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HEPATOLOGY

I N

F O C U S

Sickest First In New Guidance For HCV Treatment BY KATE O’ROURKE

ith the rollout of new drugs for the treatment of infection with the hepatitis C virus (HCV), many patients who have been warehoused—waiting for more patient-friendly medications—are flocking to doctors. see Guidance, page 33

DNA Test Bests FIT For Large Polyps BY CAROLINE HELWICK CHICAGO—For colorectal cancer screening, multitarget stool DNA testing (MT-sDNA) is substantially more sensitive than fecal immunochemical testing (FIT) for sessile serrated polyps (SSPs), which are precursors to almost one-third of cancers. see DNA, page 26

Detection of Sessile Serrated Adenomas Bedevils Specialists Lesions pose problems for colonoscopists, onoscopists, pathologists alike BY CAROLINE HELWICK CHICAGO—Colonoscopists and pathologists may agree on many things, but sessile serrated adenomas (SSAs) does not appear to be among them. The recognition of SSAs is “worrisomely variable” for the two specialists, said William E. Karnes, MD, of the University of California at Irvine, who presented the results of a study that examined rates of SSA detection and classification at Digestive Disease Week 2014 (abstract 742). “We found that colonoscopists are extremely variable in detecting all polyp types, but if they have a high adenoma detection rate they are usually also good at detecting SSAs. As for pathologists, they were all good at detecting adenomas, but their rates of classification for hyperplastic polyps and SSAs varied significantly and were inversely related,” Dr. Karnes told Gastroenterology & Endoscopy News.

The Problem of SSAs Interval colorectal cancers occur within three to five years after colonoscopy and represent 7% to 9% of new cancer diagnoses. These lesions, which are

Med Board Uses Humor—Lamely, Critics Say—To Pitch MOC

predominantly right-sided and serrated, may be new lesions that developed rapidly, or they may occur because they are missed during colonoscopy, incompletely removed or inaccurately characterized by the pathologist. “The colonoscopist’s job is to get to the right side, find the flat polyps and make sure they are completely see Sessile, page 54

I N S I D E Time to reinvent the pyramid ......................................... page 6 How not to bungle bundled billing ................................page 10

BY TED AGRES ACG issues new guidelines for focal liver lesions .......page 48

hile controversy and serious debate continue to surround the issue of enhanced requirements for maintenance of certification (MOC), the American Board of Pediatrics (ABP) attempted a bit of summertime humor by emailing animated cartoons to its diplomates as reminders to complete their MOC requirements by year’s end. But some pediatricians—including

Improving IBD care in eight simple steps ....................page 66 Is Obamacare a successful failure? .............................page 70

see Humor, page 18 THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Faculty Daniel G. Luba, MD Chairman of the Board Project DNA 501(c)(3) Medical Director Monterey Bay Endoscopy Center, LLC Monterey, California

Introduction

Risk Assessment and Screening for Lynch Syndrome

The increased risks for breast and ovarian cancers associated with the genetic mutation of the BRCA1/BRCA2 genes is relatively well known among clinicians.1 Knowledge regarding other hereditary cancer syndromes, however, is comparatively low. For example, Lynch syndrome, also known as nonpolyposis colon cancer, develops from an inherited genetic mutation and is associated with colorectal, gynecologic, and other cancers. Studies have demonstrated that although Lynch syndrome has a similar prevalence to that of BRCA1/BRCA2 mutational syndromes, clinicians often fail to conduct adequate screening for the disorder.2,3 This article discusses a novel and simple screening system to identify patients with Lynch syndrome and thereby facilitate appropriate management and improve outcomes.

Characteristics of Lynch Syndrome Lynch syndrome is the most common inherited form of colorectal cancer and accounts for 2% to 3% of all colorectal cancer cases.4,5 Individuals with Lynch syndrome have an estimated lifetime risk for developing colon cancer as high as 80%.6 Endometrial and ovarian cancers also are associated with Lynch syndrome. Patients also have an elevated risk for developing cancer of the ureter, renal pelvis, stomach, biliary tree, and small bowel (Figure).6-12 Lynch syndrome is caused by germline defects in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, which result in microsatellite instability in tumors, loss of expression of the associated protein, or both.13 Early identification of an individual with Lynch syndrome allows for the application of intensive screening for the detection of cancers as well as consideration of primary and secondary preventative measures, such as total colectomy, hysterectomy, and/or oophorectomy.14,15

Screening for Lynch Syndrome Because screening and other interventions can have a profound effect on

Hereditary Colon Cancer ● Colon

Hereditary Colon Cancer ● Uterine (Endometrial)

Risk with hereditary ≤82%a colon cancer

Risk with hereditary colon cancer

General population 2% by age 70 y risk

General population risk

● Stomach

● Ovary

One such system is the multivariable polytomous logistic regression model PREMM1,2,6, a Web-based computerized personal and family history risk assessment (Table).17-19 It is designed to allow health care professionals to estimate the cumulative and individual probabilities that an individual is an MLH1, MSH2, or MSH6 mutation carrier.17 Several studies have examined the utility of the PREMM1,2,6 model. In the original study of the model by Kastrinos and colleagues, the areas under the receiver operating characteristic curves for prediction of genetic mutation were 0.86 for MLH1 mutation carriers, 0.87 for MSH2, and 0.81 for MSH6. This corresponded to an area under the curve of 0.88 for the overall cohort, indicating that this model can successfully predict an individual’s risk for mismatch repair mutations in these genes.14 Recently, DiSario and colleagues conducted a study to determine the feasibility of performing screening with the PREMM1,2,6 model for patients within a community gastroenterology practice.15 In their study, English-speaking patients presenting to a gastroenterology clinic or ambulatory endoscopy center for any reason were

Known Family Histories Associated With Hereditary Colon Cancerc

≤71%b • 1.5% by age 70 y

•

Endometrial cancer before age 50 Two or more Lynch syndrome cancersd at any age in the same person

Risk with hereditary colon cancer

Two or more family members with a Lynch syndrome cancerd on the same side of the family, one before age 50

General population risk

<1% by age 70 y

•

Three or more family members with a Lynch syndrome cancerd on the same side of the family at any age

Risk for a second cancer

≤50%b

•

Personal or family history of 10 or more cumulative colorectal polyps (adenomas) at any age

General population risk

5% within 15 y

small intestine, 7.2%; urinary tract, 4%; brain, 3.7%; biliary tract, 2%; all by age 70 y.

≤12%b

•

Figure. Hereditary colon cancer significantly increases risks for colon, uterine, and other cancers. a

Risk related to Lynch syndrome, attenuated familial adenomatous polyposis, or MYH-associated polyposis. b Risk related to Lynch syndrome. c Assessment criteria based on medical society guidelines. d Lynch syndrome cancers include colon, endometrial, ovarian, stomach, kidney/urinary tract, pelvis, biliary tract, small bowel, pancreas, brain, and sebaceous adenoma/carcinoma. Based on references 6-12.

Colon or rectal cancer before age 50

• •

Risk with hereditary ≤13%b colon cancer <1% by age 70 y

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Best Practices in Bowel Preparation for Colonoscopy

The PREMM1,2,6 Model

General population risk

Although the following cancers are rare, risk is also increased with Lynch syndrome:

See page 8

outcomes and survival, identification of patients with Lynch syndrome is critical.14 The benefits of genetic testing also extend to at-risk family members, who may use the information as a primary means to monitor for or prevent cancer. Definitive identification of Lynch syndrome can be achieved through genetic testing. However, costs make universal screening with genetic testing unfeasible. Furthermore, the optimal manner to target a subpopulation that would benefit from genetic testing for Lynch syndrome continues to be a challenge. Traditionally, several clinical systems and algorithms (eg, Bethesda system, Amsterdam II system) have been used for this purpose, but these systems are plagued by poor positive and negative predictive values. Indeed, Syngal and colleagues reported that the sensitivity and specificity of the Amsterdam II criteria were 72% and 78%, respectively, and those of the Bethesda criteria were 94% and 25%, respectively.16 The poor utility of those systems has prompted investigators to develop other models that more accurately determine an individual’s risk for Lynch syndrome in order to guide appropriate targeting for genetic testing.

and endoscopists to understand not only why the prevalence for suboptimal preparation is high, but also what techniques can help better ensure that patients will arrive for the colonoscopy procedure well prepared.

Jack A. Di Palma, MD, FACG Professor and Director Division of Gastroenterology University of South Alabama College of Medicine Mobile, Alabama

Adequate Preparation: Consequences And Improvements

Introduction

Best Practices in Bowel Preparation for Colonoscopy

When performed successfully, colonoscopy is one of the most powerful tools for the detection and removal of adenomatous polyps as well as for the diagnosis and management of colorectal cancer and other conditions.1 Its performance can be affected, however, by suboptimal bowel preparation.2 Adequate preparation for colonoscopy allows for detection of small (6-10 mm) flat or subtle lesions along the full length of the bowel.3 This level of colonoscopic discrimination is a prime determinant of the adenoma detection and removal rate as well as the ability to identify a variety of different colonic disease processes.4 Despite the importance of high-quality bowel preparation for successful colonoscopy, suboptimal preparation is common. The Clinical Outcomes Research Initiative investigators reported a 24% prevalence of inadequate bowel preparation,4 and a study of more than 8,000 consecutive colonoscopies over 5 years in the United Kingdom reported that poor bowel preparation was the most common cause of colonoscopy failure.5 Thus, it is crucial for gastroenterologists

Table 1. Colon-Cleansing Quality in Relation to Duration of Colonoscopy Cecal Arrival Time,a min No.

Intermediate High

Mean

Total Duration,a min

16.1

11.3

9.3

27.4

14.8

14.4

9.5

11.1

8.9

Mean

25.6

13.6

ANOVA

3,445

11.9

8.5

9.8

8.2

21.7

12.4

4,535

12.7

9.0

12.7

9.0

22.8

13.0

F-statistic (2 df)

See page 26

Withdrawal Time,a min

Mean

360 730

Cleansing Quality

Total

A previously identified hereditary colon cancer mutation in the family

Suboptimal bowel preparation has numerous adverse consequences for patients, clinicians, and potentially, the clinical practice as a whole. Preparation that is “adequate” rather than “excellent” often necessitates additional intraprocedural irrigation and suctioning, which may result in prolonging the procedure time (Table 1) and increasing the risk for colonoscopy failure.6 Furthermore, inadequate bowel preparation is associated with lower detection rates of polyps of any size as well as longer time to cecal intubation and withdrawal, leading to inefficiency.6 Patients who present with inadequate preparations typically are advised to repeat colonoscopy at an interval much shorter than would otherwise be recommended. The effect on overall cost for a lengthy procedure or repeat procedures is enormous both for the individual clinical practice and the health care system as a whole.2 For clinicians, the establishment of possibly mandatory quality measures for colonoscopy by overseeing agencies, such as the American Gastroenterological Association, may mean that colonoscopic failure secondary to inadequate bowel preparation might have an effect on a specific clinical practice’s reimbursements and reputation. Also, patients

45.6

17.3

45.8

<0.001

ANOVA, analysis of variance; SD, standard deviation a For patients with completed colonoscopies. b Multiple-way ANOVA with patient gender, age, group, health status, and indication for colonoscopy as cofactors. Reprinted with permission from reference 6.

26 GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

may have to contribute more to cover the cost of a colonoscopy procedure if insurance is unwilling to reimburse for a failed procedure in addition to paying for preparations for an earlier repeat procedure.7 To avoid these consequences and to improve the rate of patients better prepared for colonoscopy, researchers have conducted a number of studies attempting to identify predictors of poor colonoscopy preparation; these include interpreter requirement, polypharmacy, increased age, and the presence of comorbidities (especially obesity, diabetes mellitus, stroke, dementia, and Parkinson’s disease).8-11 Additionally, procedure-related factors, such as poor adherence to bowel preparation instructions and erroneous timing of bowel preparation regimen, were associated with poor bowel preparation.9,11 Nevertheless, selecting newer, high-quality bowel preparation products has been shown to lead to improved patient cleansing overall regardless of other factors present.11

Why Do Clinicians Allow Preparations To Be “Adequate”? If studies are helping to predict which patients are more likely to have a lower-quality preparation and newer prep formulations are enhancing the procedural experience for clinicians, why does the suboptimal preparation prevalence remain high? This may be associated with a variety of factors. For example, some patients may exert pressure on the clinician to choose an “easier” (ie, less-complicated instructions, better-tolerated formulation) or less-expensive bowel preparation regimen. In other instances, the ability of the endoscopist to employ compensatory strategies (ie, intraprocedure irrigation/suctioning) for the patient with inadequate bowel preparation can paradoxically serve as a disincentive to improving the rate of excellent bowel preparation among their clinical population. Time constraints within most clinical practices also can limit the amount or quality of patient education with regard to importance of compliance with the bowel regimen and preprocedure dietary restrictions. Multiple studies have found that additional time and resources given to educate the patient before the procedure helps improve arrival preparation.

GASTROENTEROLOGY & ENDOSCOPY NEWS • OTOBER 2014

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Risk Assessment and Screening for Lynch Syndrome

CORPORATE SPOTLIGHT Sigma-Tau Pharmaceuticals, Inc.

Sigma-Tau Pharmaceuticals, Inc. S

igma-Tau Pharmaceuticals, Inc. (STPI), is a U.S.-based, wholly owned subsidiary of the sigma-tau Group, and is dedicated to the global development and commercialization of medicines for patients with rare diseases. STPI is based in Gaithersburg, Md. Our marketed products are focused on cancer; kidney disease; and gastrointestinal and genetically related disorders. We also have clinical development programs focused on hematologic cancer, malaria and other areas of unmet medical need.

STPI’s long history in rare diseases dates back to 1986. Our company strives to take a leadership role in the community of patients, researchers and advocates involved with rare diseases. STPI is committed to helping to seed future research, as well as enhancing lives through affiliations with related organizations and activities that share our goals. STPI believes the continued growth of the company will be driven by the progression of our product pipeline candidates together with accessing late-stage/ commercial product opportunities in rare diseases.

Marketed Rare Disease Products Disease Category

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Cystaran™ (cysteamine ophthalmic solution) Adagen® (pegademase bovine) Carnitor® (levocarnitine) Abelcet® (amphotericin B lipid complex injection)

Anti-infective

See page 23

We also have products for Hodgkin’s lymphoma and Lymphomatous meningitis

Marketed Medical Foods and Dietary Supplements Dietary supplements

Medical food

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Colief® Infant Drops

For colic-associated crying in infants with transient lactose intolerance

VSL#3®, a potent probiotic

For the dietary management of ulcerative colitis, an ileal pouch and irritable bowel syndrome

Techniques for Promoting Best Preparation Practices For cancer screening purposes, a bowel preparation that is “adequate” rather than “excellent” can result in suboptimal outcomes. Indeed, one study demonstrated that colonoscopy with suboptimal bowel preparation resulted in a significant adenoma miss rate and that repeat colonoscopy performed some years later in those patients revealed advanced adenomas in roughly 27% of resected specimens (Table 2).12 Various strategies can be employed to improve the rate of successful bowel preparation among patients undergoing colonoscopy. Precise counseling of patients regarding the relationship between dietary restrictions and appropriate use of the bowel preparation regimen and the ability of colonoscopy to effectively and safely remove precancerous lesions is vital.13,14 All members of the clinical team and office

Corporate Spotlight

Company Overview

Sigma-Tau PharmaSource, Inc. (Manufacturing), a wholly owned subsidiary of Sigma-Tau Pharmaceuticals, Inc. Sigma-Tau PharmaSource, Inc., is a biopharmaceutical contract manufacturer specializing in complex injectable formulations, including liposomal drug delivery technology and PEGylation. Our mission is to provide flexible, responsive services and innovative solutions to our clients.

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Aseptic liquid fill Bulk formulation Cold chain Full regulatory support Liposomal formulation PEGylation Process optimization and scale up Process validation Project management Technology transfer

Contact Information For general inquires: Tel: (301) 948-1041 Email: sigmatauinfo@sigmatau.com 9841 Washingtonian Blvd. Ste. 500, Gaithersburg, MD 20878 For business development inquires: Email: BD@sigmatau.com

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Fidaxomicin May Be Best Choice for Some C. difficile Infections BY MARIE ROSENTHAL

reatment costs for cancer patients with Clostridium difficilee infection (CDI) appear lower with fidaxomicin than with vancomycin, resulting in a potential cost savings of $9,051 per patient, according to new data presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). “Patients with cancer represent a vulnerable population who are at high risk for CDI, often resulting from their compromised immune system. CDI can be a devastating addition for patients who are already battling preexisting conditions,” said Sebastian Heimann, health economist at the University Hospital of Cologne, in Germany, who led the analysis. The pharmacoeconomic model combined data from a study exploring the

resolution of CDI in cancer patients treated with either fidaxomicin or vancomycin, and a recent cost-of-illness analysis on CDI conducted at the University Hospital Cologne (abstract K-364). Fidaxomicin is marketed as Dificlir (Astellas) in Europe and as Dificid (Cubist) in the United States. Although the study presented at ICAAC looked at European hospitals, CDI is also a serious and costly problem in U.S. facilities. An estimated 107,700 cases of hospital-acquired CDI occur in the United States each year, according to the Centers for Disease Control and Prevention (CDC). The estimated cost of treating these cases ranged from $6,408 to $9,124, according to a CDC report (“The Direct Medical Costs of Healthcare-Associated Infections in U.S. Hospitals and the Benefits of Prevention, 2009”). This report said the cost estimate was low for two reasons: It did not include patients with operating

room costs associated with their hospital stay and it was done in 2003. The ICAAC analysis explored direct cost parameters including drug costs, treatment on the general ward and ICU as well as microbiological diagnostics for C. difficile. Mean overall costs per patient treated with fidaxomicin and vancomycin were $35,867 and $44,910, respectively. The lower costs associated with fidaxomicin were primarily due to the significantly lower rate of recurrence in patients treated with fidaxomicin compared with vancomycin. In other data presented at ICAAC, physician perceptions of the burden of CDI and the negative health effects of recurrent infection were assessed. Nearly all of the 1,567 European health care professionals surveyed accepted that a recurrence of CDI would have a medium or strong effect on patient health, in particular immunocompromised patients and those with a severe underlying disease.

Despite this, most respondents (60%) did not often consider this impact in their treatment decisions (abstract K-350). Only 26% of respondents in the survey said they always request a laboratory test for patients presenting with diarrhea that is not clearly attributable to an underlying condition or therapy, despite recent epidemiologic data suggesting the incidence of CDI is increasing in Europe. Interestingly, physicians believed 25% of clinically significant CDI cases remain undiagnosed in a hospital setting, increasing to as much as 45% in the community. A recent epidemiologic study found that as many as 39,000 cases of CDI may be missed each year in Europe. “CDI is a huge economic and societal burden and causes additional and unnecessary suffering to already sick patients, so there is clearly more that needs to be done to improve patient care and CDI management,” said Oliver Cornely, University Hospital of Cologne, who led the survey.

GASTROENTEROLOGY & ENDOSCOPY NEWS, the independent monthly newspaper for gastroenterologists, has been providing physicians with comprehensive and objective information since 1978. The newspaper is circulated to more than 17,500 gastroenterologists, colorectal surgeons, and hepatologists, and GI-specific physician assistants and nurse practitioners (as reported to BPA Worldwide, Publishers Audit, based on circulation data as of July 2013). Gastroenterology & Endoscopy News (ISSN 0883-8348) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Please send address changes to Gastroenterology & Endoscopy News, 545 W. 45th Street, 8th Floor, New York, NY 10036. Copyright © 2014 by McMahon Publishing.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Time To Rebuild Ancient Pyra amids To the Editor:

he classic inflammatory bowel disease (IBD) treatment pyramid presented at every professional meeting that we have attended during the past 35 years has suggested that the foundational layers of IBD management include aminosalicylates, antibiotics, steroids and immunomodulatory therapy, which have historically been the treatment substructure for Crohn’s disease and ulcerative colitis. Only after the FDA approval of infliximab in 1998 was this pyramid inverted to suggest a top-down approach, with a precarious balancing act on the tip of an otherwise stable and steady structure. Newer, targeted biologics preventing trafficking of certain subpopulations of inflammatory T-cells, as well as targeting specific pro-inflammatory cytokines, have been tested in numerous clinical trials. Although biological advances in treating these diseases have transformed the lives of some patients, the limited efficacy, lack of durability, unknown long-term safety issues and enormous cost constraints demand that we question how to redesign this pyramid. Should we turn it upside

down, erect a new and solid framework, or simply renovate the pyramid layers to include a customized bedrock? It is clear in our decades of exxperience that patients with IBD need a personalized blueprint. Understanding th he pathogenesis, genetic factors and enviroonmental interactions in the early stages off this disease is fundamental in designingg specific and unique therapies for each and every patient. The idea of a customized zed plan, although idealistic, in the current fiscal environment may not be tenable. The specific treat-to-target paradigm involves measurements of drug levels of small molecules and their antibodies, and so far has been cost-prohibitive and not of proven benefit in terms of outcomes for our patients. Most of the IBD community would agree that immunomodulatory therapy is of unproven efficacy in induction and maintenance of remission apart from steroid sparing in IBD; aminosalicylates have minimal or no value in Crohn’s induction and maintenance therapy. Steroids have induction benefits in IBD, but long-term therapy has clear safety concerns that outweigh those benefits.

An affordable method for detecting disease with simple serologic and other noninvasive measures is warranted. Controlling environmental factors, including diet, stress, smoking and narcotic dependence, with appropriate collaborative efforts in these areas, is mandatory to achieve better results. An initiative among IBD specialists, in our view, should include allocation of resources and attention—particularly research funding—to provide safer and more effective alternatives for our patients. We have an opportunity to apply unique, novel therapies using agents to repair the mucosal defect and to upregulate natural defenses and other regulators of the deranged cellular immunity.

Improving our understanding of the specific role of commensal and other potentially pathogenic microbes should also be a high priority area of exploration. The bottom line is this: With all of our knowledge and advances in the treatment of patients with inflammatory bowel disease, we still need more research and discovery on causation and a cure for these patients. We need to replace the crumbling pyramid with a new edifice built with integrity, good science and novel therapies. Ira Shafran, MD Patricia Burgunder, ARNP The authors are with the University of Central Florida College of Medicine, in Orlando.

Vol. 65, No. 10 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

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Farmington Hills, Michigan

Sacramento, California

FREDRIC DAUM, MD

PETER R. MCNALLY, DO

Mineola, New York

Fort Carson, Colorado

STEVEN M. FABER, MD

TARUN MULLICK, MD

Elizabeth City, North Carolina

St. Charles, Illinois

RONNIE FASS, MD

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Cleveland, Ohio

Tampa, Florida

BARBARA B. FRANK, MD

DAVID ROBBINS, MD

Philadelphia, Pennsylvania

New York, New York

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New York, New York

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October 2014

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THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Risk Assessment and Screening for Lynch Syndrome Characteristics of Lynch Syndrome

Faculty Daniel G. Luba, MD Chairman of the Board Project DNA 501(c)(3) Medical Director Monterey Bay Endoscopy Center, LLC Monterey, California

Introduction The increased risks for breast and ovarian cancers associated with the genetic mutation of the BRCA1/BRCA2 genes is relatively well known among clinicians.1 Knowledge regarding other hereditary cancer syndromes, however, is comparatively low. For example, Lynch syndrome, also known as nonpolyposis colon cancer, develops from an inherited genetic mutation and is associated with colorectal, gynecologic, and other cancers. Studies have demonstrated that although Lynch syndrome has a similar prevalence to that of BRCA1/BRCA2 mutational syndromes, clinicians often fail to conduct adequate screening for the disorder.2,3 This article discusses a novel and simple screening system to identify patients with Lynch syndrome and thereby facilitate appropriate management and improve outcomes.

