Feb 2015

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Volume 66, Number 2 • February 2015

HEPATOLOGY

Shor Shorter Sh Hepatitis C Treatment Durations May Be a Reality

FOCUS

I N

Ledipasvir-Sofosbuvir Effective In Hard-to-Treat HCV

BOSTON—Can treatment of hepatitis C infection with new direct-acting antivirals (DAAs) be shortened to less than 12 weeks? Interim results from a recent trial suggest treatment durations of eight or even four weeks may be possible with the right combination of drugs.

Shortened regimens would help contain health care see Shorter, page 20

Esophageal Injuries From Button Batteries A Growing Concern SAN FRANCISCO—One of every eight children who swallow a 20-mm lithium battery will have a life-threatening or lethal outcome, largely due to esophageal injury, new data show.

At the American College of Surgeons 2014 Clinical Congress, experts on the topic of battery injuries discussed the

BOSTON— —The patient with a hard-to-treat hepatitis C infection is becoming harder to find.

The fixed-dose combination ledipasvir and sofosbuvir (Harvoni, Gilead) is effective in patients with the hepatitis C virus (HCV) who clinicicans until now have considered difficult to treat, according to new data presented at the 2014 Liver Meeting of the American Association for the Study of Liver Diseases.

One study demonstrated that 12 weeks of the fixed-dose combination plus ribavirin cured patients with decompensated cirrhosis of their HCV infection. Two other studies showed that the drug

was effective in patients—including those with cirrhosis—who previously failed protease inhibitor triple therapy. see Difficult, page 14

see Ingest, page 30

I N S I D E

C. difff Infection Takes Bigger Toll in Elderly

Organ transplant pioneer’s career tarnished by ties to Nazi Party ....................................page 13

PHILADELPHIA—One of the challenges in managing patients infected with Clostridium difficilee is identifying those most at risk for dying of the disease and treating them appropriately.

New research adds to mounting evidence that advanced age is a significant predictor of death from C. difficilee infection (CDI), tripling a patient’s risk for mortality compared with that of younger patients.

HEPATOLOGY

I N

FOCUS

see C. diff, page 45 Suthat Liangpunsakul, MD PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

Download the iPad App

EDUCATIONAL REVIEW see insert at page 28

Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection?

Nancy Reau, MD

Experts’ Picks From the 2014 Liver Meeting ..........page 14

Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection?

MOHAMMAD TITI, MD

NEIL GUPTA, MD

PRATEEK SHARMA, MD

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

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

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.

C

olorectal

Be prepared for EHR data breaches ..........................page 32

cancer

(CRC) is the second leading cause of

cancer-related in

the

mortality

Western

world.1

Screening colonoscopy and polypectomy have become widely accepted as the mostt effective available methods ffor or early detection and preve ention of CRC and have shown a reduction d ti in i mortality in 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 in the screened population.4 Improving detection of adenomas during colonoscopy therefore may be the key to more effective screening.

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

1

POOPMD speeds the diagnosis of biliary atresia .......page 44

2

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Gastro & Endo News @gastroendonews

Heard Here First See page 54

This study is one more

Follow us on Twitter

nail in

the coffin for the magic bullet for eating everything we want

holy grail of metabolism research, but it’s always

without gaining weight. It’s the

come up negative.

Mixing Drinks and Drugs ore than 40% of American adults who drink alcohol say they also take drugs known to interact with alcohol, such as diazepam, researchers have found. The rate was even higher for older people: Among drinkers age 65 years and older, nearly 78% reported taking medications that interact with alcohol, according to the study by investigators at the National Institutes of Health. The researchers reported their findings in the February 2015 issue of Alcoholism: Clinical and Experimental Research.

“Our findings show that a substantial percentage of people who drink regularly, particularly older adults, could be at risk of harmful alcohol and medication interactions,” said Rosalind Breslow, PhD, who led the study, in a statement. “We suggest that people talk to their doctor or pharmacist about whether they should avoid alcohol while taking their prescribed medications.”

M

—GEN Staff

Vol. 66, No. 2 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

GARY R. LICHTENSTEIN, MD

Houston, Texas

Philadelphia, Pennsylvania

ALAN F. CUTLER, MD

NIRMAL S. MANN, MD, PHD

Farmington Hills, Michigan

Sacramento, California

FREDRIC DAUM, MD

PETER R. MCNALLY, DO

Mineola, New York

Fort Carson, Colorado

STEVEN M. FABER, MD

TARUN MULLICK, MD

Elizabeth City, North Carolina

St. Charles, Illinois

RONNIE FASS, MD

JOEL E. RICHTER, MD

Cleveland, Ohio

Tampa, Florida

BARBARA B. FRANK, MD

DAVID ROBBINS, MD

Philadelphia, Pennsylvania

New York, New York

FRANK G. GRESS, MD

ELLEN J. SCHERL, MD

New York, New York

New York, New York

CHRISTOPHER JOLLEY, MD

PRATEEK SHARMA, MD

Gainesville, Florida

Kansas City, Kansas

MYRON LEWIS, MD

JEROME H. SIEGEL, MD

Memphis, Tennessee

New York, New York

February 2015

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4

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

New Study Reignites Debate Over Stretta Meta-analysis shows lack of clinical benefit for endoscopic procedure PHILADELPHIA—A new meta-analysis has found that Stretta, an endoscopic procedure for treating gastroesophageal reflux disease with radiofrequency energy, fails to provide clinical benefit—reigniting debate over the value of the controversial technology.

The study found that compared with sham treatment or proton pump inhibitors (PPIs), Stretta (Mederi Therapeutics Inc.) was favored in some studies but not in others, so no significant advantage was found in the pooled data, according to the researchers.

Stretta “cannot be recommended as an alternative to traditional medical or surgical therapies for” reflux, said Seth Lipka, MD, of the Division of Digestive Diseases and Nutrition at the University of South Florida, in Tampa, who presented the data at the 2014 annual meeting of the American College of Gastroenterology (ACG).

Conflicting Findings That conclusion was the opposite reached by a committee for the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), which found Stretta “appropriate” for adult reflux patients with symptoms lasting more than six months who decline fundoplication. The recommendation, made in the current SAGES Clinical Spotlight Review for Endoluminal Therapy for reflux, received a “strong” grade for quality of evidence based on 21 citations, including a meta-analysis of 18 studies with 1,441 patients.

The difference in the conclusions is not just based on differences in the data included in the analysis but, more importantly, in which measures of benefit were analyzed, according to two members of SAGES who participated in development of the guidelines.

The two primary end points for Dr. Lipka’s

meta-analysis were normalization of esophageal acid exposure, as measured by pH over 24 hours, and increase in lower esophageal sphincter (LES) pressure, as assessed with manometry.

“These are not the end points most important to clinical benefit,” said Brian J. Dunkin, MD, head of the Section of Endoscopic Surgery at Houston Methodist Hospital in Texas, and president-elect of SAGES. Dr. Dunkin noted that normalization of acid is not required for symptom control and healing of esophagitis and is not reliably achieved even with PPIs. In addition, the majority of reflux patients have a normal LES resting pressure, and candidates for Stretta typically do not have significant defects in the LES, such as a hiatal hernia, that would make increasing LES pressure important.

Dr. Dunkin suggested the key goals in treating reflux are control of symptoms and improved quality of life, which were the primary end points of the studies in the meta-analysis and those the SAGES guidelines committee evaluated.

Stretta, which delivers radiofrequency energy in the area of the LES to remodel muscles and tighten barrier function of the sphincter, was approved by the FDA in 2000.

The meta-analysis, now available on the Clinical Gastroenterology and Hepatologyy website, considered only randomized trials with a sham control or active comparator that included pH and LES pressure data. Of 24 studies drawn from a literature review, four, with a total of 168 patients, met these criteria. In three of the four, Stretta was compared with a sham procedure. In the fourth, PPIs served as the comparator.

For acid control, Stretta was favored in two of the studies, but the control arm was favored in the other

two. For LES pressure, two favored Stretta, but the other did not. Other end points, such as ability to discontinue PPI use and the quality of life of patients off medicine, were also equivocal in the Stretta and control arms, Dr. Lipka said.

The SAGES evaluation was not limited to controlled studies but permitted a broader survey. Based on an analysis that included 21 citations, the committee found that a preponderance of data favored Stretta as an effective procedure for reducing symptoms. It also was found to be highly statistically significant for improving quality of life (P=0.0001).

P Will Rutan, CEO of Mederi Therapeutics Inc., called the latest study an “apples and oranges” comparison.

“Curiously, the heterogeneity of the studies that were selected [by the University of South Florida investigators] was nearly 100%, rendering this analysis as lacking in scientific value,” he said in an interview.

Not Necessarily Benign Although no serious adverse events occurred in the clinical trials, Dr. Lipka said Stretta is not necessarily benign. Serious complications, although uncommon, have been reported in postmarketing registries, he said.

These include esophageal perforations directly related to performing Stretta and at least two deaths from aspiration pneumonia associated with the procedure.

Robert D. Fanelli, MD, chief of minimally invasive surgery and surgical endoscopy for the Guthrie Clinic, in Sayre, Pa., and an author of the SAGES recommendations, maintained that the group’s review was comprehensive.

“A large body of evidence was reviewed systematically by our committee. Overall, this evidence was supportive of a benefit for relevant end points of symptom control and improved quality of life,” Dr. Fanelli told Gastroenterology & Endoscopy News. “We applied the same methodology to Stretta as we did to several see Stretta, page 5

Weight Loss Surgery May Not Worsen Outcomes in Acute Pancreatitis PHILADELPHIA—People who have had bariatric surgery tend to be at increased risk for gallstones, and as a result, for developing pancreatitis. However, new research shows that this subset of patients with acute pancreatitis (AP) have no greater risk for mortality from the condition and often have shorter lengths of stay in the hospital and use fewer health care resources than patients with AP who have not undergone weight-loss surgery.

“Bariatric surgery has become increasingly common, especially in the last decade. These patients have higher risk for gallstones, and as most of us know, endoscopic access is difficult due to the altered anatomy, particularly in those who have had Roux-en-Y gastric bypass surgery,” said Somashekar Krishna, MD, MPH, assistant professor in the Department of Gastroenterology, Hepatology and Nutrition at The Ohio State University Medical

Center, in Columbus. “At this time, there are no large population studies, either in the United States or outside, evaluating the association between AP and prior bariatric surgery.”

Dr. Krishna and his colleagues presented their findings at the 2014 meeting of the American College of Gastroenterology (abstract 50).

The researchers consulted the Nationwide Inpatient Sample for 2007 through 2011, using diagnostic codes to identify all patients admitted with a primary diagnosis of AP and all those who underwent bariatric surgery and received a primary diagnosis of AP. They compared demographics, hospital factors and causes of AP, as well as complications, mortality, length of stay and total hospital charges.

The study found an increase in both hospital admissions for AP and number of patients who underwent weight loss surgery, a figure that doubled during

the five-year period. “In parallel with these two trends, there was an increasing prevalence of prior bariatric surgery among those admitted with acute pancreatitis,” Dr. Krishna said.

