digestive Disease Institute at Virginia Mason Medical Center, in Seattle.

GEN: An estimated 21% of U.S. adults admit

to risky drinking, and about 4% have fullblown alcohol dependence. Problem drinking is blamed for 88,000 deaths each year in the United States, which makes it the third leading cause of preventable deaths behind smoking and obesity. But despite these statistics, only one in six adults reported ever discussing alcohol consumption with a health professional. Why do you think primary care physicians are not screening for alcohol use more rigorously, and how would your practice change if they were?

Dr.

Shah:

There are several reasons for

this. There’s some patient stigma and physician discomfort when discussing alcohol abuse with some patient populations. Another reason is the overall time burden of primary care physician visits, which don’t always allow for in-depth interrogation of these issues. There are several screening tools used, most commonly the CAGE questionnaire [box], that are reasonably effective and do not require too much time to survey.

‘We often end up identifying and treating alcohol dependence with a reactive approach, such as in response to abnormal liver function tests or an alcoholrelated hospitalization, rather than a proactive approach involving screening to prevent these circumstances from arising in the first place.’

—Sumeet Asrani, MD

Dr. Chung: The decreasing time that primary care physicians have to spend with their patients per session often precludes screening questionnaires for alcohol use and abuse. Such questionnaires end up being deprioritized when there are only 15 minutes or less per patient encounter. If more effective screening for risky drinking were implemented, early identification of cases with potential for end-organ complications could prevent many cases of end-stage liver disease.

Dr. Liangpunsakul: This is a good question. I might

not be in the position to speculate on why the screening for alcohol misuse is not done more often in the primary care setting. One study showed that most primary care physicians do not screen for alcohol problems with questionnaires during the clinic visit. However, they often conduct a battery of clinical tests such as γγ-glutamyltransferase, mean corpuscular volume and aspartate aminotransferase. Elevation of these markers could alert physicians to possible excessive drinking.

However, the problem is that these tests are neither sensitive nor specific for excessive alcohol use. I think that in the future, identifying sensitive biomarkers would not only confirm the self-report of alcohol drinking, but it would also provide results from an objective biochemical test to help physicians to motivate patients to either stop drinking or cut back to low-risk levels.

Dr Asrani: Alcohol-related liver disease is one of the most common preventable causes of death. I think one of the most important issues is that primary care physicians are encouraged to see more patients and do more documentation, and there are a limited number of issues they can address at a given visit. It is also hard to identify a patient at risk for alcohol dependence, as there is no typical alcoholic phenotype. Because of these factors, we often end up identifying and treating alcohol dependence with a reactive approach, such as in response to abnormal liver function tests or an alcoholrelated hospitalization, rather than a proactive approach involving screening to prevent these circumstances from arising in the first place.

Dr. Kowdley: The reason primary care physicians are not screening in more depth is a function of lack of time, having to take care of many other things and maybe a general lack of awareness of the prevalence of excessive drinking that goes on within the United States. From my standpoint, because we do have an epidemic of diabetes and obesity, it is possible that even moderate alcohol consumption might exacerbate fatty liver and other liver diseases. Hepatitis C is also extremely common. Up to 5

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Variations in Alcohol Screening Race Blacks................................................ 19.4% Hispanics........................................... 22.5% Whites.................................................. 3.7%

Socioeconomic status Income below $25,000 ...................... 20.2% Income above $75,000...................... 13.6%

Sex Men ...................................................... 19% Women .............................................. 12.5% Source: Centers for Disease Control and Prevention

million individuals are affected, and only 25% to 50% of those individuals are aware that they have it. Knowing that patients with hepatitis C are at an increased risk for liver disease progression with moderate to heavy alcohol consumption, it would be extremely helpful to have a better history of alcohol consumption for these patients.

GEN: How often are you required to treat liver

damage resulting from alcohol abuse?

Dr. Shah: In many studies, alcohol is the dominant cause of liver damage, even more so than viral hepatitis. Alcohol also acts in tandem with other forms of liver damage such as obesity, to cause synergistic liver damage. Most busy hepatologists will see more than one case a day of liver damage from alcohol abuse.

Dr. Chung: Frequently. Many patients are admitted with complications of alcoholic cirrhosis or alcoholic hepatitis, and we are called on to help manage them.

Dr. Asrani: As a hepatologist, I come across the entire spectrum of alcohol-related liver disease every day, both in the outpatient and inpatient settings. This ranges from simple elevated liver tests to alcoholrelated hepatitis to alcohol-related cirrhosis and its complications. Therapy depends on the manifestations that are being addressed.

Dr. Kowdley: In our practice, it’s very much dependent on practice setting and the nature of individual practice. At tertiary care hospitals that have large liver programs, and especially those that perform liver transplantation, alcohol abuse represents a small minority of liver disease patients. If we were to describe our patients at my liver center, although we don’t have a transplant program, alcohol may contribute to liver injury in 20% to 30% of cases, but it’s a direct cause in 10% or less of cases.

GEN: A major hurdle in developing new therapies for alcoholic liver disease is a lack of understanding of the mechanisms for liver injury. Many people who drink heavily never develop liver disease, whereas others seem highly susceptible—suggesting a probable role for nutritional, environmental and hereditary factors. Does this present you with complications when diagnosing and treating patients within your practice?

Dr. Shah: This is a major problem and not well understood. At Mayo, along with Virginia Commonwealth University and Indiana University, we have a

large NIH [National Institutes of Health]-funded consortium program to better understand how alcohol leads to liver damage, why many heavy drinkers never get liver damage and what the treatments are that can be tested for potential benefit in these patients.

Dr. Chung: There is no clear predictive dose [of alcohol] that determines that liver disease will occur.

There are likely genetic predispositions, but these have not been clearly identified. Other cofactors that may accelerate presentation with advanced liver disease include iron overload, the heterozygous state for α1-antitrypsin deficiency and malnutrition generally.

Dr. Liangpunsakul: As a clinician, I do not think it is difficult to diagnose alcohol-related liver disease in those who have significant history of alcohol consumption. Alcoholic liver disease pathogenesis is a multistep and multifactorial process that progresses through a series of histopathologic stages. More than 90% of drinkers develop alcoholic steatosis or fatty liver, which is reversible on abstinence. However, if alcohol use continues, the disease can progress to fibrosis and possibly cirrhosis in up to 8% to 15% of heavy drinkers. However, in most studies, up to one-third of heavy drinkers have completely normal liver biopsies. These studies have led to the question: What factors determine whether or not a heavy drinker develops alcoholic liver disease? Clearly, this is a disease that is influenced by genetic and environmental cofactors. To date, cofactors fail to fully explain the variability in the development of alcoholic liver disease but suggest a significant

25

CAGE Questionnaire • • • •

Have you ever felt you should Cut down on your drinking?

Have people Annoyed you by criticizing your drinking?

Have you ever felt bad or Guilty about your drinking?

Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (Eye opener)?

Scoring: The answers to the questions are scored 0 for “no” and 1 for “yes,” with a total score of ≥2 considered indicative of an alcohol or drug problem.

have led to the question: What

critical to effectively managing patients, as they often guide us to the best individual strategy for that patient.

Dr. Kowdley: Patients with alcoholic liver disease generally come in three categories: those who have fatty liver from alcohol, those with alcoholic cirrhosis and those with acute alcohol hepatitis, which can be fatal. We definitely need to better understand why some patients get one form of the disease, why some patients get cirrhosis and why others aren’t affected at all. Only 10% of patients who are susceptible actually develop liver disease. Hereditary factors, diet and nutrition, environmental factors such as obesity and diabetes will all help us understand patients who are at the highest risk so we can better counsel them. In terms of treatment, there is a good understanding of the mechanism of severe alcoholic hepatitis, and treatments are available, but it’s important to first identify which patients are most at risk.

factors determine whether or not

GEN: A substantial amount of literature in recent

a heavy drinker develops alcoholic

years has supported the positive effects of light to moderate consumption of alcohol. Even a recent study in Hepatologyy reported that modest wine drinking decreased the prevalence of suspected nonalcoholic fatty liver disease [NAFLD]. How do you explain the difference between moderate and heavy drinking when counseling patients, and who exactly are the people who may benefit from that daily glass of wine?

‘In most studies, up to one-third of heavy drinkers have completely normal liver biopsies. These studies

liver disease? Clearly, this is a disease that is influenced by genetic and environmental cofactors.’

—Suthat Liangpunsakul, MD, MPH

contribution of non–sex-linked genetic factors in [alcoholic liver disease] susceptibility.

We also believe that an underlying genetic basis may account for the wide variability of liver damage observed in heavy drinkers. In fact, the genome-wide association study to determine the genetic risk factors for alcoholic liver disease, sponsored by the NIH, is underway. [Dr. Liangpunsakul is a co-investigator on the genome study.]

Dr. Asrani: Alcohol-related liver disease is not simply correlated to the amount of alcohol consumption. The pattern of alcohol consumption—binge drinking, for example, also matters. Furthermore, alcohol affects patients in different ways. As an example, patients with alcoholic hepatitis have a high risk for mortality to begin with, but patients who are obese on top of that do worse. Several recent investigations suggest that this interaction is not simply additive, but has a synergistic effect. There are likely many such interactions that we are just beginning to understand, that are

Dr. Shah: This is a complicated issue, but one drink a day may be safe and possibly helpful for the general population. However, there are risks to this advice because individuals with an addictive predisposition may commonly start drinking more than that, and the therapeutic/toxic window is small and varies between individuals. This problem is magnified in patients with NAFLD who have increased risk for heart disease, which may be benefited by a drink, but on the other hand, excess amounts of alcohol in patients with NAFLD has clearly been shown to result in synergistic liver damage. Thus, I don’t advise patients with NAFLD to drink but if they have no more than one drink per day, then I don’t strongly discourage that.

Dr. Chung: There is no hard threshold that appears to be beneficial, and it is difficult to identify those who would clearly benefit. That said, some of the see alcohol, page 48

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Full-Spectrum Endoscope Best at Detecting Colorectal Adenomas A new full-spectrum endoscope with a wider field of view than conventional devices proved superior to a standard forward-viewing endoscope for detecting colorectal adenomas.

Patients at six international sites who were referred for colorectal cancer (CRC) screening, polyp surveillance or diagnostic assessment were invited to participate in a study that compared endoscopies and adenoma miss rates. Patients were assigned to receive a colonoscopy using a standard forward-viewing endoscope, offering a viewing field of up to 170 degrees, or a full-spectrum endoscope (Fuse, EndoChoice), providing imaging from the forward tip as well as both sides, amounting to a 330-degree viewing field. After completing the initial first-pass examination with either of the randomly assigned endoscopes, patients would immediately be

given a second colonoscopy using the other technology.

The endoscopist and room would remain the same for both procedures.

In a report published in Lancet Oncologyy (2014;15:353360), Ian M. Gralneck, MD, and his co-authors confirmed that the miss rate was significantly lower in patients examined with the full-spectrum technology. Of the 88 patients (48%) who received standard colonoscopy first, 29 adenomas were identified in 25 patients. Those patients were then examined on a second pass with the full-spectrum device, and an additional 20 adenomas in 15 patients were identified (69% increase).

Five of these patients (6%) had no adenomas identified during the first examination.

In the full-spectrum colonoscopy first group, 97 patients (52%) were evaluated; 60 adenomas and two

cancers were identified in 33 patients. When those patients received a second-pass standard colonoscopy, five additional adenomas were detected. On a per-lesion analysis, the adenoma miss rate was significantly lower in the full-spectrum group than the standard group: five of 67 (7%) missed versus 20 of 49 (41%; P<0.0001).

The authors also found fewer false-negative results with the full-spectrum colonoscopy (0 of 97 patients) than the standard forward-viewing colonoscopy (five of 88; 6%). The time to complete the colonoscopies was similar, as were reports of adverse events. As this new technology offers advanced optics and a wider-angle field of view, the increased visualization should optimize surveillance of the colonic mucosa and improve the effectiveness of CRC screening.

■ —GEN Staff

Assessing Family Cancer History First-degree histories well documented, but room for improvement

BY BEN GUARINO As many as one in 10 new cancer diagnoses are attributable to genetically inherited disease, according to the American Society of Clinical Oncology, and documenting family history of cancer can have a large effect on screening and preventive decisions. In a new study published in the Journal of Clinical Oncology, investigators who reviewed medical records of patients with breast or colorectal cancer found that 79.8% included the cancer history of first-degree relatives; however, only 64.6% of records documented cancer history of second-degree relatives.

Clinicians should be pleased with the rate at which the cancer history of firstdegree relatives was documented, said Noralane Lindor, MD, a medical geneticist at Mayo Clinic in Scottsdale, Ariz., who was not involved with this research.