Lynch syndrome is the most common inherited form of colorectal cancer and accounts for 2% to 3% of all colorectal cancer cases.4,5 Individuals with Lynch syndrome have an estimated lifetime risk for developing colon cancer as high as 80%.6 Endometrial and ovarian cancers also are associated with Lynch syndrome. Patients also have an elevated risk for developing cancer of the ureter, renal pelvis, stomach, biliary tree, and small bowel (Figure).6-12 Lynch syndrome is caused by germline defects in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, which result in microsatellite instability in tumors, loss of expression of the associated protein, or both.13 Early identification of an individual with Lynch syndrome allows for the application of intensive screening for the detection of cancers as well as consideration of primary and secondary preventative measures, such as total colectomy, hysterectomy, and/or oophorectomy.14,15

Screening for Lynch Syndrome Because screening and other interventions can have a profound effect on

Hereditary Colon Cancer ●

Colon

Uterine (Endometrial)

Risk with hereditary ≤82%a colon cancer

Risk with hereditary colon cancer

≤71%b

General population risk

1.5% by age 70 y

●

2% by age 70 y

●

Stomach

Known Family Histories Associated With Hereditary Colon Cancerc •

Colon or rectal cancer before age 50

•

Endometrial cancer before age 50

•

Two or more Lynch syndrome cancersd at any age in the same person

•

Two or more family members with a Lynch syndrome cancerd on the same side of the family, one before age 50

≤13%

Risk with hereditary colon cancer

≤12%b

<1% by age 70 y

General population risk

<1% by age 70 y

•

Three or more family members with a Lynch syndrome cancerd on the same side of the family at any age

Risk for a second cancer

≤50%b

•

Personal or family history of 10 or more cumulative colorectal polyps (adenomas) at any age

General population risk

5% within 15 y

•

A previously identified hereditary colon cancer mutation in the family

colon cancer General population risk

Ovary

The PREMM1,2,6 Model

Although the following cancers are rare, risk is also increased with Lynch syndrome: small intestine, 7.2%; urinary tract, 4%; brain, 3.7%; biliary tract, 2%; all by age 70 y.

Figure. Hereditary colon cancer significantly increases risks for colon, uterine, and other cancers. Risk related to Lynch syndrome, attenuated familial adenomatous polyposis, or MYH-associated polyposis. Risk related to Lynch syndrome. c Assessment criteria based on medical society guidelines. d Lynch syndrome cancers include colon, endometrial, ovarian, stomach, kidney/urinary tract, pelvis, biliary tract, small bowel, pancreas, brain, and sebaceous adenoma/carcinoma. Based on references 6-12. b

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Supported by

administered the PREMM1,2,6 model questionnaire on a tablet computer.20 Patients were advised to obtain family history of colon, uterine, and ovarian cancers during the initial scheduling call, in mailings of registration materials, and during a confirmation telephone call. Patients with a PREMM1,2,6 model score of at least 5% were then directed to watch a 4-minute video regarding Lynch syndrome followed by counseling by the provider. These patients also were offered genetic testing. Patients referred for genetic testing submitted buccal mucosal and/or blood samples for

genetic testing at a central commercial laboratory (Myriad Genetic Laboratories, Inc). This included DNA sequencing and/or large rearrangement analysis in a panel that included genes associated with Lynch syndrome.20 In all, 3,134 patients agreed to participate in the study, and 177 (5.6%) had a PREMM1,2,6 model score of at least 5%. Ultimately, 173 of the 3,134 patients underwent genetic testing, and 6 (3.5%) were positive for Lynch syndrome–associated mutations. A post-study survey of patients and clinicians showed high satisfaction with the implementation of cancer risk assessment and subsequent

Table. PREMM1,2,6 Model: Prediction Model for MLH1, MSH2, and MSH6 Gene Mutations

Conclusion

Proband Information a cancer diagnosis.

Proband sex ❍ Male

❍ Female

Number of separate colorectal cancers ❍ None ❍ One

❍ Two or more

Has the proband had endometrial cancer? ❍ No

❍ Yes

Has the proband had another Lynch syndrome–associated cancer? ❍ No ❍ Yes Other Lynch syndrome–associated cancers include ovary, stomach, small intestine, urinary tract/kidney, bile ducts, glioblastoma multiforme (brain), sebaceous gland tumors, and pancreas.

Relatives Information—First Degree (Only from affected side of family)

How many first-degree relatives have had colorectal cancer? ❍ None ❍ One

genetic testing. The majority of providers indicated that this process was easy to implement and functioned well within their existing practices without overly burdensome time demands.20 In another study that tested the cost–benefit of predictive models to identify patients for genetic screening, Dinh and colleagues reported that this strategy was cost-effective at $26,000 per quality-adjusted life-year. This estimate is well below the accepted health care cost-effectiveness threshold of $50,000 per quality-adjusted life-year and is comparable to the cost-effectiveness of other common cancer screening protocols.16 Furthermore, this strategy resulted in improved health outcomes for mutation carriers, including significant decreases in cases of colorectal and endometrial cancers and early detection of existing cancers.21

❍ Two or more

Lynch syndrome, also known as nonpolyposis colon cancer, is the most common form of inherited colon cancers and also is associated with a relatively high risk for gynecologic and other malignancies. Failure to proactively identify patients with Lynch syndrome results in missed opportunities for intensive surveillance and prophylactic interventions, thereby resulting in poor outcomes. The PREMM1,2,6 model is a simple and effective method of risk assessment that can be conducted in the routine course of clinical care. The use of this model to identify the subpopulation of patients that would benefit from definitive genetic testing is feasible, cost-efficient, widely supported by societal guidelines, and can help improve outcomes for affected individuals.

References 1.

How many first-degree relatives have had endometrial cancer? ❍ None ❍ One

❍ Two or more

Have any first-degree relatives had another Lynch syndrome–associated

cancer? ❍ No

❍ Yes

Relatives Information—Second Degree

(Only from affected side of family)

How many second-degree relatives have had colorectal cancer? ❍ None ❍ One

❍ Two or more

How many second-degree relatives have had endometrial cancer? ❍ None ❍ One

❍ Two or more

Bellcross CA, Kolor K, Goddard KA, et al. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am J Prev Med. 2011;40(1):61-66. Chen S, Wang W, Lee S, et al; Colon Cancer Family Registry. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA. 2006;296(12):1479-1487. Batra S, Valdimarsdottir H, McGovern M, et al. Awareness of genetic testing for colorectal cancer predisposition among specialists in gastroenterology. Am J Gastroenterol. 2002;97(3):729-733. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008;26(35): 5783-5788. Lynch HT, Lynch JF, Attard TA. Diagnosis and management of hereditary colorectal cancer syndromes: Lynch syndrome as a model. CMAJ. 2009;181(5):273-280.

Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. 1996;110(4):1020-1027.

Watson P, Vasen HF, Mecklin JP, et al. The risk of extra-colonic, extra-endometrial cancer in Lynch syndrome. Int J Cancer. 2008;123(3):444-449.

Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 1999;81(2):214-218.

Feuer EJ, Wun LM. DEVCAN: Probability of developing or dying of cancer software. http://surveillance. cancer.gov/devcan/. Accessed September 3, 2014.

10. Lynch HT, Harris RE, Lynch PM. Role of heredity in multiple primary cancer. Cancer. 177; 40(4 suppl):1849-1854. 11. Ellis CN. Inherited colorectal cancer syndromes. Clin Colon Rectal Surg. 2005;18(3):150-162. 12. Vasen HF, Stormorken A, Menko FH. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol. 2001;19(20):4074-4080. 13. Lynch HT, de la Chapelle A. Hereditary colon cancer. N Engl J Med. 2003;348(10):919-932. 14. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology. 2008;134(5):1570-1595. 15. National Comprehensive Cancer Network. Recommendations for Lynch mutation carriers. 2014. www.nccn.org/professionals/physician_gls/pdf/ genetics_colon.pdf. Accessed September 3, 2014. 16. Syngal S, Fox E, Eng C, et al. Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet. 2000;37(9):641-645. 17. Dana-Farber Cancer Institute. PREMM1,2,6 calculator. http://premm.dfci.harvard.edu. Accessed September 3, 2014. 18. Kastrinos F, Steyerberg EW, Mercado R, et al. The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology. 2011;140(1):73-81. 19. Balaguer F, Balmaña J, Castellví-Bel S, et al; Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. Validation and extension of the PREMM1,2 model in a populationbased cohort of colorectal cancer patients. Gastroenterology. 2008;134(1):39-46. 20. DiSario JA, Luba DG, Rock C, et al. A prospective feasibility study to evaluate the implementation and outcomes of a systematic genetic risk assessment and counseling process to screen for Lynch syndrome. Presented at: Digestive Disease Week; May 3-6, 2014; Chicago, IL. 21. Dinh TA, Rosner BI, Atwood JC, et al. Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population. Cancer Prev Res (Phila). 2011;4(1):9-22. Disclosure: Dr. Luba reported that he received grant support from Community Hospital of Monterey Peninsula, Myriad Genetics, Inc., and Salinas Valley Memorial Hospital. He also received honoraria from, served on the speaker’s bureau for, as a consultant for, and is a stock shareholder in Myriad Genetics, Inc.

Have any second-degree relatives had another Lynch syndrome–associated cancer? ❍ Yes

Calculate probability

Reset BB1423

❍ No

Based on references 17-19.

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Bungling Bundled Billing BY MARK F. WEISS, JD

ore competition. Rising practice expenses. How do you become more competitive? How do you become more profitable? Some gastroenterologists, chiefly those with their own facilities, have turned to the concept of bundled billing to gain a competitive edge. For those not familiar with the concept, bundled billing is the combination of multiple individuals’ or entities’ fees into a single price. So, for example, in connection with a certain procedure, your fee, the facility fee, the anesthesia fee and the pathology fee could be rolled, at a discount, into a bundled price. What could be wrong with that? Nothing. That is, unless you bungle it, in which case you might be committing a crime.

the payor or patient and retains the difference after paying the pathologist his or her agreed-to discounted amount; or • Instead of discounting his or his facility’s fee, the bundler uses the pathologist’s discount, but no discount on the bundler’s part, to create a lowerpriced package. As a result, the pathologist’s willingness to take less accrues to the advantage of the bundler who is now able to collect his or her full fee.

Depending on the nature of the services provided, it is possible

Hospital-Centered History

that the arrangement violates the

The concept of bundled billing came out of the hospital world: In order to market for a discrete service— for example, a certain surgical procedure—the hospital sought to have all, or at least some, of the physician providers involved in that procedure agree with the hospital on a fixed price for their services. Those prices were then added, along with the hospital’s fixed fee, into the bundle. The idea was to present a coordinated, discounted, competitive price for the bundled procedure or service.

Stark law, the federal “self-referral” prohibition that applies to any physician who makes referrals to those with whom the physician has a direct or indirect ownership or investment interest.

Fast Forward: The ASC Setting Today, gastroenterologists and other proceduralists, particularly those with ownership in free-standing surgical facilities, are turning to the concept of bundled billing to gain a competitive edge. Even in the hospital setting, bundled billing raises several concerns about compliance. But those concerns reach a crescendo when it appears that individuals in a position to refer are using bundled billing either to capture a portion of a referral source’s fees or to make their own, lesser discounted fees more attractive to payors or patients. In a real sense, these concerns center on the same issues present in an alternative, potentially abusive structure, that of the so-called “company model.” As a quick refresher, in the company model arrangement, either the ambulatory surgery center (ASC) controlled by referring physicians or the referring physicians themselves set up a company to deliver the services of “downstream” physicians. The concept is most prevalent in connection with anesthesia services: A separate anesthesia company is established to employ the anesthesiologists and nurse anesthetists working at the facility. The owners, the referring physicians or their ASC, retain the anesthesia company’s profits. Of course, the central compliance issue in the company model arrangement is whether the deal violates federal and state anti-kickback laws. In the bundled billing scenario, instead of cajoling the downstream physicians into an employment or subcontract relationship via a company model entity, those who control referrals coax the physicians into bundling their billing, generally at a discount, together with their own. The danger occurs when bundling is misused to shift a portion of the downstream provider’s fee—for example, the pathologist’s fee—into the pocket of the bundler: • The bundler collects a larger pathology fee from

which approach the issue from the same angle as the federal provision but which may not make any distinction between the source of the patient’s funding, and others of which approach the issue from the angle of “feesplitting”—the sharing of a physician’s fee with certain third parties under certain circumstances. A bundling arrangeMark F. Weiss, JD ment that results in the transfer of the referral receiving physician’s fee to the referral source may implicate the AKS and similar state statutes. Even arrangements that do not involve transfer of wealth from the receiving physician to the person or entity coordinating the bundling may trigger a state’s fee-splitting prohibitions and its corporate practice of medicine prohibitions. Depending on the nature of the services provided, it is possible that the arrangement violates the Stark law, the federal self-referral prohibition that applies to any physician who makes referrals to those with whom the physician has a direct or indirect ownership or investment interest, or a compensation arrangement. Stark is a “strict liability” statute that imposes civil, not criminal penalties, although the severity of the penalties makes it a distinction without much difference. States, too, have counterpart self-referral statutes that, depending again on the nature of the services involved, might be triggered. And last, but by no means least, violations of Stark and of the AKS lead to federal False Claims Act liability (commonly spoken of as “whistleblower actions”) in which violators stand liable to regurgitate reimbursement, plus treble damages, and up to $11,000 per claim.

Conclusion

Compliance Quagmire The federal Anti-Kickback Statute (AKS) is designed to prohibit payments to physicians and other providers that are made in order to induce the referral of patients whose care is paid for by federally funded health care programs. The AKS is a criminal statute and intent is required, but that intent can be inferred from the circumstances and many seemingly appropriate arrangements are, on examination, viewed by the Office of Inspector General of the Department of Health and Human Services, which enforces the law, as highly suspect. The states have AKS-counterpart statutes, some of

In terms of intent, all may be above board in connection with a bundling relationship. Or, it could be a poorly designed substitute for a direct kickback, or an alternative to a kickback-infested company model arrangement. No matter which, innocent or deceitful, bundling arrangements implicate a number of federal and state compliance laws. Tread carefully before entering into a bundled billing arrangement. On the other hand, if you’ve already become involved in one without considering the risks, it’s essential that you engage in a thorough evaluation immediately. Bundled billing is often bungled billing. Mark F. Weiss, JD, is an attorney who specializes in the business and legal issues affecting physicians and physician groups on a national basis. He served as a clinical assistant professor of anesthesiology at USC Keck School of Medicine and practices with The Mark F. Weiss Law Firm, a firm with offices in Dallas, Los Angeles and Santa Barbara, Calif., representing clients across the country. He can be reached by email at markweiss@advisorylawgroup.com.

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ICD-10 Implementation Delay Gives Gastroenterologists Time To Reduce Headaches BY TED BOSWORTH CHICAGO— —The mandatory implementation deadline for the International Classification of Diseases, 10th Revision (ICD-10) coding system has been moved back from Oct. 1, 2014, to Oct. 1, 2015, easing pressure on clinicians who have not yet started the change. But this may be the only opportunity to catch up. For clinicians who continue to delay, there is strong potential for chaos and perhaps lost income from a poorly planned transition.

“Studies suggest that practices can be up to speed in six weeks,” Ms. Buckholtz said. ICD-9 has been in use for approximately 30 years; it employs five-digit codes to record clinical tasks. With up to seven digits, ICD-10 codes have more room to capture meaningful use and quality metrics.

The ICD-10 system has roughly five times the number of codes as its predecessor. For example, the handful of ICD-9 codes for the diagnosis and treatment of Crohn’s disease has been expanded to 25 codes, with capability to capture clinical information, Mr. Harano said. Single codes for diagnosis and treatment of conditions such as hemorrhoids have been

expanded to capture such characteristics as grades of severity. The transition is more evolutionary than revolutionary because the codes, although more complex, largely perform the same function. It is a matter of adjusting to the new nomenclature. According to Ms. Buckholtz, “consultants are not essential” for a successful upgrade. The

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FREE iPad App Explore the features of the new app on your iPad. Three ways to download: “It is fairly simple: If you are not billing with ICD-10 codes for services provided on or after October 1, 2015, you will not be paid,” said David Harano, MBA, executive director of Gastro One, a large gastroenterology practice in Germantown, Tenn. Speaking at Digestive Disease Week (DDW) 2014, Mr. Harano warned that implementation of ICD-10 codes “will cost you” in more staff hours for billing and perhaps less time with patients. All the potential problems are likely to be magnified with a head-inthe-sand approach, he added. “The problem is putting it on the back burner,” agreed Rhonda Buckholtz, CPC, CPMA, vice president for ICD10 education and training at the American Academy of Professional Coders (AAPC), in Salt Lake City. Ms. Buckholtz said the codes are largely limited to process adjustments. Training is required, but productivity loss can be minimized with adequate planning and testing.

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American Gastroenterological Association (AGA) has created several tools, including guides for translating the most common ICD-9 codes into their ICD10 equivalents. The AGA also offers subscription-based coding advice. When the ICD-10 codes were first released, news stories mocked examples of the most obscure descriptions, such as V91.07xD, which describes burns acquired from water skis on fire. In contrast, Ms. Buckholtz said gastroenterologists are “somewhat protected” compared with some specialty areas, such

as orthopedics, from the descriptive codes for clinical issues that might never be encountered. The biggest change in GI codes, she said, is the expansion in the numbers to allow more detail about clinical services rendered. For example, there is only one ICD-9 code for gastroesophageal reflux disease (GERD), but ICD10 has separate codes for GERD with or without esophagitis. Moreover, the alphanumeric system has plenty of room to expand codes when advances in clinical medicine make expansion appropriate. One advantage of ICD-10 over ICD-9

is a better way to capture data on valuebased health care. “If you are already focused on quality health care, the ICD10 is going to be a more natural progression,” Ms. Buckholtz said, referring to the growing number of electronic medical record (EMR) systems that capture quality metrics. One example has been the widespread efforts to amend EMR for colonoscopy in order to capture performance benchmarks independent of steps relevant to billing. This is consistent with the premise of the new ICD-10 codes. From the practical perspective,

however, preparing for the change may be the biggest burden. The training alone for physicians and staff may be expensive and it will be wise for every individual practice to conduct extensive testing before launching the full transition. Ironing out problems well before Oct. 1, 2015, is essential to prevent revenue flow disruptions, Mr. Harano said. “A line of credit may be important to avoid any cash flow issues if there are hiccups in the process,” said Mr. Harano, who added that he believes the new deadline will be enforced.

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

Combined Propofol and Fentanyl Improves Anesthesia Quality in EGD BY SHANNON FIRTH

he combination of propofol and fentanyl is more effective than propofol alone in patients having upper gastrointestinal endoscopies, researchers have found. Physicians favor using propofol because it takes effect quickly and has the advantage

of being short-acting, which equates to faster recovery times. But the drug lacks analgesic properties; consequently, larger doses are needed to adequately anesthetize patients before beginning a procedure. Gagging is common. Some clinicians use fentanyl, a powerful opiate, along with a lesser amount of propofol to curb the risk for airway

irritability. However, the two drugs in combination can increase the risk for respiratory depression and hypotension. The new study found that propofol and fentanyl, when carefully managed, can be used effectively for esophagogastroduodenoscopy (EGD) patients. â&#x20AC;&#x153;If you give the propofol and the fentanyl in this slow, controlled way, you are

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

likely to get better sedation conditions without increased risk of respiratory depression,” said Medhat Hannallah, MD, of the Department of Anesthesia at Georgetown University Hospital, in Washington, D.C., who led the study. Dr. Hannallah and his colleagues conducted a double-blind, placebocontrolled study that compared propofol with combined propofol and fentanyl in 100 patients undergoing EGD. Anesthesiologists used a 10-point scale to rate the quality of anesthesia in patients receiving

one or the other treatment during EGD. Patients were evenly divided and randomly assigned to one of two groups: a propofol group and a combined propofol and fentanyl group. The 50 patients in the combination group received initial doses of 1 mcg/kg of fentanyl followed by 0.75 mg/kg boluses of propofol. Those in the propofol-only group received initial doses of propofol as a 1.5 mg/kg bolus. Most patients needed additional propofol boluses before they reached an adequate depth of anesthesia.

Although physicians often use fentanyl and propofol together, the combination can be dangerous. “In a dark room, having any narcotic present is increasing the patient’s risk a bit, unless there is someone dedicated to monitoring the patient,” said Art Saus, MD, assistant professor of anesthesiology at Louisiana State University Health Center, in Shreveport, who was not involved with this study. EGD often is conducted in dimly lit rooms, which makes it difficult to see when a patient’s see EGD, page 14

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EGD continued from page 13

breathing has slowed, he said. For this study, a nurse anesthetist or an anesthesiologist monitored the cardiovascular and respiratory parameters, and remained in the room for the duration of the procedure, Dr. Hannallah said. Patients in both groups were given additional boluses doses of 20 mg of propofol in 1- to 2-minute intervals until an adequate depth of anesthesia was achieved. The final propofol induction

dose was 1.6 mg/kg for the combined propofol and fentanyl group and 2.5 mg/ kg for the propofol-only group. Doctors judged the depth of anesthesia using a soft rubber nasal airway, which was inserted deep into the oropharynx to test the patient’s response. Then an infusion of 150 mcg/kg/min of propofol was initiated. The infusion rate was regulated to maintain the proper depth of anesthesia for the procedure. To blind the study to the researchers, pharmacists packaged the drugs.

“Everybody received an injection that the pharmacist made for us that had either saline [control] or fentanyl. If the first syringe had fentanyl in it, the pharmacy diluted the propofol,” Dr. Hannallah said. The two drugs look different. Propofol is milky white, whereas fentanyl resembles water. Both fentanyl and saline are clear. Distinguishing between propofol and diluted propofol would probably be difficult. “I doubt that the dilution would be so much that an observer would be able to see the difference,” Dr. Saus said.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

“If you give the propofol and the fentanyl in this slow, controlled way, you are likely to get better sedation conditions without increased risk of respiratory depression —Medhat Hannallah, MD

The endoscopists evaluated the patients using a 10-point scale (10 = no response at all, 1 = patient’s airway needed to be rescued). Out of 50 patients, 44 in the combined propofol and fentanyl group had a score of 9 or 10; 31 in the propofol-only group had these scores. The mean score was 9.6 for the combination patients, and was 8.3 for the propofol-only patients. The lowest-scoring cases, those rated 4 or less, belonged to three patients in the propofol-only group. None of the patients in the combined propofol

and fentanyl group scored below 5. One patient was excluded in each group because of inadequate data. Dr. Saus said he was concerned by the description of an infusion rate that was adjusted as needed to maintain “adequate depth,” as it was not clear who determined that depth or how it was defined. Some anesthesiologists use a Richmond Agitation Sedation Scale (RASS) score to measure sedation. The type of scale used was not stated in the abstract. In addition to the endoscopists’ evaluations, all of the patients were phoned

within a week of the procedure and asked whether they experienced drowsiness or nausea and vomiting after the procedure. The patients’ overall evaluation scores showed no significant difference on a 10-point scale (average 9.3 for fentanyl with propofol, 9.5 for propofol alone). Similarly, differences in hypoxia and hypotension between groups were not significant. Dr. Hannallah said he is now “much less antagonistic toward fentanyl” after completing this study.