During the study period, among the 1.35 million patients admitted for AP, the proportion of patients who had also undergone bariatric surgery grew from 0.73% to 1.39% (P=0.001).

P Univariate analysis comparing surgery patients with the control group found that the former tended to be younger, more often female and to have private insurance. “Further, they had more frequent gallstones and needed more cholecystectomies,” Dr. Krishna said. “We observed that these patients had more frequent nonendoscopic biliary access compared with the control group, and had fewer [endoscopic retrograde cholangiopancreatography procedures], again showing difficulty in access.”

Multivariate analysis found no

association between bariatric surgery and increased mortality. “The linear regression analysis showed they had a shorter LOS and incurred fewer hospital charges,” Dr. Krishna said.

These findings were strengthened by a propensity-matched analysis of nearly 3,000 matched pairs of patients.

A possible explanation for the association between weight loss surgery and equivalent or better outcomes in AP may have to do with the effect of postsurgical weight loss on inflammation, Dr. Krishna said.

“Obesity, which is a proinflammatory state, is associated with both severity and mortality in acute pancreatitis,” he said. “There is evidence showing that those who have weight loss after bariatric surgery do have a decrease in these proinflammatory mediators. Whether this translates to better outcomes in AP remains to be studied.”

—Monica J. Smith

5

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Two Studies Support Value of Bariatric Accreditation Failure to rescue is key finding ust as the Centers of Excellence program in bariatric surgery enters its second decade, two large studies report that accreditation has led to safer outcomes, lower mortality, shorter hospital length of stay and lower total charges after these procedures.

“These two studies show that accreditation saves lives, reduces readmission, lowers cost. Across the board, we’ve seen that,” said John M. Morton, MD, MPH, chief of bariatric and minimally invasive surgery at Stanford School of Medicine, in Stanford, Calif., and president-elect of the American Society for Metabolic and Bariatric Surgery (ASMBS).

Dr. Morton, who authored one of the studiees, is the national co-chair of the Metabolic and Barriatric Surgery Accreditation and Quality Improvem ment Program (MBSAQIP), the accreditation progrram created by the American College of Surgeons and the ASMBS.

J

doubled at unaccredited centers, reaching 0.97% compared with 0.55% at accredited centers. The investigators attributed the difference to the “enhanced ability of accredited centers to recognize and rescue patients with complications.” Dr. Morton added that he believed accreditation aids all obese patients, not just bariatric patients.

‘The whole idea that you can’t do surgery unless you’re accredited is frustrating because we have good volumes for one surgeon with low mortality and low morbidity. We have no deaths, going on nine years.’

—Timothy J. Pitchford, MD

‘The accrediting body already did the homework for the patient.

The patient essentially needs to ask only one question: Is this an MBSAQIP-accredited center?’

—Ninh T. Nguyen, MD

In Dr. Morton’s study, investigators analyzed nearly 120,000 bariatric patient discharges from 2335 unique hospitals in the Nationwide Inpatient Sample for 2010.

They found that, compared with accredited d centers centers, unaccredited institutions had a higher mean length of stay (2.25 vs. 1.99 days; P<0.0001) and greater total charges ($51,189 vs. $42,212; P<0.0001). Complications occurred more often at unaccredited centers (12.3% vs. 11.3%; P=0.001). In a multivariable logistic regression analysis, unaccredited status was identified as a significant predictor of complications (odds ratio [OR], 1.08; P<0.0001) and mortality (OR, 2.13; P=0.013).

At least eight other studies have shown that patients benefit from surgery at accredited centers, although two studies have called into question the value of the accreditation program.

What sets this most recent study apart from earlier research is that it is the first to look at accreditation and failure-to-rescue rates in bariatric surgery. The investigators found that failure-to-rescue rates nearly

Stretta continued from page 4

other endoluminal procedures for which we did not find adequate supportive evidence.”

Dr. Fanelli noted that SAGES used the GRADE (Grades of Recommendation Assessment, Development and Evaluation) system (BMJJ 2008;336:924926) to analyze the literature. “We did not set out to perform a meta-analysis;

chance of dying from bariatric surgical complications after the 2006 implementation of the CMS policy compared with the preceding period (0.23% mortality in 2006-2010 vs. 0.56% previously).

Serious morbidity also dropped significantly, from 9.92% to 6.98%, after the CMS accreditation requirement.

Non-Medicare patients experienced improved out-

The study was presented at the 2014 annual meeting of the American Surgical Association (2014;260:504-508; discussion 508-509) and published in Annals of Surgery.

A second study, published in the September edition of the Journal of the American College of Surgeons, reported that outcomes of bariatric surgery in Medicare beneficiaries improved substantially after 2006, when the Centers for Medicare & Medicaid Services (CMS) issued a National Coverage Determination requiring bariatric procedures to be performed only at accredited centers (2014;219:480-488).

Analysis showed that the percentage of Medicare patients who had serious complications decreased from nearly 10% between 2001 and 2005 to less than 7% between 2006 and 2010. On average, hospital stays decreased from four days to three during those periods, the study data showed.

In a key finding, Medicare patients had a 59% reduced

we stringently reviewed the body of literature regarding Stretta and determined, using GRADE standards, that it is a safe and effective procedure. The GRADE system supports a strong recommendation when a large body of literature, one unlikely to be influenced by the addition of more literature, supports an intervention; this is the case with Stretta.”

But Dr. Lipka said the SAGES evaluation of Stretta was not sufficiently rigorous. He particularly objected to the use

comes over the same period, with a reduction in inhospital mortality from 0.18% to 0.08% (P<0.01) aand serious morbidity, which fell from 6.84% to 5.08% (P<0.01).

However, the improvement in patient outcomes was most pronounced at accredited centers, the wa in nveestigators noted. Compared with patients who un nd derwent stapling bariatric procedures at accrediteed d centers, patients treated at unaccredited centers haad d a significantly higher risk-adjusted in-hospital morrtality (OR, 3.53; 95% confidence interval [CI], 1.01 1-6.52) and serious morbidity (OR, 1.18; 95% CI, 1.07 7-1.30).

“II suggest that patients considering a bariatric operation look for, and go to, an accredited bariatric center,” said study co-investigator Ninh T. Nguyen, MD, professor of surgery and chief of the Gastrointestinal Surgery Division at UC Irvine Health, in Orange, Calif.

“The accrediting body already did the homework for the patient. The patient essentially needs to ask only one question [to learn the facility’s capabilities]: Is this an MBSAQIP-accredited center?”

Although the Centers of Excellence program has been criticized in the past as restrictive, expensive and bureaucratic, it is also widely credited with raising the bar for bariatric surgery in the United States. Even hospitals that do not have Centers of Excellence status improved patient outcomes and data collection since 2004, studies have shown.

More than 700 bariatric surgery centers throughout

of the term “strong” to characterize the quality of evidence.

“The design of our meta-analysis was to protect the patient from the recent recommendation by SAGES,” Dr. Lipka explained. Although he acknowledged that some evidence suggests Stretta reduces LES relaxations, he argued that there is not yet sufficient data to demonstrate that this effect translates into a meaningful clinical advantage.

Dr. Dunkin said Dr. Lipka’s warning

see Accreditation, page 6

about the serious adverse events associated with Stretta was misleading and not based on current information. He added that SAGES is preparing an article for publication that will include a more detailed response to the new report.

—Ted Bosworth None of those quoted in this article, with the exception of Will Rutan, CEO of Mederi Therapeutics, reported any financial conflicts of interest.

6

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Liver Transplant May Not Boost Survival for Dialysis Patients

D

ialysis patients who undergo liver transplantation are less likely to survive in the near term than those with normal kidney function, according to a new study that suggests that such patients should be given priority on organ transplant waiting lists.

Although the study did not identify causes of death, the researchers observed that mortality rates were higher than those published by the United Network for Organ Sharing (UNOS).

Researchers from the University of Pittsburgh who set out to identify a pattern in renal recovery for patients receiving a liver transplant found lower survival rates for dialysis patients who underwent orthotopic liver transplantation (OLT). The researchers presented their findings at the 2014 annual meeting of the American Society of Anesthesiologists (abstract 1205).

The retrospective study found liver graft survival was 70.3% and patient survival was 71.9% for this population after OLT—far off the national averages, which are 82% and 86.3%, respectively, according to UNOS. Renal failure and renal dysfunction are common problems in end-stage liver disease, mostly caused by hepatorenal syndrome. But not much is known

about renal function recovery after liver transplant.

“These patients are more prone to have their survival impaired after the liver transplant,” said study co-author Daniela Damian, MD, clinical assistant professor in the Department of Anesthesiology at Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center. “Their survival is worse than their counterparts who were not on dialysis pretransplantation.”

to avoid nonrecovery of renal function.

“There is a good chance of recovery of renal function after liver transplant if the liver transplant is done within 90 days of the development of renal failure,” Dr. Hilmi said.

The researchers analyzed data from January 2005 to December 2011 from 64 patients at a single transplant center. All patients were on dialysis and were receiving a liver transplant for the first time.

According to the results, seven (10.9%)

Ibtesam Hilmi, MBCHB, associate professor of anesthesiology at the University of Pittsburgh School of Medicine, who led the study, said the presence of renal failure and the requirement for dialysis should move a patient waiting for a liver transplant to a higher spot on the list

of the 64 patients did not require dialysis after OLT, and 16 (25%) recovered kidney function 30 days after OLT. Four of the patients who required dialysis died: one during surgery and three in the 30-day period after OLT. Of the remaining 37 patients who required dialysis,

eight (12.5%) recovered and two died (3.1%) at three months post-OLT. Researchers analyzed kidney function in the first year after transplant and found that five more patients no longer needed dialysis (5.7%), whereas 10 patients remained on dialysis (15.6%).

Dr. Damian stressed that the study was limited by its retrospective methodology and because patients’ end dates for dialysis were not precise and had to be determined from multiple sources. In addition, complications, comorbidities and certain therapy regimens, such as the use of immunosuppressant drugs, were not accounted for and might have influenced patient outcomes regarding their survival and recovery, she said.

She also said more research is needed to directly correlate the amount of time in days spent on dialysis before OLT and how that is related to a patient’s full recovery and the elimination of dialysis after OLT. “I think that was the ultimate goal— to find a cutoff [for days on dialysis] and predict when the patient who is going for a liver transplant should be doing both a liver and kidney transplant because they will have a better outcome,” Dr. Damian added.

—Loren Bonner

By the Numbers: Alcohol-Related Deaths

Accreditation continued from page 5

the United States are accredited or seeking accreditation through the MBSAQIP. Today, patient outcomes at both accredited and unaccredited centers are quite good, with greatly reduced mortality and complication rates compared with a decade ago. Any differences in patient outcomes at accredited and unaccredited centers, although statistically significant, are “tiny” clinically, several surgeons pointed out.