“This is a dramatic change from 10 to 15 years ago,” she said.

“These rates are higher than we thought we’d find, but there is room for improvement,” said Marie Wood, MD, co-author of the study and director of the familial cancer program in the Hematology/Oncology Division at the University of Vermont in Burlington.

By analyzing the records of 10,466 patients diagnosed with breast or colorectal cancer, representing more than 200 cancer centers, the authors were able to determine the rate at which family history of cancer was recorded ((J Clin Oncoll 2014;32:824829). For patients with breast cancer as well as those with colorectal cancer, fewer than half of medical records documented the age of relatives at diagnosis.

Providers do a good job of documenting first-degree family history, Dr. Wood said, but are not as completely recording

second-degree family history and are “not great” at reporting age. Age at cancer diagnosis is important, she said, as it can indicate ate hereditary cancer syndromes syndrom rom iff diagn nosis was made a at an early ag age. ge.

Patients tend to be more forthcoming about breast cancer than colorectal cancer, said Kevin Hughes, MD, co-director of the Avon A on Comprehensive Avo Av m Breast Ev Evaluation ion Ce Center and n a surgeon ge at Masssachu-

‘This paper highlights that we are missing candidates for genetic testing.’

—Marie Wood, MD The rate at which providers recorded the history of first-degree relatives was significantly higher for patients with breast cancer than for those with colorectal cancer (81.2% vs. 77.4%, respectively; P<0.001); similarly, the records for patients with breast cancer also included history of second-degree relatives at a higher frequency (68.9% vs. 57.3%, respectively; P<0.001).

The difference in rates of family history between colorectal and breast cancer “reflects the knowledge gap between the two diseases,” Dr. Lindor said.

setts General Hospital in Boston, who helped conduct the study. The difference may stem in part from a cultural taboo surrounding the discussion of colorectal problems, he said. “People don’t talk about their colons, usually, at the dinner table.”

The study also evaluated the rates at which doctors referred patients to receive genetic counseling or testing. For patients with breast cancer, 29.1% were referred, whereas of patients with colorectal cancer, 19.6% were referred for genetic counseling or testing (P<0.001).

But looking solely at the rates of referral

for genetic tests may be deceptive. “It’s the right percentage of the practice,” Dr. Hughes said, “but not the right patients.”

Of the patients who met the criteria for referral, only 52.2% of those with breast cancer were referred for genetic testing or counseling, and 26.4% of individuals with colorectal cancer were referred. “This paper highlights that we are missing candidates for genetic testing,” Dr. Wood said.

Changes to education or infrastructure could have beneficial effects on family history documentation and subsequent referrals, Dr. Wood said. In an accompanying article in the Journal of Clinical Oncology, the study investigators issued a set of guidelines to help providers assess family history (2014;32:833-840). These recommendations include establishing history for both maternal and paternal first- and second-degree relatives, ethnicity and, for each instance of a relative with cancer, the age at diagnosis and the primary type of cancer. Clinicians should gather this information at the initial visit, the authors said, and reevaluate family history at periodic intervals.

Electronic health records (EHRs) have the potential to improve the documentation of familial risk, Dr. Hughes said, although most EHRs do not currently have a useful family history section. By giving “just-in-time suggestions,” Dr. Lindor said, EHRs could prompt doctors to ask their patients about family history of cancer.

■ Drs. Lindor and Wood reported no conflicts of interest. Dr. Hughes has received honoraria from Myriad Genetics and is a co-inventor of HughesRiskApps.com, which offers software to assess cancer risk in patients.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Coverage From the 13th Annual Surgery of the Foregut Symposium Held February 15-19, 2014, in Coral Gables, Florida ALL ARTICLES BY MAYANK ROY, MD, MRCS, GENERAL SURGERY RESIDENT, CLEVELAND CLINIC FLORIDA, WESTON

Introduction From Symposium Director Raul J. Rosenthal, MD It is my pleasure to share a few highlights from the 13th Annual Surgery of the Foregut Symposium, held at the Biltmore Hotel in Coral Gables, Florida.

John Fung, MD, PhD, a pioneer and world leader in organ transplantation, delivered the third Annual

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Robert E. Hermann Lecture. Dr. Fung presented an overview on the evolution of organ transplantation in parallel with the understanding and implementation of new immunosuppressive drugs.

Fernando Dip, MD, reviewed the routine use of fluorescent cholangiography, and what I believe will become the new standard in imaging when performing laparoscopic cholecystectomy.

The last featured speaker was Almino Ramos, MD, current president of the Brazilian Society of Bariatric Surgeons and secretary-treasurer of the International Federation for the Surgery of Obesity and Metabolic Disorders. Dr. Ramos analyzed the current incidence and treatment modalities of staple-line disruption after sleeve gastrectomy.

Long-Term g Survival After Liver Transplantation A triumph of surgery and immunosuppression John J. Fung, MD, PhD, from the Cleveland Clinic, in Ohio, delivered the Annual Robert E. Hermann Keynote Lecture on the successful history of liver transplantation surgery (LTS) and an insight into the future of the procedure.

Although experimental, LTS dates back to 1952, after which Thomas Starzl, MD, performed the first human liver transplant in 1963, with the longest surviving patient living for 22 days. Dr. Starzl and others subsequently performed the first successful LTS, and in 1982 published long-term survival data of liver transplant patients, showing that five-year survival had doubled since 1978 to 40% (Hepatologyy 1982;2:614636). These data led to approval of LTS as a therapeutic modality by the National Institutes of Health (NIH) in 1983. Over the next 20 years, liver transplant centers worldwide increased dramatically, leading to a donor shortage and the need for partial-graft transplantations.

In the 1980s, Henry Bismuth, MD, pioneered the first reduced-size orthotopic liver transplant (Surgeryy 1984;95:367370), and Strong and Lynch performed the first successful living donor liver transplantation from mother to child (N Engl J Medd 1990;322:1505-1507). This ushered in adult-to-adult living donor liver transplantation.

Despite an initial rise in living related donor (LRD) use between 2000 and 2002,

31

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

several centers in clinical transplantation, and in 1972, the immunosuppressive properties of cyclosporine were identified.

Cyclosporine was found to be effective in clinical transplant trials and was approved by the FDA in 1983, the same year it approved LTS as a therapeutic modality, thus setting the stage for dramatic improvements in LTS. The next big breakthrough in immunosuppression came with the development of tacrolimus, in 1989, at the University of Pittsburgh.

The FDA approved tacrolimus for clinical use in 1994. From 1998 to 2007,

the use of tacrolimus and mycophenolate mofetil steadily increased, while the use of cyclosporine and steroids steadily decreased. The use of the mammalian target of rapamycin (mTOR) inhibitor sirolimus remained relatively low during this time (Figure 1).

Dr. Fung noted that the incidence of acute rejection after liver transplant decreased from 85% to less than 10% with the combined use of tacrolimus, mycophenolatemofetil and steroids.

The highest mortality rate after LTS is within the first year, Dr. Fung said. The

most common cause of late mortality after LTS is complications secondary to immunosuppressant use; other causes include disease recurrence and cardiovascular complications. Risk for renal failure associated with immunosuppression in LTS gradually increases over the years after transplantation.

Dr. Fung reported one retrospective analysis showing that patients who were more than 10 years post-orthotopic liver transplant developed chronic renal failure and end-stage renal disease at see Foregut, page 32

Figure 1. Changes in medication use for liver transplantation.

2008 Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients annual report

with the best-read gastroenterology publication.

20 18

CRF + ESRD ESRD KTX

Morbidity, %

16 14 12 10 8 6 4 2 0 0

2

4

6

8

10

12

Years from Liver Transplantation

Figure 2. Renal disease and failure after liver transplantation.

CRF, chronic renal failure; ESRD, end-stage renal disease; KTX, kidney transplantation Source: Transplantation 2001;72:1934.

♦ ♦

verage issue readers

♦

otal readers

♦ stringent regulations requiring high levels of resources and concerns related to donor risk and recipient complications resulted in a decline in LRD. Dr. Fung reported that mortality rates for right- and leftlobe liver donors are approximately 0.5% and 0.1%, respectively.

Dr. Fung went on to explain that success in LTS would not have been possible without advances in immunosuppressant medications. Development of 6-mercaptopurine in 1951, followed by azathioprine in 1957, led the way for chemical immunosuppression. By 1960, azathioprine was being used by

gh readers

♦

gh readers (% total readers) verage page exposures sed on data from Kantar Media, June 2013

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Foregut continued from page 31

a high rate secondary to the use of calcineurin inhibitor (Figure 2). Data such as these prompted the need to develop new strategies for long-term immunosuppression as a means to decrease this complication. Sirolimus and everolimus (mTOR inhibitors) appear to lack nephrotoxicity. Dr. Fung discussed the results of a recent multi-institutional trial that showed early initiation of

everolimus facilitated early minimization of tacrolimus, with comparable efficacy and superior renal function.

Dr. Fung concluded that despite the numerous advances in LTS, many issues remain that challenge the wider application, improved survival and enhancement in quality of life for these patients. Dr. Fung proposed that organ preservation at body temperature, and treating unhealthy livers

and transplanting them at a later stage are innovations that could change the face of transplant surgery in the future.

Although the modern history of LTS spans only five decades, great achievements have been made. Advances in surgery, anesthesia, critical care and pharmacologic therapies have all contributed to improvements in patient and graft survival.

OPT IN to receive your free monthly e-new e-n sletter l at www. w gastroendonews.com d Be the first to get the latest news delivered r directly r to your computer.r The new interactive format has embedded Web W site links that give you instant access to gastroe r ndonews.com, where r you will find additional information as well as unique searc r h feature r s and article printing capabilities.

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Intraoperative Incisionless Fluorescent Cholangiography Fernando Dip, MD, visiting professor at Cleveland Clinic Florida from Hospital de Clinicas Buenos Aires, Argentina, discussed fluorescence-guided surgery as a newly emerging technology and the role of intraoperative incisionless fluorescent cholangiography (IOFC) in biliary tract surgery.

Eric Muhe, MD, performed the first laparoscopic cholecystectomy in 1985, and this approach has rapidly become the gold standard for symptomatic gallbladder disease (Langenbecks Arch Chir Suppl Kongressbdd 1991:416-423).

However, the rate of bile duct injury increased from 0.2% with the open approach to 0.4% with the laparoscopic approach, Dr. Dip reported. Approximately 750,000 cholecystectomies are performed in the United States every year, with more than 300 reported bile duct injuries (Surg Endoscc 2013;27:1051-1054). Most patients can be managed by endoscopic retrograde cholangiopancreatography and/or percutaneous drainage. However, some patients will require multiple interventions, which is associated with increased morbidity, mortality and litigation, Dr. Dip said.

It has been reported that bile duct injury is the most common source of litigation ((Ann Surgg 2010;251:682-685). The learning curve, lack of tactile feedback, visual perception from two-dimensional images and anatomic variation are reasons suggested for bile duct injury with laparoscopic cholecystectomy, Dr. Dip said ((Ann Surgg 2003;237:460469; Br J Surgg 1996;83:171-175; J Am Coll Surgg 1995;180:101-125; Surg Todayy 2010;40:507-513; J Am Coll Surg 2010;211:132-138).

Intraoperative cholangiography (IOC) has been proposed to avoid bile duct injury during laparoscopic cholecystectomy.

However, published studies have not shown any robust evidence to support or abandon the use of IOC to prevent bile duct injury, Dr. Dip noted. Moreover, there is much variation in the use of IOC among surgeons and hospitals ((J Am Coll Surgg 2012;214:668-679). Dr. Dip noted that although IOC does not necessarily prevent injury, it may reduce the severity of the lesion if recognized intraoperatively (Br J Surgg 2012;99:160-167).

There is currently a need for a technique that will improve the surgeon’s visual field during laparoscopic cholecystectomy, said Dr. Dip. The technique should add value to the existing options, be financially viable and be easily adopted by any surgeon.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Figure 3. When prints and other fluorescent trace are illuminated with green (or blue) light, the fluorescence is easy to distinguish from scattered light using an orange filter.

Illumination source: Coherent Trace Laser.

use in humans for various medical purposes such as measurement of hepatic function, cardiac output, renal perfusion and angiography. In 2010, Ishizawa and colleagues, from the University of Tokyo, published their results of IOFC using ICG. The authors reported that they were able to identify the cystic and common hepatic duct sin 100% of the cases ((J Am Coll Surgg 2009;208:e1-e4).

The technique of IOFC during laparoscopic cholecystectomy involves a xenon light (Karl Storz Endoskope) source and a laparoscope with a charge-coupled

device that filters out light wavelengths below 830 nm with a specific 780nm infrared light source. During the procedure, alternate exposure from xenon and infrared light (by pressing a pedal) is used to identify extrahepatic biliary structures before and after the dissection.