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

No Glimmer of Sun After the STORM Trial CHICAGO—Patients with hepatocellular carcinoma (HCC) who receive sorafenib after resection or ablation of their tumor are not protected from recurrence of the cancer, according to new Phase III data. Because sorafenib (Nexavar, Bayer/ Onyx) has become a standard of care in unresectable HCC, clinicians had predicted that it would be beneficial when used in earlier stages of liver cancer. So these new findings, from the Phase III STORM (Sorafenib as Adjuvant Treatment in the

Prevention Of Recurrence of Hepatocellular Carcinoma) trial, came as a surprise and disappointment to experts. “This is a major disappointment in the field, and questions are being asked about why this happened,” said Milind Javle, MD, associate professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, in Houston, who was not involved with the study. The STORM investigators randomized

patients without residual HCC after surgical resection or local ablation to receive sorafenib (n=556) or placebo (n=558). Patient characteristics were well balanced between the two arms with respect to the region of the world they lived in, as well as their risk for recurrence, Child-Pugh A and B status, presence of liver cirrhosis, Eastern Cooperative Oncology Group performance status, number of lesions, maximum tumor size and other factors. Presenting the results at the 2014

annual meeting of the American Society of Clinical Oncology (abstract 4006), investigator Jordi Bruix, MD, reported that sorafenib did not improve the primary end point of recurrence-free survival, which was defined as first documented recurrence of disease by independent radiologic assessment or death from any cause, whichever occurred first (hazard ratio [HR], 0.940; P P=0.26). Dr. Bruix, head of the Oncology Liver Unit at Hospital Clínic de Barcelona, in Spain,

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

also said there was no difference in overall survival among patients who received sorafenib compared with those who received placebo (HR, 0.995; P=0.48). P Subgroup analysis failed to identify any cohort of patients who benefited from sorafenib. Adverse events were more common in patients who received sorafenib. Discontinuation rates were similar in the two arms—84.7% in the investigational arm and 80.1% in the placebo arm. However,

19 7 8

—

‘We are asking a cytostatic drug to do a cytotoxic job.’ —Lee Ellis, MD

although investigators had planned to provide adjuvant therapy for four years, the median duration of treatment was only 12.5 months in the sorafenib arm

and 22.2 months in the placebo arm. The mean dose of sorafenib (578 mg/day) was roughly half of what was planned. Both Dr. Javle and Lee Ellis, MD, professor of surgery and molecular and cellular oncology at MD Anderson, pointed out that the study planned for four years of treatment, but despite similar rates of recurrent disease, early discontinuation of sorafenib was much higher than that of placebo. “Anyone who has used the drug knows that [four

years of sorafenib] is somewhat hard to achieve,” Dr. Javle said. Both clinicians noted that the purpose of adjuvant therapy is to increase the cure rate by eradicating microscopic deposits of tumor. However, for the most part, sorafenib and other agents that target vascular endothelial growth factor are not directly cytotoxic to tumor cells, Dr. Ellis said, noting, “We are asking a cytostatic drug to do a cytotoxic job.” —Kate O’Rourke Dr. Bruix reported relationships with ArQule, Bayer, Biocompatibles, BristolMyers Squibb, Daiichi Sankyo, Novartis and Roche. Dr. Ellis reported relationships with Amgen, Genentech, Kanghong Biotechnology, Lilly/ImClone and Roche. Dr. Javle reported no relevant financial conflicts of interest.

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Humor

The American Medical Association’s House of Delegates

continued from page 1

those who say the ABP had threatened them with legal action over their antiMOC organizing efforts—found the “Nick Jr.”–style cartoons to be, well, juvenile and offensive. “The cartoons appear to be designed for my youngest patients rather than their pediatrician,” said Joseph Zanga, MD, chief of pediatrics at Columbus Regional Healthcare System, in Columbus, Ga., and a former president of the American Academy of Pediatrics. “It makes me angry that they’d spend our money on demeaning junk such as [this].” “I’m glad the ABP has a sense of humor, but I was not amused by the videos,” said Victor Strasburger, MD, distinguished professor of pediatrics and chief of adolescent medicine at the University of New Mexico School of Medicine, in Albuquerque. “They could be spending their time reviewing how MOC works— or doesn’t work—and make it much more palatable to the average pediatrician.” In late June, the ABP emailed links to three short musical cartoons to about 15,000 pediatricians who had MOC requirements to fulfill in 2014. “Summer’s here and we’re having some fun!” the ABP explained on its Facebook page. “We’ve created three MOC videos explaining requirements. The content in these videos may not pertain to every diplomate (so be sure to check your ABP Portfolio for YOUR specific requirement needs), but we hope you get a giggle to lighten your day.” The first animation featured “a friendly bluegrass farmer who can sure play that banjo!” The second video presented a classical motet entitled, “If ye loves being certified …” The third was a rap song, peculiarly titled, “Now this is the story ALL about how my points got flipped, turned upside down … ” Virginia A. Moyer, MD, MPH, vice president for maintenance of certification and quality at the ABP, said the idea was to remind physicians of the December deadline for completing their Part 4 MOC requirements, which involve quality improvements performance in practice. “I wanted to send a ‘Harry Potter’– style ‘howler’ but couldn’t figure out a way to do it,” Dr. Moyer explained, referring to the magical letter that screams its written message to the unfortunate recipient. “The videos were one way to get their attention,” she said. Paul M. Kempen, MD, PhD, an anesthesiologist at the Cleveland Clinic, in Ohio, and an outspoken critic of MOC, said the cartoons are evidence that “the [medical] boards have become so arrogant that they feel they can use any means to force this [MOC] down the throats of physicians.”

Getting Into Trouble Over MOC In 2010, Dr. Zanga launched an Internet-based anti-MOC petition drive using his email account at Columbus Regional. “The communications director at ABP called expressing concern,” Dr. Zanga said in an interview. “She stated that the information in the petition was blatantly wrong, bordering on libelous. The hospital was not happy and told me to take it down,” he said. After moving the petition to another website, Dr. Zanga said he collected 2,000 signatures opposing ABP’s enhanced MOC requirements. Dr. Moyer said she had “no information” about the matter, but noted that ABP did not have a communications director in 2010. In the April 2010 issue of Clinical Pediatrics, Dr. Strasburger coauthored a commentary article with Donald E. Greydanus, MD, then at the Kalamazoo Center for Medical Studies, in Kalamazoo, Mich., critical of both ABP and MOC as it was then being developed. In the commentary, titled “Maintenance of Certification: The Elephant in the Room,” they proposed several less burdensome ways by which pediatricians could demonstrate that they were keeping up with developments in the field (Clin Pediatrr 2010;49:307-309). “The ABP threatened to sue me personally and SAGE Publications [the journal publisher] for libel,” said Dr. Strasburger, who was also a member of the journal’s editorial board. “They demanded a retraction. It took SAGE countless hours to review the complaint. Obviously, they were not happy.” The lawsuit never materialized, and in July 2011, Dr. Strasburger wrote another editorial, “Ain’t Misbehavin’: Is It Possible to Criticize Maintenance of Certification (MOC)?” This time, the editorial was endorsed by 10 members of Clinical Pediatrics’’ editorial board. “The ABP has tried to shut down any disagreement or even discussion about MOC,” Dr. Strasburger’s editorial said. “Several petitions to put a moratorium on the MOC process have generated >2000 signatures; yet the ABP has tried to shut down Web sites and any discussion. Pediatricians initially train within an academic system that prides itself on questioning everything. MOC should be no exception” (Clin Pediatrr 2011;50:587-590). “I do know that the board [of directors] was very unhappy with the two editorials that Dr. Strasburger wrote,” Dr. Moyer said when asked to comment. “If there was any legal action, I know absolutely nothing about it,” she said. Formal legal action would have had to come before the board, which did not happen, she added.

directed AMA to ‘oppose mandatory maintenance of certification as a condition of medical licensure.’

In this cartoon from the American Board of Pediatrics, a “friendly bluegrass farmer” encourages physicians to complete their maintenance of certification requirements by year’s end. Some critics have called the approach “juvenile and offensive.”

Dr. Moyer said she has “no access” to any informal communications that may have occurred with Dr. Strasburger at the time. “No one should feel threatened about speaking their mind about something,” she said. “We really want the same thing; we all want pediatricians to be keeping up and improving the quality of their care.” However, according to Dr. Strasburger, “the threatened lawsuit shows that the ABP doesn’t have much of a sense of humor. It needs to look critically at the product it’s producing, like all of the medical boards need to do, and see how to make it more user-friendly. Making half-hearted attempts at funny videos is not going in the right direction. Pediatricians are very upset about this but feel they are powerless,” he said. “What does a single practicing pediatrician do? They feel completely helpless.”

MOC Required for Licensure? In January, the American Board of Medical Specialties (ABMS), composed of 24 member boards including the American Board of Colon and Rectal Surgeons, approved new MOC standards that emphasize continuous learning and assessments. The new standards

are to be adapted and implemented by each specialty board starting Jan. 1, 2015. Backlash in some specialties has been accelerating. For example, an ongoing petition drive protesting new MOC requirements by the American Board of Internal Medicine (ABIM) had collected so many signatures that in April, ABIM president Richard J. Baron, MD, issued a lengthy statement defending the organization’s efforts. As of July 2014, the petition had gathered 17,400 signatures. Alarmed over escalating MOC requirements, including the apparent melding of MOC with maintenance of licensure (MOL) requirements, the American Medical Association’s House of Delegates approved several resolutions in June. They included opposing mandatory MOC in favor of self-regulation, the establishment of a “critical review” of the effect of MOC on physician practice and patient outcomes, and a resolution opposing mandatory participation in MOC as a condition for licensure. The delegates directed AMA to “oppose mandatory MOC as a condition of medical licensure, and encourage physicians to strive to constantly improve their care of patients by the means they find most effective.”

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Simple Menthol Spray Can Reveall More Adenomas Findings seen as potentially practice-changing BY CAROLINE HELWICK

he use of a menthol spray during colonoscopy helped control peristalsis and improved detection of adenomas, researchers have found. The use of menthol raised the adenoma detection rate (ADR) by nearly 30%, and increased the number of patients who did not experience peristalsis during colonoscopy by almost 40%, according to the study. Colonic peristalsis during colonoscopy can be an obstacle to an optimal ADR because it hides neoplastic lesions, and may require treatment with an antispasmodic agent. In upper endoscopy, LSM CAP-menthol, the major constituent of peppermint oil, has been shown to suppress gastric peristalsis.

“We suspected that L-menthol could be very useful for colonoscopy, if it can be effective against the colonic folds and colonic peristalsis that hide neoplastic lesions,” said Ken Inoue, MD, of Kyoto Prefectural University of Medicine, in Japan, and the Lawson Health Research Institute, in London, Ontario, Canada. “It is relatively safe, easy to administer and cost-effective.” Dr. Inoue presented his group’s findings at Digestive Disease Week 2014 (abstract 740). The randomized, single-blind, placebo-controlled trial involved 226 patients scheduled for colonoscopy. Patients were randomized to receive 20 mL of 1.6% L-menthol, diluted in distilled water, during the procedure, or a placebo compound of water and

Pre-Op Routines Reduce Post-Op Risk for Obese Patients BY AJAI RAJ

edicated protocols for heavier patients undergoing abdominal surgery can greatly reduce their risk for complications after the procedure, researchers have found. Ensuring that patients are physically fit and knowledgeable about the procedure, combined with steps to minimize the risk for blood clots and other complications, might be key to preventing adverse outcomes and hastening recovery, the researchers said. “This gives us a good opportunity to have patients go through major surgery and still prevent the more frustrating complications of surgery, like developing a clot, or developing pneumonia after an operation,” said David Shaz, MD, a pulmonary intensivist at the James J. Peters VA Medical Center in New York City, where the retrospective chart review was conducted. Dr. Shaz and his colleagues presented their findings at the 2014 annual meeting of the Society of Critical Care Medicine (abstract 603). The study included 105 morbidly obese patients (90 men) who had been referred for laparoscopic sleeve gastrectomy surgery by their primary care physicians. The average age of the patients was 51, and their average body mass index was 45 kg/m . To qualify for the surgery, patients first had to undergo a fitness and nutrition regimen that lasted between six and 12 months, to ensure that the regimen did not aid significantly with weight loss. The surgeries were performed over a span of about three years, between January 2010 and June 2013. Once accepted for surgery, patients were required to comply with a strict exercise and dietary program, and

were thoroughly educated about the procedure and its risks. Psychologists and psychiatrists worked with the patients to ensure that they were prepared not only physically, but also mentally and emotionally, for the procedure. Before surgery, doctors administered heparin and applied compression boots to prevent blood clots. In addition, 95 patients were given heparin on postoperative day 1. Continuous or bilevel positive airway pressure was applied to 30 patients on the first night postsurgery, to assist with sleep apnea. To prevent lung collapse, 70 patients were encouraged to walk more than 100 feet within five hours of undergoing surgery.

On average, the patients were discharged 2.44 days after the procedure. No patients experienced blood clots or collapsed lungs, although a few contracted pneumonia or bronchitis. These results suggest that following dedicated protocols can lead to better patient outcomes, Dr. Shaz said. Patient preparedness is the key factor, he said. “If you’re running a marathon, you don’t just get up and run; you want to prepare for that procedure. And so I think patients should be prepared for their procedures in the same way they would prepare for a significant race,” Dr. Shaz said. “You want to be somewhat in shape for it; you want to know what to expect; you want to know what the course is going to be like; and how to prevent problems.” The protocols show promise not just for laparoscopic sleeve gastrectomy procedures, but other types of surgery as well, said Megan Anders, MD, assistant professor of anesthesiology at the University of Maryland Medical Center, in Baltimore. “In the prior literature, there are mixed data on the relative rate of complications after bariatric surgery, with some authors noting that an apparent lower rate of [venous thromboembolism] in some studies, for example, may be due to use of stricter protocols in these populations,” Dr. Anders said. “The data from this abstract, although limited in sample size, would support that theory. “This report does a nice job of demonstrating the importance of diligently measuring the outcomes we believe we are impacting with targeted protocols,” she added. “Being able to demonstrate that their complication rate is low when using this protocol can help maintain enthusiasm among the medical professionals who are tasked with ensuring heparin administration or assisting with ambulation.”

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

‘Data that excite me as a practitioner are those that examine colonoscopy techniques and that allow physicians like me to improve my procedures, and therefore ADRs. This approach using L-menthol spray can be adopted into our practices immediately. It’s easy to obtain and yields impressive outcomes without increasing costs.’ —Colleen Schmitt, MD dimethicone. The solutions, in prefilled syringes, were sprayed onto the cecum by one of three experienced colonoscopists, who performed the insertion “as quickly as possible, without looking for lesions,” Dr. Inoue said. The active treatment arm also was eligible to receive additional applications elsewhere in the colon, if grade 2 or 3 peristalsis occurred; 34 patients had a second application, four had a third one and one patient had a fourth application, mostly in the sigmoid colon. All lesions suspected to be neoplasms were biopsied and evaluated. Colonic peristalsis was graded as 0/ none (no movement observed with colon dilated); 1/mild (colon movement not observed, but haustral septae with mild spasm remained); 2/moderate (colon movement); and 3/severe (severe spasm). Baseline characteristics were similar between the arms. Importantly, the median withdrawal time did not differ significantly between the arms: 571 seconds for the placebo group and 643 seconds for the patients given menthol (P=0.16). P

Improved Detection, Diminished Peristalsis Use of the menthol spray significantly increased the ADR: 60.2% versus 42.6% for patients who did not receive the spray (P=0.0083). P The proportion of patients who did not experience peristalsis also was higher in the menthol group: 71.2% versus 30.9% (P<0.0001), according to the researchers.

Endoscopists detected 174 lesions using the menthol spray compared with 115 lesions for placebo. Most of these were low-grade adenomas. Peristalsis scores of patients treated with menthol were also significantly lower after treatment with menthol than before (P<0.0001), whereas no such difference was observed in the control arm. No adverse events occurred in either group of patients, the researchers reported.

Dr. Inoue acknowledged limitations of the study: It was a single-center trial, in which the colonoscopists were not blinded; peristalsis was evaluated by the endoscopists themselves; and applications were repeated only in the menthol group. Nevertheless, he said, the findings show that “the suppression of colonic peristalsis by L-menthol sprayed directly onto the colonic mucosa improves the adenoma detection rate.” Colleen Schmitt, MD, president of

the American Society for Gastrointestinal Endoscopy, said, ““Data that excite me as a practitioner are those that examine colonoscopy techniques and that allow physicians like me to improve my procedures, and therefore ADRs. This approach using L-menthol spray can be adopted into our practices immediately. It’s easy to obtain and yields impressive outcomes without increasing costs.” Drs. Inoue and Schmitt reported no relevant financial conflicts of interest.

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Best Practices in Bowel Preparation for Colonoscopy and endoscopists to understand not only why the prevalence for suboptimal preparation is high, but also what techniques can help better ensure that patients will arrive for the colonoscopy procedure well prepared.

Jack A. Di Palma, MD, FACG Professor and Director Division of Gastroenterology University of South Alabama College of Medicine Mobile, Alabama

Adequate Preparation: Consequences And Improvements

Introduction When performed successfully, colonoscopy is one of the most powerful tools for the detection and removal of adenomatous polyps as well as for the diagnosis and management of colorectal cancer and other conditions.1 Its performance can be affected, however, by suboptimal bowel preparation.2 Adequate preparation for colonoscopy allows for detection of small (6-10 mm) flat or subtle lesions along the full length of the bowel.3 This level of colonoscopic discrimination is a prime determinant of the adenoma detection and removal rate as well as the ability to identify a variety of different colonic disease processes.4 Despite the importance of high-quality bowel preparation for successful colonoscopy, suboptimal preparation is common. The Clinical Outcomes Research Initiative investigators reported a 24% prevalence of inadequate bowel preparation,4 and a study of more than 8,000 consecutive colonoscopies over 5 years in the United Kingdom reported that poor bowel preparation was the most common cause of colonoscopy failure.5 Thus, it is crucial for gastroenterologists

Table 1. Colon-Cleansing Quality in Relation to Duration of Colonoscopy Cecal Arrival Time,a min

Withdrawal Time,a min

Total Duration,a min

No.

Mean

Low

360

16.1

11.3

9.3

27.4

14.8

Intermediate

730

14.4

9.5

11.1

8.9

25.6

13.6

High

3,445

11.9

8.5

9.8

8.2

21.7

12.4

Total

4,535

12.7

9.0

12.7

9.0

22.8

13.0

Cleansing Quality

ANOVAb F-statistic (2 df ) P

45.6

17.3

45.8

<0.001

26 GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Supported by

staff, including nurses, medical assistant, and schedulers, should be prepared to answer questions and guide patient efforts during the clinical visits, when patients contact the staff with questions or requests for guidance, and during a reminder telephone call 1 to 2 days before the procedure. For the busy clinician, conveying this depth of information can be challenging. Durable education material and instructions with simple checklists can be useful. For example, one study-validated booklet produced by the UCLA and Veterans Affairs health systems, entitled “Preparing for Your Colonoscopy,” provides detailed instructions with pictures and diagrams and answers to common patient questions.15 Strategies that enhance the compliance and tolerability of the prescribed bowel preparation regimens also have a marked effect on the success of preparation. For example, studies have demonstrated that split-dose regimens are associated with better compliance and increased tolerability when compared with single-dose regimens, and hence can improve the rate of successful bowel preparation.16 Although use of high-quality bowel preparation formulations is necessary to provide visualization without need for washing, suction, and additional intraprocedural bowel cleaning, there are no definitive guidelines or comparative studies to suggest which regimen is best suited to which patients. FDA-approved regimens for bowel preparation for colonoscopy include 4-L polyethylene glycol 3,350 electrolyte solutions (PEG-ES), including GoLYTELY® (Braintree). NuLYTELY® (Braintree) with flavor packs are 4-L PEG-ES without sulfates.17 Low-volume 2-L PEG-ES preparations include HalfLytely® and Bisacodyl Tablet Bowel Prep Kit (Braintree) and MoviPrep® (Salix) with ascorbic acid.17

Oral sodium sulfate (SUPREP®, Braintree) is a newer splitdose bowel cleansing preparation that contains sodium sulfate, magnesium sulfate, and potassium sulfate in an aqueous form supplied in two, 6-ounce bottles.17,18 Unlike some over-the-counter oral products, it does not contain sodium phosphate, which has otherwise been associated with an increased risk for acute phosphate nephropathy.17 The efficacy of oral sodium sulfate as a bowel cleansing preparation for colonoscopy was established in a study that investigated the randomized use of split-dose SUPREP® versus split-dose 4-L PEG-ES among 364 patients.19 The rate of “excellent” preparations was higher in the SUPREP® group than in the 4-L PEG-ES group (63.3% vs 52.5%; P=0.043). Furthermore, there was no difference in adverse events of clinically significant laboratory findings when comparing the 2 groups.19

Conclusion Suboptimal bowel preparation is a common problem and limits the overall efficacy and safety of colonoscopy while increasing costs for the patient, practice, and society.2,6 Many factors contribute to suboptimal bowel preparation, and it is incumbent on the endoscopist to address these factors in a systematic fashion, including providing comprehensive education to the patient regarding the relationship between quality of bowel preparation and outcomes. Further study to identify which bowel preparation regimens are best suited to specific patient populations would be of benefit. Of the currently marketed formulations for bowel preparation, only SUPREP® has been demonstrated to have superiority to 4-L PEG-ES with regard to cleansing quality.19

References 1. Levin B, Lieberman DA, McFarland B, et al; American Cancer Society Colorectal Cancer Advisory Group; US Multi-Society Task Force; American College of Radiology Colon Cancer Committee. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology. 2008;134(5):1570-1595. 2. Rex DK, Imperiale TF, Latinovich DR, et al. Impact of bowel preparation on efficiency and cost of colonoscopy. Am J Gastroenterol. 2002; 97(7):1696-1700. 3. 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. 4. Harewood GC, Sharma VK, de Garmo P. Impact of colonoscopy preparation quality on detection of suspected colonic neoplasia. Gastrointest Endosc. 2003;58(1):76-79. 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. Gut. 2011;60(suppl 1):A201. 6. 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. 7. 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. 8. Borg BB, Gupta NK, Zuckerman GR, et al. Impact of obesity on bowel preparation for colonoscopy. Clin Gastroenterol Hepatol. 2009;7(6): 670-675. 9. 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. 10. 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. 11. Romero RV, Mahadeva S. Factors influencing quality of bowel preparation for colonoscopy. World J Gastrointest Endosc. 2013;5(2):39-46.