“The differences that we see are pretty minimal. The mortality rate [at unaccredited centers] is still very low, lower than colon resections for diverticulitis, yet nobody questions the validity of that particular operation,” said Timothy J. Pitchford, MD, a bariatric surgeon at the Marshfield Clinic, in Eau Claire, Wisc.

His center is not accredited, although Dr. Pitchford performs 80 to 100 bariatric operations annually. As the only bariatric surgeon at his hospital, the center’s volume had been too low to qualify for accreditation under the old ASMBS criteria. “The whole idea that you can’t do surgery unless you’re accredited is frustrating because we have good volumes for one surgeon with low mortality and low morbidity. We have no deaths, going on nine years,” he said.

Despite his frustration with the discrepancy, Dr. Pitchford supported the Center of Excellence concept. “It’s good in that it forces people to submit their data and has helped bariatric surgery achieve the status where we can now go to companies and say, ‘this is what we can do with bariatric surgery now.’”

Today, his practice is constrained by tight restrictions on coverage and misperceptions about bariatric surgery other than accreditation status, he said. “There’s still this idea that people can just diet their way to a healthier lifestyle, and that’s not the case.”

—Christina Frangou

A

ge-adjusted alcohol poisoning death rates, by state, between 2010 and 2012. States with the highest death rates were located mostly in the Great Plains and western United States, but also included two New England states (Rhode Island and Massachusetts).

Source: U.S. Centers for Disease Control and Prevention.

1978

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37th Anniversary â&#x20AC;&#x201D; 2 0 1 5

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We are proud to be the best-read gastroenterology publication in the marketplace, and we look forward to continuing to be your #1 source for gastroenterology news in decades to come.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

RAND Corporation: Biosimilars Could Save Billions

T

he introduction of biosimilar versions of complex biologic drugs in the United States could cut spending on biologics by an estimated $44 billion over the next decade, according to a new analysis from RAND Corporation.

The calculations were based on several variables, including future use of biosimilars and the effect of increased competition and acceptance of the drugs by physicians,

patients and payors. Experience with the drug class in the European Union, where biosimilars have been available for a decade, was also considered, as were U.S. sales figures for more than 100 biologics, including all blockbuster biologics with sales of more than $1 billion annually.

In total, the drugs had sales of $66.3 billion in 2013 across all distribution channels. Assuming that biosimilars will penetrate 60% of the market, the

researchers estimated that savings with biosimilars would be $44.2 billion over 10 years or about 4% of the total sales for biologics over that period.

“However, the magnitude of savings will depend on a number of factors, including forthcoming decisions from the FDA,” said Andrew Mulcahy, the report’s lead author and a policy researcher at RAND, a nonprofit research organization.

That’s why the researchers cited a range of

potential savings, he noted—from a low of $13 billion to a high of $66 billion.

Sandoz, a Novartis company, supported the analysis. In July, the FDA accepted the company’s biologics license application for filgrastim, which was filed under the agency’s new biosimilar pathway. The reference product, Neupogen (Amgen), is a human granulocyte colony-stimulating factor indicated to reduce infection manifested by febrile neutropenia in certain cancer patients.

Not ‘Generics’

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HEPATOLOGY

Fecal Transplants for IBD Show Mixed Results in Trials

F O C U S

I N

Probiotics Could Prevent Hepatic Encephalopathy

BY DAVID WILD

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

see Probiotics, page 11

Studies Challenge Conventional Wisdom In Biliary Stent Cost

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

Chicago—Fecal transplant has reached a critical milestone: testing in the first randomized controlled trial of the therapy to treat inflammatory bowel disease.

Although this step might be good for science, the news was not quite so encouraging for patients. The treatment did not appear to be better than placebo transplant at alleviating symptoms of ulcerative colitis (UC), according to the researchers.

“Although we did not find a statistically significant effect of FMT [fecal microbiota transplantation] in active UC, there is the possibility that FMT may be effective when administered longer than six weeks,” the researchers said, noting that there were no major adverse events.

The study, led by Paul Moayyedi, MBChB, PhD, MPH, acting director of the Farncombe Family Digestive Health Research Institute and director

of the Division of Gastroenterology at McMaster University, in Hamilton, Ontario, Canada, was one of several trials of FMT whose results were presented at Digestive Disease Week (DDW) 2014.

In the trial, the researchers randomized 27 patients with mild to moderate UC to receive an FMT enema and 26 patients to receive a placebo

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see Fecal, page 19

I N S I D E EXPERTS’ PICKS

Inside Ins ide the Electronic Health Record

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

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

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

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

Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection?

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

NEIL GUPTA, MD

PRATEEK SHARMA, MD

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

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

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

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

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olorectal

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cancer

(CRC) is the second leading cause of

cancer-related in

the

mortality

Western

world.1

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

See page 20

CRC and have shown a reduction in i mortality t lit within the screened population.2 However, colonoscopy remains imperfect and several studies have raised concerns about the miss rate of adenomatous polyps during screening.

The overall miss rate is approximately 20%, and ranges from 6% for large (10 mm) adenomas to 26% for diminutive (<5 mm) lesions.3 Missing these adenomas is one of the proposed mechanisms in the development of interval colon cancers that occur within the screened population.4 Improving detection of adenomas during colonoscopy therefore may be the key to more effective screening.

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

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

1

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

Biosimilars are highly similar versions of branded biologic “reference” products.

Because of that similarity, many people will think of biosimilars as “generic” fomulations, but the FDA’s Leah Christl, PhD, said in an interview that the term is incorrect. “Unlike generic drugs, whose structure can usually be completely defined and entirely reproduced, biologic products are typically more complex,” said Dr. Christl, associate director for therapeutic biologics at the FDA’s Office of New Drugs.

“Biosimilars and interchangeable biological products are unlikely to be shown to be structurally identical to a previously licensed biologic product.”

Draft materials released by the FDA underscore that point, making it clear that not all biosimilars will be deemed interchangeable with their reference products. In addition, nearly all biosimilars will require at least one head-to-head clinical trial to confirm similarity to the original biologic, a more stringent process than required for standard generics. This confirmation is not required in the European Union.

Huge Market As the U.S. approval pathway for biosimilars continues to play out, one factor remains clear: the huge size of the pharmaceutical market that will be affected when biosimilars are finally passed. In 2011, eight of the top 20 drugs in this country in terms of sales were biologics, and the annual spending on the class has increased three times faster than for other prescription medications, acording to the latest industry figures.

—Marie Rosenthal

CONTACT THE

EDITOR amarcus@ mcmahonmed.com

9

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Alexis Carrel: Nobel Winner, Brilliant Career Tarnished by Nazi Party Link ust one year after Allvar Gullstrand, MD, PhD, received the Nobel Prize in Physiology or Medicine in 1911, another surgeon, Alexis Carrel, won the prize “in recognition of his work on vascular sutures and the transplantation of blood vessels and organs.”

Although French by birth, Dr. Carrel did much of his pivotal work while living in America, and is considered the first medical scientist working in America to win a Nobel Prize.

“Dr. Carrel has been called a visionary,” said L.G. Walker Jr., MD, former chairman of the Department of General Surgery at Carolinas Medical Center, in Charlotte, N.C., who has studied the life and work of Dr. Carrel. “He was hardworking, precise, inquisitive and honest.”

But Dr. Carrel remains a controversial, and often misunderstood, figure. Despite his many notable accomplishments, his quirky, oftentimes provocative ideas landed him in hot water several times in his career, Dr. Walker noted.

Dr. Carrel’s early triumphs, including a novel suturing procedure that changed the surgical landscape and a method for cleaning wounds that saved countless lives in World War I, may be overshadowed in part by his later endeavors. In the 1930s, intrigued by the idea of creating a class of genetically elite human, he became focused on the study of eugenics. Given free rein to pursue his ideas during World War II, under the auspices of the Nazi regime, Dr. Carrel became inextricably linked to the political party, which damaged his reputation.

“The end of his life was a tragedy,” Dr. Walker said.

“His death marked an unhappy ending, which undermined his standing as a brilliant investigator and his friendships with colleagues.”

J

Rise to Fame Born on June 28, 1873, Dr. Carrel spent his childhood in Lyon, France. Dr. Carrel’s father, a successful textile merchant, died of pneumonia when Dr. Carrel was 5 years old. As the eldest of three children, Dr. Carrel became “the man of the house” and forged a close bond with his mother.

After the father’s death, the family’s finances took a downturn, but Mme. Carrel made sure her children received a Catholic education. Initially, she homeschooled Dr. Carrel, but later sent him to St. Joseph’s, a Jesuit school in Lyon. Although never known as an outstanding student, Carrel received a Bachelor of Letters in 1889 and a Bachelor of Science in 1890 from the University of Lyon.

When choosing a path after university, Dr. Carrel opted for a career in medicine rather than in the army.

In 1893, he graduated from medical school at the University of Lyon, and held an externship for two years at the Red Cross Hospital Antiquaille.

In 1895, Dr. Carrel’s life took an unanticipated turn.

In 1894, a knife-wielding assassin had stabbed French President Sadi Carnot in the abdomen, lacerating the portal vein. Surgeons could not save him and the president bled to death.

Dr. Carrel, however, thought that President Carnot could have been saved with the appropriate suturing technique. This notion inspired him to develop a method to repair blood vessels by using fine sutures and

meticulous technique. Mathieu Jaboulay, MD, a French surgeon at the University of Lyon, had already sutured blood vessels successfully, and was the first to publish his results, but his technique was not effective for small blood vessels.

During Dr. Carrel’s years at the HôtelDieu hospital in Lyon from 1896 to 1900, he began developing new techniques for suturing blood vessels, looking for finer needles and thread and employing an over-and-over continuous stitching, putting the stitches only partially through the vessel wall, instead of Dr. Jaboulay’s single interrupted method, which penetrated the vessel.

In 1901, Dr. Carrel completed his doctorate in medicine. Despite his notable work on suturing, he struggled to find a surgical staff position at the university hospital, and became an instructor of anatomy and surgery. In his spare time, he continued to experiment with suturing.

His persistence and exceptional surgical skill became evident in his experiments Alexis Carrel, MD, received the Nobel Prize in 1912 for his work in transplantation and suturing. on dogs, in which he first successfully sutured the femoral artery and saphenous vein, and later sewed carotid arteries to jugular veins. He also published his first articles on vasSoon, Ms. Bailly made a full recovery. Dr. Carrel and cular anastomosis, in which he foreshadowed his interest several physicians in Lourdes examined her, but could in organ transplantation (Lyon Medd 1902;99:114; and not find an explanation for her recovery. (Ms. Bailly 1902;99:152). remained in good health, until her death at age 58.) Dr. Carrel’s inquiry caused a backlash from members of the A Man of Science and Miracles church, who felt that by studying what had happened he Although a man of science, Dr. Carrel was also deeply was not accepting an “act of God.” His trip to Lourdes religious and fascinated by “miracles, magic and telepa- also upset his scientific colleagues, who thought that thy,” Dr. Walker wrote in a 1989 article (Surg Gynecol entertaining the possibility of a miracle damaged Dr. Obstett 1989;168:365-370).