Biliary structures are then visualized under the NIR light (780-830 nm) with fluorescent light (Figures 4 and 5).

Dr. Dip discussed the results of a prospective study of IOFC during laparoscopic cholecystectomy conducted at Cleveland Clinic Florida, which is

at

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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

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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).

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

Fluorescence image-guided surgery has emerged as a new surgical revolution.

Fluorescence is the emission of light by a substance that has absorbed light of another electromagnetic radiation, Dr. Dip explained (Figure 3). Chemically, fluorescence is brought about by absorption of photons in the singletground state promoted to a singletexcited state. The spin of the electron is still paired with the ground-state electron. As the excited molecule returns to ground state, it involves the emission of a photon of longer wavelength and lower energy than the absorbed photon.

One of the first reports of illumination of the biliary tract with fluorescent bile acid in rabbits came from Switzerland in 2001. Indocyanine green (ICG) is a dye excreted by the liver that becomes fluorescent near-infrared (NIR) light.

In 1959, the FDA approved ICG for

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

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Figure 5. Calot’s triangle under infrared light.

see Foregut, page 34

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

1978 —

Figure 4. Calot’s triangle under xenon light.

pending publication. Routine IOC was performed in every patient to compare and confirm the results. IOFC was performed in all 45 patients, whereas IOC could be performed in 42 of the 45 patients (93%) (P<0.078, c2 test).

Individual median cost of performing IOFC was lower than IOC ($13.97±4.3 vs. $778.43±0.4 per patient; P=0.0001) and IOFC was faster than IOC (0.71±0.26 vs. 7.15±3.76 minutes; P<0.0001). The cystic duct was identified

by IOFC in 44 of 45 patients (97.77%).

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34

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Foregut continued from page 33

All third- and fourth-year surgical residents were able to easily identify the extrahepatic structures including the bile duct in the 45 cases using IOFC, without any direction from the attending surgeon. No surgical complications that might have been related to the use of IOFC were noted. Also, no allergic or adverse reactions secondary to the injection of the dye were noted.

Dr. Dip concluded that IOFC is a

1978

—

useful tool in the laparoscopic surgeon’s armamentarium. Dr. Dip proposed that IOFC should be routinely performed during laparoscopic cholecystectomy as it is safe, feasible, fast and inexpensive; avoids radiation exposure; and provides the surgeon with the ability to directly visualize the biliary anatomy and provide tactile perception. Most importantly, Dr. Dip noted, IOFC can be used in realtime surgery, guiding the surgeon during

dissection, transection and resection around the biliary anatomy. Although IOFC has proven quite useful, Dr. Dip did not suggest it is intended to replace IOC. Instead, he proposed IOFC as a complementary method, with its main goal being to visualize bile duct structures when visualization is not possible with xenon light.

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20 Years of Experience in Laparoscopic Fundoplication Bernard Dallemagne, MD, from the University Hospital Strasbourg, France, discussed the principles and controversies in laparoscopic antireflux surgery.

Over the past two decades, laparoscopic antireflux surgery has proven to be safer than and as effective as the open technique, Dr. Dallemagne said. Diagnostic work-up is crucial to the selection of appropriate patients. Dr. Dallemagne discussed the broad principles of laparoscopic antireflux surgery, namely: 1) restoring the length of abdominal esophagus, 2) permanently augmenting the resting distal esophageal sphincter pressure, 3) using only the fundus of the stomach to construct the fundoplication, and 4) ensuring that the resistance of the reconstructed valve matches the propulsive power of the esophagus.

Failures and complications continue to present challenges to antireflux surgery. Wrap herniation (39%) and slippage (35%) remain the most common causes of failure after laparoscopic fundoplication (Figure 6); in all, 3% to 6% of these patients require reoperation, Dr. Dallemagne reported.

Six technical aspects of antireflux surgery include trocar placement, dissection of the gastroesophageal junction, ensuring appropriate length of the esophagus, crural repair, fundic mobilization (with special attention to short gastric vessels) and architecture of the fundoplication.

Dr. Dallemagne emphasized the importance of ensuring appropriate length of the esophagus to minimize axial tension, a potential Achilles heel even after a technically good fundoplication operation. Dysfunction of the lower esophageal sphincter leads

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Figure 6. Collis gastroplasty.

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Reprinted with permission.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

to acid/alkaline regurgitation, causing an inflammatory response. Repetition of this injurious cycle can lead to fibrosis of deeper muscular layers and esophageal shortening, and this occurs in 5% to 10% of patients.

Most patients can be appropriately managed with extensive mediastinal mobilization of the esophagus; 20% of patients, however, will require an aggressive surgical approach in the form of Collis gastroplasty. With experience gained from sleeve gastrectomy, gastroplasty should be used when in doubt to decrease the risk for tension.

Dr. Dallemagne mentioned the importance of a good crural repair. In his own technique, he mobilizes the gastric fundus after dividing the short gastric vessels to prevent torsion. The fundoplication should not be too tight because that also can increase the tension, he advised.

Dr. Dallemagne also discussed controversies surrounding the use of mesh to prevent recurrence. Studies have reported recurrence rates of zero to 8% and 22% to 24% with or without the use of polytetrafluoroethylene mesh, respectively ((Arch Surgg 2002;137:649-652; J Am Coll Surgg 2011;213:461-468). However, studies have shown no difference in recurrence between using mesh and not using mesh after a follow-up of 58 months (54% vs.

59%) ((J Am Coll Surgg 2011;213:461468). Dr. Dallemagne said he was aware of the associated risk for mesh erosion in the stomach and esophagus. He shared some of his personal experiences, including the need to remove eroded mesh endoscopically from the stomach.

Dr. Dallemagne concluded by addressing developments such as the assessment of functional diameter and geometric reconstruction of the esophagogastric junction using the functional lumen impedance probe.

Gastrectomy for Chronic Leak After Lap Sleeve Gastrectomy Almino Ramos, MD, from Brazil, discussed the management of leak after laparoscopic sleeve gastrectomy (LSG).

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.

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Celiac continued from page 1

‘These data suggest that the

gastrointestinal (GI) complaints are at higher risk for the disorder. Current guidelines from the American Gastroenterological Association (AGA) and the American College of Gastroenterology (ACG) recommend routine celiac screening in patients with chronic GI symptoms suggestive of malabsorption, such as chronic diarrhea with weight loss, postprandial abdominal pain or steatorrhea. However, data presented at Digestive Disease Week 2014 show that this recommendation is not followed routinely (abstract 654).

“These data suggest that the case-finding technique utilized at a tertiary care academic practice [is] inadequate,” said Heba Iskandar, MD, assistant professor in the Division of Gastroenterology at Emory University School of Medicine, in Atlanta. Dr. Iskandar led and conducted this study at Washington University in St. Louis, while completing her fellowship. “The data suggest a gap in patient care and a target for future quality assurance initiatives.”

Dr. Iskandar and her colleagues analyzed the electronic medical records (EMRs) of all patients evaluated during a three-month period at Washington University’s GI center. Of 616 patients, 336 (54.2%) fulfilled indications for celiac disease screening using compatible criteria published by the AGA in 2006 and the ACG in 2013. In more than half the cases, chronic GI symptoms consistent with malabsorption was the criterion for screening. Another 9% of patients were defined as candidates due to elevated serum transaminases, but most of the other criteria in the guidelines—such as type 1 diabetes, osteopenia or a first-degree relative with celiac disease—identified at least some of the candidates for screening.

After eliminating people who already had a known diagnosis of celiac disease, only 43.4% of those with an indication for screening received any test for the condition, whether anti-tissue transglutaminase IgA screening or another guideline-recommended option. Of the 145 patients screened, four had serology consistent with celiac disease, and two of these cases were confirmed with duodenal biopsy. If the unscreened patients yielded a similar case identification rate, the data predict that at least two celiac disease patients were missed during the three months that the data were collected.

Rates of screening varied markedly among the specific clinics within the GI center. In the luminal GI clinic, the rate of screening among appropriate candidates was 53.5%, but it was 39.2% in the inflammatory bowel disease clinic and 27% in the hepatology clinic. The

case-finding technique utilized at a tertiary care academic practice [is] inadequate,’ —Heba Iskandar, MD

Table. Conditions in Which Celiac Disease Occurs at Least Twice as Frequently as in the General Population Abnormal elevated liver enzymes Chronic diarrhea with or without abdominal pain Chronic iron deficiency and anemia Dermatitis herpetiformis Diarrhea with weight loss Discolored teeth or developmentally synchronous enamel loss Down and Turner syndromes Growth failure Incidental discovery of villous atrophy endoscopically or histologically Irritable bowel syndrome Metabolic bone disease and premature osteoporosis Oral aphthous ulcers Peripheral neuropathy Postprandial bloating and gas Symptomatic malabsorption Thyroid disease Unexplained weight loss Based on Am J Gastroenteroll 2013;108:656-676.

proportion of candidates screened in a biliary clinic was 34.3%.

Celiac disease is among the most common causes of chronic malabsorption and remains greatly underdiagnosed in the United States and elsewhere, according to the ACG guidelines. The heterogeneous presentation of celiac disease makes it easy to miss. The substantial health risks posed by celiac disease, including inadequate nutrient uptake and an impaired quality of life, generally can be greatly reduced with a gluten-free diet.

With adherence, the case-finding approach advocated by the AGA and the ACG is a reasonable approach to improving diagnosis, according to Dr. Iskandar, but she concluded that these data suggest that a more rigorous strategy of identifying candidates is needed.

Raising awareness is important, but other initiatives, such as programming EMR systems to generate reminders, may result in testing of a greater number of candidates.

Alberto Rubio-Tapia, MD, who helped write the 2013 ACG celiac disease guidelines ((Am J Gastroenteroll 2013;108:656-676), said his own recent data also support the flaws in the case-finding method.

“Only 5% of residents of Olmsted County with positive serologies consistent with undiagnosed celiac disease, followed for a period of five years, get a clinical diagnosis,” according to Dr. Rubio-Tapia, of the Division of Gastroenterology and Hepatology at Mayo Clinic, in Rochester, Minn. Case finding in high-risk populations, such as first-degree relatives and patients with Down syndrome, unexplained irondeficiency anemia, infertility or abnormal liver function, deserve to be “more rigorously followed in clinical practice,” he said (Table).

Although Dr. Rubio-Tapia said the latest data have not convinced him to endorse population-based screening for celiac disease, case finding is “effective but insufficient” as currently practiced to catch most cases.

■ Dr. Iskandar reported no relevant financial disclosures. Dr. Rubio-Tapia has had financial relationships with Alba Therapeutics and Alvine Pharmaceuticals.

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38

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Simple Addition to Colonoscopy Can Increase Adenoma Detection

BY CAROLINE HELWICK CHICAGO—The addition of a rubber device with flexible, circular rings to the distal end of a colonoscope can substantially boost detection of polyps and adenomas, researchers have found.

In a randomized study, the device, called EndoRings (EndoAid, Ltd), missed only 13% of adenomas, far less than the standard miss rate of conventional colonoscopy, the investigators said. Colonoscopy with the EndoRings took about four minutes longer, on average, in the study.

“Colonoscopy with the EndoRings is safe and has a significantly lower adenoma and polyp miss rate, as compared with standard colonoscopy,” said Peter D. Siersema, MD, of University Medical Center Utrecht in the Netherlands, who led the study and reported the findings at Digestive Disease Week 2014 (abstract 929b).

Tandem studies with standard colonoscopies have shown that adenoma miss rates range between 25% and 40%.

The lack of detection is largely caused by inadequate visualization of the proximal aspects of folds and inner curves of flexures, Dr. Siersema noted. This inadequate visualization can be solved with use of the EndoRings.

Available in the United States and Europe, EndoRings is a silicone rubber device with flexible circular rings that is fitted onto the distal end of the colonoscope. The device improves visualization by contacting and stretching colonic folds during withdrawal. “This allows us to more easily identify and remove lesions,” Dr. Siersema explained.

Dr. Siersema and his colleagues conducted a multicenter, randomized tandem study at centers in the Netherlands and Israel, in which 106 patients (aged 40-75 years) underwent same-day, back-to-back colonoscopies by the same endoscopist, with indications for screening, surveillance or diagnostic procedures. Arm A had standard colonoscopy followed by EndoRings colonoscopy, and arm B had EndoRings first, then standard colonoscopy.

Patients underwent standard bowel preparation and had conscious sedation that included midazolam, fentanyl or propofol, or a combination of these.

Colonoscopy was performed with the Olympus (Evis Exera II 180 series) or Pentax (EC-3890 series) scopes. Patients were evaluated only if minimal withdrawal time was six minutes. Polyps found during the first procedure were removed immediately; diminutive (1-2

The EndoRings device helped clinicians detect signficantly more cancerous lesions, while adding minimally to the duration of colonoscopy.