Table 2. Adenoma Miss Rates for Patients With Suboptimal Preparation and Complete Repeat Colonoscopy Within 3 Years (n=216)

12. Lebwohl B, Kastrinos F, Glick M, et al. The impact of suboptimal bowel preparation on adenoma miss rates and the factors associated with early repeat colonoscopy. Gastrointest Endosc. 2011;73(6):1207-1214. 13. Spiegel BM, Talley J, Shekelle P, et al. Development and validation of a novel patient educational booklet to enhance colonoscopy preparation. Am J Gastroenterol. 2011;106(5):875-883.

First Exam

Second Exam

Miss Rate, %

95% CI

All adenomas

115

35-49

≤5 mm

39-57

6-9 mm

29-59

≥10 mm

17-41

Proximal

33-51

Distal

23-54

18. SUPREP [prescribing information]. Braintree, MA: Braintree Laboratories, Inc.; 2012.

≥10 mm or advanced histologic features

17-41

Adenocarcinoma

–

19. Di Palma JA, Rodriguez R, McGowan J, et al. A randomized clinical study evaluating the safety and efficacy of a new, reduced-volume, oral sulfate colon-cleansing preparation for colonoscopy. Am J Gastroenterol. 2009;104(9):2275-2284.

Location

15. UCLA Health System. Preparing for your colonoscopy. www.uclahealth. org/workfiles/documents/brochures-programs/preparing-colonoscopyen.pdf. Accessed August 27, 2014. 16. Aoun E, Abdul-Baki H, Azar C, et al. A randomized single-blind trial of split-dose PEG-electrolyte solution without dietary restriction compared with whole dose PEG-electrolyte solution with dietary restriction for colonoscopy preparation. Gastrointest Endosc. 2005;62(2):213-218. 17. Pharmacist’s Letter. Comparison of bowel preps. http://pharmacistsletter.therapeuticresearch.com/pl/ArticlePDF.aspx?cs=&s=PL&DocumentFil eID=0&DetailID=300301&SegmentID=0. Accessed August 27, 2014.

Disclosures

BB1411

CI, confidence interval Reprinted ep ted with t permission pe ss o from o reference e e e ce 12..

14. 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.

Dr. Di Palma reported that he is a consultant for and has received grant/ research funding from Braintree.

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

DNA continued from page 1

MT-sDNA detected 10 times more SSPs of at least 1 cm than FIT, which relies on finding blood in the stool, according to the investigators of Cologuard (Exact Sciences), the stool DNA test that was approved by the FDA in August. “The detection of patients with SSPs is a clinically important issue in the consideration of noninvasive screening techniques,” said Barry M. Berger, MD, chief medical officer of Exact Sciences, who presented the findings at Digestive Disease Week (DDW) 2014 (abstract 113). SSPs are associated with genetic abnormalities. MT-sDNA includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 4 and BMP3 methylation and β-actin, plus a hemoglobin immunoassay. SSPs typically are flat and non-hemorrhagic and most commonly located in the proximal colon, making them more challenging to identify endoscopically than conventional adenomas. Study co-investigator David Ahlquist, MD, the Carol Gatton Professor of Gastrointestinal Research at Mayo Clinic, in Rochester, Minn., said ““SSPs are much harder to detect by colonoscopy and they don’t bleed, so they are not detected well by fecal blood testing. Stool DNA testing is really the only noninvasive approach to detecting these lesions.” de

DeeP-C Details The DeeP-C (Detection of Colorectal Advanced Adenomatous Polyps and Cancer) study was conducted at 90 sites in the United States as a head-to-head comparison of MT-sDNA and FIT in an average-risk population of 9,989 men and women aged 50 to 84. Participants collected a single stool sample before preparing for colonoscopy. The sample was used for both MT-sDNA and FIT testing. An MT-sDNA assay score of 183 or higher is considered positive, as were FIT results greater than 100 ng of hemoglobin/mL of buffer. The study’s main finding, recently

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

published in The New England Journal of Medicinee (Imperiale TF et al. N Engl J Medd 2014;370:1287-1297) was the significantly greater ability of MT-sDNA to detect colorectal cancer, demonstrating a sensitivity of 92.3% versus 73.8% with FIT (P=0.002). P The sensitivity for detecting advanced precancerous lesions was 42.4% with MT-sDNA testing and 23.8% with FIT (P<0.001), and for detecting high-grade dysplasia it was 69.2% and 46.2%, respectively (P=0.004). P Dr. Berger presented the results of a prespecified analysis focusing on the epidemiology of SSPs of at least 1 cm in this population and the test’s sensitivity for detecting them compared with FIT. An advanced precancerous lesion was detected in 757 (7.6%) of patients. Of these, 99 (13.1%) had an SSP of at least 1 cm as the only advanced finding, which is 1% of the overall study population. These lesions were proximally located in 79%, and occurred with similar frequency in men and women and across all age groups. The SSP prevalence was 9 in 1,000 for people aged 50 to 64 years; 11 in 1,000 for those aged 65 to 74; and 4 in 1,000 in people aged 75 and older. The analysis sheds light on the epidemiology of SSPs, showing that those of at least 1 cm are uncommon and com-prise a minority of advanced precancerous lesions among asymptomatic, average-risk individuals, Dr. Berger said.

The sensitivity for these large SSPs was 42.4% with MT-sDNA versus 5.1% for FIT (P<0.001), with specificity rates of 87% and 95%, respectively (P<0.001). The sensitivity did not vary significantly for either test with respect to sex, age or location of the polyps. The test detected 38% of SSPs in the proximal colon and 55% in the distal; FIT detected 5% in either location, Dr. Berger reported. The low sensitivity observed with FIT did not improve as polyp size increased, whereas a trend was observed for greater sensitivity with MT-sDNA in proportion to size: 37% for polyps 1 to 1.4 cm, 48% for polyps 1.5 to 1.9 cm and 67% for polyps of at least 2 cm.

Altering the Screening Algorithm? In a panel discussion on colorectal cancer screening at DDW, Dr. Ahlquist said the DNA test would be his first choice for screening patients. “We are hoping the stool DNA test will become a legitimate part of our armamentarium,” he said. Although the test is noninvasive—an advantage over colonoscopy—it would be performed more often—probably every three years—with referral to colonoscopy for patients with positive findings. “Fine-tuning of this algorithm will require additional observation,” he said.

‘I have a hard time between FIT and fecal DNA, because fecal DNA is going to cost significantly more up front, and especially for the health care system at large I think this will be a big, expensive transition.’ —Douglas Rex, MD Other experts praised i d the h h high sensitivity of the test but raised a few questions regarding its place in the screening algorithm. Douglas Rex, MD, Distinguished Professor of Medicine at Indiana University School of Medicine, in Indianapolis, who often speaks about the potential “disruption” of colonoscopy as the preferred screening approach, called the 92% sensitivity “remarkable for a noninvasive test.” He predicted, however, that the test could be expensive—the price has not yet been set—which may limit its use. “I have a hard time between FIT and fecal DNA, because fecal DNA is going to cost significantly more up front, and especially for the health care system at large I think this will be a big, expensive transition,” Dr. Rex said during the panel discussion. “For individual patients who can choose it, I think fecal DNA is fine. But I don’t think colonoscopy is off the map as a screening option. Ideally, it will be done with more transparency, including the adenoma detection rate of the clinician and the cost of the colonoscopy. With FIT having more consistent results and fecal DNA being more sensitive, we are wrestling with several legitimate strategies right now.”

Thomas ImpeTh ria MD, of Indiana riale, University School of U Medicine, in IndianapoM lis, and first author of the li DeeP-C study, predicted that D the MT-sDNA test might best th be used selectively. b “How this new test integrates in nto the current options for screening wil ill depend on its comparative effecttiveeness and cost-effectiveness, metrics thaat may be best delineated through the th usee of microsimulation modeling,” Dr. u Im mperiale said. “Based on its test charaaccteristics alone, MT-sDNA may be best ffor persons between 50 and 64 years for fo whom the prevalence of disease is lower w aand test specificity is higher, characteristics s that minimize the false-positive risk i and optimize the negative predictive vvalue of the test.” David Lieberman, MD, professor of medicine and chief of the Division of Gastroenterology at Oregon Health & Science University, in Portland, added, “We need to recognize that this test has gone through some hoops but not all of them”—particularly the U.S. Preventive Services Task Force. “They play a major role in what Medicare decides to pay for,” he said of the task force. “Once Medicare approves it, third-party payors often will as well. But these steps will have to take place.” Dr. Lieberman agreed with Dr. Rex that realistically, cost will be an issue. “An accountable care organization will want to just check off a box that says, ‘My patient got colon cancer screening.’ I think it will be compelling for them if they can avoid the downstream costs of cancer care with a test, even if the upfront cost of that test is higher, and that test could become the preferred screening test. I predict interesting and complicated decision-making discussions.” Dr. Berger is an employee of Exact Sciences Corporation. Dr. Rex reported consulting and board membership with Exact Sciences Corporation. Dr. Lieberman serves on the scientific advisory board for Exact Sciences Corporation. Dr. Imperiale reported no relevant financial conflicts of interest.

Advancing Your GI Practice. Experience Fuse at ACG 2014 - EndoChoice Booth #335 In a multi-center tandem study recently published in Th T e Lancet Oncolo l gy g , the Fuse® endoscope system demonstrated the miss rate on adenomas with Tr T aditional, Forw r ard Viewing (TFV) colonoscopes was 41%. Conversely, when the patient received a colonoscopy with Fuse first, followed by TFV, V the re r searc r hers had an adenoma miss rat ae of only 7%1. Overall, Fuse enabled this international team of endoscopists to find 69% more r adenomas aft f er TFV had been used.

Traditional Colonoscope

Limite t d 170° Field of o View e

How was this achieved? Tr T aditional endoscopes pro r vide endoscopists only a limited forw r ard r view (up to 170 degre r es) s causing them to potentially miss adenomas that a hide behind folds. Leveraging a pro r prietary r design of thre r e lenses and thre r e monitors, Fuse Full Spectrum Endoscopy pro r vides a panoramic field of view (3 ( 30° Colonoscope / 245° Gastro r scope) e thus enabling endoscopists to see forw r ard r and on each side of the colonoscope.

Fuse® Colonoscope In the end d, Fuse empowers ph hysiiciians to ad dvance their GI practice clinically, y economically, y and thro r ugh market diff f ere r ntiat a ion.

Panora r mic 33 330° Field of o View e

Adenoma Miss Rate

As Cited in The Lancet Oncology Traditional, Forward Viewing (TFV) Colonoscope

41%

Miss Rate

69 %

Incremental adenoma find rate with Fuse®

T learn how To o Fuse can help adva vance yo y ur GI pra r ct c ice, conta t ct c yo y ur EndoChoice sales representative, or the EndoChoice Headquart rters r , a 88 at 888.68 682.36 3636 x.5, or email fuse@endochoice.com. EndoChoice.com/Fuse | FuseColonoscopy.org | FuseCases.com (1) Gralnek et al. Th T e Lancet Oncology g , 2014

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

VIROLOGIC RESPONSE. LONG-TERM RESISTANCE.

TWO REASONS TO CHOOSE VIREAD Complete response achieved at 1 year The primary endpoint in Studies 102 and 103 was complete response to treatment at 48 weeks as defined by HBV DNA <400 copies/mL + histological response (Knodell necroinflammatory score improvement of ≥2 points without worsening in Knodell fibrosis score).1,2

71%

of HBeAg– VIREAD patients vs 49% of adefovir dipivoxil patients1,3

67%

of HBeAg+ VIREAD patients vs 12% of adefovir dipivoxil patients1,4

In Study 102 (HBeAg–, n=375) and Study 103 (HBeAg+, n=266), a combined total of 641 adult patients with CHB and compensated liver disease who were nucleoside treatment naïve entered a 48-week, randomized, double-blind, active-controlled treatment period comparing VIREAD 300 mg to adefovir dipivoxil 10 mg. Subjects who completed double-blind treatment at Week 48 were eligible to roll over with no interruption in treatment to open-label VIREAD. Of 641 patients enrolled in the initial trials, 489 (76%) completed 240 weeks of treatment.1-5

VIREAD should not be administered in combination with adefovir dipivoxil.1

Indication and Usage

Important Safety Information

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 HBeAg-positive 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

BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS

Please see VIREAD Important Safety Information continued and Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages.

s 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 s Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. therapy VIREAD Hepatic function should be monitored closely with both clinical and laboratory followup 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

NO HBV RESISTANCE DEVELOPED THROUGH YEAR 7 Annual evaluation of resistance was a prespeciﬁed secondary endpoint. Cumulative VIREAD genotypic resistance has been evaluated for up to 240 weeks in Studies 102, 103, 106, 108, and 121.1,3,4 s In the nucleotide-naïve population from Studies 102 and 103, HBeAg+ subjects had a higher baseline viral load than HBeAg– subjects and a signiﬁcantly higher proportion of the subjects remained viremic at their last time point on VIREAD monotherapy (15% vs 4%, respectively) Not an actual patient, but is representative of a real patient type. Models are used for illustrative purposes only.

s HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions; however, no speciﬁc substitutions occurred at a sufﬁcient frequency to be associated with resistance to VIREAD (genotypic and phenotypic analyses)

Important Safety Information (cont’d) 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, adjust 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. Consider assessment of BMD in adult and pediatric patients who have 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 VIREADtreated 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 treatment-emergent adverse reactions reported in >5% of patients treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash 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

In clinical trials (Studies 102 and 103), no HBV resistance developed at Years 1, 2, 3, 4, 5, 6, or 7 in adult nucleoside-naïve patients with CHB and compensated liver disease.1,6

N0 HBV RESISTANCE DEVELOPED

YEAR 1 through YEAR 7 in clinical trials (Studies 102 and 103)1,6 s 68% (437/641) retention rate at Week 336: 283/426 patients given VIREAD—>VIREAD; 154/215 patients given adefovir dipivoxil —>VIREAD6

For more information, visit LearnAboutViread.com

Important Safety Information (cont’d) s HIV-1 protease inhibitors: Coadministration decreases ataazanavirr concenttrations and increases tenofovir concentrations; use ataazanavirr given with w ritonavir. Coadministration of VIREAD with ataazanavirr and ritoonavir, darunavir and ritonavir, or lopinavir/ritonavir inccreases tenofoviir concentrations. Monitor for evidence of tenofovir tooxicity s Drugs affecting renal function: Coadministration of VIREA AD with drugs that t reduce renal function or compete for active tubularr secretioon may increase concentrations of tenofovir

Dosage Adjustment for Patients with Altered Creatinine Clearance

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 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

Creatinine clearance (mL/min)a

Recommended 300 mg dosing interval a

Hemodialysis patients

≥50

30-49

10-29

Every 24 hours

Every 48 hours

Every 72 to 96 hours

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

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.

s 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 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 VIREAD Important Safety Information continued and Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages. References: 1. VIREAD Prescribing Information, Foster City, CA: Gilead Sciences, Inc.; October 2013. 2. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. d 2008;359(23):2442-2455. 3. Data on file - Gilead Sciences, Inc. Study 102 CSR. 4. Data on file - Gilead Sciences, Inc. Study 103 CSR. 5. Marcellin P, Gane E, Bhuti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Published online December 10, 2012. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61425-1/fulltext. Accessed May 31, 2013. 6. Data on file - Gilead Sciences, Inc.

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.

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

H E PAT O L O G Y I N F O C U S

Guidance continued from page 1

Newly released guid-ance details a way to prioritize treatment of these patients. Experts say the advice, available at www.hcvguidelines.org, is needed because limitations of workforce and resources may crimp thee ability to treat everyone seekking treatment within a sh hort period of time. The guiidance advises treatment for thosee who are sickest, followed by those att great risk for spreading the virus, then to other patients with HCV as resources allow. Gary Davis, MD, co-chair of the guidance and secretary for the American Association for the Study of Liver Diseases (AASLD), said the priority list was always planned, but recent events underscore its importance. “The importance of the [priority] section became clear as people started coming out of the woodwork to get treatment,” Dr. Davis said. “Doctors started seeing more patients than they could handle at one time and the insurance companies were getting this bolus of people coming for this expensive therapy all at once because people had warehoused themselves. It is important to prioritize patients, so that everybody can get treated in a reasonable order, to get the most benefit for the greatest number. To do that, we elected to have the sickest treated first and move down the line as resources allow thereafter.” Earlier this year, the AASLD, the Infectious Diseases Society of America and the International Antiviral SocietyUSA launched HCVguidelines.org in response to the whirlwind of new directacting antivirals coming on the market. The site provides hepatitis C treatment guidance that can be updated and published quickly. Donald Jensen, MD, one of the guidance chairs and director of the Center for Liver Disease at the University of Chicago Medical Center, said the documents on the website are referred to as “treatment guidance” rather than “treatment guidelines.” Technically, a guideline must fulfill certain criteria to be included in the guideline clearinghouse, such as the use of a methodologist and the GRADE (Grades of Recommendation Assessment, Development and Evaluation) system for evidence rating. Although the guidance incorporates the evidence rating used by many current guidelines, it was not prepared with the help of a methodologist, which would have significantly delayed its release. The new section of the guidance,

T Table 1. Patients at Highest Priority for Treatment Due to Highest Risk for Severe Complications D Clinical Condition

Evidence Rating

Advanced fibrosis (METAVIR F3) or compensated cirrhosis (METAVIR F4)

Class I, level A

Organ transplant

Class I, level B

Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations (e.g., vasculitis)

Class I, level B

Proteinuria, nephrotic syndrome or membranoproliferative Class IIa, level B

T Table 2. Patients at High Priority for Treatment Based on High Risk for Complications B “When and in Whom to Initiate HCV Therapy,” outlines criteria for prioritizing patients. Patients with advanced fibrosis (METAVIR F3), those with compensated cirrhosis (METAVIR F4), liver transplant recipients and patients with severe extrahepatic HCV should be given the highest priority for treatment (Table 1). Patients at high risk for liver-related complications and severe extrahepatic complications of HCV are given the next highest priority (Table 2). Also at the top of the list are patients particularly likely to transmit HCV, such as men who have sex with men who engage in high-risk sexual practices, active injection drug users, incarcerated persons and those on long-term hemodialysis. According to Dr. Davis, clinicians should use their judgment in prioritizing patients in the third group. “It is more of an individualized decision with the third group, those that are at risk for transmitting the disease,” Dr. Davis told Gastroenterology & Endoscopy News. “It is not that you would treat everybody in this group, but you would treat those who would be deemed to be highest risk for transmitting to others.” Dr. Davis said clinicians have already been prioritizing treatment of patients with HCV. “We did this with the last protease inhibitor to come on the market,” he said. “We had a long list of patients to be treated; we treated the sickest first and we worked down the list. We could only treat 250 at a time in our group. As soon as somebody came off therapy, we would treat someone else.”

Feeling Pushback Some clinicians said the notion of prioritizing care was not sitting well with patients. Andrew Muir, MD, chief of gastroenterology at Duke University Medical Center, in Durham, N.C., said his practice is in line with the guidance but the “endorsement is key.” “It is important for us at the local level to have this endorsement for our

Clinical Condition

Evidence Rating

Fibrosis (METAVIR F2)

Class I, level B

HIV-1 coinfection

Class I, level B

HBV coinfection

Class IIa, level C

Other coexistent liver disease (e.g., NASH)

Class IIa, level C

Debilitating fatigue

Class IIa, level B

Diabetes mellitus (insulin-resistant)

Class IIa, level B

Porphyria cutanea tarda

Class IIb, level C

HBV, hepatitis B virus; NASH, nonalcoholic steatohepatitis

practice from this national group,” Dr. Muir said. He said he was unaware of any other disease where treatment guidelines prioritized patient treatment. He has encountered pushback from patients with a low burden of disease who want treatment immediately and cannot be fit into the clinic schedule. “In some cases, the responses are extremely emotional. I have patients in tremendous distress over this. We have been telling these patients for years that we have been working on new therapies that would cure HCV. The drugs are now here, and we have to tell them that they may not get them,” Dr. Muir said. “Even if their liver disease appears mild, patients worry about future risk for cirrhosis and liver cancer. They also worry that many of their symptoms of fatigue, malaise and poor concentration are related to HCV. They want it gone.” David Bernstein, MD, chief of hepatology at North Shore University Hospital in Manhasset, N.Y., said he has not yet had to prioritize patients for HCV treatment. He has been able to treat all of the increased number of patients who walk through his doors, he said, largely in part due to his large staff of physicians and physician extenders. But Dr. Bernstein noted that location is a big factor in patient workload. He practices on Long Island. Clinicians in New York City, without the large support staffs, might be getting an influx

of patients that is harder for them to handle, he said. “I do think the guidance is important, but it is important that all patients with HCV be treated. There is data that shows that even patients who don’t have advanced disease of [stage] 3 or 4 benefit from therapy, with improved morbidity and mortality,” Dr. Bernstein said. “The FDA approved these therapies to treat all patients with HCV. They didn’t mention prioritizing.” Clinicians should be able to treat four times as many patients with HCV, he added. “The therapies that were a year long with a lot of side effects required many visits, many calls, using up a lot of resources,” Dr. Bernstein said. “Now the therapies, especially the ones coming out that are all pills, have minimal side effects and are only 12 weeks long. Each practitioner should be able to get in four times as many patients for treatment.” Dr. Davis is on the data safety monitoring committee for non-hepatitis drugs manufactured by Bristol-Myers Squibb and Gilead. Dr. Jensen is a clinical trial investigator with AbbVie, BMS, Boehringer Ingelheim, Genentech, Gilead and Janssen. Dr. Bernstein has received research support from AbbVie, BMS, Gilead, Janssen and Merck, and served as a consultant with AbbVie, BMS, Gilead and Merck. Dr. Muir has received research grants from AbbVie, BMS, Gilead and Merck, and has served on the advisory boards of AbbVie, BMS, Gilead and Merck.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Q&A With AASLD President-Elect Gyongyi Szabo, MD, PhD Gyongyi Szabo, MD, PhD, president-elect of the American Association for the Study of Liver Diseases (AASLD), shared some of the association’s priorities for the coming year. Here are some highlights from that conversation. GEN: What is the AASLD’s broad vision for 2015? Dr. Szabo: We will continue to implement our most recent strategic plan, which was rolled out at the 2013 Liver Meeting. It prioritizes advancing the science of hepatology and helping clinicians to stay abreast of the growing treatment of liver diseases. It also recognizes the importance of supporting our young researchers and growing our membership, and the hepatology workforce in general. GEN:: What are some of the most promising developments you are seeing today in the field of hepatology? Dr. Szabo: It has been an exciting time for basic scientists and clinicians working in hepatology. The new oral drugs for treatment of hepatitis C virus (HCV) and the increased interest in hepatology related to these developments are bringing many clinical opportunities for physicians. There also are pilot clinical trials underway for the treatment of nonalcoholic fatty liver disease (NAFLD), and trials for alcoholic liver disease treatment are set to begin soon. Most are using a translational science approach and testing therapeutic treatments based on current understanding of the basic pathomechanisms of the disease. These are all extremely exciting areas that we will continue to watch very closely. GEN:: How is the AASLD helping clinicians stay on top of the rapid developments in liver disease treatment that you mentioned? Dr. Szabo: We’re doing this in several ways. First, although the Liver Meeting is our primary educational event, we think learning opportunities should be available on a 24/7 basis. So, one thing we will be doing in 2015 is holding our inaugural mid-summer course, which will focus on best clinical practice in key areas of liver diseases including viral hepatitis, fatty liver disease, fibrosis and liver transplantation. We’re very excited about that. We also have 13 special interest groups (SIGs) that we plan to increase to about 17. Any AASLD member can join these. Although most SIGs are focused on basic and clinical research, we have created a clinical practice SIG, to provide a platform for hepatologists who focus on areas related to clinical practice, including state-ofthe-art developments in clinical practice, delivery of care and needs assessment. We are also developing webinars for SIG members, so that they can stay in contact with each other on a monthly basis and review new research, share their own insights and learn about best practices. Additionally, we are creating other Web-based learning opportunities. For example, in recent years we launched Act-on-HCV, an online curriculum focusing on HCV treatment, including use of the new oral HCV agents. This year we partnered with In-Practice [a third party, continuing medical education company] to provide our members with constantly updated resources on HCV, and we plan to expand its scope to include other topics in hepatology,