Carrel’s reputation.

In May 1902, Dr. Carrel decided to venture to “He danced around the miracle issue,” Dr. Walker Lourdes, France, known for its miraculous cures, to said. “At that time, there was a strong feeling of antistudy such wonders firsthand. On a train filled with sick clericalism in the scientific community in France. So he passengers, Dr. Carrel met Marie Bailly, a dying woman got in trouble with the Church because he didn’t forthpresumed to have peritoneal tuberculosis. rightly talk about this as a miracle, and [also] with [the] Several conflicting accounts of what transpired on scientific community for even implying this could have this journey exist, but according to Ms. Bailly’s own been a miracle.” descriptions, she begged her friends to smuggle her onto the train bound for Lourdes. Along the journey, Carrel in North America Dr. Carrel found her in critical condition. He gave her Dr. Carrel was subsequently denied a full faculty posimorphine and stayed with her until the train reached its tion at the University of Lyon, prompting his journey destination. overseas to North America to find work, in 1904. Dr. On arriving at Lourdes, Ms. Bailly went to the Carrel’s first stop was a conference in Montreal, where famous baths, where she was doused with a bucketful he presented an article on blood vessel anastomosis and of holy water three times. In his short novel, “The Voy- transplantation. At this point, he had altered his suturage to Lourdes,” published after his death by his wife ing approach in favor of Dr. Jaboulay’s through-andwho found it among his papers, Dr. Carrel recounted through stitching, and had settled on using the finest watching the blanket covering the woman’s distended lace needles and thread, which allowed him to work on abdomen flatten as the swelling subsided. Uncomfort- delicate vessels. He also devised a triangulation techable with what he had witnessed, Dr. Carrel, who refers nique, which involved holding the vessel open and keepto himself as Lerrac (his name backward), wrote: “There ing the back wall clear of the stitching in front, a method was no denying that it was distressingly unpleasant to that is still used today to deal with difficult end-to-end be personally involved in a miracle. But [Lerrac] had to anastomosis. come to Lourdes, he had seen something happen, and Impressed with his work, George Stewart, MD, he had no more right to distort the results of his obser- invited Dr. Carrel to work alongside Charles Guthrie vation here than in a laboratory experiment at home.” see Carrel, page 40

10

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Experts Picks From the 2014 Liver Meeting Compiled and edited by Adam Marcus

The 2014 Liver Meeting of the American Association for the Study of Liver Diseases (AASLD)was largely a coming-out party for new data on the effectiveness of direct-acting antiviral agents for hepatitis C infection. But not entirely: Researchers presented data from important studies involving other liver ailments, from alcoholic hepatitis to hepatitis B. Gastroenterology & Endoscopy News asked two experts to discuss the abstracts from the meeting they found most compelling.

Dr. Liangpunsakul: Suthat Liangpunsakul, MD Associate Professor of Medicine, Biochemistry and Molecular Biology in the Division of Gastroenterology and Hepatology at Indiana University, in Indianapolis

140.

Combinative Use of Baseline and Dynamic Models in Patients With Severe Alcoholic Hepatitis: Prediction of Death as a Continuum in Risks of Mortality Predicting the prognosis of patients with severe alcoholic hepatitis (AH) typically involves the single use of baseline or dynamic models. Combining the two approaches may allow clinicians to assess outcomes as a continuum in probabilities of death.

The researchers used data from patients with severe AH (Maddrey Discriminant Function [mDF] ≥32) treated with steroids to combine baseline (mDF or Model for End-Stage Liver Disease [MELD] score) and on-treatment (Lille score) models. The study included 897 patients, with an average age of 50.6 years (Table). The majority (58.5%) were men; six-month survival was 64.1%.

Lille score and six-month survival had a linear relationship, but the association was nonlinear between mDF and survival, with a threshold at an mDF of 90.

Using a Cox regression mode, the researchers assessed the likelihood of survival using mDF at day 0 and Lille model at day 7. A patient admitted with an mDF of 100 with a Lille model of 0.25 at day 7 has a 73% chance of being alive after six months. That figure drops to 27.7% if Lille model is 0.7, according to the investigators. The joint-effects model was superior to a model based only on Lille (P=0.016).

P The joint-effects model also was better than each model individually, according to the researchers (P<0.001). A patient with a MELD score of 28 and a Lille model of 0.25 has a 73% chance of being alive at six months. That figure falls to 30.3% if the Lille model is 0.7.

“The present study stratifies the risk for death in AH, based on severity status at admission and evolution upon therapy,” the researchers wrote. “Such approach results in a balanced evaluation instead of giving a yes/no Manichean prediction of death aiming to define a new therapeutic strategy.”

AH is an acute hepatic inflam-mation associated with significant morbidity and mortality. In severe cases, patients have a very poor prognosis, with short-term mortality of approximately 30% to 50%. Several clinical scoring systems—the Child-Turcotte-Pugh score, the mDF, the Lille modell, MELD scores and the Glasgoow alcoholic hepatitis score—have been derived to predict the clinical outcom mes of patients with AH. The MELD scorre, which was calculated using baseline intern national normalized ratio, creatinine and biliru ubin, is useful for predicting the three-month mortality of patients with AH. The Lille model was developed to determine cases that respond to steroid therapy, using the evolution of laboratory tests (from days 0 and 7). It is also useful in predicting survival: Those with Lille scores below 0.16 and above 0.56 had survival rates of 87% and 21%, respectively. This study is novel, as it proposed to use both baseline MELD and Lille to provide the better mortality assessment for patients with AH and perhaps define those who need therapeutic intervention.

Table. Patient Characteristics Bilirubin 156 µmol/L Prothrombin time 20.2 sec Creatinine 8 mg/L mDF 55 MELD 25.2 Lille model 0.34 mDF, Maddrey Discriminant Function; MELD, Model for End-Stage Liver Disease

141.

Impact of Intensive Enteral Nutrition in Association With Corticosteroids in the Treatment of Severe Alcoholic Hepatitis: A Multicenter Randomized Controlled Trial Severe alcoholic hepatitis (AH) is associated with a high short-term risk for mortality. Although nutritional support is recommended for these patients, they often have trouble consuming the adequate calories and protein. This study assessed the effects of intensive enteral nutrition (EN) plus steroid therapy on six-month survival in patients with severe AH. The randomized controlled trial was conducted in 18 Belgian and two French hospitals. Patients received

either intensive EN through a feeding tube, and methylprednisolone or conventional nutrition and methylprednisolone. EN consisted of Fresubin HP Energy (Fresenius Kabi) based on the following regimen: 1 L per day for patients with body weight less than 60 kg; 1.5 L per day for body weight 60 to 90 kg; and 2 L per day for body weight above 90 kg.

The study included 136 patients with a severe biopsyproven AH (68 per group). Mean daily calorie intake was 2,206±754 versus 1,754±656 for the EN and conventional groups, respectively (P=0.001); P mean daily protein intake was 106±37 versus 80±32 g, respectively (P<0.001). Most patients in the EN group (63.2%) received at least 80% of the planned calorie intake.

In an intention-to-treat (ITT) analysis, six-month survival was similar for patients in the EN and convenP=0.316). In a per-protocol tional groups (55.9 vs. 47%; P analysis, six-month survival was higher in the enteral feeding group: 69.8% versus 46.8% (P=0.015).

P Mean calorie intake also was associated with a higher sixmonth survival (P=0.002).

P

Dr. Liangpunsakul: Patients with P h AH invariably bl experience some d degree of malnutrition. The severity of this protein–calorie malnutrition has been shown to closely correlate with mortality rate. A previous randomized controlled trial (Hepatologyy 2000;32:36-42) compared the therapeutic efficacies of corticosteroid therapy (40 mg/day) versus EN (2,000 kcal/day) and assessed outcomes at 28 days (the end of therapy) and one year later, or until death.

The two therapies produced similar initial outcomes; however, patients who received EN developed fewer long-term infections. see Liver Meeting, page 12

ScopeGuide Real-time, 3D visualization of the scope configuration

Physicians: Identify and mitigate loops.

Nurses: Document precise locations for biopsies.

Assistants: Apply abdominal pressure to the correct location.

Patients: Experience a more comfortable colonoscopy.

Watch Video or visit www.medical.olympusamerica.com/scopeguide/gen Contact a sales representative at 800-848-9024 Š2014 Olympus America Inc. Registered Trademark of Olympus or its afďŹ liates. I www.medical.olympusamerica.com/scopeguide/gen I OAIGI0813AD11548

12

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Liver Meeting continued from page 10

In this randomized controlled study, the investigators observed no difference in survival at six months (by ITT analysis). However, patients who achieved the targeted daily calorie intake experienced improved shortterm survival, according to the researchers. The findings emphasize the importance of nutritional support in patients with AH.

117.

Alcoholic Liver Disease is the Primary Driver of Increased Inpatient Charges Among Patients with Cirrhosis The study analyzed trends in inpatient charges for patients with cirrhosis to determine the drivers of health care costs related to the condition. The researchers used the National Inpatient Sample to identify patients at least 18 years old admitted to a U.S. hospital with a diagnostic code including the word “cirrhosis” between 2002 and 2010 (N=781,700).

Nearly half (47.4%) of all patients had received a diagnosis of alcoholic cirrhosis (AC). Admissions for AC rose 30% during the study period, as total charges for AC doubled, from $1 billion to $2 billion, to account for half of all inpatient costs related to cirrhosis.

Patients with AC have been getting sicker, and staying in the hospital longer, than those with other forms of the condition, although length of stay for those with AC fell from 7 to 6.1 days between 2002 and 2010, according to the study.

Dr. Liangpunsakul: Th study This d found f d that h alcoholic l h l liver l disease d accounts for nearly half (47.4%) of all hospital cases of cirrhosis.

Admissions increased by 30% between 2002 and 2010 for patients with AC. Total charges for AC increased 100% over the time period from $1 billion to $2 billion, accounting for approximately 50% of all inpatient cirrhosis-related charges during the time period. Early detection of alcohol misuse and appropriate intervention are of importance for the prevention of alcoholic liver disease, which might lead to the reduction in health care costs.

Dr. Liangpunsakul reported no relevant financial conflicts of interest.

Nancy Reau, MD Associate Professor of Medicine at University of Chicago Medicine in Chicago, Illinois

LB-1.

Steroids or Pentoxifylline for Alcoholic Hepatitis: Results of the STOPAH Trial

Alcohol-related liver disease is a common cause of mortality in the United States. Severe liver inflammation caused by drinking alcohol is called alcoholic hepatitis (AH). This condition carries a high mortality in those severely affected, with short-term mortality greater than 30%.

Several scoring systems exist to help identify those at highest risk for death with the Maddrey Discriminant Function (mDF) being commonly used (4.6 × [patient’s PT-control PT in seconds] + serum bilirubin). An mDF score of 32 or higher is associated with severe disease.