Table. Adenoma Miss Rates: Per-Lesion Analysis Arm A Standard Colonoscopy Followed by EndoRings

Arm B EndoRings Followed by Standard Colonoscopy

Standard: 17 adenomas

EndoRings: 46 adenomas

EndoRings: 19 additional adenomas

Standard: 7 additional adenomas

Adenoma miss rate: 53%a

Adenoma miss rate: 13%

a

P<0.001

mm) rectal polyps with hyperplastic appearance were not removed.

The final analysis included 47 patients in arm A and 49 in arm B. The arms were similar in mean age, bowel preparation quality and indication, but arm A had

more women (53% vs. 31%; P=0.03).

P

Adenoma Miss Rates Significantly Lower With EndoRings In a per-lesion analysis, the adenoma miss rate was 13% with EndoRings

colonoscopy first, versus 53% with standard colonoscopy first (P<0.001) (Table).

Similarly, the miss rates for polyps were 11% and 58%, respectively (P<0.001), the researchers found. There were no differences in characteristics of the missed polyps between arms. The majority of polyps in both arms were sessile (76%-80%), and located in the proximal colon (53%-80%).

In a per-patient analysis, the adenoma detection rate was 28% with standard colonoscopy and 49% with EndoRings (P=0.03), P and the polyp detection rate was 38% and 67%, respectively (P<0.01).

“The study had an impact on surveillance intervals,” Dr. Siersema continued.

The surveillance interval was shortened for eight subjects in arm A (standard colonoscopy followed by EndoRings) and for two subjects in arm B. The procedure added about four minutes to the total procedure time— including washing, suctioning and polypectomies—which was about 18 minutes with standard colonoscopy and about 22 minutes with EndoRings (P<0.001).

Time to reaching the cecum and withdrawal time were similar. No adverse events were recorded, according to the researchers.

Dr. Siersema said the use of the EndoRings adds little to the cost of colonoscopy, indicating that the single-use devices are inexpensive.

EndoRings Could Improve Skills In an interview, Colleen Schmitt, MD, president of the American Society for Gastrointestinal Endoscopy, said, “This study further highlights our need to carefully examine the proximal colon, especially for flat polyps, the most common site and type of polyp overlooked by the standard procedure in this tandem study performed by colonoscopy experts. These experts found no difference in time to cecum, which could potentially be the most challenging part of the procedure with the new device. It will be important to find out if these results can be duplicated in typical, community-based practices.

“In clinical practice, we appreciate improvements in our skills to identify and remove adenomas,” Dr. Schmitt continued. “EndoRings provide a novel but practical way to potentially enhance these skills. Also, the addition of EndoRings leverages our existing technology platforms, an appealing feature from a cost–benefit standpoint.”

■ The study was funded by EndoAid, Ltd. Dr. Siersema consulted for the company during the study. Dr. Schmitt reported no relevant financial conflicts of interest.

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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 OFFERS SIMPLE DOSING FOR PATIENTS WITH HCV GT 1, 2, 3 OR 41 A 12-week regimen for HCV GT 1 and 41 • SOVALDI is taken in combination with Peg-IFN + RBV for treatment-naïve or treatment-experienced patients with HCV GT 1 or 41 • SOVALDI in combination with RBV for 24 weeks can be considered as a therapeutic option for patients with GT 1 infection who are ineligible to receive an IFN-based regimen. The treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient1 An all-oral regimen for HCV GT 2 and 31 • SOVALDI + RBV is the first all-oral regimen for treatment-naïve and -experienced GT 2 patients (12 weeks of SOVALDI + RBV) and GT 3 patients (24 weeks of SOVALDI + RBV)1 Additional dosing considerations • The recommended dose of SOVALDI is one 400 mg tablet taken once daily with or without food in combination with RBV or Peg-IFN + RBV1 • No response-guided therapy is necessary with SOVALDI regimens1 • The recommended dosing is the same for both HCV mono-infected and HCV/HIV-1 co-infected patients1 • See next page for more dosing information

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/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.

• 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.

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

sovaldi.com/hcp

SIMPLE DOSING WITH SOVALDI (CONTINUED) • In patients with hepatocellular carcinoma (HCC) awaiting liver transplantation, SOVALDI in combination with RBV is recommended for up to 48 weeks or until the time of transplantation, whichever occurs first, to prevent post-transplant HCV reinfection1 • If the other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should also be discontinued1 • No SOVALDI dose adjustments are necessary based on advanced age, race, mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2) or mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C). The safety and efficacy of SOVALDI have not been established in patients with severe renal impairment, end stage renal disease (ESRD) or decompensated cirrhosis1 • 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 the peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose1

IMPORTANT SAFETY INFORMATION (CONTINUED) 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

4%

15%

16%

29%

25%

Pruritus

8%

11%

27%

17%

17%

Anemia

0%

10%

6%

12%

21%

Asthenia

3%

6%

21%

3%

5%

Rash

8%

8%

9%

18%

18%

Decreased Appetite

10%

6%

6%

18%

18%

Chills

1%

2%

2%

18%

17%

Influenza Like Illness

3%

3%

6%

18%

16%

Pyrexia

0%

4%

4%

14%

18%

Diarrhea

6%

9%

12%

17%

12%

Neutropenia

0%

<1%

<1%

12%

17%

Myalgia

0%

6%

9%

16%

14%

Irritability

1%

10%

10%

16%

13%

CONTRAINDICATIONS: When SOVALDI is used in combination with ribavirin or peginterferon alfa/ 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. a

Brief Summary (cont.)

Table 2 Percentage of Subjects Reporting Selected Hematological Parameters Interferon-free Regimens Hematological Parameters

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

Hemoglobin (g/dL) <10

0

8%

6%

14%

23%

<8.5

0

1%

<1%

2%

2%

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

1%

<1%

0

12%

15%

0

<1%

0

2%

5%

3%

<1%

1%

7%

<1%

0

0

0

0

0

9

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: 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 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.

SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 Refer also to ribavirin prescribing information for patients with CrCl<50 mL/min. weeks groups, respectively.

DRUG INTERACTIONS: Potential for Drug Interactions: After oral administration of SOVALDI, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir accounts for approximately 4% of drug related material. In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses. Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS 331007 is not. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John’s wort) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of SOVALDI and thus should not be used with SOVALDI. Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, SOVALDI may be coadministered with P-gp and/or BCRP inhibitors.

Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these transporters. The intracellular metabolic and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs.

Based on Drug Interaction Studies or Predicted Interaction: Drug interaction information for SOVALDI with potential concomitant drugs is summarized as follows and the list is not inclusive. The drug interactions described are based on potential drug interactions that may occur with SOVALDI. Anticonvulsants: Coadministration of SOVALDI with carbamazepine, phenytoin, phenobarbital, oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Such coadministration is not recommended. Antimycobacterials: Coadministration of SOVALDI with rifabutin or rifapentine is expected to decrease the concentration 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 Supplements: SOVALDI should not be used with St. John’s wort (Hypericum perforatum), a potent intestinal P-gp inducer. HIV Protease Inhibitors: Coadministration of SOVALDI with tipranavir/ ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended.

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.

Hepatic Impairment: No dose adjustment of SOVALDI is required for patients with mild, moderate not been established in patients with decompensated cirrhosis. See peginterferon alfa prescribing information for contraindication in hepatic decompensation.

Patients with HCV/HIV-1 Co-infection: HCV/HIV-1 co-infected subjects. See Dosage and Administration for dosing recommendations in that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving SOVALDI + ribavirin in Phase 3 trials.

Patients with Hepatocellular Carcinoma (HCC) Awaiting Liver Transplantation:: SOVALDI was studied in HCV-infected subjects with HCC prior to undergoing liver transplantation in an pre-transplant to prevent post-transplant HCV reinfection. See Dosage and Administration for dosing and ribavirin in HCV-infected subjects prior to liverr transplantation was comparable to that observed in subjects treated with SOVALDI and ribavirin in Phase 3 clinical trials.

Post-Liver Transplant Patients: post-liver transplant patients.

CHC Patients with Genotype 5 or 6 HCV Infection: Available data on subjects with genotype 5 or

Reference: 1. SOVALDI® (sofosbuvir). US Prescribing Information. Gilead Sciences, Inc. Foster City, CA. December 2013.

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. SVDP0106 06/14

45

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Some Bariatric Patients Face More Lung Problems

BY MANDY ARMITAGE, MD, WITH ADDITIONAL REPORTING BY

ADAM MARCUS San Francisco—Patients with metabolic syndrome who undergo bariatric surgery are more likely to experience pulmonary complications after the procedure than are those without the syndrome, a new study has found.

In a previous study, researchers from Tufts Medical Center, in Boston, found that roughly 1% of patients undergoing weight loss surgery experience postoperative pulmonary complications, including pneumonia, pneumothorax and atelectasis. But the latest work is the first to connect metabolic syndrome (MetS) with such problems in these patients.

“There have been studies with MetS surrogates that have looked at mortality, but not specifically pulmonary complications. This topic was attractive because this particular database in a specific patient population consists

Antibiotics

Table 1. Pulmonary Complications After Bariatric Surgery Condition

Odds Ratio

95% CI

P Value

Atelectasis

1.40

1.13-1.74

0.002

Pneumonia

1.78

1.40-2.26

<0.001

Pneumothorax

0.52

0.12-2.22

0.57

Pleural effusion

1.46

1.04-2.05

0.03

Respiratory failure

3.86

3.01-4.93

<0.001

ARDS

2.24

1.27-3.93

0.008

Composite pulmonary adverse event

1.87

1.65-2.13

<0.001

ARDS,, acute respiratory p y distress syndrome; y ; CI,, co confi onfidence interval

of prospectively collected information, including patient conditions,” said Roman Schumann, MD, vice chair for academic affairs in the Department of Anesthesiology at Tufts, who led the study. Dr. Schumann presented his team’s findings at the 2013 annual meeting of the American Society of Anesthesiologists (ASA;

abstract BOC05).

Comorbid conditions of MetS, such as obesity, dyslipidemia, hypertension and glucose intolerance, often improve after bariatric surgery, according to the researchers. However, the incidence of MetS among obese patients who undergo bariatric surgery has not been

see Bariatric, page 50

different bacterial populations.” Future studies could try to find the mechanism by which antibiotics could be have substantial consequences on the functional stainfluencing cancer incidence. bility of microbiota in the colon. Previously, research “There are certain bacteria that might promote a proin mice and humans has suggested that tumor tisinflammatory environment,” Dr. Yang said. “Others may sues from colon cancers have lower levels of microbial alter or generate toxins that might potentially be carcidiversity and enrichment of certain bacterial strains nogenic or might transform certain dietary or intestinal (PLoS Onee 2011;6:e20447; Gastroenterology content into carcinogenic components.

Table. Multivariable Analysis of Number of Penicillin 2014;146:1534-1546).

From a standpoint of looking at what “The study suggests that long-term and Courses and Colorectal Cancer Risk are more biologically plausible effects of repeated antibiotic exposure might increase antibiotics on colorectal cancer risk, we Cases Controls Adjusted Odds Ratio colorectal cancer risk,” said Ben Boursi, MD, a Courses of should be looking at longer-term expoPenicillin (n) N=20,990 (%) N=82,054 (%) (95% CI, P Value) medical oncologist from the Integrated Cansure or exposure in the more distant past.” cer Prevention Center in Tel Aviv Sourasky 1-5 Richard Peek, MD, director of 8,926 (42.5) 33,320 (40.6) 1.10 (1.06-1.14; <0.0001) Medical Center, in Israel, who led the study. the Division of Gastroenterology at Dr. Boursi’s group presented its findings at 5-10 Vanderbilt University Medical Cen2,057 (9.8) 7,360 (9.0) 1.14 (1.08-1.21; <0.0001) the 2014 annual meeting of the American ter, in Nashville, Tenn., who was not 913 (4.4) 3,096 (3.8) 1.2 (1.11-1.31; <0.0001) Society of Clinical Oncology (abstract 1599). >10 involved with the study, called the The researchers evaluated the association research significant.

CI, confidence interval between the type, timing, cumulative dura“This is a very large study evaluating the tion and intensity of antibiotic exposure and effect of past exposure to multiple antibicolorectal cancer (CRC) risk, using data from the Health number of exposures to penicillin, with ORs ranging otics on colorectal cancer risk. It is hypothesis-generating, Improvement Network. This population-representative from 1.10 for one to five courses, to 1.2 for more than and provides a framework for more detailed mechanistic electronic medical records database in the United King- 10 courses (P<0.0001). The adjusted risk increase associ- studies to be performed that can determine the cause of dom contains information on 11.7 million patients, with ated with each additional antibiotic course per year was this effect,” Dr. Peek told Gastroenterology & Endoscopy follow-up as long as 18 years.