such as hepatitis B virus, NAFLD/NASH [nonalcoholic steatohepatitis], alcoholic liver disease and advanced liver disease, just to mention a few. Our clinical practice guidelines and guidance documents also will remain important avenues for helping clinicians navigate new treatment developments. Earlier in 2014, we issued a guidance document on HCV management, on which we collaborated with the Infectious Diseases Society of America (IDSA) and the International Antiviral Society-USA (IAS-USA). Given the emergence of the new oral HCV drugs, that was very timely and, I believe, helpful. We also recently issued an addendum to that guidance detailing which HCV patients should be prioritized for HCV treatment using these new agents. We will continue to update the guidance in a timely fashion as new HCV treatments become available. We will also be creating clinical practice guidelines on other topics, including portal hypertension and hepatocellular carcinoma. Our journal, Hepatology, will continue to be a source of high-quality clinical information, and we are planning to extend the scope of our journal, Liver Transplantation, to include articles on end-stage liver diseases that are not directly related to transplant. Finally, our online journal, Clinical Liver Disease, provides excellent state-of-the-art resources to help our members learn about best practices and developments. GEN:: With the new HCV treatments and a growing prevalence of NAFLD, there is a need for more trained hepatologists. How is the AASLD addressing that demand? Dr. Szabo: One thing we’re doing is simplifying the membership process to make it easier for young clinicians, scientists and practitioners to join the AASLD. At the 2014 annual meeting, AASLD will also announce the new “AASLD Fellow” membership, which will be offered to qualified members with distinguished scholarly activities. We are also offering mentoring programs for junior faculty members. Two years ago, we introduced the Emerging Liver Scholars Program, which allows medical residents thinking about specializing in hepatology to shadow distinguished AASLD members at the Liver Meeting. This is an opportunity for them to learn more about the field, and hopefully some residents will continue with hepatology as their focus, partly as a result of this experience. GEN:: What type of research funding will the AASLD be providing over the next year or two? Dr. Szabo: In 2013, we awarded approximately $2.4 million in research funding and with the recent creation of the AASLD Foundation, we hope to raise more money for research and expand the number of awards. In terms of basic science and translational and clinical research awards, the Career Development Award in Liver Transplantation is a two-year award of $45,000 per year for individuals performing clinical or translational

research in liver transplantation. We also have the Clinical and Translational Research Award, which is a two-year award of $75,000 per year for clinical or translational research in any liver-related area. Past award recipients have conducted research on topics such as the use of lipid biomarkers of NAFLD and the way human liver cells or hepatocytes use interferon to defend against HCV infection. In 2015, we will introduce the Pinnacle Research Award in Liver Disease, which provides $300,000 in basic science funding over three years to a young researcher, with the goal of enabling them to compete for research awards from national sources like the National Institutes of Health. We will also attempt to introduce a couple of other new awards in 2015 or 2016. Those awards will support research on patient outcomes evaluation and clinical practice effectiveness. Although the AASLD does not currently directly address health care policy issues, addressing cost-effectiveness is important, and these awards will support research relevant to that topic. GEN:: There is concern that the costs of the new oral HCV treatments are prohibitive. What is the AASLD’s position on this issue? Dr. Szabo: The AASLD has not been addressing the cost issue directly. However, the HCV guidance addendum I mentioned earlier addresses the societal costs of HCV treatment. I think our experience with pegylated interferon and ribavirin [PEG-IFN/RBV] treatment when these drugs first came out 10 to 15 years ago was instructive. It showed us that, although many patients were interested in treatment, immediate therapy with PEG-IFN/RBV for chronic HCV did not significantly improve outcomes for some of these patients. The document, which is available online, states that liver transplant recipients and patients with advanced fibrosis and compensated cirrhosis should receive the highest priority for treatment, followed by patients at high risk for liver-related and extra-hepatic HCV complications. For more information visit www.aasld.org/practiceguidelines/Pages/hcvpatientslimitedresources.aspx. Dr. Szabo has received grant or research support from Conatus Pharmaceuticals, Genfit, Gilead, GlaxoSmithKline, Intercept Pharmaceuticals, miRAGen Therapeutics, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, Takeda Pharmaceutical Company, Tobira Therapeutics and Vertex Pharmaceuticals.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER OCTOBER 2014 2014

Latest HCV Therapies Return Solid Results in Recent Trials Combo regimens shine in two Lancet articles BY MONICA J. SMITH

ew drugs for hepatitis C treatment, oral interferon (IFN)- and ribavirin (RBV)-free regimens, are showing promise, even in sicker patients and those previously unresponsive to IFN and RBV treatment, researchers have found. “These are tremendous advances—high response rates, much better tolerability— and obviously [are] desirable for treating hepatitis C,” said K. Rajender Reddy, MD, director of hepatology at the Hospital of the University of Pennsylvania, in Philadelphia. “We’re advancing toward all-oral regimens without interferon, and hopefully no ribavirin in select cases, and with shorter treatment durations.”

respectively. Serious AEs were seen in four (2%) patients, all of whom were on the 24-week regimen. The addition of RBV and/or a longer treatment duration (24 weeks) were not necessary to achieve higher SVR rates in any of the cohorts studied, according to the researchers, who concluded that the combination of simeprevir and sofosbuvir

was effective and well tolerated even in difficult-to-treat patients. “The publication of results from the COSMOS study in The Lancett on World Hepatitis Day underscored the significance of these data to the hepatitis C community,” said lead author Eric Lawitz, MD, vice president for scientific and research development at The Texas

‘These are tremendous advances, high response rates, much better tolerability and obviously desirable for treating hepatitis C. We’re advancing toward all-oral regimens without interferon, and hopefully no ribavirin in select cases, and with shorter treatment durations.’ —K. Rajender Reddy, MD

Liver Stiffness Guided HCV Management • Determine treatment urgency

Two recent studies in The Lancet reported on data from the two trials looking at combination therapy for the treatment of hepatitis C infection (HCV). In the COSMOS trial, researchers investigated the combination of simeprevir (Olysio, Janssen Therapeutics) plus sofosbuvir (Sovaldi, Gilead) in treatmentnaive patients and previous nonresponders to pegylated IFN (PEG-IFN) and RBV. Patients were randomized to receive simeprevir plus sofosbuvir with or without RBV for 24 weeks or 12 weeks in two cohorts: previous nonresponders with no or moderate liver fibrosis (cohort 1), and previous nonresponders and treatmentnaive patients with advanced liver fibrosis including cirrhosis (cohort 2). Of the 167 patients who started treatment, sustained virologic response (SVR) was achieved in 154 (92%)—72 of 80 (90%) patients in cohort 1 and 82 of 87 (94%) in cohort 2. Fatigue, headache and nausea were the most common adverse events (AEs), reported by 52 (31%), 33 (20%) and 26 (16%) patients,

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Liver Institute, in San Antonio. “These data demonstrate that the all-oral, interferon-free combination of simeprevir and sofosbuvir offers a highly effective 12-week treatment option for patients, including prior null responders and those with advanced fibrosis who are considered difficult to treat.” see HCV Therapies, page 47

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36 GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

32014 6 GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER

Developments in Approaches to Liver Resection Joseph Buell, MD, is

—COMPILED BY COLLEEN HUTCHINSON

the director of the Tulane Transplant Institute and the Children’s Hospital of New Orleans and hepatobiliary surgeon; Dr. Buell hosted the first International Consensus Conference on Laparoscopic Liver Surgery, in Louisville, and was the first author on the consensus statement.

Statement: Oncologic results with laparoscopic liver resection (LLR) of hepatocellular carcinoma (HCC) or metastatic colorectal cancer are comparable to open liver resection.

David Geller, MD, is the

Dr. Geller: Agree.

Richard L. Simmons Professor of Surgery, chief of the Division of HPB Surgery, and director of the UPMC Liver Cancer Center, at the University of Pittsburgh.

Numerous studies have reported comparable five-year overall survival for LLR of HCC or limited metastatic colorectal cancer (one or two tumors) in case–cohort matched studies comparing LLR to open liver resection. Of note, there have been no prospective, randomized controlled trials published comparing laparoscopic to open hepatic resection, and it is important to recognize that inherent selection bias exists, even in well-matched case–cohort series.

Horacio Asbun, MD, is professor of surgery at Mayo Medical College, chairman of the General Surgery Division, and co-director of HPB Program, at Mayo Clinic, Florida; Executive Council member of the American Hepato-Pancreato-Biliary Association; board member of SAGES; and editor-in-chief of the American College of Surgeons “Multimedia Atlas of Surgery” series.

Thomas Aloia, MD, is a husband and a father to the two most wonderful kids in the world, a recovering transplant surgeon, HPB and MIS surgeon at University of Texas MD Anderson Cancer Center, in Houston.

Allan Tsung, MD,

is the Roberta Simmons Associate Professor of Surgery at the University of Pittsburgh Medical Center.

William Jarnagin, MD, is attending surgeon, Enid A. Haupt Chair in Surgery, and chief of the Hepatopancreatobiliary Service at Memorial Sloan-Kettering Cancer Center; and professor of surgery at Cornell University Weill College of Medicine, in New York City.

Dr. Geller has served as a consultant to Medtronic (course director for annual Laparoscopic Liver Resection course). Dr. Tsung has served as an instructor at the Laparoscopic Liver Course sponsored by Medtronic (2014).

Editor’s note: This feature first appeared in our sister publication, General Surgery News.

Dr. Aloia: On the fence. There are competing oncologic issues related to surgical approach. Experience indicates that laparoscopically, it is more difficult to assess the liver and less liver comes HCC patients undergoing laparoscopic hepatic resecout of the patient. From margin and missed lesion per- tions compared with open cohorts. This is with the spectives, this is likely to be oncologically unfavorable. caveat that laparoscopic hepatic resection is performed However, as we learn more about the immunosuppressive by surgeons who are well trained and experienced in effect of surgery, we may find that less invasive approaches sound oncologic liver surgery, and should be utilized in have an intrinsic oncologic benefit. Also, laparoscopic appropriate cases—ie, tumors smaller than 5 cm. This approaches may win in terms of the return to intended tumor size was advocated by the Louisville Consensus oncologic therapy (RIOT) rate group and will be a point of [[J Surg Oncoll 2014; in press]. discussion at the second With our current level of ‘There have been no prospective, consensus meeting in Japan understanding, however, one this coming October, and has to come back to this: randomized controlled trials published may, in fact, be increased. “Biology is King. Selection is As far as the oncologic Queen. Technical maneuvers comparing laparoscopic to open integrity of laparoscopic are the Prince and Princess. hepatectomy, in the right hepatic resection, and it is important Occasionally the prince and hands, the procedure is a princess try to overthrow the to recognize that inherent selection sound one. powerful forces of the King and Queen, sometimes with bias exists, even in well-matched Dr. Jarnagin: Agree. temporary apparent victories, but usually to no long-term case–cohort series.’ There are no published avail.” —Blake Cady, MD data to suggest the superi—David Geller, MD ority of one approach over the other for these diseases. Dr. Tsung: Agree. We must remember, however, that the only data available Although there were initial concerns of adequate mar- for analysis are derived from uncontrolled, retrospective gins and tumor seeding for LLR of malignant tumors, studies that are laden with bias regarding patient selecthere have been no significant differences in margin-free tion for minimally invasive procedures. Prospective ranresection and five-year overall survival in multiple stud- domized data are lacking. ies comparing LLR and open liver resection for either HCC or metastatic colorectal cancer. There are currently Dr. Asbun: Agree. prospective, randomized trials ongoing that will confirm whether oncologic results are similar. Even though there are no prospective, randomized trials, the available literature favors the statement that Dr. Buell: Agree. oncologic results are equal between laparoscopic and The publications produced from the Louisville Con- open surgery. There is an implicit selection bias, howsensus clearly demonstrated comparable oncologic out- ever, and a key component to attaining adequate oncocomes in the short term for colorectal [cancer] and logic resection is appropriate patient selection.

7 H E PAT O L O GY IN F O C U NEWS S • OCTOBER32014 GASTROENTEROLOGY & ENDOSCOPY

37 GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Statement: Patients who undergo LLR experience greater clinical benefits and decreased perioperative morbidity compared with open liver resection.

Dr. Jarnagin: On the fence. It is true that patients who undergo laparoscopic partial hepatectomy appear to have less perioperative morbidity and shorter LOS compared with patients submitted to open resection, but in most studies, the groups are not comparable. Open procedures are more often undertaken for disease that is more advanced or for resections that are more difficult technically than is generally undertaken laparoscopically. High-quality prospective data are not available to adequately address this question.

Dr. Geller: Agree. This is supported in the literature with advantages consisting of less estimated blood loss (EBL), less need for packed red blood cell (PRBC) transfusion, less postoperative pain, less narcotic use and shorter length of stay [LOS] in the hospital. Many, but not all, studies ‘At this stage, there is no evidence show decreased postoperative that robotic surgery results in morbidity.

Dr. Buell: Agree.

Decreased operative times, lower blood losses, early postbetter outcomes. But it is not about operative recovery and rapid the robot versus laparoscopy— return to normal activities Dr. Asbun: Agree. have been confirmed by mulit is about doing it right either In the right hands, for the tiple studies. In a recent review right case, in the right patient. laparoscopically or robotically of nearly 700 resections, with There is a need for prospec- assisted.’ the majority being laparotive trials, but realistically this scopic, we identified a lower —Horacio Asbun, MD may not be feasible or pracincidence of complications in tical. Establishing a laparoour laparoscopic group. Both scopic hepatic registry can be groups had an equivalent accomplished; interestingly, it should not be limited to incidence of major resections, redo hepatectomies and the laparoscopic approach. As for laparoscopy, open liver cirrhotic resections. This study also confirmed that a surgery outcomes should be monitored and evaluated laparoscopic approach reduced complications in overequally. weight and obese patients. Dr. Aloia: On the fence. In their book, “Redefining Health Care,” Porter and Teisberg have described well three tiers of patient-centered value in health [cancer] care. In lay terms, they are: 1) Did you hurt me? 2) To what level did I recover function? and 3) Am I cured? With regard to No. 1, laparoscopic approaches are thought to result in fewer complications; however, if you let a skilled surgeon do 100 open liver wedge resections, his or her complication rate would be pretty low, too. To date, for hepatectomy, we have not compared minor-to-minor versus major-to-major well enough to know which approach wins the complication race for sure. With regard to No. 2, laparoscopic approaches likely win on earlier return to normal function, although enhanced recovery protocols are significantly leveling the playing field. We are now doing open major liver surgery using Enhanced Recovery In Liver Surgery (ERILS) protocols with recovery trajectories equivalent to laparoscopic approaches. With regard to No. 3, until the oncologic question is definitively answered, I will be having my liver metastasis resection [done] open. Dr. Tsung: Agree. Similar to other minimally invasive operative procedures, LLR has been shown to improve immediate postoperative outcomes, including pain control, time to oral intake and LOS. Importantly, future studies will investigate whether timing to chemotherapy is also faster following LLR compared with open resection, and whether this translates to oncologic benefits.

Statement: LLR has a steep learning curve and should only be performed in high-volume centers of excellence.

access as a result of its location underneath the rib cage, and potential for bleeding during parenchymal resection. Surgeons performing LLR should have expertise in both liver surgery and minimally invasive techniques. Dr. Buell: Agree. LLR has a steep learning curve and should be approached carefully, selecting smaller and less complex resections first rather than jumping into larger and often more complex resections initially. Surgeons who possess the appropriate expertise should proceed along the learning curve in a slow manner. Dr. Geller: Agree. The learning curve is 50 to 60 cases, and requires ongoing high volume to be facile. For laparoscopic major hepatectomy, a team approach is required and [it] should only be performed in high-volume hepatobiliary centers of excellence. Dr. Jarnagin: Agree. LLR should be undertaken only by surgeons with substantial experience with open liver resection and advanced laparoscopic techniques. Liver resection, in general, remains a complex procedure that requires specialized training to master; this is particularly true of major resections. Expertise in laparoscopic surgery alone does not equate to competence in laparoscopic liver procedures. It is impossible for a surgeon to anticipate the potential difficulties that may be encountered during LLR, unless he or she has been trained in open liver resection.

Statement: Robotic liver resection is becoming increasingly common and is warranted.

Dr. Aloia: Agree. Period! Dr. Jarnagin: On the fence. I agree that robotic liver surgery is being performed I would agree with the statement that “high-vol- more commonly, but whether or not it is warranted ume surgeons/institutions” are usually associated with is debatable. There are many unanswered questions decreased morbidity. A minimum number of major regarding the role of robotic liver surgery, most notably resections per year should be entertained as a require- the adequacy of the instruments, the added cost, and the ment. A key mandatory component is multispecialty ability to rapidly convert to an open procedure in the coordinated care. Anyone event of major vascular doing laparoscopic or major injury. The introduction open liver surgery should do so ‘Patients who undergo laparoscopic of new technology into following their outcomes and practice remains probideally maintaining a prospec- partial hepatectomy appear to have lematic. We learned tive database. this lesson the hard way less perioperative morbidity and shorter [I am] on the fence with the with laparoscopic chodesignation of centers of excel- LOS compared with patients submitted lecystectomy, which was lence. There is a precedent in to open resection, but in most studies, associated with horother areas that the designarific bile duct injuries in tion of centers of excellence the groups are not comparable.’ many patients early in is not necessarily associated —William Jarnagin, MD its history. We face the with better outcomes. This same issue with robotic may depend, however, on the liver surgery. It is my appropriate selection of qualifications to become a cen- opinion that the robotic approach is not as adaptable ter of excellence. to hepatic resection compared with laparoscopy; it currently has a limited role; and it should be used only by Dr. Tsung: Agree. surgeons with great experience with open and laparoLaparoscopic liver surgery is complex due to the vas- scopic liver surgery. cular and biliary structures of the liver, difficulties with see Resection, page 39 Dr. Asbun: Agree.

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9 H E PAT O L O GY IN F O C U NEWS S • OCTOBER32014 GASTROENTEROLOGY & ENDOSCOPY

39 GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Resection continued from page 37

Dr. Asbun: On the fence. Dr. Buell: Agree. At this stage, there is no evidence that robotic surRobotic liver surgery has been adopted increasingly by gery results in better outcomes. But it is not about the multiple centers due to several recent advances, including robot versus laparoscopy—it is about doing it right optics, instrument motion and now a single-access plateither laparoscopically or form. I have adopted robotic robotically assisted. Surliver surgery for small antegeons learning the proce- ‘For major hepatectomy, you still rior and left lateral sectionecdure should not think of tomy to refine a technique for the robot as a shortcut; they need to make an incision to get the single-port robotic resection. should be committed to put- specimen out, so why struggle for Robotic surgery is innately ting forth the effort to learn hours laparoscopically in a pseudosafe more complex and costly, but it well either way. The future in certain instances, such as for robotics in liver surgery environment when you are going to single-port surgery, it simpliis very promising, however. make an incision anyway?’ fies the procedure, reducing Augmented reality and betoperative times. There are —Thomas Aloia, MD ter identification of strucseveral large-volume centers tures by computer-enhanced around the world that have imaging will be a key factor in making robotic-assisted adopted routine use of the robot, but these are also centers liver surgery the better approach. In 2014, though, we with extensive laparoscopic resection experience. Robotics are not there yet. has a current and future role in liver resection. Dr. Aloia: Agree. Conceptually, we need to understand the advantages of using instruments with the ability to “wrist” and rotate in multiple planes. The robot has clear utility in hard-to-reach places that require fine movements, namely the porta hepatis and the right superior and posterior liver. However, there are three main issues with the robot in liver surgery: 1) We need to maintain a healthy respect for the vascularity in and around the liver. Bottom line: If you make a hole in the cava, can you get that machine out of your way in time to save the patient? 2) The operative times are long, and even in the most experienced hands, they reduce to a plateau that is longer than other approaches; and 3) You still need to make an incision to get the specimen out. Dr. Tsung: On the fence. The application of robotic technology to liver surgery has grown because it has the potential to overcome many limitations of conventional laparoscopy (e.g., [three-dimensional] view, “wristed” instruments, easier suturing). Currently, there are multiple downsides, such as increased cost and longer operative times, compared with the laparoscopic approach that should be considered. However, future advances in its technology, more experience and decrease in cost may potentially further facilitate minimally invasive liver surgery and improve clinical and economic outcomes.

benefit from a hybrid/hand-assisted approach for several reasons. Oncologically, identification of small subcapsular lesions missed on preoperative imaging is facilitated by liver palpation. With a hand in the abdomen, the speed of the operation is faster, while the safety is increased as manual compression of bleeding is the most effective temporizing measure and inflow occlusion is simplified. As well, for major hepatectomy, you still need to make an incision to get the specimen out, so why struggle for hours laparoscopically in a pseudosafe environment when you are going to make an incision anyway? (And please don’t answer “cosmesis!”) Last but not least, the presence of a hand port allows me to teach trainees in a more controlled setting, as I know that I can rapidly rescue them from trouble without forcing conversion to open surgery.

Dr. Buell: Agree. LLR was developed by the French to emulate traditional open techniques using pure laparoscopy. I initially used a hand-assist device in the majority of Dr. Geller: On the fence. cases for safety, and now after nearly 400 laparoscopic Even though robotic liver resection is becoming more cases, the majority of cases are now purely laparocommon, it is definitely more expensive than LLR. The scopic. The hybrid and hand-assisted techniques are robot excels at a few tasks, alternative strategies that such as sewing and working can minimize the learnin tight spaces. Hopefully, ‘The application of robotic technology ing curve, providing an as costs come down (if they extra safety measure or ever do) and instrumenta- to liver surgery has grown because it “training wheels.” Pure tion improves, the robot will has the potential to overcome many LLR appears to provide become cost-effective. the most significant benlimitations of conventional laparoscopy efit with the least surgical trauma. Whether it’s (e.g., [three-dimensional] view, “wristed” Statement: LLR is hybrid, hand-assisted superior to hybrid/hand- instruments, easier suturing).’ or pure laparoscopy, we assisted approaches. —Allan Tsung, MD are all heading toward the same operation with Dr. Geller: Agree. excellent surgical techAlthough patients with hand-assisted or hybrid liver nique and being oncologically sound. resection still do better than open liver resection, patients who have pure LLR seem to do the best. They have less Dr. Asbun: When feasible, pain and shorter LOS, often going home on postoperative the goal should be to do the procedure totally lapaday 1 or 2. There are also less wound infections/hernias roscopically. However, there is no such thing as a with a pure laparoscopic approach. superior or inferior approach. The approach should be tailored to the patient, the type and location of the Dr. Aloia: Disagree. lesion, and surgeon experience. In fact, conversion from For subsegmental hepatectomies, because the speci- laparoscopic to hand-assisted, hybrid or open approach men is small, these are likely best done with a totally should never be considered a complication. It usually laparoscopic approach. In contrast, larger resections shows good judgment.