Pharmacologic interventions are aimed at this subset in hopes of decreasing mortality.

Appropriate identification and management of AH is vital as disease burden from this condition continues to increase. Data from the National Inpatient Sample confirm that hospitalizations linked to AH have increased significantly from 2002 to 2010 with substantial increases in health care cost.

Prednisolone and pentoxifylline are the most commonly used agents in patients with severe AH. However, management of the condition has been controversial, and studies have reported conflicting evidence for the benefit of these drugs. To determine which, if either, of these agents is effective, Thursz and colleagues conducted a prospective randomized, double-blind, placebo-controlled trial involving 1,103 patients with AH; 1,053 were available for primary analysis. The primary end point was 28-day mortality, with mortality at 90 days and one year the secondary end points.

‘Early detection of alcohol misuse and appropriate intervention are of importance for the prevention of alcoholic liver disease, which might lead to the reduction in health care costs.’

—Suthat Liangpunsakul, MD

Patients with an mDF score of at least 32 were randomized to one of four interventions: prednisolone 40 mg a day, pentoxifylline 400 mg three times daily, combination prednisolone and pentoxifylline or placebo.

Arms were well matched for disease severity and other comorbid conditions.

Only treatment arms containing prednisolone had better 30-day mortality. Combination therapy did no better than prednisolone monotherapy and pentoxifylline performed no better than placebo.

The presence of hepatic encephalopathy was linked to 28-day mortality with an odds ratio of 3. Other factors associated with 28-day mortality included elevated prothrombin time, bilirubin, age, white blood count and levels of urea and creatinine.

Prednisolone use was associated with a higher rate of infections (13.5% vs. 7.9%) but reduced the 28-day mortality risk by 39%.

After 28 days, neither drug was associated with a survival benefit. The only factor that affected one-year survival was abstinence from alcohol consumption or decreasing alcohol intake below safe limits.

Dr. Reau: This well-controlled Th ll ll d triall will ll have h a significant f impact on our current management of this precarious population. Prednisolone should be used in severe AH to decrease short-term mortality, despite a higher

risk for infections. Pentoxifylline should no longer be considered appropriate first-line therapy. Use of pentoxifylline in AH was supported by a single-center trial that demonstrated a lower mortality rate compared with placebo (Gastroenterologyy 2000;119:1637-1648). The results strongly refute the role of this agent. Ultimately, long-term prognosis is driven by behavioral modification—nutrition and abstinence. In those individuals who cannot change abusive behaviors, as one would expect, outcomes will be poor.

Treatment

Patient Number (N=1,053)

30-d Mortality, %

Prednisolone + pentoxifylline

260

13.5

Prednisolone + placebo

266

14.3

Pentoxifylline + placebo

258

19.4

Placebo + placebo

269

16.7

6.

Liver Transplantation (LT) with the “Oldest Old” (>80 years) Donor Livers: The U.S. National Experience Oral presentation.

Liver transplantation (LT) is limited by supply and demand. A dearth of donors exists compared with those in need of transplant. Organ shortages are only expected to increase with growing numbers of individuals with end-stage liver disease and liver cancer from fatty liver disease and hepatitis C. Donor characteristics can significantly affect transplantation outcomes. Using national data, Cox regression models identified seven donor characteristics that independently predicted increased risk for graft failure.

The most impactful factors included donor age over 40 years (and particularly over 60 years), donation after cardiac death (DCD) and split/partial grafts. Black race, short stature, cerebrovascular accident and “other” causes of brain death were only modestly associated with graft failure ((Am J Transplantt 2006;6:783-790). These factors were used to generate a donor risk index, which is now used by procurement organizations and transplant physicians to help match appropriate donors to recipients.

Still, the shortage of acceptable organs requires ways to expand the donor pool without compromising outcomes. Repeatedly, donor age is identified as one of the most significant independent predictors of time-to-graft failure (Transplant Procc 2013;45:2077-2082). However, not all centers believe advanced age should exclude donation and liver grafts from donors over age 60 years have been shown to be used effectively, especially in recipients with low Model for End-Stage Liver Disease (MELD) scores (Transplant Procc 2014;46:2762-2765).

As the general population ages, the age of donors also increases. If older donors can be safely used, this could expand the organ pool.

Dr. Reau: Sharpton and Sh d colleagues ll presented d data d at the h AASLD meeting addressing use of the “oldest old” donors (OOD), or those 80 years and older. Using d data from the United Network for Organ Sharing from 132 transplant centers, 36,316 recipients of deceased donor livers were evaluated. Centers were

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

categorized by both the number of OOD organs used and the average MELD at transplant in their region. A very small minority—244 OOD organs—were transplanted. OOD donors were more likely to be women and to have comorbid conditions such as diabetes and hypertension. None was DCD. Recipients of the OOD organs were more likely to be older, female, carry a diagnosis that was not HCV and have a low MELD score. Centers that used OOD organs also varied. Only 28% of centers used OOD organs and 71% of OOD organs were transplanted by six centers (considered high utilizers). Although three of these centers were in high-MELD regions, the other three were in mid- to low-MELD regions. Graft survival with OOD livers was acceptable and did not vary between centers that were high or low utilizers.

It will be several years before effective antiviral therapy decreases the need for LT in patients with viral hepatitis C. LT offers the best long-term prognosis for

‘Donor age long has been one of the most important factors used to predict transplant outcomes, yet this may be too simplistic an approach.’

—Nancy Reau, MD hepatocellular carcinoma (HCC) and liver cancer rates also are expected to increase, with HCC becoming the third most lethal malignancy in the United States by 2030. Thus, the organ shortage for livers will continue

to be an issue. Safely expanding the donor pool is a high priority. The new data confirm that organs traditionally excluded from consideration for transplantation can be effectively used. Few centers currently take advantage of this organ pool; however, experience with older donors does not appear to affect outcomes. Donor age long has been one of the most important factors used to predict transplant outcomes, yet this may be too simplistic an approach. This study clearly demonstrates that carefully chosen octogenarian organs are an effective resource that should not be overlooked and potentially wasted.

LB-10.

A Multi-Center Randomized Study on the Efficacy and Safety of Switching to Peginterferon α-2a (40KD) for 48 or 96 Weeks in HBeAg-positive CHB Patients With a Prior NUC History for 1 to 3 Years: an Interim Analysis of NEW SWITCH Study Unlike hepatitis C, hepatitis B virus (HBV) infection is currently not curable. The goals of treatment are decreasing long-term morbidity and mortality through chronic viral suppression. This is generally achieved by either chronic or finite oral antiviral therapy or finiteduration interferon therapy. Surrogate end points are typically used to gauge success and include normalization of liver enzymes, viral suppression, hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) loss and seroconversion, with the latter considered the ideal end point. Unfortunately, few therapies in patients with chronic active HBV lead to reliable loss of HBsAg. NEW SWITCH sought to evaluate if giving peginterferon (PEG-IFN) α-2a to HBeAg-positive patients

13

who had inadequate response after one to three years of oral nucleoside/nucleotide (NUC) therapy would effectively lead to HBsAg loss. Partial response was defined as HBV DNA below 200 IU/mL and HBeAg loss but not HBsAg loss or seroconversion. Partial responders (n=303) were switched to PEG-IFN α-2a treatment for either 48 or 96 weeks after a period of 12 weeks overlap with existing NUC therapy. Patients were then followed for 48 weeks after treatment discontinuation for HBsAg loss and seroconversion. Baseline levels of HBsAg were 3.105 (±0.7844) log IU/mL. After 48 weeks of treatment, HBsAg loss was 16.2% and seroconversion 12.5%; however, the majority of participants decreased HBsAg levels below 1,000 IU/ mL. Nearly 92% of patients maintained suppression of HBV DNA.

Dr. Reau: Chronic HBV is a ffrustrating virall infection Ch f ffrequently l requiring lifelong viral suppression to decrease the risk for liver-related morbidity and mortality. Individuals with chronic disease often require decades of treatment with oral antiviral agents. Interferon offers the only finite therapy, but viral suppression rates and seroconversion are lower than desired. Strategies to identify individuals who could achieve HBsAg loss or seroconversion are attractive. This study suggests that HBeAg-positive patients who fail to lose HBsAg with oral antiviral therapy may benefit from switching to PEG-IFN–based treatment, especially if they have low levels of HBsAg (<1,500 IU/ mL) at the time of the switch.

Dr. Reau has received consulting fees, research grants and/or honoraria from AbbVie, Bristol-Myers Squibb, Gilead and Merck.

Study Spotlights Natural History of Pediatric NASH BOSTON—An evaluation of biopsies from the Nonalcoholic Steatohepatitis Clinical Research Network has provided a glimpse into the natural history of liver diseases in obese children.

The NASH CRN Natural History Study, found that early patterns of nonalcoholic fatty liver disease (NAFLD) in children appear to evolve into more adult presentations of steatohepatitis.

The researchers presented the findings at the 2014 Liver Meeting of the American Association for the Study of Liver Diseases (AASLD; abstract 185).

“Knowledge of long-term outcomes for pediatric NAFLD will assist in education for clinicians treating children, because now there is biopsy-based data to back up what cross-sectional studies have been showing for several years about NAFLD being a potentially serious disease,” said Elizabeth Brunt, MD, section head of liver/GI pathology at Washington University School of Medicine, in St. Louis, who led the study. “Additionally, data such as these assist planning of clinical trials in that expectations for

outcomes can be realistically set in both control and intervention groups.”

Clinicians are concerned about the increasing number of obese children who are developing NAFLD and its more severe form. Adrian Di Bisceglie, MD, president of AASLD and a professor of internal medicine at Saint Louis University, in Missouri, said children under age 10 years have been known to present with cirrhosis from fatty liver disease.

Until now, little has been known about changes in liver histology over time in children with NAFLD. To shed light on the issue, Dr. Brunt and her colleagues compared two sets of biopsies from 102 overweight or obese children with liver disease. The biopsies were obtained from the placebo group of the Treatment of NAFLD in Children (TONIC) trial or the NAFLD Database studies (all run through NASH CRN).

Samples were collected between one and 11 years apart, with a median separation of 2.2 years. The children were predominantly boys (72%); Hispanic (68%); and see NASH, page 20

Table. Changes in NASH and Fibrosis in the NASH CRN Natural History Study From First to Second Biopsy in 102 Children Following Standard of Care First Biopsy, %

Second Biopsy, %

27.5

9.8

Zone 3 NASH, perisinusoidal/ pericellular fibrosis (“adult pattern”)

14.7

18.6

Definite steatohepatitis

28.4

29.4

Zone 1C, portal-predominant fibrosis (“pediatric pattern”)

30.4

15.7

No fibrosis

28.4

40.2

Bridging fibrosis

12.8

17.7

Cirrhosis

2.9

2.0

Diagnosis of steatohepatitis

(“pediatric pattern”)

Fibrosis stage

NASH CRN, Nonalcoholic Steatohepatitis Clinical Research Network

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

14

Difficult continued from page 1

The FDA approved Harvoni in October 2014 for use in difficult-to-treat patients: a 12-week course in treatmentnaive patients with or without cirrhosis, 12 weeks for treatment-experienced patients without cirrhosis and 24 weeks for treatment-experienced patients with cirrhosis. However, the new trials are the first to test the drug in large numbers of these subpopulations.