4% on average (P=0.008).

P News. “This study adds to the growing body of literature The investigators identified cases of CRC, excluding “This is the first study that has looked at whether supporting the role of the microbiota on diseases that patients with a known family history of CRC or inflam- or not, from an epidemiological standpoint, there is an develop within the gastrointestinal tract. It would be matory bowel disease and those who were diagnosed association between antibiotic use, which is a very com- helpful to discern whether particular combinations of with CRC before the age of 40 years. These patients mon exposure in the population, and colorectal cancer,” antibiotics exert a synergistic effect on cancer risk.” were matched with up to four controls based on age, sex, said Yu-Xiao Yang, MD, assistant professor of medicine Dr. Peek added that “the opportunity to enhance the practice site and duration of follow-up. and epidemiology at the Perelman School of Medicine diversity of the microbiome may be a strategy that can Dr. Boursi and his colleagues controlled for known at the University of Pennsylvania, in Philadelphia, and raise the threshold for malignant transformation. Howrisk factors for CRC, including obesity, diabetes, senior researcher on the study. ever, this requires much more detailed study.”

■ smoking, alcohol consumption, chronic use of aspirin According to Dr. Yang, the differences in effect likely Drs. Boursi, Peek and Yang reported no relevant financial and nonsteroidal anti-inflammatory drugs, as well as show that “different antibiotics behave differently on conflicts of interest. continued from page 1

previous screening colonoscopies.

The risk for developing CRC was increased by 6% in patients first exposed to penicillin more than one year prior to diagnosis (P=0.002), P and remained statistically significant for patients who used penicillin more than 10 years before a diagnosis of cancer, with an odds ratio (OR) of 1.11. The risk increased significantly with the

well studied.

The longitudinal database is a prospective collection of data from participating bariatric centers of excellence and is affiliated with the American Society for Metabolic and Bariatric Surgery and the Surgical Review Corporation, a nonprofit company that accredits centers of excellence in bariatric surgery. The Tufts team looked at data covering procedures between January 2008 and December 2010 and included demographics, procedural information, ASA status (≥2), the presence or absence of MetS-associated comorbidities and pulmonary complications.

Dr. Schumann and his colleagues analyzed data from 158,405 primary bariatric procedures (52% gastric bypass; 40% gastric banding; 4% sleeve gastrectomy).

Pulmonary complications included atelectasis, pneumonia, pneumothorax, pleural effusion, respiratory failure and acute respiratory distress syndrome.

The mean patient age was 45.7 (±11.8)

46

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Lap Chole Rates Surge in Younger Patients Trend correlates with rise in obesity

BY CHRISTINA FRANGOU SAVANNAH, GA.—The number of young people undergoing laparoscopic cholecystectomy nearly quadrupled over a 12-year period, a shift due largely to the growing prevalence of obesity, according to a study presented at the 2014 Scientific Meeting of the Southeastern Surgical Congress.

Between 1998 and 2010, laparoscopic cholecystectomy rates rose from 3.4% to 13% for individuals aged 15 to 24 years.

The increase far outpaced that seen for any other age group, and was almost entirely limited to obese individuals.

“Gallstone disease in childhood was once considered rare but clearly there has been a noticeable change in demographics. No longer is this a disease of women in their 40s who have had multiple childbirths,” said lead author James J. Tucker, MD, chief surgical resident at York Hospital, in York, Pa.

Dr. Tucker and his colleagues examined International Classification of Diseases, Ninth Revision, codes in the National Inpatient Sample to identify patients who underwent laparoscopic cholecystectomy or laparoscopic partial cholecystectomy between 1998 and 2010. They then classified the 4.5 million patients into age groups: 15 to 24, 25 to 34, 35 to 54, and 55 years and older.

The 15- to 24-age group experienced the largest surge in rates of laparoscopic cholecystectomy at 3.2%, compared with 2.2% for patients aged 24 to 35, 1.3% for patients aged 35 to 54, and 0.7% for the oldest patients (P<0.001).

Similarly, this youngest age group also underwent the largest increase in obesity, with prevalence rising 10.8% over 12 years. Among other groups, obesity climbed between 8.9% and 10.2%.

Among young patients, factors associated with obesity included being female, being white, residing in an urban location

or the southern region of the United States, undergoing treatment at a nonteaching hospital or a large hospital, and having a Charlson comorbidity index score of 3 or higher.

Analysis showed that obesity was the most significant independent driver for the escalating laparoscopic cholecystectomy rates among younger patients.

Laparoscopic cholecystectomy rates rose 10.8% in obese individuals. In comparison, there was only a 2.3% increase among nonobese 15- to 24-yearold patients.

This equates to substantial costs and health care burden, Dr. Tucker said. Total charges per procedure rose more than $3,000 to $22,802 for obese patients aged 15 to 24 years (P<0.001). Hospital stays increased from two to three days (P<0.001).

“This study clarifies and quantifies the challenges that surgeons see every day as a result of the growing number

of surgical patients presenting with obesity as a comorbidity,” said Michael S. Nussbaum, MD, professor of surgery and chief of general surgery at the University of Florida College of Medicine in Jacksonville.

“Gallbladder disease is such a common problem that the changing demographics demonstrated in this study may get overlooked. However, with the increased incidence of gallstones and the need for cholecystectomy in the younger obese population, this will add further to the overall health care costs related to obesity.”

Dr. Tucker identified several other factors likely contributing to the rise in laparoscopic cholecystectomy, including an increased use of ultrasound, the lithogenic effects of estrogen and a reduced threshold for surgery.

The investigators note that the correlation between obesity and laparoscopic cholecystectomy does not address causality. They used electronic medical records, which likely resulted in significant underreporting of body mass index.

■

Type 1 Diabetes Patients Benefit From Bariatric Surgery in Small Study More complications seen in type 1 patients than other bariatric patients

BY CHRISTINA FRANGOU Overweight patients with poorly controlled type 1 diabetes can experience significant improvements in glycemic status and comorbid conditions after bariatric surgery, a small study suggests.

“These patients will enjoy the metabolic benefits of bariatric surgery even if we can’t put their diabetes in remission,” said lead author Stacy A. Brethauer, MD, a bariatric surgeon at the Cleveland Clinic in Ohio.

In a letter published in the journal Diabetes Care, Dr. Brethauer and colleagues describe 10 morbidly obese patients with poorly controlled type 1 diabetes who underwent laparoscopic bariatric surgery between 2005 and 2012.

Patients included one man and nine women with a mean age of 45.6 years and a mean baseline body mass index of 41.6 kg/m2. Most had been diagnosed with diabetes more than two decades earlier.

They were considered higher-risk patients as each had approximately 10 obesity- or diabetes-related comorbidities.

Following surgery, nine of 10 patients

achieved an excess weight loss greater than 60%, a rate similar to that expected for a general bariatric surgery population.

Patients who lost weight experienced improvements in key diabetic measures, including reductions in glycated hemoglobin (10%±1.6% vs. 89%±1.1%; P=0.039) P and daily insulin requirements (0.74±0.32 vs. 0.40±0.15 U/kg per day; P=0.004).

P They also improved in low-density lipoP=0.007) and triglycprotein (–23±19.3; P erides (–30.5±17.1 mg/dL; P=0.007).

P Hypertension resolved or improved in five of seven patients, and albuminuria resolved in one of the two patients with preoperative microalbuminuria.

Sivamainthan Vithiananthan, MD, associate professor of surgery (clinical) and chief of bariatric surgery at Brown University, in Providence, R.I., said the findings could have significant implications for the 15% to 20% of individuals with type 1 diabetes who are obese.

“These patients, who are often young or adolescents, don’t have just type 1 diabetes when they are obese but may have some degree of type 2 diabetes as well, meaning they have insulin resistance on account of their weight. It becomes a vicious cycle.

“What bariatric surgery can do is help stop that process by addrressing the obesity and adiposity th hat’s driving their insulin resisttance.

Therefore, they can be at a mu uch lower dosage of insulin, have better control of their sugar and experience bettter longterm outcomes.”

Dr. Vithiananthan, who was not involved with the study, has performed bariatric surgery on people witth type 1 diabetes. Generally, these pattients are referred after an event like a heart attack or failing kidneys. “Hopefully, this study will encourage people to send people for surgery earlier rather than after an event,” he said.

Patients with type 1 diabetes who underwent bariatric surgery do have a higher risk for postoperative complications compared with other bariatric patients, a trend expected with a sicker patient population, said Dr. Brethauer.

Five postoperative complications occurred including diabetic ketoacidosis, one deep vein thrombosis, an ulcer at the gastrojejunal anastomosis, esophageal dysmotility and persistent nausea.

Physicians should monitor these patients carefully after surgery to watch for ketoacidosis as they adapt to a new diet, Dr. Brethauer said.

No intraoperative complications were

reported and no patient was converted to laparotomy.

Before this study, fewer than 12 cases of bariatric surgery in type 1 diabetes were reported in the literature. The reports generally showed significant weight reduction and glycemic control, although the reports were not consistent.

Dr. Brethauer said the favorable metabolic effects of bariatric surgery may facilitate medical management of type 1 diabetes in the setting of morbid obesity.

But the true role of bariatric surgery in these patients requires longer follow-up studies, he said.

“The take-home point is that type 1 diabetics may be candidates for surgery.

You can have good metabolic outcomes in these patients even though they may be higher-risk from a medical standpoint.” ■

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48

Snare continued from page 1

Best Approach Still Unclear Polyps of intermediate size have presented a challenge for clinicians, who have no standard method for how to resect the lesions, Dr. Kim said. Incompletely resected lesions are responsible forr 10% to 27% of interval cancers (Gastroenterologyy 2013;144:74-80).

Surveys that are approximately five to 10 years in duration have found HSP used in 50% to 80% of 5- to 9-mm polyps, butt the more recent trend has been toward greater use of CSP. CSP is believed to be safer than HSP, yet it remains unclearr whether it compromises resection.

The new study aimed to compare HSP and CSP in terms of their ability to completely resect 5- to 9-mm polyps and theirr complication rates, and to identify factors that predict an incomplete resection.

In the single-center, prospective, randomized controlled trial conducted between August 2011 and Septemberr 2013, investigators randomly assigned 203 patients with at least one flat or sessile polyp of 5 to 9 mm in size (mean, 6.40 mm), to undergo HSP or CSP. The HSP group had 103 polyps analyzed; the CSP group had 110 analyzed. Lesions were sessile in 71% of cases and flat in 29%; proximal in 61% and distal in 39%; and tubular/tubulovillous adenomas in 81% and serrated in 19%.

The endoscopists used single snaring as the standard procedure for each polyp.

One expert and three fellows performed the colonoscopies.

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

The primary outcome was the complete resection rate after HSP or CSP. Secondary outcomes were clinically significant bleeding or perforation rates and tissue retrieval rates.

Complete C l R Resection i M More Likely Lik l With Hot Snare The rate of complete histologic resection was significantly higher for patients in the HSP group (92%) than for those in the CSP group (79%; P P=0.012). Visual eradication, however, was not significantly different (88% vs. 82%, respectively; P P=0.254), Dr. Kim reported.

Neither group experienced clinically significant bleeding or perforations.

Intraproce-

dural bleeding occurred in 6% of the HSP group and 9% of the CSP group ((P P=0.504).

0 504) M Mostt was caused by quadrantic forceps biopsies rather than snaring, Dr. Kim said.

Failure of tissue retrieval occurred in 4% of polyps resected by CSP, compared with 0% for HSP, but the difference was not statistically significant.

In the multivariate analysis, use of CSP and the presence of serrated polyps

showed the strongest association with incomplete resection. Incomplete resection occurred in 21% of CSP cases, compared with 8% of HSP cases, for an odds ratio of 2.94 (P=0.017).

P Serrated polyps were significantly more likely to be found than tubular adenomas or tubulovillous adenomas in polyps completely resected: 63% versus 37% in incompletely resected polyps, for an odds ratio of 5.35 (P<0.001). Size, gross morphology and location of the polyp were not significantly associated with incomplete resection.

Complete Eradication the Goal Dr. McQuaid said two things in particular about the presentation caught his attention. “One is the fact that we really do want to be completely eradicating polyps. Last year at DDW, we heard that cold snare did a much better job than cold forceps in this regard,” he said. “Especially

in polyps 5 mm and larger, we have moved away from doing multiple biopsies, focusing on the snare technique. What has been attractive about cold snare is that it’s a relatively quick procedure, and we all thought it might be safer.

