October 2014

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Pl AC ease AA G b Vis SL oo it U D b th s oo #51 ! th 2 #1 17

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

HEPATOLOGY

I N

F O C U S

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

W

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

W

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.

8

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

SD

Total Duration,a min

SD

16.1

11.3

11.3

9.3

27.4

14.8

14.4

9.5

11.1

8.9

Mean

25.6

13.6

SD

ANOVA

P

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

b

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

<0.001

<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.

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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

Product

Oncology

Oncaspar® (pegaspargase)

Metabolic disorders

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

Product

Suggested Use/Designations

Proxeed® plus, a complete carnitine formula

Supports sperm development, male fertility and reproduction

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

23

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.

The following outlines PharmaSource’s core competencies: • • • • • • • • • •

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


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