Michael Fried, MD, director of the

University of North Carolina Liver Center, in Chapel Hill, called the results notable. “The SVR [sustained virologic response] rates demonstrate that these drugs are very effective, even in this very sick population,” Dr. Fried said.

Dr. Fried pointed out that in patients with decompensated cirrhosis, antiviral treatment was capable of improving clinical status. “Patients, including those with cirrhosis who previously failed protease inhibitor–based or sofosbuvir-based therapy, can be rescued with some of the drugs that we currently have available,” he said.

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

SOLAR-1 Steven Flamm, MD, professor of medicine and surgery, and chief of the Liver Transplantation Program at Northwestern University, in Chicago, presented preliminary results of the prospective, multicenter SOLAR-1 trial (abstract 239). Investigators randomized patients with genotype 1 or 4 hepatitis C and decompensated cirrhosis to ledipasvir-sofosbuvir plus ribavirin for 12 (n=52) or 24 weeks (n=47). Patients had decompensated cirrhosis with ChildPugh class B or C, determined by liver

‘Patients, including those with cirrhosis who previously failed protease inhibitor– based or sofosbuvir-based therapy, can be rescued with

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some of the drugs that we currently have available.’

—Michael Fried, MD

function biomarkers and symptoms.

Most patients had a Model for EndStage Liver Disease (MELD) score greater than 10. Roughly 15% of ChildPugh class B patients and 40% of class C patients had MELD scores between 16 and 20.

In the Child-Pugh class B cohort, 60% had a history of ascites and 60% had hepatic encephalopathy. In the class C cohort, nearly all patients had a history of ascites, and 90% had hepatic encephalopathy. The investigators excluded liver transplant recipients, as well as individuals with very high MELD scores or bilirubin, extremely low platelet counts (below 30,000), serious kidney dysfunction or hepatocellular carcinoma.

Three patients discontinued treatment early because of adverse events (AEs), and four serious AEs were considered to be related to treatment. The SVR rate at week 12 (SVR12) was 87% in patients who received 12 weeks of treatment and 89% in patients who received 24 weeks of treatment. Response rates were similar in Child-Pugh class B and C patients.

Most individuals had an improvement in their Child-Pugh scores, with 10 having no change and only four having higher (worse) scores. Most patients also had improvements in their MELD scores. Dr. Flamm said the regimen “resulted in a high SVR12 rate in HCV patients with genotype 1 and 4 and advanced liver disease.”

In a second study presented at the meeting, researchers provided 12 weeks of ledipasvir-sofosbuvir plus ribavirin to 51

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

“There was no difference in SVR12 rates among patients with or without NS3/4A RAVs at baseline,” said Marc Bourlière, MD, head of the HepatoGastroenterology Department at Hospital Saint-Joseph in Marseilles, France, who presented the study. Pretreatment frequencies of these RAVS have been determinants of treatment outcomes with other drugs. Ledipasvir-sofosbuvir with or without ribavirin was safe and well tolerated, with most AEs being mild or moderate in severity, Dr. Bourlière said.

Dr. Fried added that future research should examine how the new medications affect transplantation rates in the long term.

—Kate O’Rourke

OPT IN

Dr. Fried has received grant/research support from and consulted for Gilead.

Dr. Bourlière is on the medical advisory board of Gilead. Dr. Flamm has received research support from Gilead and is also on the company’s speakers’ bureau.

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CATCH HER PBC BEFORE PBC CATCHES HER patients with HCV genotype 1 who had failed previous sofosbuvir-based regimens (abstract 235). Roughly 29% had cirrhosis, 59% had genotype 1a and 12% had NS5A resistance-associated amino acid variants (RAVs) at baseline. High rates of SVR12 were seen in all patients, those who had received prior treatment with peginterferon-ribavirin-sofosbuvir (100%), sofosbuvir-ribavirin (95%) and peginterferon/ ribavirin (100%). (The lone failure turned out to be a patient who was incorrectly genotyped and in fact had genotype 3 infection, according to the researchers.)

A third trial enrolled cirrhotic patients with HCV genotype 1 who had failed protease inhibitor–based triple therapy (abstract LBA6). The double-blind randomized trial involved a placebo design in which patients received either 12 weeks of placebo plus 12 weeks of fixeddose ledipasvir-sofosbuvir plus ribavirin (n=77) or 24 weeks of ledipasvir-sofosbuvir plus placebo (n=78). Patients were included if they had not achieved an SVR after sequential peginterferonribavirin treatment and triple therapy (protease inhibitor plus peginterferon and ribavirin).

Approximately 18% of patients had platelet counts less than 100,000/mcL and 13% had serum albumin less than 3.5 g/dL. The average MELD score was 7. Roughly 73% had baseline NS3/4A RAVs. The SVR12 rates were 96% in patients who received ledipasvir-sofosbuvir plus ribavirin for 12 weeks and 97% in patients who received the 24-week treatment.

For many patients, before symptoms of primary biliary cirrhosis (PBC) appear, elevated alkaline phosphatase (ALP) levels indicate the beginning of liver damage.1,2 Early treatment to lower ALP levels can help patients avoid progression to cirrhosis and liver transplant.3

Learn more at interceptpharma.com References: 1. European Association for the Study of the Liver. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol.

2009;51(2):237-267. doi:10:1016/j.jhep.2009.04.009. 2. Hohenester S, Oude-Elferink RPJ, Beuers U. Primary biliary cirrhosis. Semin Immunopathol.

2009;31(3):283-307. doi:10.1007/s00281-009-0164-5. 3. Lammers 9J, van Buuren HR, Hirschƒeld )/, et al; )lobal PB% Study )roup. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology.

2014;147(6):1338-1349.e5. doi:10.1053/j.gastro.2014.08.029.

i2014 +ntercept Pharmaceuticals, +nc. All rights reserved. +%P6.14.12.001

15

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

16

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Prognostic Index May Identify HCV Patients At Risk for Deterioration

A

new prognostic index shows that patients with cirrhosis related to hepatitis C virus (HCV) infection are seven times more likely to experience hepatic decompensation, and six times more likely to die of liver-related illness, if they have a constellation of genetic and clinical indicators that put them at high risk for poor outcomes.

The prognostic index is composed of a 186-gene signature and several clinical measures. It was developed specifically to identify HCV patients with cirrhosis who are at high risk for disease progression.

The index has several potential applications, such as stratifying patients in clinical trials and identifying those most in need of treatment with the newest—and

most expensive—therapies for the infection, researchers said. It also is relevant for treated patients with liver damage even after achieving a sustained viralogic response (SVR).

In addition to the highly significant prognostic accuracy for decompensation and death from liver-related causes (P<0.001 for both), patients who met the

index criteria had a more than threefold increased risk for death from any cause (P=0.002) P compared with those who did not, according to a collaboration that included investigators from the Liver Center at Massachusetts General Hospital (MGH), in Boston, and the Icahn School of Medicine at Mount Sinai Hospital, in New York City. The results of the multicenter validation study were published in a recent issue of Gutt (King et al.

2014 August 20. [Epub ahead of print]).

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The 186-gene signature in the tool was derived from a previously validated, genome-wide profiling study. It was coupled with other clinical factors, including an elevated bilirubin (>1 mg/dL) and a suppressed platelet count (<100,000/ mm3). The index was first tested using tissue samples and clinical data in a training cohort of 216 HCV patients in Italy, for whom there was a median 10-year follow-up period. The index was then assessed in a validation cohort, which consisted of 145 patients with HCV infection in the United States, who had been followed for a median of eight years.

The prognostic index demonstrated similar performance in the two tested populations. In the validation cohort, for example, hazard ratios (HRs) for patients who met criteria for high risk, compared with those having intermediate or low risk, were 7.36 for hepatic decompensation, 6.49 for liver-related death, 4.98 for liver-related adverse events and 3.57

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

17

FDA Approves Lanreotide To Treat GI Neuroendocrine Tumors he FDA has approved Ipsen’s lanreotide (Somatuline Depot) for the treatment of patients with unresectable, well- or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival (PFS), the agency announced.

Lanreotide was previously approved for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option.

The new approval was based on demonstration of improved PFS in a multicenter, international, randomized , double-blind, placebocontrolled study that enrolled

T

for all-cause mortality. All HRs were statistically significant, according to the researchers.

As assessed with the index, 16% of the validation cohort was identified as at high risk, with the remainder evenly divided between intermediate and low risk.

The researchers, led by Lindsay Y. King, MD, of MGH, and Yujin Hoshida, MD, PhD, of Mount Sinai Hospital, characterized the prognostic index as “readily available for clinical use.” Dr. Hoshida told Gastroenterology & Endoscopy News. that efforts to develop a commercially viable version of the index are now underway.

The data are encouraging because there is a major unmet need for better methods of predicting outcomes, said Thomas Baumert, MD, a hepatologist and professor of medicine at the University of Strasbourg, in France. Dr. Baumert noted that although the development of highly effective antiviral regimens has increased opportunities for eradication of HCV, he said patients with advanced liver disease remain at risk for liver failure even after HCV has been eradicated.

“Treatment-induced viral cure reduces, but does not eliminate, the risk for disease progression and development of liver cancer in patients with cirrhosis,” Dr. Baumert said in an interview. “Furthermore, in settings with limited resources, better tools for prognosis may identify those HCV patients most in need of the effective, but very expensive, antiviral regimens that have become available.”

—Ted Bosworth Drs. King, Hoshida and Baumert reported no relevant financial conflicts of interest.

204 patients with unresectable, wellor moderately differentiated, locally advanced or metastatic, nonfunctioning GEP-NETs. More than half of the patients (55%) had NETs outside the pancreas. Patients were randomized to receive either lanreotide 120 mg or placebo subcutaneously every 28 days.

The trial demonstrated a significant prolongation of PFS for the lanreotide

arm (hazard ratio, 0.47; 95% confidence interval, 0.30-0.73; P<0.001).

The median PFS in the lanreotide arm had not been reached at the time of the final analysis and is at least 22 months.

The median PFS in the placebo arm was 16.6 months.

Safety data were evaluated in 101 patients who received at least one dose of lanreotide. The most commonly

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reported adverse events in lanreotidetreated patients were abdominal and musculoskeletal pain, vomiting, headache, injection site reaction, hyperglycemia, hypertension and cholelithiasis.

The most common serious adverse event of lanreotide observed in this trial was vomiting, which occurred in 4% of treated patients.