“But this study showed cold snare is not as effective in achieving complete eradication, especially of serrated adenomas, and that is concerning,” he said. “The sample size is too small ll tto really ll kknow about b t complications, li ti and perhaps we need a larger comparative trial to get our arms around this.”

Meanwhile, Dr. McQuaid said the findings make him wonder, “Am I doing a disservice to my patients by not doing hot snares? That’s the question.”

■ Drs. Kim and McQuaid reported no relevant financial conflicts of interest.

Alcohol continued from page 25

benefits touted for modest consumption might be most experienced by those at risk for cardiovascular disease.

However, as a hepatologist caring for those with established liver disease, it is difficult in most instances to support any consumption of alcohol.

Dr. Kowdley: It has generated quite a lot of controversy, but there’s no question that mild or light alcohol consumption—say along the lines of one glass of wine per day—has been shown repeatedly to have a favorable effect. What we don’t know is if it’s a surrogate for other lifestyle factors, such as coffee consumption, socioeconomic status, lifestyle or other factors that might be confounding what appears to be alcohol consumption. What we can deduce from this data, for patients without liver disease who might be enjoying a glass of wine per day is that mild alcohol consumption in an otherwise healthy person is OK. But the key is to not recommend alcohol as a healthy choice in patients that already have liver disease.

GEN: The CDC recently reported that there

is a bias in screening for alcohol abuse. Poor, uninsured, non-white men were far more likely to report ever having a conversation than, for

example, elderly white women in a higher socioeconomic bracket. What are some of the hurdles in overcoming this bias in screening?

Dr. Shah: This relates to your first question. We need to overcome the stigma of alcohol abuse and overcome the misperception that only poor people abuse alcohol. Alcohol abuse and alcoholism and alcohol liver damage affect members of all socioeconomic, sex and ethnic strata.

Dr. Chung: One way of overcoming such a bias may be the use of standardized simple questionnaires that could be administered in the office before the appointment to all patients. Conversations could then ensue among those whose responses exceeded a trigger threshold.

Dr. Liangpunsakul: My take is that we have to find a way to increase awareness among clinicians. Every health care provider should realize that alcohol misuse can occur in any age group, including the elderly, and in any subjects with wide range of socioeconomic status.

Dr. Asrani: We are beginning to recognize that we as physicians also have preconceived notions of who

is affected by certain diseases. For example, heart disease was always thought of as a problem mainly for men, but now it is equally recognized in women. Similarly, we have to realize that alcohol-related liver disease can affect anyone. Also, alcohol-related liver disease is often stigmatized, so patients do not share their experience with others. Finally, there is also media portrayal of a “typical” alcoholic stereotype that often influences our perception of who might be susceptible to alcohol-related liver disease.

Dr. Kowdley: There is a bias in screening, but it also may be that the factors that drive liver disease with alcohol may be heavily influenced by socioeconomic status and nutrition. For example, studies have shown that if you eat when you drink, you almost never get liver disease. There is some bias in screening, but there is also probably some basis in science, in that that subgroup may be more likely to develop a phenotype in that disease. However, those biases do need to be corrected because surreptitious drinking that is unsafe can clearly be a factor in anyone. From an educational perspective, we need to recognize that anyone is at risk for alcoholism and we need to make that a routine part of our historical data gathering.

■

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GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Bariatric continued from page 45

years, and 78.5% were women. The majority of patients (65.3%) had an ASA physical status of 3.

MetS was present in 20,158 patients, or 12.7% of the total. A significant association was found between MetS and all pulmonary complications except pneumothorax (Table 1). Pneumonia and respiratory failure were most strongly associated (both P<0.001).

“It is unclear whether the presence of

MetS merely reflects a generally impaired physiological status that explains these findings, or whether the particular combination of the defining comorbidities is responsible,” the authors concluded.

“Medical optimization of patients with MetS prior to surgery appears to be warranted.”

Stephanie B. Jones, MD, president of the International Society for the Perioperative Care of the Obese Patient and associate professor of anesthesia at Harvard Medical School and Beth Israel Deaconess Medical Center, both in Boston, said the

results were unsurprising. “I personally feel that obesity hasn’t gotten the full attention of anesthesiologists because the majority of patients do fine, but with MetS, that’s where you start seeing the higher risk population. That’s who we should be looking at going forward, in terms of prospectively intervening.”

Dr. Schumann added, “We don’t really know if these patients are just sicker and it makes sense that they run into trouble after surgery, or if it’s a special combination of changes that puts them at higher risk for certain adverse outcomes.

We suspect inflammatory changes in the physiology may play an important not yet defined role in some of these observations.”

Dr. Jones said, “Part of the problem with these studies on MetS in general is that the definition has been sort of a moving target. But I do think it’s MetS rather than the comorbidities individually.”

In an unrelated study presented at the 2013 PostGraduate Assembly in Anesthesiology, New York City researchers found that a diagnosis of obstructive sleep apnea (OSA) and being overweight independently predicted a patient’s odds of being transferred to a step-down unit after surgery (P-9006).

“Transfers reflect patient outcomes and clinical decisions undertaken to prevent morbidity and mortality, suggesting increased postoperative complications in the OSA and the higher” body mass index, the authors wrote.

‘It is unclear whether the presence of MetS merely reflects a generally impaired physiological status that explains these findings, or whether the particular

OPT IN to receive your free monthly hl e-newsletter l at www. w gastroendonews.com d Be the first to get the latest news delivered r directly r to your computer.r The new interactive format has embedded Web W site links that give you instant access to gastroe r ndonews.com, where r you will find additional information as well as unique searc r h feature r s and article printing capabilities.

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combination of the defining comorbidities is responsible.

Medical optimization of patients with MetS prior to surgery appears to be warranted.’

—Roman Schumann, MD

Naum Shaparin, MD, director of the Pain Service in the Department of Anesthesiology at Montefiore Medical Center, in New York City, who helped conduct the study, said patients who use continuous positive airway pressure (CPAP) machines at home are “automatically continued on CPAP postoperatively.” However, CPAP generally is not started postoperatively on other patients, for fear that the increased pressure into the esophagus and stomach might adversely affect the surgical site, Dr. Shaparin said.

Dr. Shaparin said the results have not changed practice at Montefiore—yet.

“Once the final analysis is complete, we will arrange to present the data to the bariatric surgeons and the administration,” he said. “So, at the moment, there has been no change but we expect there will be a change once the data is presented.”

■

OPINION

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

51

Standard of Care: Donâ&#x20AC;&#x2122;t Try This at Home

BY NICHOLAS V. COSTRINI, MD, PHD, MBA I live in Savannah, Ga., on the east coast of the United States and site of the 1996 Olympic sailing competition.

It is a great place to learn how to sail. I have been sailing for 30 years, and, like almost all sailors, every time I take the boat out I learn something. I have had the good fortune of learning from real experts in the art, science and sport of sailing. I also have had the same mentor for a quarter-century. He has tried his best to ensure I am not the worst sailor in Savannah. At times, I think he worries that he has failed. I have run aground in the seemingly deep, clear blue waters of Wausau Sound so often that the dolphins know me by my first name. I have lost steerage, ripped sails, gotten lost and, on one occasion, nearly sank the yacht in a storm.

These mishaps occur less often now and my mentor and friends donâ&#x20AC;&#x2122;t run for the bar when I suggest we go for a Sunday sail. I have taken sailing seriously.

All sailors do or they take up golf, music or watch too much sports on television. Being committed to sailing applies to weekend day sailors just as it applies to the otherworld sailors of the Americaâ&#x20AC;&#x2122;s Cup billion-dollar enterprises. Serious sailors have a checklist of issues to be addressed before leaving the dock. The list always includes weather forecast, wind speed and direction, tide times and current speeds, sail conditions, lines, motor status, depth finder working order, maps of channel and general waterway depth, crew competence, boat security

items and sailing plan for exiting and entering a marina.

If I pay attention to all of these items, odds are good the sailing will be pleasant and uneventful. However, when man enters the world of Mother Nature and the sea, she will have her fun. I prefer to have my mentor on board to this day. Mentors give us all an edge in every endeavor. That is what mentors and experts are supposed to do, but even the best can get into trouble.

I recall the North Carolinaâ&#x20AC;&#x201C;South Carolina Governors Cup sailboat race of a few years ago. The winds were strong and the seas were rough. A magnificent 45-foot Beneteau yacht was making its maiden race; its crew was uniformed and moved with the ease and coordination of a Navy SEAL team. We were right behind them. They rounded the race buoy and threw up a huge

spinnakerâ&#x20AC;&#x201D;a big, colorful, parachute sail for downwind sailing. It was an awesome sight to see.

Suddenly a huge gust of wind and a massive wave came to visit. The huge sail was too much for them. A massive explosive sound rose from the Beneteau as its bow dug into the deep heart of the wave. The spinnaker, the mailsail and the mast itself were ripped from the deck and fell into the ocean. The experts had de-masted the yacht. No one was injured and a committee boat rescued the crew. We quietly kept our spinnaker in the bag and sailed on. Expert advice of sorts.

When I am not checking the weather reports and looking for a crew, I read gastroenterology articles. How else is one to keep up with the new observations, know see Sailing, page 52

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

Sailing continued from page 51

what the current standard of care is, make the professional decisions about what new techniques to learn and programs to establish in a community practice?

Among other things, I, like most of you, have been doing a good deal of reading about Barrett’s metaplasia, dysplasia, mucosal T1a cancer, endoscopic mucosal resection and dissection. One of this year’s articles from a leading academic center made it clear that it can be

difficult to make an accurate diagnosis of low- and high-grade dysplasia and T1a malignant disease and that the endoscopic decisions may be life-changing. I read on. In the summary, the experts offered that such patients should be referred to a center that has the expertise ((JAMA 2014;311:1209-1214).

Am I the only one to notice or does that advice not pose a problem? At this point, the standard of care for management of Barrett’s and all its challenges includes ablation, endoscopic mucosal resection (EMR), endoscopic mucosal

dissection and correct pathologic staging of T1a cancer. The management is indeed a life-altering decision: EMR versus esophagectomy.

As I monitor the medical literature, the academic advice is more often to refer the patient rather than assume, encourage and expect the metropolitan community gastroenterologist to deliver the standard of care. This dynamic is being expressed in numerous ways across the medical sea; and just as in sailing, it is important to know if the winds are going in one direction and the current in another. Yacht progress

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depends on it.

The forces pulling care into medical mega-centers are these: • The research and first expertise is there.

• The experts tell us we should route them—lawyers love this.

• The Leapfrog Group has proclaimed the commandment that volume equals quality.

• Gastroenterologists are older and their skills may not be the state of the art.

• Obtaining privileges for new procedures is a serious challenge.

• Mega-medical centers are purchasing metropolitan hospitals or developing agreements to increase referrals.

• For necessary financial reasons, referrals are encouraged for even the basic care items such as routine endoscopy.

The opposing forces pushing care into the local, metropolitan sector are these: • Most health care is provided in metropolitan areas of less than 1 million inhabitants.

• The National Cancer Institute (NCI) has established community cancer centers with the intent of “providing cancer care at home.”

The leading cancer clinical trials of the NCI have limbs to include local enrollment.

• The entire academic community and specialty gastoenterology societies from Indiana to India offer hands-on courses for the very technology experts wish referred.

• Insurance companies support local referrals and not university center referrals.

• For necessary financial reasons, hospitals, clinics and private physicians wish to keep care in their own hands.

All this may seem like the old “townand-gown” competition of the past century, but now it portends more conflict, less cooperation, blurring of the roles of academia and the private sector, and most importantly poses a serious threat to patient care. If the standard of care is relegated to our deeply needed and appreciated mega-centers of excellence, only a minority of patients will have the standard of care available.

The Way Forward A serious sailor does not simply list the problems. He discusses the issues with the crew and assigns duties and responsibilities and charts the best course given the situation. So, too, in this situation.

Role of the Academic Community • Fulfill the mission of research and training of a new generation of

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • JULY 2014

physicians.

• Recognize that most advances in gastroenterology care, standard of care must be designed and translated in such a manner that it can be practiced in the community.

Kenneth Wang, MD, of Mayo Clinic, offers this as the true definition of progress.

• The academic community can develop training programs for the practicing gastoenterologist that offer clear, attainable goals, establish measures of competence in the community, offer testing and importantly, certification that will be accepted by a metropolitan hospital credentials committee. Currently, hands-on courses offer no such support. The reasons are understandable and numerous but not insurmountable, if the goal is a priority.

• When mega-centers of excellence make agreements with metropolitan hospitals, as much effort must go into providing expertise locally as goes into encouraging referrals to the mega-center. This will promote a local standard of care for a broader public.