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H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

ACG Releases Evidence-Based Guidance on Focal Liver Lesions

ocal lesions in the liver found incidentally through imaging represent a common dilemma for clinicians faced with the challenge of avoiding unwarranted invasive procedures while encouraging appropriate diagnostic studies and, if necessary, treatment of disease. New evidence-based guidelines from the American College of Gastroenterology (ACG) should help. “The result of more imaging in clinical medicine has been more lesions

identified incidentally. Better resolution allows detection of ever smaller lesions, but many of these are not clinically significant,” explained K. Rajender Reddy, MD, director of hepatology at the University of Pennsylvania, in Philadelphia. Dr. Reddy, who led the group that crafted the recommendations, said the majority of incidental lesions in the liver are benign, so the challenge is making the diagnosis while imposing minimal risk. Of the 38 recommendations drawn up

by the ACG Practice Parameters Committee from a critical review of published studies, none may be more important than those intended to counsel clinicians on when and when not to biopsy. Not only may biopsy add needless cost and discomfort when definitive diagnosis can be made on the basis of imaging alone, it can lead to unwanted complications, such as bleeding in patients with a hemangioma. “The guidelines are specifically

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designed to help clinicians recognize the probability of one diagnosis relative to another based on history, symptoms, risk factors and appearance on imaging,” Dr. Reddy told Gastroenterology & Endoscopy News. “The goal is to follow the shortest route to diagnosis without performing unnecessary procedures.” Of potential pathologies represented by focal liver lesions, hepatocellular carcinoma (HCC) generates some of the greatest concern. The likelihood of HCC in the absence of cirrhosis is low, but early detection of HCC represents a major opportunity to improve prognosis. The guidelines specifically state that HCC should be the presumed diagnosis until proven otherwise in patients with a solid focal liver lesion and chronic liver disease resulting from causes such as infection with the hepatitis B or C viruses. “Experts are generally aware that a high index of suspicion for HCC is appropriate in patients with viral hepatitis and a focal liver lesion, but clinical gastroenterologists may not fully appreciate that HCC needs to be formally ruled out,” Dr. Reddy said. However, he noted that biopsy is not necessarily required. The guidelines outline when computed tomography (CT) and magnetic resonance imaging scans are sufficient for a diagnosis. Biopsy also may be unnecessary in suspected cases of intrahepatic cholangiocarcinoma (CCA), although for different reasons. According to the guidelines, a definitive diagnosis of CCA is difficult on the basis of imaging alone. But biopsies are not required because surgery is indicated in most cases, and biopsy could produce seeding. The exceptions are cases when the lesion is nonoperable, according to the recommendations.

Use With Caution Judicious use of biopsy is a recurring theme in the new guidelines. In suspected hepatocellular adenomas found incidentally, for example, biopsy is advised when the information is likely to alter management but not if conservative management is planned. The same holds for focal nodular hyperplasia, one of the more common incidental findings in the liver. Imaging generally suffices for a diagnosis, and treatment is not recommended when the lesions are asymptomatic. In the broad array of potential pathologies underlying an incidental liver lesion, biopsy might be considered in the event of an asymptomatic condition, such as suspected cases of nodular regenerative hyperplasia. However, the guidelines narrow the indications by directing clinicians to features and characteristics for which biopsy might be superfluous. Dr. Reddy

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER OCTOBER 2014 2014

Key Points • A definitive diagnosis of incidental lesions should be considered mandatory for patients with chronic viral infections, such as hepatitis B or C, to rule out hepatocellular carcinoma.

• The diagnostic approach for incidental lesions should be guided by the specific clinical risk factors that make one type of lesion more likely than another in a specific individual.

metastatic lesions, it often is difficult from an imaging standpoint to discriminate [the lesions] and it would be helpful guidance to the clinician to address

the risk that a lesion with a particular imaging appearance is primary versus metastatic,” he said. The guidelines were published in

August on the website of the American Journal of Gastroenterology. Drs. Reddy and Berland reported no relevant financial conflicts of interest.

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reiterated that most incidental findings do not represent a significant threat, and emphasized the need for a rational approach. “A focal lesion found by chance on a CT scan represents a significant dilemma for clinicians,” Dr. Reddy said. “The guidelines provide a framework for a reasonable and evidence-based approach.” Lincoln N. Berland, MD, professor emeritus of radiology at the University of Alabama, Birmingham, and chairman of the American College of Radiology (ACR) Body Imaging Commission, expressed overall support for the recommendations but did offer some reservations. Although the guidelines “provide invaluable direction in diagnosing and managing liver lesions,” Dr. Berland emphasized the importance of differentiating lesions identified by chance from lesions that prompted diagnostic studies. “I believe that the risk to the patient is substantially less with incidental lesions than with symptomatic lesions, even when they have similar appearances, and management should often differ,” Dr. Berland said. Alternative consensus guidelines for specific indications, such as those developed by the ACR, can provide added detail about how to proceed when the pathology of the lesion, whether identified incidentally or as a result of symptoms, is known. He offered HCC as an example. “The ACG writing group indicated that they wished to avoid discussion of HCC. However, given their inclusion of this topic, it should be recognized that elaborate systems have been employed to address the diagnosis and management of such lesions, including the ACR’s LiRADS [Liver Imaging Reporting and Data System],” Dr. Berland said. Dr. Berland also expressed concern about omitting discussion of metastatic lesions. “Although the writing group indicated that it would not discuss

• A conservative approach that limits use of biopsy should be taken to liver lesions found incidentally as a result of imaging studies because the majority is not clinically meaningful.

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

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

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

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

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

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

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

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

sovaldi.com/hcp

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

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

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

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

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

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

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

SOVALDI® (sofosbuvir)

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

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

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

N=71

N=650

N=250

N=243

N=327

Fatigue

24%

38%

30%

55%

59%

Headache

20%

24%

30%

44%

36%

Nausea

18%

22%

13%

29%

34%

Insomnia

15%

16%

29%

25%

Pruritus

11%

27%

17%

Anemia

10%

12%

21%

Asthenia

21%

Rash

18%

Decreased Appetite

10%

18%

Chills

18%

17%

Influenza Like Illness

18%

16%

Pyrexia

14%

18%

Diarrhea

12%

17%

12%

Neutropenia

<1%

12%

17%

Myalgia

16%

14%

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

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

Interferon-containing Regimens

PBO 12 weeks

SOVALDI + RBV Va 12 weeks

SOVALDI + RBV Va 24 weeks

Peg-IFN + RBVb 24 weeks

SOVALDI + Peg-IFN + RBV Va 12 weeks

N=71

N=647

N=250

N=242

N=327

<10

14%

23%

<8.5

<1%

Hematological Parameters Hemoglobin (g/dL)

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

<1%

12%

15%

<1%

Platelets (x10 /L) ≥25 - <50 <25 a

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

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

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

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

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

H E PAT O L O G Y I N F O C U S

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER OCTOBER 2014 2014

Model Predicts Sharp Decline in Hep C Burden More screening, better treatments should curb infection rate, researchers find BY MONICA J. SMITH

he public health burden posed by chronic infection with the hepatitis C virus (HCV), which claimed more lives in 2007 than HIV and is associated with an annual cost in the United States of about $6.5 billion, may be greatly diminished by 2036, according to a recently published computer simulation study ((Ann Intern Med 2014;161:170-180). Significant changes have occurred since the release of prior predictive analyses that were limited to the scenario of treatment with peginterferon and ribavirin (PEG-RBV) in an HCV screening-free setting, or that evaluated only the cost-effectiveness of new drugs. The launching of direct-acting antiviral medications in 2011, the increasing availability of oral drug therapies, the continuing development of new drugs that increase sustained virologic response rates with fewer adverse effects, and the Centers for Disease Control and Prevention (CDC) recommendation for a one-time HCV screening of all people born between 1945 and 1965 may have a profound effect on the burden of the infection in the United States. “We anticipated that the HCV burden would go down, but we wanted to quantify how quickly that would drop,” said Jagpreet Chhatwal, PhD, assistant professor of health services research at the University of Texas MD Anderson Cancer Center, in Houston, who helped conduct the study. To predict the effect these recent developments may have on chronic HCV infections and associated outcomes, including cirrhosis, hepatocellular carcinoma, the demand for liver transplants and liver-related mortality, Dr. Chhatwal and his colleagues at MD Anderson and the University of Pittsburgh developed an

HCV Therapies continued from page 35

In another study, researchers analyzed an all-oral regimen of daclatasvir plus asunaprevir in a Phase III randomized trial that included patients from 116 sites and 18 different countries. The study cohort

individual-level state transition model capable of simulating the HCV-infected population spanning a 50-year range, from 2001 to 2050. The model simulated the current clinical practice: treatment with PEG-RBV or protease inhibitor–based triple therapy before 2014, then with sofosbuvir- and simiprevir-based therapies and new drugs as they develop. The model also acknowledged one-time birthcohort screening starting in 2013. The researchers validated their model using several sources: the National Health and Nutrition Examination Survey 2003-2010 report, data from the CDC, a multicenter follow-up study of individuals with advanced fibrosis and earlier studies. Their model predicted a decrease in the number of chronic HCV cases from 3.2 million in 2001 to 2.3 million in 2013 in the general population, noting that screening baby boomers should identify nearly 490,000 cases over the next decade. One-time universal screening, on the other hand, could identify nearly twice as many. “We should not be limiting ourselves to screening baby boomers, but explore other screening policies,” Dr. Chhatwal said, adding that expanding screening would require an evaluation of the effects of broader screening and of its cost-effectiveness. “We could look at geography, if the disease burden seems more prevalent in some areas, or by other settings. For example, there is a high prevalence of HCV among prison inmates; screening that population could be a very efficient and cost-effective way to reduce disease burden.” The model also predicted that the availability of the most recently approved therapies for HCV could prevent a substantial number of HCV-related outcomes, reducing the number of new cases of cirrhosis by 124,200, the number of cases of hepatocellular carcinoma by 78,000, the number of liver-related deaths by 126,500 and the number of liver transplants by 9,900.

was comprised of 307 treatment-naive patients, 205 previous nonresponders to PEG-IFNα plus RBV, and 235 patients previously identified as intolerant and/or ineligible for PEG-IFNα plus RBV. Treatment-naive patients received treatment or placebo for 12 weeks, after which the treatment group continued

Type 1 Strain Accounts For Nearly Half of Cases Of HCV’s six genotypes, type 1 appears to be the most prevalent, affecting more than 83 million people worldwide, according to the findings of one of the largest prevalence studies to date (Hepatology 2014 July 28. [Epub ahead of print]). To estimate trends in genotype prevalence, researchers in the United Kingdom reviewed 1,217 studies reporting HCV genotypes. The studies, published between 1989 and 2013, represented 117 countries and about 90% of the global population. The researchers also used prevalence estimates generated by the World Health Organization’s Global Burden of Disease project. Their analysis showed that genotype 1 made up 46% of all HCV cases. Genotype 3 accounted for 30%, with genotypes 2, 4 and 6 making up 23%, and genotype 5 making up less than 1%. The authors noted that although genotype 1 is the most common, non–genotype 1 HCV cases account for more than half of all cases and are generally less well served by advances in vaccination and drug treatment.

open-label treatment for another 12 weeks and the placebo group entered into an open-label arm consisting of daclatasvir plus asunaprevir. Nonresponders and treatment-intolerant/ineligible patients received daclatasvir plus asunaprevir for 24 weeks, also open-label. At 12 weeks post-treatment, 182 (90%) of the treatment-naive patients, 168 (82%) of the prior nonresponders and 192 (82%) of the intolerant and/or ineligible group achieved SVR. Serious AEs were reported in 12 (6%) patients from the treatment-naive group, 11 (5%) of the nonresponders and 16 (7%) of the intolerant and/or ineligible patients. The most common reason for discontinuation was a reversible increase in alanine or aspartate aminotransferase. The researchers concluded that daclatasvir plus asunaprevir was effective and well tolerated in patients with HCV genotype 1b, including those with cirrhosis. The FDA has approved both simeprevir and sofosbuvir, and the regimen investigated in the COSMOS trial has been

—M.S.

used in clinical practice for months now, Dr. Reddy said. The agency is now considering a cocktail of daclatasvir plus asunaprevir (Bristol-Myers Squibb), which already has been approved in Japan. The challenge, however, is not with proving the efficacy of treatment, but with identifying patients with HCV and linking them to care, he continued. “Also, the cost of the drugs is the topic of debate now. If we successfully eradicate the disease, there would be downstream benefits. When people achieve SVR, which has been demonstrated with interferon-based therapy, they have decreased liver-related morbidity and mortality, and also non–liver-related morbidity because HCV may affect other organs as well. That’s the argument,” Dr. Reddy said. Both studies appeared online July 28. Dr. Lawitz has collaborated on research with many pharmaceutical companies in the HCV space, including Janssen, which funded the COSMOS trial. The daclatasvir plus asunaprevir trial was funded by Bristol-Myers Squibb.

H E PAT O L O G Y I N F O C U S

Hepatocellular Carcinoma Risk Persists In HCV Patients With Another Malignancy BY TED BOSWORTH CHICAGO—Patients with hepatitis C who develop both a liver cancer and a non-liver malignancy appear to respond poorly to traditional antiviral therapies such as pegylated interferon and ribavirin, according to an analysis from a large U.S. cancer center. In data published in conjunction with the 2014 annual meeting of the American Society of Clinical Oncology (abstract e15092), sustained virologic response (SVR) was achieved in 65% of patients who had a non-liver primary malignancy but only 29% of those with both a non-liver malignancy and hepatocellular carcinoma (HCC) as a second primary (P=0.05).

malignancies (82% vs. 47%), although the difference was not significant (P=0.07). P The researchers found no significant differences between cases and controls for risk factors such as alcohol abuse, obesity, family history of HCC or steatohepatitis. In most of the cases (75%), HCC was found incidentally; few patients had tumors on routine screening. Significantly fewer cases than controls received chemotherapy for their primary malignancy (29% vs. 76%; P=0.01). In patients with both a non-liver malignancy and HCC, targeted therapy was the most common therapeutic strategy, used in 55% of cases. The data from this study confirm that patients with HCV remain at substantial risk for HCC even after development of a non-liver malignancy. Previ-

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Obesity at a Glance

Figure 1. Prevalence of self-reported obesity among U.S. adults, by state, 2011.

Figure 2. obesity among U.S. adults, by state, 2012. In this retrospective case–control evaluation, 75% of the 32 cases with both liver and non-liver malignancies received hepatitis C virus (HCV) treatment, reported Harrys A. Torres, MD, assistant professor in the Department of Infectious Diseases at the University of Texas MD Anderson Cancer Center, in Houston. Based on the low rate of SVR, Dr. Torres suggested that HCV-infected individuals with two primary malignancies may be particularly resistant to the treatments that were available at the time when these patients were initially treated. Although earlier treatment resulting in higher SVR rates “may reduce the risk of HCC as a second primary malignancy,” Dr. Torres also suggested that SVR rates might improve in HCV patients with two primary malignancies, using newer direct-acting antiviral agents (DAAs). He indicated that a prospective trial is needed. Data from this study, which were derived from a review of patient records at MD Anderson for 2008 to 2011, also reinforce other evidence that HCV patients remain at risk for HCC even after developing a non-liver malignancy. In this series of 32 patients with a non-liver malignancy and HCC as a second primary, the majority of the cases were men (75%) and white (63%). Most patients had HCV genotype 1 (77%). When the cases were compared with 17 matched controls, nearly twice as many cases as controls had solid primary tumors as opposed to hematologic

ous studies have estimated that 7% of HCV patients with a non-liver primary malignancy develop HCC as a second primary. Surveillance for HCC “should be continued as recommended in other HCV-infected patients,” said Dr. Torres, who suggested that increased awareness regarding the importance of screening for HCC is needed among oncologists. Amit G. Singal, MD, MS, medical director of the Liver Tumor Program at the University of Texas Southwestern School of Medicine, in Dallas, said the study “helps highlight the benefit of treatment in HCV-infected patients, given that HCV eradication is able to significantly reduce risk of HCC and other cirrhosis-related complications. The introduction of the new antiviral therapies provides an exciting opportunity to curb the growing HCC burden in this country. “HCC surveillance is important in patients with HCV-related cirrhosis,” Dr. Singal added. “Patients with cirrhosis and persistent HCV viremia are at high risk for HCC and other cirrhosis-related complications. Although sustained virologic response significantly reduces the risk of HCC development, the risk is not zero, so these patients warrant continued HCC surveillance.” However, the new case–control study suggests that these patients may have unique risks. Dr. Torres reported a financial relationship with Genentech. Dr. Singal reported no relevant financial conflicts of interest.

Figure 3. Prevalence of self-reported obesity among U.S. adults, by state, 2013.

15%–<20%

20%–<25%

25%–<30%

30%–<35%

≥35%

Prevalence estimates reflect methodological changes started in 2011 and should not be compared with estimates before 2011. Source: Centers for Disease Control and Prevention

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Landmark Crohn’s Microbiome Study Yields Important Findings BY DAVID WILD CHICAGO—One of the largest microbiome-focused studies to date has identified several distinct microbial species and communities that correlate with both the presence and severity of Crohn’s disease. The findings, which analyzed the microbiome of 447 treatment-naive pediatric patients with Crohn’s disease and 221 without the condition, could pave the way for microbiome-based diagnostics and therapies for the illness, one expert said. “This was an excellent study, both in terms of its design and implications,” said Colleen Kelly, MD, assistant professor of medicine at Warren Alpert Medical School of Brown University, in Providence, R.I., who was not involved in the research. “Clinically, the findings suggest we may eventually be able to use specific bacterial taxa as biomarkers to more reliably diagnose Crohn’s disease, and that these biomarkers could be derived from rectal tissue biopsies obtained through minimally invasive methods such as proctoscopy.” Senior investigator Ramnik Xavier, MD, professor of medicine, chief of the gastrointestinal unit and director of the

Center for the Study of Inflammatory Bowel Disease at Massachusetts General Hospital, in Boston, and his colleagues at 28 centers in North America genetically sequenced ileal and rectal tissue samples from 447 recently diagnosed Crohn’s patients. The patients had not yet been treated for the disease, although 57 had previously received antibiotics for other indications. The researchers also collected fecal samples from 233 of these individuals. The 221 control patients did not have inflammatory conditions but some presented with gastrointestinal symptoms. Tissue sample analyses revealed that children with Crohn’s generally had less species diversity, according to the researchers. Crohn’s disease also was associated with smaller populations of Erysipelotrichales, Bacteroidales and Clostridialess and larger populations of Enterobacteriaceae, Pasteurellaceae, Veillonellaceae and Fusobacteriaceae, the latter of which is associated with colorectal carcinoma (Genome Res 2012;22:292-298). Based on the patterns they uncovered, Dr. Xavier and his colleagues developed and tested the Microbial Dysbiosis Index (MD-Index), which uses the presence and density of specific microbial populations

as variables. They found that higher scores on the MDIndex, which reflect reduced species diversity and greater microbial dysbiosis, strongly correlated with disease severity as measured by the Pediatric CD Activity Index (PCDAI). A higher MDIndex also strongly correlated with the presence of several serological markers of Crohn’s activity. “The association suggests that there is a potential link between the presence of these microbes and the serologic biomarkers, but that needs to be determined in future studies,” said Dr. Xavier, who presented the study at Digestive Disease Week 2014 (abstract 850a). Detailed results related to the serology-microbial link will be reported in an upcoming publication, he added. In the subgroup of patients who had received antibiotics for indications other than Crohn’s disease, Dr. Xavier’s team found more pronounced microbial dysbiosis. That finding is consistent with prior epidemiologic and clinical research, he said (see, e.g., Gut 2011;60:49-54). Dr. Kelly said this finding is clinically significant, given that antibiotics are

commonly used as treatment for Crohn’s. “The result suggests that antibiotic therapy in Crohn’s disease may not always be beneficial and it helps explain why there is a higher risk of Clostridium difficilee infection in [irritable bowel disease] patients,” she said. The researchers effectively enlarged their study population to more than 1,500 by sequencing samples from several other Crohn’s study cohorts. Individuals in those cohorts had longer disease duration (mean seven years), were older (mean age 41 years) and some had received treatment for their illness. That analysis confirmed their findings, they said. Dr. Xavier reported no relevant financial conflicts of interest. Dr. Kelly reported being a site investigator for a trial of an encapsulated FMT product manufactured by Seres Health.

Intermittent PPI, Continuous Infusion Equally Effective e For Post-Endoscopy Ulcer Hemostasis BY DAVID WILD CHICAGO—A new meta-analysis of therapy for bleeding ulcers suggests that current treatment recommendations warrant revision. The 13-study review, presented at Digestive Disease Week 2014 (abstract 331), concluded that intermittent therapy with oral proton pump inhibitors (PPIs) following endoscopic treatment of bleeding gastric or duodenal ulcers is as effective in preventing rebleeding as boluscontinuous IV infusion of the drugs, but at a lower cost. “Current American College of Gastroenterology guidelines that call for continuous drip are based on data showing a benefit with this approach compared with no PPI therapy after endoscopy,” said Hamita Sachar, MD, a clinical fellow in the Section of Digestive Diseases at Yale University School of Medicine, in New Haven, Conn., who led the study ((Am J Gastroenterol 2012;107:345-360). “Our meta-analysis looked at a different comparison and showed that no clinical outcomes are poorer with intermittent oral PPI therapy. In my opinion, there are robust data from randomized controlled trials to support intermittent therapy as a preferable approach, given that it is as effective and requires less resources.”