—GEN Staff

ONE SHE’S BEEN WAITING FOR IS HERE

HARVONI, the HARVONI logo, GILEAD and the GILEAD logo are trademarks of Gilead Sciences, Inc., or its related companies. ©2014 Gilead Sciences, Inc. All rights reserved. GILP0374 10/14

One tablet contains ledipasvir and sofosbuvir

20

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

Shorter

Table. Virologic Response of HCV Genotype 1 Patients Treated With Sofosbuvir, Grazoprevir and Elbasvir

continued from page 1

costs, with 12-week courses of new DAAs hovering close to $100,000. Prolonged treatment may also compromise patient adherence to therapy, experts said.

“Optimized regimens may allow an eight-week duration that may be broadly applicable across diverse patient groups,” said Eric Lawitz, MD, vice president of scientific and research development at The Texas Liver Institute, in San Antonio, who led the study. Dr. Lawitz, also clinical professor of medicine at the San Antonio University of Texas Health Science Center, said large randomized trials are needed before changes to clinical practice can be made.

In the new study, presented at the 2014 Liver Meeting of the American Association for the Study of Liver Diseases (abstract LB33), Dr. Lawitz and his colleagues hypothesized that a regimen of DAAs that target different components of the replication cycle of the hepatitis C virus (HCV) would allow for a shorter duration of therapy than what is currently used—12 to 24 weeks for most patients. The Phase II C-SWIFT trial tested four, six or eight weeks of sofosbuvir (Sovaldi, Gilead), an NS5B nucleotide polymerase inhibitor, plus Merck’s fixed-dose combination of grazoprevir, an NS3/4A protease inhibitor, and elbasvir, an NS5A inhibitor.

The study enrolled treatment-naive patients with HCV genotypes 1 and 3, but only results from genotype 1 patients were presented at the meeting. At two weeks of follow-up after the end of treatment, no patient in any of the treatment arms had detectable levels of virus. However, only patients who received eight weeks of therapy had sustained virologic responses (SVRs) similar to those seen with the 12-week regimens currently used (Table).

The shortened regimen was well tolerated, according to the researchers. Patients relapsed most commonly with either wild-type virus or with resistance-associated amino acid variants already present at baseline. Factors associated with the likelihood of achieving an SVR in the arms that received only four or six weeks of treatment were subgenotype, viral load at baseline, IL28B

continued from page 13

between 11 and 17 years old (67%) at the time of the first biopsy.

Changes in fibrosis and diagnostic categories represent changes in patterns of injury, from the patterns associated more with “pediatric” NAFLD and NASH to those of “adult” NAFLD and NASH, Dr. Brunt said. These changes most clearly occurred in 28 children (Figure).

From the first to the second biopsy, the frequency of a zone 1 (portal only) diagnostic pattern decreased from about 28% to 10%, and the incidence of a zone 3 pattern and definite steatohepatitis patterns—considered the adult patterns of fatty liver disease—increased by about 10% each (Table). At the same time, fibrosis patterns also changed, with a decrease in portal-predominant (1c) fibrosis from about 30% to 16%.

Biopsies with no fibrosis increased from about 28% to 40% of the total group.

Advanced fibrosis, characterized by both

Treatment Arm

HCV RNA Undetectable at End of Treatment, %

HCV RNA Undetectable at 2 wk After End of Treatment, %

SVR4/SVR8, %a

4 wk treatment in noncirrhotic patients (n=31)

81

100

38.7

6 wk treatment in noncirrhotic patients (n=30)

97

100

86.7

6 wk treatment in cirrhotic patients (n=20)

100

100

80.0

8 wk treatment in cirrhotic patients (n=19)

100

100

94.7

HCV, hepatitis C virus; SVR, sustained virologic response a

A small subset of patients did not reach SVR8, so SVR4 data were included.

status and the pharmacokinetics of component medicines in the regimen.

Dr. Lawitz reported that 12 of 31 patients receiving four weeks of treatment were cured of HCV. “Although there were a number of patients that relapsed, I think it is important that it is biologically plausible to cure a very selected subset of patients at four weeks,” Dr. Lawitz said. “The study teaches us what the phenotype might be for patients who have an opportunity to be successful with a shorter duration of therapy.”

Dr. Lawitz added that he hoped the findings will be used to design future trials to test shorter durations of therapy.

“It is also encouraging to see that a three-drug regimen achieved a 95% SVR at eight weeks in the setting of cirrhosis,” Dr. Lawitz said, pointing out that many currently approved regimens are approved for 24 weeks in cirrhotic patients. “This suggests that we may be able to feasibly get an eight-week regimen for all patient types. Obviously we need large, prospective studies to

evaluate the question, but it is a proof of principle.”

The interim results from the Phase II trial will be updated later with SVR12 data.

Michael Fried, MD, director of the University of North Carolina Liver Center, at Chapel Hill, said researchers were focused on shortening the treatment time of patients with hepatitis C. “This is a very important study because it sets the limits, if you will, of where we might be able to go with these drugs,” Dr. Fried said. “Perhaps we can identify certain subgroups of patients that would be able to get treated for four weeks, but that will certainly require a lot more research.”

—Kate O’Rourke Dr. Lawitz has a financial relationship with Merck.

Dr. Fried has received research grants from AbbVie, BristolMyers Squibb, Genentech, Gilead, Janssen, Merck and Vertex, and has consulted for AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck and Vertex.

First biopsy: Bdl 1b, Z1 n=28

Def SH

Bdl 1a, Z3

Bdl 1b, Z1

NAFLD, Not NASH

Not NAFLD, Not NASH

Last biopsy:

7

3

5 (no change)

7

6 (<5% steatosis)

■ First ■ Last 30 25 20 Percent

NASH

GASTROENTEROLOGY GASTROENTEROLOGY & ENDOSCOPY & ENDOSCOPY NEWS NEWS • FEBRUARY • FEBRUARY 2015 2015

15 10 5 0 Not NAFLD

NAFLD, not NASH

Bdl, Z3

Bdl, Z1 Pediatric

Def SH

Figure. Pediatric pattern biopsies.

Def SH, definite statohepatitis; NAFLD, non-alcoholic fatty liver; NASH, nonalcoholic statohepatitis

bridging (stage 3) or cirrhosis (stage 4), increased and were seen in nearly 20% of all children in the second biopsy.

“I think what is interesting about this is there is a so-called pediatric pattern of NAFLD with the zone 1 steatosis, and over time, it appears that it evolves to a more adult pattern of steatohepatitis,” Dr. Di Bisceglie said. “Some of the children had resolution of their NASH, but most of them appear to transition to this adult kind of NAFLD. We know that among adults, fatty liver disease is the condition that is rising at the largest rate as an indication for liver transplantation. It is also rising as a risk factor for liver cancer. As we more effectively treat hepatitis C, we may be doing fewer liver transplants for hepatitis C, but we are going to be doing more for fatty liver disease. We need a clear understanding of what happens to these children over time.”

—Kate O’Rourke Drs. Brunt and Di Bisceglie reported no relevant financial conflicts of interest.

21

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Biomarker Can Predict Benefit From Cetuximab in CRC MADRID— —The biomarker miR-31-3p predicts cetuximab’s efficacy in patients with all-RAS S wild-type metastatic colorectal cancer, according to research presented during the European Society for Medical Oncology (ESMO) 2014 Congress.

This biomarker is the first that pinpoints a patient population likely to experience detriment from cetuximab, post-hoc analyses from New EPOC Study showed.

“The results of our study demonstrate that all-RAS S wild-type metastatic colorectal cancer patients with high expression levels of miR-31-3p experience inferior progression-free survival when treated with the combination of chemotherapy plus cetuximab,” said study co-author John Primrose, MD, a professor of surgery at the University of Southampton, in England, and the chief investigator for the study.

of patients treated with chemotherapy alone (13 vs. more than 35 months; hazard ratio, 2.7; 95% confidence interval, 1.16.4; P P=0.02). However, when only patients with low levels of miR-31-3p were evaluated, PFS was no worse with the addition of cetuximab.

In addition, the study identified a correlation between miR-31-3p expression in primary tumors and metastases in patients receiving chemotherapy alone but not in those receiving chemotherapy

a

plus cetuximab, suggesting that miR31-3p affects the EGFR pathway, Dr. Primrose said.

“MiR-31-3p is a biomarker of harm from cetuximab, but we need to now understand the pathways involved and which genes are being regulated,” he said.

Co-investigator John Bridgewater, MD, a gastrointestinal oncologist at the University College London Hospitals, in London, England, said oncologists should take two key messages from the results.

“Do not use EGFR inhibitors in a neoadjuvant setting, and there are complex molecular events about which we still understand very little.”

Investigators called for thorough testing of RAS S status in all patients before giving an anti-EGFR antibody.

—Christina Frangou Dr. Primrose reported financial relationships with Bayer, Merck, Roche and Sanofi-Aventis. Dr. Bridgewater reported financial relationships with AstraZeneca, Merck, Roche and Sanofi.

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The the Phase III New EPOC Study, randomized patients to receive chemotherapy alone or chemotherapy plus cetuximab before and after resection of colorectal liver metastasis.

The trial results, published last spring in The Lancet Oncologyy (15:601-611), showed that KRAS S exon 2 wild-type patients who received cetuximab along with standard chemotherapy and surgery for operable colorectal liver metastases had significantly reduced progression-free survival (PFS) compared with patients who did not receive cetuximab.

Surprisingly, the greatest detriment was seen in patients with better prognoses and occurred even in those who responded to treatment, leaving investigators searching for a biological explanation.

Dr. Primrose and his colleagues conducted the post-hoc analysis to look at biomarkers that could identify patients who benefit from treatments targeting epidermal growth factor receptor (EGFR). They focused on patients without a KRAS S or NRAS S mutation.

The analysis revealed a strong relationship between miR-31-3p expression and patients’ outcome after treatment with chemotherapy plus cetuximab.

Among patients with high expression of miR-31-3p, those who received the combination of chemotherapy plus cetuximab had just over one-third of the median PFS

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Battling the Financial Toxicity of Cancer Treatment BOSTON— —At age 39, Chris was diagnosed with localized rectal cancer. He received treatment with capecitabine (Xeloda, Roche) and radiation, and initially responded well to therapy. Immediately before surgery, however, his doctor discovered the cancer had metastasized and began talking to him about further chemotherapy options, including continuing him on the capecitabine regimen. Chris flatly rejected this option.

“It wasn’t the physical toxicity that Chris was concerned about; it was the financial toxicity,” said Yousuf Zafar, MD, MHS, associate professor of medicine at Duke Cancer Institute, in Durham, N.C. “Chris had a job and was insured, but he had no prescription drug coverage. For the five and a half weeks he was taking oral capecitabine, he was paying for all of it out of pocket. He never once mentioned to me his problem, and what is worse, I never asked him.”

As a result, Chris was in serious medical debt, a common outcome for cancer patients. The average amount that an insured cancer patient pays out of pocket per year is $4,800 (J ( Clin Oncoll 2011:29;2821-2826). Half of Medicare beneficiaries with cancer spend more than 10% of their income on out-of-pocket health care expenses; 28% spend more than 20% (Cancerr 2013;119:12571265). “Our patients are paying a lot, probably more than we realize,” Dr. Zafar said, presenting some of the latest financial toxicity data at the American Society of Clinical Oncology Quality Care Symposium.