Role of the Private-Sector Metropolitan Gastroenterologist • As progress moves ever faster, practicing gastroenterologists must accept the fact that new technologies require greater commitment to learning. Given the success of the gastroenterology society meetings, that should not be difficult. What is new is that to meet a standard of care, the effort will have to be greater.

• Seek mentorship for the new work.

That may be more difficult than it sounds.

• Do not work in a vacuum. For example, to do EMR work, the pathology department will have to be encouraged to augment its own expertise.

An interested chest surgeon and oncologist should be enlisted to share in the efforts. The hospital administration must be willing to provide the support in terms of staff and resources needed for standardof-care quality work. To have a flow of patients, one should develop a marketing plan with all of the above involved.

• Avoid the “see one, do one” mentality. That only serves to make everyone nervous.

If all of the above is really about money, then we should face up to it in a manner that assists the various competing but mutually legitimate issues just raised.

When a fellow leaves training, he or she can be offered the following program.

In five years after leaving the academic nest, he or she will support the activities of the division with an annual contribution of perhaps 1% of collections. Given the collection rates for mega-center care, the real value of a gift compared with doing the work in the mega-center is colossal. It is estimated that a direct gift, cash contribution of $5,000 would require gross revenues to the institution of $200,000 to $250,000 (assuming a 2% profit margin). The gift also would represent a return on investment, as the fellow learned his or her craft from

the mentors in the academic center. In return, the institution offers career-long mentorship; free continuing medical education programs; and an opportunity for the physician to return periodically for short, specific training programs without cost. Such a program would strengthen the relationship between the academic and private sectors, promote career-long learning, develop a system in which the academic center has a reason to ensure ongoing success in its products—that is, the practicing gastroenterologist. Such a plan would promote the standard of

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care at home. Indeed, that goal would establish a progressive triad rationale for mega-medical centers to exist: research, teaching and promotion of the standard of care at home.

I hasten to add that when I suggested this program to leading academic gastroenterologists, it was roundly and thoroughly dismissed. I was almost made to walk the plank! I don’t know if the weather will get better, but sailors are always optimistic that the sky will clear.

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Endoscopic Eradication Therapy for Barrett’s Esophagus SHREYAS SALIGRAM, MD, MRCPa,b PRASHANTH VENNALAGANTI, MDa PRATEEK SHARMA, MDa,b a

Department of Veterans Affairs Medical Center Kansas City, Kansas b University of Kansas School of Medicine Kansas City, Kansas

Dr. Sharma has received grant support from Barrx Medical, CDX Labs, Coo ok Medical, Ninepoint Medical, and Olympus Inc. Drs. Saligram and Vennalaganti reported no relevant conflicts of interest.

B

arrett’s esophagus (BE) is the precursor lesion to esophageal al adenocarcinoma adenocarcinoma,

which in an invasive stage causes significant morbidity and mortality.

Surgery was the mainstay of treatment for patients with high-grade

dysplasia (HGD) and adenocarcinoma associated with BE. However, surgery in itself carrie es substantial morbidity. There has been tremendous progress in the t minimally invasive treatment of BE in the past decade.

The premise to be aggressiv ve in treating dysplastic BE and ea arly stage of adenocarcinoma is to prevent progression to an adva anced stage cancer. Most interventio onal endoscopists are comfortable treatting dysplasia and intramucosal esophageal cancer, ca although recently there have been emerging data on the treatment of early submucosal cancer in BE. This article reviews the different modes of and strategies for endoscopic treatment of BE with emphasis on newer techniques.

Introduction Barrett’s esophagus is defined as displacement of squamocolumnar junction by intestinal metaplasia (IM; goblet cells) proximal to the gastroesophageal junction.

The overall population prevalence is estimated at 1.6%1 with an annual incidence of 62 per 100,000.2 In patients with BE, the annual incidence of esophageal adenocarcinoma is reported to be between 0.12% and 0.5%.3-6 Intestinal metaplasia can have a histologic transformation from no dysplasia to low-grade dysplasia (LGD), HGD, and eventually to esophageal adenocarcinoma.7

Patients with HGD have the highest tendency to progress to esophageal adenocarcinoma. Therefore, endoscopic eradication therapy increasingly is used to treat HGD and early esophageal adenocarcinoma to decrease the progres-sion to invasive disease. Data fro om the US National Cancer Institute sshow a 6-fold increase in the incidence of esophageal adenocarcinoma in 2001; the disease now is considered the fastest rising cancer in the United States.8

Rationale for Endoscopic Eradication Barrett’s esophagus has the potential to transform itself into esophageal adenocarcinoma by genetic alteration of IM, where there is unregulated cell growth due to inactivation of tumor suppressor genes and activation of oncogenes. This genetic activity causes a morphologic change in the lining of the epithelium of the esophagus called dysplasia (cytologic atypia, architectural complexity due to nuclear pleomorphism and hyperchromatism confined to basement membrane).9,10 The aim of ablation/eradication therapy is to destroy

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this abnormal lining of the esophagus and reinstate the neosquamous epithelium.

Natural History of Dysplasia in BE Before embarking on endoscopic therapy for BE, it is important to understand the risks for dysplasia and cancer in these patients. Contemporary literature suggests that the reported rate of progression of cancer or dysplasia from IM, or nondysplastic BE, is low.6 Nondysplastic BE, which is the early stage of the condition, has the lowest incidence of transforming to dysplasia or esophageal adenocarcinoma. A retrospective study of 1,204 patients diagnosed with nondysplastic BE during index endoscopy and followed for a mean period of 5.52 years found that 98.6% and 97.1% were cancer free after 5 and 10 years, respectively. Per-year incidence of esophageal adenocarcinoma was reported to be 0.27%, 0.48% for HGD, and 3.6% for LGD.11 A recent meta-analysis, which included 11,434 patients diagnosed with nondysplastic BE and followed for 58,547 patient-years, reported a low annual incidence of cancer, at 0.3%.12 Similar findings were reported from a large population-based study from Denmark, which found that the risk for cancer in patients with nondysplastic BE was less than 0.2% per year.

Low-grade dysplasia has a lower degree of dysplastic cells and is the initial stage of dysplasia. Several studies have shown varying results for LGD developing into HGD or cancer. A multicenter study including 210 patients with LGD followed for an average of 6.2 years reported a low incidence of esophageal adenocarcinoma (0.44% per year) and HGD (1.6% per year). Combined esophageal adenocarcinoma and HGD was 1.83% per year with a mean time of progression to esophageal adenocarcinoma of 4.41 years. Based on survival analysis, 97.4% of patients were cancer free after 5 years of follow-up.13 Based on this study, only 2.6% of patients developed cancer at the end of 5 years; overall, patients with LGD had a low risk for developing malignancies.

However, other studies found a higher incidence (up to 13.6% per year) of combined HGD and esophageal adenocarcinoma developing from LGD.14-16 This inconsistent incidence in the rate of LGD that becomes HGD and cancer was long suspected to reflect a sampling error and significant interobserver variability among pathologists.13,17 The natural course of LGD thus appears to be highly variable. A recent multicenter randomized controlled trial from Europe suggested higher rates of progression of LGD to cancer. The study included 136 patients with LGD, with 68 randomized to undergo radiofrequency ablation (RFA) and 68 monitored by surveillance endoscopy every 6 to 12 months. After 3 years of follow-up, 1.4% of patients undergoing RFA and 8.8% being followed without RFA developed esophageal adenocarcinoma.18 By comparison, a recent meta-analysis of cancer risk in patients with LGD (24 studies; 2,694 patients) showed a 0.5% risk for cancer.19 Clearly, LGD remains a difficult disease to diagnose.

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High-grade dysplasia has a greater prevalence of dysplastic cells and is the advanced stage of dysplasia. Timely treatment at this stage can prevent dysplasia from progressing to cancer. A 2008 meta-analysis found a high incidence of esophageal adenocarcinoma (6% per year) in patients with HGD who had not undergone ablation or surgery. Of the 236 patients who met the inclusion criteria for the study, 69 developed esophageal adenocarcinoma within 1.5 to 7 years of followup.20 A multicenter sham control trial in 2009 assigned 63 patients with HGD randomly to receive either RFA or sham procedure and followed them for 12 months.

Although 19% of the patients in the control group experienced spontaneous regression of dysplasia, a significant proportion progressed to esophageal adenocarcinoma.21 These data and the meta-analysis show beyond doubt that untreated HGD has a significant risk for developing into cancer.

Endoscopic Eradication Esophagectomy is effective in treating early-stage esophageal adenocarcinoma but is a radical therapy and carries a significant morbidity (30%-40%) and mortality (1%-4%).22-27 Therefore, it is used for patients at a high risk for or with the presence of lymph node metastasis.

A systematic review of 1,350 patients who underwent esophagectomy for intramucosal (T1a) esophageal adenocarcinoma showed that only 26 (1.39%) had lymph node metastasis in the final pathology.28 A retrospective review of 70 patients with T1a esophageal adenocarcinoma and 56 patients with submucosal (T1b) esophageal adenocarcinoma revealed lymph node metastasis in 1.3% and 22%, respectively. Lymphovascular invasion, tumor size of at least 2 cm in diameter, and poor differentiation were associated with an increased risk for lymph node metastasis.29 All T1b lesions, regardless of the depth of T1b (SM1 indicates invasion into the superficial third of the submucosa, SM2 invasion into the middle third, and SM3 invasion into the deepest third of the submucosa), were associated with significant lymph node metastasis (12.9%-20.4%).30 The risk for lymph node metastasis in early esophageal adenocarcinoma therefore is low and endoscopic eradication therapy can be attempted in the vast majority of patients with T1a lesions. However, endoscopic eradication therapy typically is precluded in patients with T1b esophageal adenocarcinoma because of the higher risk for metastasis to the lymph node.

To obtain accurate tumor staging of visible lesions and patients with esophageal cancer, endoscopic mucosal resection (EMR) is performed to assess depth of the lesion. In patients with known cancer on biopsies, the accuracy of TNM staging is enhanced when endoscopic ultrasound is combined with EMR.31 After accurate staging and resection of early esophageal adenocarcinoma, it is important to ensure that the rest of the BE is eradicated completely to prevent recurrence of cancer. A retrospective study of 349 patients treated with ablation therapy for BE found occurrence of metachronous

MODALITIESS

Table. Endoscopic Eradication Therapy for Barrettâ&#x20AC;&#x2122;s Esophagus Thermal ablation therapy

Argon plasma coagulation Laser therapy Multipolar electrocoagulation

Nonthermal ablation therapy

Cryotherapy Photodynamic therapy Radiofrequency ablation

Endoscopic resection

Endoscopic mucosal resection Endoscopic submucosal dissection

lesions in 21.5% of patients at a median of 15 months. The metachronous lesions were not found in the group that had undergone complete eradication of IM (CE-IM).32 The current practice for endoscopic eradication therapy of BE is resection of any visible lesions by EMR, ablation of residual BE to prevent metachronous lesions or recurrent neoplasm, and follow-up surveillance. Multimodal endoscopic eradication therapy with EMR and RFA commonly is used. Visible or flat lesions are described by Paris classification33 and endoscopic inspection for visible or flat lesions is performed under white light endoscopy. Advanced imaging techniques including chromoendoscopy and virtual chromoendoscopy; optical frequency domain imaging; or confocal laser endomicroscopy are available but underused. A recent meta-analysis showed that detection of HGD or cancer increased by 34% when clinicians used advanced imaging techniques.34 Based on the available evidence, the American Gastroenterology Association issued guidelines for endoscopic surveillance and eradication therapy of BE. Endoscopic surveillance should be performed every 3 to 5 years for nondysplastic BE, every 6 to 12 months for LGD, and every 3 months for HGD if endoscopic eradication therapy is not performed. All patients with dysplasia should have the diagnosis confirmed by at least 2 experienced gastrointestinal pathologists.

The treatment of early-stage dysplastic lesions is controversial given the variability in the diagnosis and natural history. In a recently concluded multicenter study, which classified LGD as inflammatory and dysplastic, interobserver agreement among expert pathologists was poor, with kappa values for inflammatory and dysplastic lesions of 0.03 and 0.04, respectively.

The overall kappa value for LGD was 0.2.35 The aim of endoscopic eradication therapy should be to eradicate BE completely once dysplasia has been eradicated to prevent the progression of residual IM to recurrent or metachronous neoplasia.36

OF

ENDOSCOPIC ERADICATION

The different modalities of endoscopic eradication therapy are listed in Table. The advent of RFA as primary therapy has displaced some of the older therapies like thermal (multipolar electrocoagulation, argon plasma coagulation, Yag laser) and nonthermal (photodynamic therapy) methods.37 Argon plasma coagulation for eradication of residual BE tissue after use of EMR and/or RFA is still used for the treatment of focal areas.

Endoscopic resection consists of 2 approaches, EMR and endoscopic submucosal dissection (ESD), depending on the depth of the tissue removed.