Dr. Sachar and her colleagues searched several medical databases as well as abstracts from several gastroenterology meetings for randomized controlled trials comparing the efficacy of intermittent PPI use following endoscopic therapy in patients with bleeding ulcers and high-risk endoscopic features with the currently recommended regimen of an IV bolus of 80 mg followed by infusion of 8 mg per hour for 72 hours. The 13 studies that met these criteria included 1,691 patients. Their noninferiority analysis, which defined clinical significance as a difference between treatments of 3% or greater, showed that the two treatment approaches had similar rates of rebleeding at three, seven and 30 days after the procedure. Moreover, rates of mortality and need for surgical or endoscopic interventions were similar between patients taking either regimen. Although the researchers found that intermittent PPI use was associated with fewer blood transfusions and shorter lengths of stay in the hospital, Dr. Sachar said the study’s design precluded drawing definitive conclusions about these differences. Nevertheless, she said, with intermittent PPI use, therapy “is less expensive; less nursing and pharmacy staff resources are needed; it does not require an infusion pump; and it is easier to administer.” The results support an approach that Lawrence

Friedman, MD, chai airr of the Digestive Disease Weekk Council and chairr of the Department of Medicine at Newton-Wellesley ey Hoospital, in Newton, Mass., already has implemented d in hiis practice. “I’ve long bel elieved that intermittent oral PPI use is probably as effectivve as a continuous PPI infusion, based on severaal studiees that have demonstrated that,” Dr. Friedman said. “H However, physicians are naturally interested d in haviing data reviewed thoroughly before implem menting a change in practice, and this study provides that analysis.” Dr. Sachar noted several limitations in the meta-analysis. Sp Specificcally, eight of the studies were not blinde ded an nd the trials included a variety of intermitt itten nt PPI regimens. “However, subgroup p analyses showed no significant correlaations ns bet between efficacy and dose, frequency or route of administratioon,” , she said. “These results indiicatee intermittent PPI should bee thee regimen of choice in this poopullation.” Drs. Friedman and Sachar reported no relevan nt financial conflicts of interrest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Angelita Habr-Gama, MD, Pioneer in Colorectal Surgery BY VICTORIA STERN

ngelita Habr-Gama, MD, helped pave the way for future generations of women in surgery. During the 1940s and 1950s, few women entered the medical profession and still fewer became surgeons. Despite the paucity of women, Dr. HabrGama knew that surgery was her calling. In the early 1950s, Dr. Habr-Gama worked tirelessly until she was accepted to the top medical school in Brazil, The University of São Paulo School of Medicine. She was one of a handful of female students in her class. Unfazed by the imbalance, she continued to pursue her passion. Throughout her career, Dr. Habr-Gama has accrued an impressive list of firsts. In 1958, she was the first female resident in general surgery at the University of São Paulo School of Medicine Clinics Hospital (FMUSP). In 1961, she became the first female fellow at St. Mark’s Hospital in England, although it took two years of applying before she was accepted to the all-male program. By 1966, she finished her doctoral degree and became one of the first female surgeons in Brazil. After completing her thesis in 1972, which focused on a new technique to conserve the anus in patients with rectal cancer, Dr. Habr-Gama was promoted to associate professor at FMUSP. Twenty-six years later, in 1998, Dr. Habr-Gama became the first female full professor at the university, a post that she still holds.

Before this time, FMUSP had not allowed women to become full professors. But after years of petitioning for equality, Dr. Habr-Gama was finally awarded the title. Currently, Dr. Habr-Gama is also director of the Department of Gastroenterology and the Colorectal Unit at FMUSP. Among her many accomplishments, Dr. HabrGama introduced colonoscopy, mechanical suturing and video laparoscopy to Brazil; pioneered advances in the field of coloproctology; and developed Brazil’s first anorectal physiology laboratory. She was also the first, and so far the only, woman to become president of the Latin American Association of Coloproctology and the Brazilian Society of Coloproctology as well as vice president of the Brazilian College of Surgeons and governor of the American College of Gastroenterology in Brazil. Throughout her career, Dr. Habr-Gama has been a strong advocate of the controversial “watch-andwait” approach for patients with anal and rectal cancer who have achieved a complete clinical response following neoadjuvant chemoradiation ((Ann Surg 2004;240:711-718; Dis Colon Rectum 2013;56:11091117; Int J Radiat Oncol Biol Physs 2014;88:822828). She has participated in the Genome Project and the Human Cancer Genome Program (PNAS 2013;100:13418-13423). More recently, she has been an active spokeswoman for colorectal cancer prevention ((Arq Gastroenteroll 2005;42:23; Nutr Hosp 2005;20:18-25).

Gastroenterology & Endoscopy News s recently interviewed Dr. Habr-Gama to learn more about her accomplished career in surgery and medicine. GEN:: Where did you grow up? Dr. Habr-Gama: I was born on Ilha de Marajó, an island in the middle of the Amazon River in Brazil. At age 7, I moved to São Paulo with my family and I continue to reside there today. GEN: When did you know you were interested in medicine? Was your family supportive of this? Dr. Habr-Gama: Since I was a teenager I knew that I did not want to become a schoolteacher, which was the expected occupation for women at that time and a profession my parents approved of. However, my strong interest in biology and human sciences led me to choose medicine despite being against my family’s wishes. GEN: Was the transition from your desire to be a doctor to actually attending medical school a difficult one as a woman? Dr. Habr-Gama: Yes, it was very difficult. Women hardly entered medical schools at that time—six women a year on average. There were few medical schools in São Paulo and only two public universities. However, I turned difficulties into challenges and I studied hard to enter the most highly regarded medical school in Brazil:

The University of São Paulo School of Medicine. After overcoming this initial barrier, I must say I did not suffer much discrimination throughout my medical career. GEN: When during medical school did you gravitate toward surgery? Dr. Habr-Gama: I felt especially attracted to gastroenterology and cardiology, but during my internship, which corresponded to the sixth medical year, I rotated in the surgery ward. During one surgery, the resident doctor offered me the opportunity to close the patient’s abdominal wall. At that moment, I knew I had discovered my actual vocation. GEN: What was your experience training in such a male-dominated world? Dr. Habr-Gama: My experience training in a male-dominated world was very interesting. Patients would sometimes ask me, “When will the surgeon come?” When I would answer, “I am the surgeon,” some patients became very anxious. One of my greatest difficulties was being accepted by nurses, particularly in the operating room setting. It was even difficult to get gowns in my size (some cutting was often necessary) and to go to restrooms. Slowly over time, these attitudes and impediments changed and people gained confidence in my abilities.

Dr. Habr-Gama accepts full professorship at Sao Paulo School of Medicine Clinics Hospital in 1998.

GEN: Why the interest in colorectal surgery specifically? Dr. Habr-Gama: My interest in colorectal surgery developed after a fellowship at St. Mark’s Hospital in London. I was the first woman accepted as a fellow, which was not an easy feat. The first answer I received when I applied for the scholarship was that St. Mark’s was a hospital for men, not women. However, my repeated efforts were rewarded and, after two years of applying, I was accepted. GEN: Can you describe a few of your most notable accomplishments that propelled your career? Dr. Habr-Gama: There were several pivotal points in my career. The first was being a resident in the Surgery Department headed by Professors Alipio Correa Neto and Arrigo Raia. Both men were outstanding surgeons and professors. They had a special sense of leadership, and did their best to help us improve our knowledge and achieve success. My time as a fellow at St. Mark’s Hospital was also a turning point in my career. After my fellowship, I started being accepted by my professor, colleagues and patients. GEN: What about significant publications? Dr. Habr-Gama: I have been publishing throughout my career, but the most relevant scientific papers came in the 1990s (e.g., Dis Colon Rectum 1998;41:10871096). I have devoted part of my efforts to colorectal cancer prevention and to changing rectal cancer management (Updates Surgg 2013;65:43-52; CA Cancer J Clin 2012;62:173-202; Tech Coloproctoll 2011;15:45-51), and have always been interested in sphincter preservation (Hepatogastroenterologyy 2004;51:1703-1707). GEN: Can you describe the impetus for the controversial watch-and-wait protocol? Dr. Habr-Gama: My thesis to obtain the title of associate professor in 1972 was on coloanal anastomosis for the treatment of rectal cancer, a technique intensely debated at the time. As of 1981, like many other specialists, I started using multimodal treatment with neoadjuvant chemotherapy, particularly to manage distal rectum tumors. After performing radical surgeries, either abdominoperineal amputation of the rectum or rectosigmoidectomies with coloanal anastomoses, and observing no tumor in the surgical specimen, I changed see Pioneer, page 57

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Sessile continued from page 1

resected. The pathologist’s job is to properly classify them,” Dr. Karnes said. “Inaccurate distinction of hyperplastic polyps and SSAs by pathologists may be an underrecognized cause of interval cancers.” The UC Irvine investigators, led by Sarah L. Flores, MD, hypothesized that SSA detection would vary significantly among colonoscopists, and that their classification would vary among pathologists. They looked at the UCI colonoscopy Quality Database—a real-time collection of colonoscopy quality indices. The analysis involved 1,878 colonoscopies, of which 1,175 were adenomas, hyperplastic polyps or SSAs. Seven colonoscopists performed the procedures included in the analysis. Eight pathologists analyzed 3,239 polyps, 1,810 adenomas, 760 hyperplastic polyps and 232 SSAs. The researchers observed high variability among the colonoscopists (Table 1). For SSAs, in particular, the mean detection rate was 7%, ranging between 2% and 14%. The correlation between the detection of adenomas and SSAs was significant (r=0.871; P P=0.011), Dr. Karnes said. “If colonoscopists were good at one thing, they were good at another,” he noted. “The adenoma detection rate is a surrogate marker of quality, and these findings support that.” Among colonoscopists, the classification of hyperplastic polyps and SSAs also varied greatly (Table 2), and detection of hyperplastic polyps and SSAs was inversely related (r=0.802; P=0.017). P “What’s more remarkable is how pathologists with the highest hyperplastic classification rate had the lowest SSA classification rate, whereas those with the highest SSA rate had the lowest detection rate for hyperplastic polyps,” Dr. Karnes said. What this means, he said, is that certain pathologists are not differentiating appropriately between these two lesion types. Some pathologists are “overcalling” the findings, so patients undergo unnecessary surveillance, whereas others may be missing dangerous lesions, he said. “The correct pathologic diagnosis of serrated polyps determines the appropriate intervals for surveillance or ‘second-look’ colonoscopies,” he said. The group of pathologists included three gastrointestinal pathologists and six general pathologists; less variability was observed among the specialists. “We are not using the general pathologists anymore,” he added. Dr. Karnes said the results suggest that “if SSAs represent the precursor lesions of interval colorectal cancers, prevention of these cancers will require more accurate methodologies for detection by colonoscopists and distinction of SSAs from hyperplastic polyps by pathologists.” In his own practice, he said, “If I’m convinced I have an SSA, I don’t care what the pathologist says. I have the patient return in three to six months.”

A GI Pathologist Responds Jerrold Turner, MD, PhD, associate chair of the Department of Pathology at the University of Chicago, said the findings were consistent with his personal experience as a gastrointestinal pathologist, and also his personal experience on the patient side. His mother had a polyp removed and the pathologist called it hyperplastic. Dr. Turner examined the biopsy himself and found the lesion was in fact an SSA. He was surprised to learn the pathologist was not a pathologist who had trained

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Table 1. Polyp Detection Rates Per 100 Colonoscopies Lesion Detection Rate

Mean ± SD, %

Range, %

P Value

56 ± 14

27-69

<0.0001

Adenomas

40 ± 9

27-54

0.0004

Hyperplastic polyps

21 ± 8

7-33

0.042

SSAs

7±4

2-14

0.0046

SSAs, sessile serrated adenomas

Table 2. Polyp Classification Rates Among Pathologists Lesion

Mean ± SD, %

Range, %

P Value

54 ± 3

47-58

Hyperplastic + SSAs

31 ± 4

28-38

0.0024

Hyperplastic polyps

22 ± 6

16-35

<0.0001

SSAs

9±5

3-18

<0.0001

SSAs, sessile serrated adenomas

‘If SSAs represent the precursor lesions of interval colorectal cancers, prevention of these cancers will require more accurate methodologies for detection by colonoscopists and distinction of SSAs from hyperplastic polyps by pathologists.’ —William E. Karnes, MD

long ago, before SSA became a classification—as he had assumed—but had recently completed his training at a high-quality institution. “The pathologist pulled the slide again, re-read it and agreed with me, much to his embarrassment. This tells the story,” said Dr. Turner, who also is editor-in-chief of the journal Cellular and Molecular Gastroenterology and Hepatology. “He was well trained and practiced in a wellrespected center, and he still misclassified the lesion.” Much of the confusion lies in the fact that SSA is a fairly new entity that can have subtle features that not all pathologists recognize, he continued. The crypt region is important in differentiating between SSAs and hyperplastic polyps, but may not be well represented in poorly oriented tissue sections. Semantics further complicate the issue. “Some pathologists will call this an SSA while others will call it a sessile serrated polyp,” Dr. Turner said. Those who favor SSA are attempting to communicate the biology and expected clinical behavior, although SSAs typically lack the cytologic features of dysplasia that characterize

traditional adenomas. In contrast, pathologists who use the second term wish to avoid confusion with a third lesion, the serrated adenoma, and prefer not to describe a lesion lacking cytologic features of dysplasia as an adenoma. The solution to this problem of recognition and nomenclature is education and communication, Dr. Turner said. For the time being, many pathologists have compromised and use the term sessile serrated adenoma/polyp. This amalgam avoids confusion with other lesions while still communicating that the SSA should be managed as an adenoma. The latter is important because SSA is a newer entity that physicians may not fully understand— leading to insufficient treatment after a biopsy diagnosis of polyp, rather than adenoma. If either the pathologist or gastroenterologist is uncertain about the histology of a lesion, the case should be mutually discussed. If necessary, the case can be referred to a gastrointestinal pathologist if consensus cannot be reached, Dr. Turner added.

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Rectal Cancer Care Varies by Region, Other Factors, Study Shows BY CHRISTINA FRANGOU

eople living in the midwestern region of the United States are nearly 30% more likely to receive neoadjuvant chemoradiation for rectal cancer than those who reside in the South. Furthermore, patients treated in hospitals that perform more than 30 rectal cancer resections annually are more likely to receive neoadjuvant chemoradiation. So, too, are people who are younger, who earn more than $46,000 annually, who graduated from high school and who undergo treatment at academic centers. Variations in delivery of rectal cancer care are numerous and significant, with only 75% of patients receiving care that meets the 2002 guidelines of the National Comprehensive Cancer Network (NCCN), according to a study presented at the 2014 annual meeting of the American Surgical Association (ASA). “There is clear evidence of unexplained variability in care delivery in rectal cancer,” said study co-author John R. T. Monson, MD, professor of surgery at the University of Rochester School of Medicine, in Rochester, N.Y. As a result, Dr. Monson and surgeons from more than 50 other institutions formed a group, the OSTRiCh (Optimizing the Surgical Treatment of Rectal Cancer) Consortium. The group aims to eliminate discrepancies in rectal cancer care by establishing centers of excellence (COEs) in rectal cancer. All designated centers would adhere to five “core principles” of evidence-based rectal cancer care, principles that organizers believe will improve national outcomes in rectal cancer. The five core principles are: 1. Total mesorectal excision 2. Measurement of surgical quality by specific techniques of pathology assessment 3. Specialist imaging techniques to identify patients at high risk for local recurrence 4. Use of newer neoadjuvant and adjuvant therapies including radiotherapy and chemotherapy 5. A multidisciplinary team approach to treatment on a patient-bypatient basis Patricia L. Roberts, MD, professor of surgery at Tufts University School of Medicine, Boston, and chair of the Division of Surgery at Lahey Clinic, in Burlington, Mass., said regionalization of cancer care may help ensure that rectal cancer patients in the United States are given all the options for treatment.

“Here we are, 12 years after the NCCN guidelines, and one-quarter of patients are not getting neoadjuvant chemoradiation. Of these who didn’t get it, for whatever reason, it just wasn’t planned. The question is how can we do better?” said Dr. Roberts, who was the official discussant on the paper. She is also a member of the OSTRiCh Consortium. “I think the

center of excellence concept is a good one for rectal cancer.” The OSTRiCh Consortium estimates that about 100 to 120 COEs are needed across the country to meet the needs of Americans with rectal cancer. That would mean a reduction from about 2,000 hospitals currently caring for these patients. “The ultimate model is one that has

more patients treated in fewer centers, but at centers that have better outcomes,” Dr. Monson said. “It’s time to move forward from an entirely unregulated system that’s simply not good enough for the patient.” Dr. Monson said the organizers hope that the American program would be modeled after a program in the United see Rectal Rates, page 56

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Rectal Rates continued from page 55

Kingdom that helped improve shortand long-term outcomes for rectal cancer patients during the past decade. He acknowledged that the British experience coincided with significant developments in the field of rectal cancer that improved survival and reduced morbidity for patients. But, he said, that country’s program of regionalizing cancer care helped ensure that patients were treated at hospitals that possessed the

infrastructure and the personnel needed to deliver optimal treatments for patients. Members of OSTRiCh believe that a corresponding program could produce similar results in the United States. “Based on European data, it is possible to reduce the local recurrence of rectal cancer by 15% to 20% if all rectal cancer cases were treated at Centers of Excellence,” they argued in a report this past winter (Dis Colon Rectum 2014;57:252-259). OSTRiCh started with 16 centers in 2011, and has nearly tripled during the past three years.

Despite this progress, it is not clear what the final model will be for rectal cancer care in the United States. As with similar programs created to accredit centers that perform bariatric surgery or breast cancer surgery, OSTRiCh’s proposal for COEs in rectal cancer will require some patients to travel to major centers for treatment. Heidi Nelson, MD, professor of surgery at Mayo Clinic, in Rochester, Minn., said the difficulty is in finding a balance between access for patients and the highest quality of care, “which is always the dilemma.”

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She applauded the OSTRiCh Consortium’s efforts to advance care for patients with rectal cancer and agrees with the guidelines. She added that she would be interested in exploring alternatives to the COE approach. Other options could make greater use of existing accreditation bodies or create referral networks to allow patients to move up a chain of affiliated centers based on their individual needs and preferences. “Rectal cancer is unique in that for most patients, it requires 10 months of care. You’re going to disrupt someone’s life, their family, their work. This is not to say that they should get low-quality care so that they can be close to home, but these are factors to consider. I would like to see a broader and deeper understanding of the patient, family and provider issues sorted out before we settle on a one-size-fits-all answer.” One thing is clear: Treatment, and consequently outcomes, for rectal cancer vary wildly across the country. In a 2011 study that looked at proctectomies in 11 states between 2003 and 2004, 40% of surgeons performed only nonrestorative abdominoperineal resection (Dis Colon Rectum 2011;54:12101215). The same report noted that local recurrence rates, which have been reported between 0% and 13% for colorectal surgeons, are in the range of 21% to 37% for patients treated by general surgeons. Mortality rates hover around 1.4% for patients operated on by colorectal surgeons, and increase to 7% for patients treated by general surgeons. Data presented at the ASA meeting showed that the highest rates of neoadjuvant chemoradiation were observed at academic centers (radiation 79%; chemotherapy 78%), whereas the lowest rates occurred in community programs (radiation 71% and chemotherapy 70%; P<0.001). This variation was mirrored by geographic location. “This is suboptimal for the United States,” Dr. Monson said. Surgeons interested in OSTRiCh can find more information at www.ostrichconsortium.org. “Registering on the website doesn’t make [your institution] a COE, but it does bring you into the community of discussion about how to move forward in what is really a very important issue,” Dr. Monson said. The consortium is in dialogue with the American College of Surgeons (ACS) about establishing rectal cancer as the next ACS program for COE accreditation. The ACS currently administers COE programs in breast cancer and bariatric surgery. OSTRiCH had applied for funding from the Centers for Medicare & Medicaid Services, but the request was denied.

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Pioneer continued from page 52

the protocol. With their consent, patients with apparent complete clinical response to neoadjuvant chemoradiation therapy did not undergo surgery but were kept under close observation. These patients were informed about the possibility of tumor recurrence, and knew if that happened, they would require surgery. When local recurrence occurs, if it is detected early, a salvage operation may be possible with good results. This watch-and-wait protocol remains a controversial issue and has been heavily criticized. However, gradually, some colleagues have accepted this strategy and have reported results similar to ours.

Paulo School of Medicine. We both have the same academic titles and share the same interests. GEN: You have enjoyed many years of marriage. How have you balanced career and relationship so successfully? Dr. Habr-Gama: Yes, we have been married for nearly 50 years. My husband has always had a superior mindset; he admires women’s activities and never needed to compete with me because he trusts himself and his

competence. At the social and family level, we have the same interests. We travel together a lot, especially to scientific congresses, courses and specialized centers. We share the same interest in music, movies, theater, literature and sports, especially tennis and walking. We decided to have no children so that we could devote all our time to our careers, which we have always valued so much. However, we have a lot of nephews and nieces as well as groups of beloved assistants who are always by our side, filling our life with enthusiasm and renovation.

GEN: How do you see the evolution of women in surgery? Do we still have a way to go before men and women are on equal footing? Dr. Habr-Gama: The evolution of women in surgery has been very slow. Nowadays, our numbers are bigger and growing, but even so there are not as many women as men surgeons. There are ways for men and women to be on equal footing, but since the roots of inequality are mostly cultural, it will take longer to get there.

GEN: What are some of the things you’re most proud of in your career? Dr. Habr-Gama: I am very proud of numerous aspects of my career. Among these, I have prized caring for an uncountable number of patients not only from São Paulo but also from many other cities in Brazil. I have loved teaching and being a mentor to students, residents and fellows throughout South America, and I have continued to work on assimilating new advances, continuously improving my knowledge and making new friendships. I am also proud of founding the Brazilian Association for Colorectal Cancer Prevention in 2004. This association was the first in Brazil to start an awareness program centered on the importance of colorectal cancer prevention, and I have been its president since 2004. We constructed a giant colon, which people of all ages can go inside and visualize different lesions and listen to explanations about colon cancer prevention from a character called Dr. Preventino. This giant colon has been exhibited in many cities all over Brazil, and also in 2006, Sidney Winawer, MD, invited us to exhibit it in Montreal during the World Congress of Gastroenterology and in other cities in Canada. After this, the Canadian Society of Coloproctology built a model similar to our giant colon, using the voice of Dr. Preventino. GEN: How did you meet your husband, Joaquim Gama-Rodrigues? Dr. Habr-Gama: I met him in medical school when we were students. He was an excellent student and great athlete, representing Brazil in the South American championships. However, only after we finished residence in surgery and began assisting Dr. Raia in operations did we start dating and later got married. My husband is also professor of surgery at the University of São

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New IBD Management Paradigm Calls for Holistic Care Eight steps for optimal patient outcomes

ith health care shifting from a volume- to a valuebased model, experts are calling for clinicians to rethink their approach to managing patients with inflammatory bowel disease (IBD). According to one prominent IBD researcher, caring for “the whole patient and not just their IBD” likely will lead to the best outcomes. “We are entering an era of patient-centered care, which means managing IBD patients’ mental health, nutrition, use of vitamins and supplements, cigarette smoking, preventative care and remote monitoring via telemedicine, among other things—all of these are becoming paramount to ensuring optimal clinical outcomes,” said Miguel Regueiro, MD, co-director of the Inflammatory Bowel Disease Center in the Division of Gastroenterology, Hepatology and Nutrition at the University of Pittsburgh Medical Center. To help clinicians transition from a “crisis care model to a personalized medicine and chronic care model,” David Rubin, MD, chief of gastroenterology at the University of Chicago Medicine, and Gary Lichtenstein, MD, director of the Center for Inflammatory Bowel Disease at the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania, in Philadelphia, created a list of recommendations they believe gastroenterologists should keep in mind.