ENDOSCOPIC MUCOSAL RESECTION The 2 types of EMR that can be performed are focal and radical, or wide area.38 Focal EMR is a technique used to excise visible polypoid, flat, or nodular lesions of esophageal mucosa suspected to be harboring cancer. It serves both as a diagnostic tool for tumor staging and also as a therapeutic tool for excising the neoplastic lesion. Two commonly used techniques are the multiband ligator and the cap-assisted device.39 The multiband ligator40 uses suction to draw lesions into a cap and a rubber band is applied to create a pseudopolypoid lesion, which is then snared using electrocoagulation and the specimen is subsequently retrieved. The cap-assisted technique41 uses saline or diluted epinephrine (1:100,000) to lift the suspected lesion. A prelooping of the snare to the rim of the transparent cap attached to the endoscope tip is performed after raising the suspected lesion. The raised lesion is then sucked into a cap, creating a pseudopolyp, which is then snared by electrocoagulation before the specimen is retrieved (Figure 1).

Radical EMR is used to remove larger areas of BE. Side-by-side resections can achieve complete eradication of the neoplastic and metaplastic tissue, and the procedure is repeated every 2 to 3 months until all visible BE has been removed. This technique frequently is used in patients with noncircumferential BE, and those with maximal extents of lesions up to 4 to 5 cm in diameter.

SHORT-TERM RESULTS Few studies have used EMR as the sole treatment for eradication of all BE tissue. The majority of studies have used a multimodal approach, such as initial focal EMR followed by ablation to evaluate the efficacy of EMR in treating HGD and early esophageal adenocarcinoma. A retrospective study of 49 patients (67% HGD and 33% T1a adenocarcinoma) who underwent radical EMR with a mean follow-up of 22.9 months reported CE-IM in 97% of cases. No recurrence of dysplasia or cancer was observed in the 32 patients who completed the eradication protocol. However, nearly one-third of patients developed symptomatic stenosis that was successfully dilated.42 A multicenter randomized clinical trial enrolled 25 patients in a radical EMR group and 22 patients in combined modality group (focal EMR with ablation

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Figure 1. Barrett’s esophagus with visible lesion pre– and post–endoscopic mucosal resection. therapy). During a mean follow-up of 24 months, 92% of patients in the radical EMR group achieved CE-IM compared with 96% in the combined modality group; similar high rates of CE-dysplasia or cancer were observed (100% in the radical EMR group vs 96% in the group receiving combined modality).43 Based on these studies and several others, radical EMR appears to have good short-term efficacy in treating HGD and early esophageal adenocarcinoma.44,45

LONG-TERM RESULTS Robust data now exist for long-term efficacy of EMR in patients with HGD and early esophageal adenocarcinoma. A prospective study of 100 T1a patients who underwent EMR with a mean follow-up of 36.7 months revealed CE-dysplasia or cancer in 99%—with metachronous lesions noted in 11%—that was successfully retreated with EMR.46 A retrospective study of 132 T1a patients with a mean follow up of 43 months found that of the 75 patients who underwent EMR alone, 96% achieved CE-dysplasia or cancer, with 11% recurrences.

All were successfully treated with a repeat EMR.47 Another recent retrospective study of 76 patients with HGD or T1a cancer who underwent radical EMR and were followed for a mean of 40.6 months reported a CE-IM rate of 71% and CE-dysplasia or cancer in 100%.48

COMPLICATIONS Adverse events associated with EMR generally are uncommon. Dysphagia, strictures requiring dilation,43,49-53 bleeding—both immediate and delayed for more than 48 hours after the procedure42,53-56—chest pain, and perforation are among the reported complications.57 Resection of more than 50% of the esophageal circumference is associated with higher rates of strictures.50 Radical EMR has been linked to more

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complications than focal EMR, including a high rate of strictures.42,43,57-62

ENDOSCOPIC SUBMUCOSAL DISSECTION This technique is used for en bloc resection of larger lesions. Pioneered in Japan mainly for early gastric lesions, the practitioner uses a coagulation tip to mark around the lesion. Diluted epinephrine with 10% glycerol (multiple other agents like hyaluronidate, mannitol, epinephrine, and indigo carmine can be used as well) is injected into submucosa to separate the lesion from the muscle layer. The mucosa initially is resected by needle knife and subsequently submucosal fibers and vessels by hook knife. The resected lesions are obtained for histopathology. The advantage of ESD over EMR is that larger lesions (7 cm) can be resected en bloc and more accurate information about depth of the lesion can be obtained.63,64

SHORT-TERM RESULTS A single published study evaluated the outcome of ESD. The trial included 29 patients known to have large T1a cancers, with a median diameter of 2 cm, in the setting of BE. The patients underwent ESD. They were followed for a mean period of 17 months. An R0 resection was achieved in only 38.5% of the patients. CE-IM and neoplasia was achieved in 53.6% and 96.4% of patients, respectively. The CE-IM rate increased to 80% when additional treatment with RFA was performed.65

LONG-TERM RESULTS As ESD is relatively new, few studies have reported the long-term efficacy of the technique. One such study, of 25 patients (both T1a and T1b) who underwent the procedure with a mean follow-up of 30.6 months, showed that en bloc resection was achieved in 100% of

Figure 2. Barrett’s esophagus pre– and post–radiofrequency ablation. patients but R0 resection was attained in only 72%. The mean size of resected lesions was 1.6 cm. There were no reports of neoplasia recurrence among patients who achieved R0 resection.64

COMPLICATIONS Although the data are limited, published reports suggest that complications in expert hands are minimal.

Some of the known complications are delayed bleeding, sudden cardiac death, incomplete R0 resection, and strictures.64,65

RADIOFREQUENCY ABLATION Radiofrequency ablation is the most commonly used and best studied ablative therapy currently available for the treatment of BE (Figure 2). RFA can be performed with either a circumferential or focal device.

The circumferential ablation device has a 3-cm cylindrical balloon with circular electrodes delivering the preset energy to ablate in a circumferential fashion. The focal ablation device is placed over the tip of the endoscope to ablate smaller areas with preset energy.

SHORT-TERM RESULTS Several published studies have evaluated the shortterm efficacy of RFA, which appears to be excellent. A retrospective registry study from 19 centers in the United Kingdom included 335 patients (HGD, 72%; T1a esophageal adenocarcinoma, 24%; and LGD, 4%) treated with either focal EMR and RFA (49%) or RFA alone (51%).

After a mean of 2.5 treatments and 12 months of followup, CE-IM and CE-dysplasia were achieved in 62% and 81% patients, respectively. Invasive cancer developed in 3% of patients and the cumulative risk for cancer progression more than 5 years was 8%.66 Another retrospective study of an American cohort of 54 patients

with T1a cancer who underwent focal EMR combined with ablation therapy (81%) with a mean follow-up of 23 months, reported CE-dysplasia/cancer in 96% and CE-IM in 59%.53 A recent meta-analysis that included 3,802 patients from 18 studies evaluated the efficacy of RFA in treatment of BE during a 20.5-month follow-up period. The overall rates of CE-IM and CE-dysplasia were 78% and 91%, respectively.67 A recent Cochrane review of 1,074 patients from 16 studies evaluated the efficacy of RFA in treatment of BE during a 12-month follow-up period. The overall rates of CE-IM and CE-dysplasia were 82% and 94%, respectively.37 Thus, based on the available evidence, short-term efficacy for RFA for CE-IM has been reported to be 62% to 82%, and CE-dysplasia as 81% to 94%. Cancer recurrence was seen in 3% of patients at the end of 12 months.

LONG-TERM RESULTS Several recent studies have focused on the longterm efficacy of RFA therapy after achieving initial successful eradication of BE. A multicenter analysis of 448 patients (HGD, 60%; T1a esophageal adenocarcinoma, 11%; LGD, 15%; and nondysplastic BE, 14%) who underwent EMR (55%) and RFA revealed that CE-IM was achieved in 26%, 56%, and 71% at 1, 2, and 3 years, respectively. Kaplan-Meier analysis showed that the incidence of recurrent IM at 1 and 2 years was 20% and 33%, respectively. Younger patients and those with short-segment BE responded much better to RFA.68 A single-center long-term retrospective study on BE was conducted of 72 patients (HGD, 49%; T1a esophageal adenocarcinoma, 22%; and LGD, 17%). All patients underwent RFA alone. After a mean of 2.3 treatments and 9.5 months of follow-up, CE-IM and CE-dysplasia were achieved in 79% and 89% of patients, respectively. Superficial adenocarcinoma persisted in 5% of

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Figure 3. Barrett’s esophagus pre- and post-cryotherapy.

patients requiring esophagectomy. Thirty-four patients who achieved CE-IM were followed for 3 years with no further recurrences noted. The overall rate of CE-IM was 73%.69 RFA therefore appears to have excellent short-term efficacy in achieving CE-IM (71%-93%) and CE-dysplasia (98%-100%). However, during long-term follow up, 15% to 30% of the patients can experience recurrence of IM within 2 to 3 years of achieving CE-IM, thereby requiring ongoing surveillance.

COMPLICATIONS RFA is generally well tolerated. Bleeding, mucosal tears, dysrhythmias, chest pain, buried metaplasia (IM buried under neosquamous epithelium),70 recurrent esophageal adenocarcinoma, and HGD66,71-75 are among the reported complications. A systematic review in 2011 showed that of 1,004 patients who underwent RFA, only 0.9% had buried metaplasia.70

CRYOTHERAPY Cryotherapy is a relatively new technique to ablate BE, using an extremely low temperature—between –76°C and –158°C76—to target tissue for destruction and ablation (Figure 3). A repetitive cycle of rapid-freezing and slow-thawing results in the formation of extracellular and intracellular ice, which disrupts cell membranes and tissue ischemia through vascular thrombosis due to vascular stasis.76-78 Two types of cryotherapy devices are available: CSA Medical, Inc., with a modified cryodecompression tube, delivers liquid nitrogen at –196°C, and GI Supply, with a suction catheter attached to the tip of the endoscope, uses high-pressure gas carbon dioxide at –78°C. The depth of the tissue injury depends on the duration of the freeze time.

The technical advantage of cryotherapy over other ablative therapies is that it is easy to spray over large areas of mucosa, causing destruction without precise

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close contact. Hence, it is particularly helpful in tortuous esophageal anatomy and at the area of the gastroesophageal junction. However, both robust short- and long-term results are lacking with this technique.

SHORT-TERM RESULTS Two small observational studies reported the shortterm efficacy of cryotherapy. A retrospective study of 60 patients followed for a mean period of 10.5 months found that after a mean of 3.4 treatments of liquid nitrogen cryotherapy, CE-dysplasia was achieved in 87% and CE-IM in 57% of treated patients.79 In another small study, 30 patients with BE (HGD-25 and T1a-5) underwent liquid nitrogen cryotherapy and were followed up for a mean of 12 months. There was downgrading of pathology in 90% of the patients with a mean of 5 sessions. The reported rates of CE-IM, and CE-dysplasia/cancer were 3.3% and 60%, respectively.80 Finally, a trial of 23 patients treated with 6 treatments of carbon dioxide cryotherapy and followed for a mean of 11.5 months found CE-IM and CE-dysplasia in 95.6% of patients. Twenty-five of these patients had failed earlier treatment with RFA, photodynamic therapy, and EMR.81

LONG-TERM RESULTS A single retrospective study including 32 patients with HGD evaluated the long-term efficacy of cyrotherapy. Patients underwent a mean of 4 treatments and were followed for a mean 37 months. In this study, CE-HGD was achieved in 96% and CE-IM in 81% of patients.82

COMPLICATIONS Adverse effects reported with cryotherapy usually are self-limiting. Chest pain and dysphagia are the predominant complications with minimal stricture and rare perforation. Odynophagia and sore throat are some of the other known complications.79,80,83

Summary Current evidence suggests that multimodal endoscopic eradication therapy with focal EMR and RFA is the best therapy for treatment of BE with HGD and T1a esophageal adenocarcinoma and should be the preferred management option over surgery. Defining LGD continues to remain a challenge with poor interobserver agreement and wide variability rates in cancer progression reported in the literature (0.5% in a recent meta-analysis to 8.8% in a randomized controlled trial in Europe).

Radical EMR is associated with more complicatio ns than focal EMR. Endoscopic submucosal dissection is technically challenging, with low R0 resection rates, making it less attractive. Therefore, the procedure is still in an incipient stage. Cryotherapy appears promising due to its low cost and the ease of the procedure, but more evidence regarding its longterm efficacy is required. Continued surveillance after achieving CE-IM is recommended due to risk for recurrence of intestinal metaplasia, buried metaplasia, and subsequent development of neoplasia.73,84

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