1. For Milder Ulcerative Colitis, Hold Off on Steroids One significant mistake clinicians make in managing patients with IBD is improperly using corticosteroids, particularly in patients with ulcerative colitis (UC), Dr. Rubin told Gastroenterology & Endoscopy News. Corticosteroids are accompanied by a host of well-documented adverse effects and are associated with a worse course of disease (Targownik LE et al. Inflamm Bowel Dis 2014;20:622-630). “Mesalamine should be the first line of treatment for mild to moderate cases of UC, but we know from a number of studies that clinicians often use steroids instead, or administer both drugs together,” Dr. Rubin said. “One should only step up to steroid treatment when patients are not responding to optimized mesalamine treatment.”

2. Combine Biologics With Immunosuppressants A growing body of evidence has shown that biologic therapies are more effective when administered with immunomodulators (Colombel JF et al. N Engl J Med 2010;362:1383-1395). However, some clinicians are reluctant to follow this approach because of concerns that combination therapy will increase the risk for adverse events, Dr. Rubin said. “In a comparative effectiveness study, the six-month evidence showed there is no significant difference in safety between combination therapy and monotherapy,” he said. “And for most patients, this is the most effective treatment approach.” Edward Loftus Jr., MD, professor of medicine, chair of the Inflammatory Bowel Disease Interest Group and a consultant in the Division of Gastroenterology & Hepatology at Mayo Clinic, in Rochester, Minn., agreed

that more clinicians should follow the more evidencebased approach of using combination treatment. “The practice of biologic monotherapy is driven by a fear of incredibly rare side effects such as lymphoma, but the potential benefit to the patient in terms of preventing loss of response to the biologic is huge,” said Dr. Loftus, who was not involved in assembling the IBD recommendations.

serum 25-hydroxy vitamin D [25(OH) D] levels experience improved quality of life, less fatigue, greater handgrip strength and improved social functioning when their vitamin D levels are brought up to at least 30 ng/mL of 25(OH)D through supplementation ( G a s t r o e n te r o l o g y & Endoscopy News 2013;64:23). “We’ve come to appreciate that low vitamin D levels are related to disease activity, although it is unclear whether the low levels are a cause or consequence of disease,” Dr. Rubin said. “All IBD patients need to be assessed for adequate vitamin D and have these levels replenished if necessary.”

3. Ensure Drug Levels Are Adequate

6. Consider Surgery Earlier

Certain groups of patients with IBD may be “underdosed,” meaning they have inadequate drug concentrations despite receiving the recommended drug doses, Dr. Rubin said. This problem is specific to 5-aminosalicylic acid, thiopurines and biologics, he added. “Drug concentrations can also be affected by patients’ individual pharmacokinetics,” he explained. “This is a particular problem in patients with severe disease burden, those with intestinal protein leakage and, in the case of biologics, with associated monoclonal antibody drug loss.” Dr. Rubin urged clinicians to test biologic drug levels in patients who do not experience a clinical response. Assay results can help guide therapy, including dosing adjustments, he said.

According to Dr. Rubin, clinicians and patients too often consider surgery only after all medical therapies have been exhausted. However, prolonging ineffective medical treatment places patients at unnecessary risk for drug toxicity and extends a poorer quality of life associated with disease activity, he said. Instead, surgery should be moved up the treatment algorithm when patients have a short segment of disease, when symptoms are clearly due to an obstruction and if patients have not experienced adequate response to a brief course of anti-inflammatory therapy, he said. “A laparoscopic ileal resection is the most effective way to induce remission in Crohn’s disease,” Dr. Rubin said. “And once remission is induced surgically and maintained medically, the course of disease and quality of life can be improved and extended use of antiinflammatories can be avoided.”

4. Vaccinate Patients The American Gastroenterological Association, the Crohn’s and Colitis Foundation of America, and the Centers for Disease Control and Prevention all recommend that clinicians vaccinate patients with IBD for most preventable illnesses, including HPV, influenza and Pneumococcus (Sands BE et al. Inflamm Bowel Dis 2004;10:677-692). Despite these recommendations, survey results indicate that up to 20% of patients with IBD are not appropriately vaccinated (Wasan SK et al. Inflamm Bowel Dis 2014;20:246-250). One recent study highlighted the consequences of this gap in care, documenting a significantly increased risk for pneumonia in IBD patients (Kantsø B et al. Digestive Disease Week 2014; abstract Tu1186). “Gastroenterologists and primary care providers should ideally be vaccinating patients prior to initiating immunosuppressive therapy, but even patients already on such therapy should receive regular vaccinations,” Dr. Rubin said. He said patients may be too sick at the time of scheduled vaccination, or may refuse to be vaccinated because of safety fears, or primary care physicians asked to vaccinate IBD patients may not do so due to lack of education.

5. Monitor Vitamin D Levels Findings presented at Digestive Disease Week 2013 indicated that patients with Crohn’s disease and low

7. Address Mental Health Issues Although mental health does not seem to affect the course of IBD, patients with IBD and psychiatric concerns report a reduced quality of life, Dr. Rubin said (Walker JR et al. Am J Gastroenterol 2008;103:19891997). Because the risk for depression and anxiety is higher in this population—with one study from 2012 indicating that 41% of patients with IBD report anxiety (Nahon S et al. Inflamm Bowel Dis 2012;18:20862091)—clinicians should evaluate their patients’ psychological well-being. Referral to a mental health professional can “help IBD patients develop disease coping skills and lead to diagnosis and treatment of any concomitant psychiatric issues,” he said.

8. Take Patient’s Interest in Alternative Treatments Seriously Although up to 50% of patients with IBD turn to complementary and alternative medicine, Dr. Rubin said he has met many patients who feel their gastroenterologists do not take their interest in complementary and alternative medicine seriously. “Rather than being dismissive, clinicians should try and understand what is driving the patient to seek out see IBD Management, page 63

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Blood Clotting for Liver Donors Worse Than Suspected BY LOREN BONNER

ealthy liver donors may be at increased risk for blood clots after hepatectomy, Japanese researchers have found. The retrospective study looked at 55 adult donors, all from the University of Tokyo Hospital, and found that hepatectomy influenced coagulation status, especially in the extrinsic pathway of coagulation. According to the study, one-third of the healthy liver donors showed a level of prothrombin time-international normalized ratio (PT-INR) of at least 1.5 after hepatectomy. According to guidelines from the American Society of Regional Anesthesia and Pain Medicine, manipulation of an epidural catheter in patients whose PT-INR is more than 1.5 raises their risk for epidural hematoma. “Coagulation capacity after hepatectomy may be impaired by both reduction in hepatic production of coagulation factors and consumption of extrahepatically stored coagulation factors,” said Yuho Tamai, MD, assistant professor of anesthesiology at the University of Tokyo Hospital, who led the study. Researchers found that PT-INR did show significant prolongation in hepatectomy patients, which usually does not occur in patients after major abdominal surgeries with equivalent blood loss or operation times. Results of the study also showed that PT-INR increased significantly on postoperative day 1 (1.43±0.13) and continued through day 7, then fell to the preoperative level at discharge. Of the 55 donor patients, 18 showed a PT-INR of at least 1.5 at any postoperative point. The decreased production capacity of coagulation factors is mostly influenced by the volume of the liver graft. Consumption of coagulation factors stored outside the liver is likely determined by both half-life and distribution of each coagulation factor, Dr. Tamai said. “I think the best we can do at the present time is to identify donors who may be at a greater risk of having hypercoagulable states,” said David Mulligan, MD, director of the Yale-New Haven Transplantation Center, in New Haven, Conn. “Donors are healthy people. We owe it to them.” Although safety always is a top concern for donor surgery of living donor liver transplantation (LDLT) with measures like epidural catheter for postoperative analgesia performed on a routine basis, Dr. Tamai said it is important to know as many details as possible about coagulation status to ensure optimal postoperative management. “It may be better to pay more attention

to coagulation status to prevent postoperative hemorrhagic complications including epidural hematoma after hepatectomy,” Dr. Tamai said. The study investigators reviewed the medical and anesthesia records of 24 male and 31 female patients who underwent donor hepatectomy for adult LDLT from January 2010 through December 2012. The researchers analyzed several measures of coagulation, including amount of bleeding, blood transfusion volume and

“

liver ischemia time. Baseline characteristics, including age, sex, body weight, amount of bleeding, operating time and graft site also were examined in the donors. Dr. Mulligan said looking at PT-INR for blood clotting is complicated because minor factors can influence clotting not reflected in the PT-INR. Graft site— left or right lobe—was the only factor found to influence coagulation status in this study.

Dr. Tamai said data on blood coagulation factor concentration at any given point—something that was missing from this study—would be important to know. His group plans to conduct further research in order to know more about which coagulation factor was affected most by hepatectomy. The researchers presented their study at the 2014 annual meeting of the American Society of Anesthesiologists (abstract 1205).

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GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Deconstructing Veterans Health Care BY JON C. WHITE, MD

WE’RE FOR PATIENTS WITH CROHN’S DISEASE After Crohn’s surgery, it is common for the disease to return within a few months despite anti-inﬂammatory medicine. At UPMC, our multidisciplinary team developed a new post-op treatment approach that has reduced the recurrence of Crohn’s disease by nearly three fourths. And now many other hospitals are adopting this novel approach. Because when you make patients feel better, it’s normal to want them to stay that way. Learn more at UPMCPhysicianResources.com/Crohns.

UPMC is afﬁliated with the University of Pittsburgh School of Medicine.

s a long-serving surgeon in the U.S. Department of Veterans Affairs (VA), I find the recent controversy disheartening. Let me start by pointing out that patient satisfaction with the VA system is as high or even higher than that of the private health care system in the United States. An estimated 80% of the 9 million veterans receiving health care at the VA are satisfied. To cull from this population a minority of dissatisfied people who report negative things about the VA is not responsible investigative reporting; it is just tabloid journalism. Employing sound bites to link “secret lists” to an undocumented number of patient deaths is, at best, disingenuous. The tenor of this investigation has turned a legitimate conversation about health care access into a media circus. I hope that, after the circus leaves town, calm heads will prevail and we can have a frank discussion about what is good and what is bad about the VA system. VA health care is an example of entirely socialized medicine, and its successes and failures suggest how elements of socialized medicine might fare were they to be adopted more generally in the United States. Thoughtful observers have already recognized that features of socialism such as medical insurance, Medicare, capitated care, diagnosis-related groups and, more recently, elements of the Affordable Care Act have been introduced into the U.S. health care system over the past 100 years. Let me also state up front that as a VA provider, I do not think that the entire country should adopt VA-style socialized medicine without significant changes. I hasten to add that VA health care is a fine system that has many important aspects that should be used as a model for developing a national health care system. In this sense, VA health care represents an initial direction for our country but not our final destination. The VA system should be deconstructed to reveal the things that it does very well, as well as certain things that must be changed.

What Works It is not an exaggeration to say that the VA is one of the most innovative health care systems in the country. It has pioneered or has been quick to adopt new ways to deliver health care to its patients, who tend to be sicker than the rest of the population and are scattered widely across the continental United States and beyond. It should be noted that 153 VA

hospitals cover the same geographic area served by the 5,700 U.S. hospitals registered with the American Hospital Association. This is no insignificant feat. In the 1990s, the VA began to replace its traditional model of hospital-based health care delivery with a system of more than 700 community-based outpatient clinics feeding into its major referral hospitals. This model, which has come to be known as an accountable care organization, is similar to those adopted to a lesser extent by some of the best health care systems in the country such as Geisinger Health System (Danville, Pa.), Intermountain Healthcare (Salt Lake City) and Mayo Clinic (Rochester, Minn.). The system employs primary care physicians (PCPs), who each manage and promote the health of a panel of patients. The VA has smoking cessation clinics, substance abuse clinics, post-traumatic stress disorder clinics, obesity clinics, health fairs, wellness clinics and many other programs intended to promote healthy living and to avoid or minimize hospitalization. The PCPs see patients in the community and even encourage them to stay home and make contact online. The main focus is to avoid hospitalization by keeping patients healthy rather than rescuing them when they become ill. The VA excels in data-driven, transparent self-reporting. In the early 1990s, VA surgeons introduced risk-adjusted reporting of their surgical results, which has evolved into the VA Surgical Quality Improvement Program (VASQIP). Over the ensuing 23 years, VA surgeons have monitored their own results and learned from their adverse outcomes. As a consequence, operative mortality has dropped by 70% while morbidity has fallen by 50%. The results of this program were so impressive that VASQIP engendered a similar program sponsored by the American College of Surgeons, the National Surgical Quality Improvement Program. Many other aspects of care at the VA hospital are tracked by quality data analysis including hemoglobin A1c levels for diabetic control, blood pressures and suicide rates. Like the VASQIP data, most metrics that are tracked have improved over time, and those that have not remain under intense scrutiny.

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Compared with non-VA care across the country, the clinical results obtained by the VA are equivalent and more often superior to those reported by the private sector. In 2005, the Rand Corporation reported that the VA outperformed non-VA health care in most of the 294 health care markers measured. To manage the enormous amount of data generated by these metrics and coordinate clinical care, the VA introduced its electronic medical record (EMR) system, Veterans Health Information Systems and Technology Architecture (VistA) in 1998. Its clinical arm, the Computerized Patient Record System (CPRS), is the oldest, and, in my judgment, still the most effective EMR in use. An effective EMR is an essential component of an accountable care organization, and VistA and CPRS have filled this role for years. Many other EMRs that have been developed are mainly used for billing and administrative purposes, but CPRS was developed by front-line providers for patient care. In 2006, VistA won Harvard University’s prestigious Innovations in American Government Award. The VA’s tort arbitration works within the confines of the U.S. legal system and is an improvement over what occurs outside of the VA. Malpractice claims brought against VA physicians are reviewed by noninvolved physicians and specialists in the VA network, and legal defense is provided by government lawyers. The medical reviewers are selected from appropriate specialists working within the VA who have real expertise in the fields and who also have access to all of the medical records through CPRS. These reviews help the VA legal office defend the accused physician, but providers who are found to be at fault are reported to the National Practitioner Data Bank. Errors are acknowledged up front, and veterans are given complete access to the U.S. legal system. The physicians, who know that the system is fair, practice less defensive medicine than their non-VA counterparts. Several inherent features of the VA system also make it a more effective way to deliver health care. The most important of these is universal coverage, which aims to get qualified veterans all of their care at appropriate times and in the appropriate

clinics. Although recently the system has been overwhelmed by a massive influx of veterans, the VA’s stated mission is to provide the “right care, at the right place at the right time.” Another important feature of the VA system is that it has long-term relationships with its patients, which allows the VA to spend resources on health maintenance and preventative care. Because the VA reaps the rewards, it is in its best interest, financially as well as medically, to keep the patients healthy. Most physicians in my experience are hard-working,

compassionate and devoted to the wellbeing of their patients. It is still axiomatic that non-VA physicians profit most when patients are sick and require their services (capitated care is an exception). Non-VA physicians, in general, do not get financial compensation for keeping patients well. This brief account demonstrates the tremendous strides the VA has made over the past two decades and why in many aspects the VA has consistently outperformed the rest of the health care industry. Although it has proven to be a good system for caring for a challenging group

of aging and wounded individuals, the system has problems that must be addressed.

What Doesn’t Work In my opinion, VA socialized health care suffers from the same affliction that plagues most socialized government programs and that is, simply stated, a lack of capitalism-driven incentives. The results of the great socioeconomic experiment of the 20th century—socialism versus capitalism—was revealed in 1985 when the Berlin Wall came down. I believe that see Veterans Health, page 63

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Obamacare a Successful Failure ‘Whether we voted for or against our current president, whether we register to vote as Republicans or Democrats, whether we are in private practice or academics, the ACA leaves our health care landscape in the same shape as before: a complete shambles.’

BY SAMUEL METZ, MD

s the Affordable Care Act a failure? For some of us, the answer is simple: If you voted for President Obama, it must be a success. If you voted against the president, it must be a failure. But if you think the legacy of Barack Obama is irrelevant to health care reform, the answer gets more complex. Will the Affordable Care Act (ACA) achieve anything at all? Maybe. More Americans will own health insurance policies, especially if they are young and employed. Government spending on health care will decrease, despite the added cost of new computer programs and 17 different state insurance exchanges. Also, the financial burden of Medicare patients who have excessively costly diseases will move from the payor (the U.S. government) to the providers (us). But these changes hardly qualify as reform. For patients, physicians and employers, none of these potential achievements has the slightest bearing on health care reform.

Patient Expectations What do patients want from reform? Simple: access, lower costs and better health outcomes. The ACA misses all three. Access?? According to the Congressional Budget Office (CBO), despite the new law, the ACA will leave 10 million to 30 million Americans under-insured, putting them at risk for bankruptcy or death if they get the wrong disease at the wrong time. Another 30 million will be left with no insurance at all. In other words, when their incomes end, so does their health care—and maybe their lives. And that’s if the ACA works perfectly.

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Lower costs?? Although the CBO anticipates a $100 billion annual decrease in government health care spending, it also predicts a net increase of $100 billion in total health care spending. That means patients and employers will pay $200 billion more annually than they pay now. And that’s if the ACA works perfectly. Improved outcomes?? The Massachusetts experience says no. Six years after implementing its version of the ACA ( Jonathan Gruber, the Massachusetts Institute of Technology economist who worked on both the Massachusetts program and the ACA, called them “the same [expletive deleted] bill”), 95% of state residents own insurance policies. Yet outcomes are unchanged, medical bankruptcies are 30% higher, and costs are increasing faster than anywhere else in the country. (This is not entirely true. Those Massachusetts residents newly covered by Medicaid expansion now enjoy better health and lower medical debt. The same can’t be said, however, for those with private insurance.) If you’re a patient, the ACA is a failure.

Physician Expectations What do physicians want from reform? First, payment. Given the amount of pro bono work that physicians provide, sometimes unwillingly, payment is not a slam dunk. It’s one thing to voluntarily perform charity care in Third World countries to prevent patients from dying of easily treatable diseases. But it’s a real tragedy to realize that without our charity work, many Americans similarly will die of easily treatable diseases. In no other industrialized country do the poor and sick get charity care—physicians caring for them get paid the same amount as the physicians would if they cared for the rich and the famous. Only in the United States do physicians go unreimbursed if they care for the wrong patients. Second, our payment should reflect the value of our services, not the value of the insurance policies of our patients. If we are paid more for patients with pearls

than we are for those with tattoos, then financial motive favors care for the pearls. Lastly, physicians want easy billing and prompt payment. Most of us haven’t seen that for decades. The ACA makes no pretense of simplifying either.

Physician-Employer Expectations What should health care reform provide to employers? First, employers want healthy employees. When office staff call in sick, it doesn’t matter if they are full-time or part-time—it’s lost productivity. Next, employers want out of the health benefit management business. Just to manage the complexities of employee benefits costs employers an extra 2% of payroll. Can we rid ourselves of this added cost of doing business? Employers want health care benefits removed from labor–management negotiations. To remain competitive, employers want costs for employee health care to be no more than what our competitors pay. Similarly, our employee benefits should be no worse than what our competitors offer. Lastly, employers want health care costs to be predictable and consistent. The ACA addresses none of these needs.

Health Care Basics Whatever else the ACA may achieve, it completely fails to address the basic health care needs of patients, physicians and employers. Whether we voted for or against our current president, whether we register to vote as Republicans or Democrats, whether we are in private practice or academics, the ACA leaves our health care landscape in the same shape as before: a complete shambles. It’s disappointing that this massive opus strives so valiantly to make a difference, yet falls so short of achieving what we really need. Is the ACA a wellintended piece of legislation? Yes. Is it reform? Sadly, no. Maybe Congress will have better luck next time, if there iss a next time. Let’s hope so. Dr. Metz is a private practice anesthesiologist who lives and works in Portland, Ore.

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • OCTOBER 2014

Veterans Health continued from page 61

capitalism turned out to be the more successful political and economic philosophy. It resulted in greater productivity, more discriminating consumerism and better services. Socialism’s indiscriminate consumption and low productivity very quickly leads to problems with access. The most critical charge against the VA currently is that access is limited and wait times are longer than in the private sector. It is this issue that caused the VA to link bonuses to reducing wait times, which in turn caused officials in Phoenix, and other medical centers, to game the system. Fortunately, the VA recognizes this problem and is moving toward a relative value unit–based productivity model. Linking productivity to compensation will go a long way toward solving the nagging issue of low productivity. The VA also has a limited policy of means-tested copays for consumers, which might be applied more broadly and to more veterans. Such a means-based policy would give the consumer “skin in the game” and have the dual benefit of encouraging responsible use of the system and promoting healthy habits. These two measures alone would inject a little needed capitalism into the system, because in this country we have no chance to control medical costs without employing principles of capitalism to make health care both better and cheaper. Another factor that makes the VA less effective is its dependence on a large and increasingly removed government bureaucracy. Ken Kizer, the visionary VA under secretary who is frequently credited

with the dramatic turnaround of VA health care in the 1990s, wrote a recent editorial in which he pointed out that the VA of the late 1990s had 800 employees in its central office; that number increased to 11,000 by 2012. One of the advantages the VA had over the private sector is that it did not need a third-party insurance bureaucracy. Unfortunately, it is replacing that private-sector bureaucracy with a less nimble government bureaucracy. Clearly, all has not been ideal with VA health care. My observations are not the misty-eyed musings of a sentimental VA

provider. There is well-documented and credible evidence that the VA does some things better than anyone else, but it must be recognized that there are other aspects in which the VA lags behind the private sector. It would be a mistake to dismiss its true accomplishments, but it also would be a mistake to be blind to its shortcomings. The VA should serve as an example of how an accountable health care organization that is dedicated to patient wellness; has an effective EMR; practices data-driven, evidence-based care; uses a sensible tort review process; provides

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Fecal Transplants p for IBD Show Mixed Results in Trials

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BY DAVID WILD

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

see Probiotics, page 11

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

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

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

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I N S I D E EXPERTS’ PICKS

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

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

IBD Management continued from page 58

these alternative approaches,” he said. “This needs to be understood as an opportunity to create and strengthen a therapeutic alliance, which can ultimately improve every dimension of IBD treatment.” Dr. Loftus has consulted for and received research support from AbbVie, Janssen, Takeda Pharmaceuticals and UCB. Dr. Rubin reported serving as a consultant for Abbott Pharmaceuticals, Bristol-Myers Squibb, Elan Pharmaceuticals, Ironwood, Janssen, Lifecore Biomedical, Prometheus Laboratories, Santarus Pharmaceuticals, Takeda Pharmaceuticals, Telsar Pharmaceuticals, UCB and Vertex Pharmaceuticals. He also has received research grants from Abbott, Elan Pharmaceuticals, Procter and Gamble/Warner Chilcott, Prometheus Laboratories and Shire Pharmaceuticals.

universal coverage; and has a lifelong relationship with its patients can deliver superior care. It is also a cautionary tale about the limitations of socialism that cannot match the productivity of the private sector. The events in Phoenix and other related revelations have certainly dirtied the bath water, but the baby should not be thrown out as well. Dr. White is professor of surgery at George Washington University, and chief of surgical services at the Veterans Affairs Medical Center, in Washington, D.C.

The #1 best-read gastroenterology publication in the USA. Anytime. Anywhere. The Independent Monthly Newspaper for Gastroenterologists

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

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

NEIL GUPTA, MD

PRATEEK SHARMA, MD

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

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

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

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

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