Drug prices are a common scapegoat for spiraling health care costs. According to Peter Bach, MD, of Memorial Sloan-Kettering Cancer Center, in New York City, from the 1970s to the 1990s, the average cost of a month of chemotherapy was roughly $100. Today, the average price is $10,000 per month. Biologics, with their hefty price tags, are a huge factor (see article, page 12).

Just last month, Amgen’s new bispecific antibody leukemia drug, Blincyto (blinatumomab), hit the market with a price tag of $178,000, making it one of the world’s most expensive cancer medications.

In some cases, drugs have risen in price after entering the market. According to a recent investigation by Bloomberg News, between 2007 and 2014, the price of erlotinib 100 mg (Tarceva, Genentech) increased by 91% and the price of imatinib 400 mg (Gleevec, Novartis) increased by 158%. Dana Cooper, a Novartis spokesperson, explained that the company periodically adjusts the prices of its products to balance the cost of current products with the cost of developing new drugs. “The majority of CML [chronic myeloid leukemia] patients pay less than $100 out of pocket per month for our CML treatments,” Ms. Cooper said. Susan Wilson, a spokesperson for Genentech, offered a similar comment, saying prices are occasionally adjusted so that the company can continue drug development.

Burden Falling on Patients As drug prices surge, patients are bearing a greater burden of the cost in the form of cost sharing. According to the 2013 Kaiser Family Foundation/Health Research and Educational Trust Survey of Employer-Sponsored Health Benefits, between 1999 and 2013, worker contributions to premiums have increased by 196%. Deductibles have almost doubled, with the average annual individual deductible in 2013 at $1,135.

In a recent survey of 174 individuals being treated for cancer, one-third of people reported hardship as a result of their cancer costs, with 16% reporting

difficulty paying for basic necessities and 19% reporting using up all or most of their savings (Oncologist 2014;19:414-420). A pivotal study by Ramsey et al found that cancer patients were 2.65 times more likely to go bankrupt than people without cancer (Health Aff 2013;32:1143-1152).

Treatment adherence often is one of the first victims of financial toxicity. One study (J ( Clin Oncol 2014;32:306311) found that patients with higher copayments ($53 or more) were 70% more likely to discontinue therapy in the first six months of treatment. The authors also pointed out that the financial toxicity of cancer treatments can reduce quality care by making patients spread out chemotherapy appointments, decline tests, delay care and replace prescriptions with over-the-counter medications.

A partial antidote to financial toxicity is to promote health care literacy. A 2014 survey showed that only 60% of U.S. citizens understood what a deductible was (Proc Natl Acad Sci USA A 2014;111:5497-5502). In another survey, roughly half of patients expressed interest in talking to doctors about cost, but only 19% had such a discussion ((J Clin Oncoll 2013;31[suppl]; abstract 6506).

Of those who discussed costs with their doctor, 57% reported that they felt the discussion helped decrease costs. Cost containment was achieved through various mechanisms: physician referrals to financial assistance (53%), clinicians advocating for patients with insurance companies (25%), a switch to a less expensive medication (19%), a decrease in tests (13%) and a decrease in doctor visits (6%).

“When I talk about financial toxicity with oncologists,” Dr. Zafar said, “I often am asked, ‘I have no idea how much these drugs cost, and even if I did, most of the time, I would not have an alternative treatment for my patients; so what do I do?’”

Identifying Those at Risk Pointing patients to financial assistance is one solution, and identifying patients at risk for financial toxicity early is key. “Financial counselors and social workers

have told us that it is much easier to help patients early than it is to actually dig them out of that medical debt,” Dr. Zafar said. New tools to identify patients at risk for financial toxicity should help. Once patients are identified as being at risk, they can be directed to resources such as company-run patient assistance programs.

Many companies, including Novartis and Genentech, have patient access programs, copay cards and other initiatives to help patients who are uninsured, underinsured or unable to afford their medicines. “We [Novartis] estimate that we provide support to approximately 35% of the CML patients taking one of our medicines, either through offering our CML medicines for free or providing copay support through our own copay card or through our financial support of charitable copay foundations,” Ms. Cooper said.

Genentech also provides similar programs. “The Genentech Access to Care Foundation, which provides free medicine to people without insurance, changed its eligibility criteria, with the goal of helping more people who may be struggling with high out-of-pocket costs,” Ms. Wilson said. The company also provides assistance with copays, such as an oncology copay card that helps people with commercial insurance so they will not pay more than $100 per copay, she explained.

Although these programs exist, it is clear that many patients don’t know about them. “Our studies have shown that patients are signed up for inappropriate, insufficient insurance plans. They don’t know that patient assistance programs exist, and when they get to those programs, it might be too late,” Dr. Zafar said.

“We have done a lot to describe this problem of financial toxicity, but now is the time to intervene. We need to start corralling our resources in health literacy, patient– physician communication and patient engagement in health system delivery, and start intervening on this problem of financial toxicity.”

—Kate O’Rourke Dr. Zafar has served as an unpaid consultant for Genentech and his spouse is employed by GlaxoSmithKline.

26

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Be Prepared for Electronic Record Breaches, Experts Warn

I

f you have not yet endured an electronic patient data theft, you most likely will experience one before too long, experts warn. They say the transition to electronic health records (EHRs) has not been accompanied by adequate safeguards, and they are calling on physicians to do more to protect patient data.

“Health care systems will be seeing large-scale hacks of the type we’ve seen with retailers like Target,” said Katherine Downing, MA, director of

Health Information Management Practice Excellence at the American Health Information Management Association, in Chicago. Ms. Downing noted that the FBI recently warned health care providers about the likelihood of such cyberattacks.

Health data are much more valuable than data from other industries because EHRs typically contain far more information, Ms. Downing said. A complete EHR profile can include information

on health insurance, prescription drugs, financial details and Social Security numbers. That bounty of information means a record can sell for $50 on the black market, while a Social Security number fetches only $1, according to Pam Dixon, executive director of the World Privacy Forum, a data integrity group in San Diego, Calif.

Thieves use that information to do everything from accessing medical care, obtaining prescription drugs and,

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according to a recent report, filing false income tax returns that, in one case, resulted in more than $175,000 in tax refunds being issued to the thief.

The list of breaches is long and continues to grow: The Identity Theft Resource Center cites 247 reported breaches of health care data as of September 2014, with more than 7 million patient records were compromised as a result.

The largest health care breach in 2014 resulted in 4.5 million patient EHRs being compromised. That breach occurred at Community Health Systems, which is the second-largest for-profit hospital chain in the United States. Although large breaches like this make the news, the Identity Theft Resource Center’s website indicates that many breaches occur at smaller health care settings.

Despite Ongoing Breaches, Feds Tout Regulatory Measures As the incidence of EHR breaches continues relatively unabated (the number dropped slightly in 2014 compared with 2013), the Department of Health and Human Services (HHS) claims federal measures addressing the problem have helped.

In its most recent breach notification report, the HHS pointed to the effect of Section 13402 of the Health Information Technology for Economic and Clinical Health (HITECH) Act, which requires entities covered under HIPAA to notify affected individuals, the HHS, and in some cases, the media, of health care data breaches. HITECH also requires business associates such as data analysis companies to report breaches of their systems to covered entities.

“The breach notification requirements are achieving their twin objectives of increasing public transparency in cases of breach and increasing accountability of covered entities and business associates,” the report concluded. “At the same time, more entities are taking remedial action to provide relief and mitigation to individuals and to secure their data and prevent breaches from occurring in the future.”

In an email, a representative from the Office of Civil Rights (OCR) said no additional regulatory steps were currently being taken by the HHS to reduce the risk for health care data breaches.

Matthew Hollingsworth, the founder and president of ChangeMed, a Dayton, Ohio-based company that provides services, support and advice related to health care information technology (IT), said that an HHS requirement that HIPAA-covered entities conduct security risk assessments of their EHR systems provides a big incentive for providers to

27

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

tighten EHR security.

Failure to perform such an assessment proved costly for NewYork-Presbyterian (NYP) Hospital and Columbia University, both of which paid the OCR $4.8 million after electronic patient health information (ePHI) of about 6,800 individuals, including data about patient status, vital signs, medications and lab results, was exposed in 2010.

An OCR investigation concluded that neither organization had conducted “an accurate and thorough risk analysis that identified all systems that access NYP ePHI.” This case underscores the importance of taking steps to institute preventive measures. “The potential for fines when you do have a data breach is significantly lower when you can show you’ve done all you can to prevent a breach,” Mr. Hollingsworth stressed.

Things You Can Do Now Smaller practices that do not have staff with specialized IT security knowledge might find it daunting to consider the challenge of securing data, given that large organizations like NYP and Columbia University have fallen victim to breaches.

“However, there are steps even small practices can take to tighten the security of their EHRs,” Mr. Hollingsworth said.

For example, the HHS has an online risk assessment tool that any office staff can use.

Changing passwords often, ensuring there are sufficient firewall protections, using highly encrypted data and installing up-to-date antivirus software can help as well, Mr. Hollingsworth said.

“Although a determined hacker can break into almost any system, these steps might encourage them to move on to a less secure system,” he said.

Many Still Email Patient Information Emailing unencrypted patient data also places that information at risk for falling into the wrong hands, said health IT expert Cary Presant, MD, professor of clinical medicine at the University of Southern California Keck School of Medicine and a staff oncologist at City of Hope Hospital, both in Los Angeles.

“HIPAA rules prohibiting the use of non-encrypted digital communications that contain patient health information are not being widely implemented,” Dr. Presant said. For patients, email is an easy mode of communication; physicians may

‘The potential for fines when you do have a data breach is significantly lower when you can show you’ve done all you can to prevent a breach.’

—Matthew Hollingsworth

succumb to patient pressure. However, Dr. Presant urged physicians to educate patients about the associated risk for identity theft.

Dr. Presant also urged both clinicians and office staff to take advantage of educational opportunities offered by organizations such as the American Society of Clinical Oncology.

Ms. Downing echoed that recommendation. “Make sure you and your staff are educated and trained as to how EHRs can be used in the most secure way,” she said. “Human error is one way for breaches to occur.”

Ms. Downing also said that granting EHR access only to staff members who truly need such access is a preventive measure practices can take.

“And when you’re auditing access [to EHRs], make sure you document the process, and do the same with any other security-related policies,” Ms. Downing said. “That documentation will reduce your liability in case there is a breach.”

For additional tips on how to protect your patients’ records, visit www.hhs. gov/ocr/privacy/hipaa/understanding/ training.

—David Wild

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IN THE NEWS

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

New Tool Estimates Risks for Patients Having Sleeve Gastrectomy BOSTON—Investigators have developed a calculator for estimating early postoperative morbidity and mortality in patients undergoing laparoscopic sleeve gastrectomy (LSG).

The use of LSG for the treatment of obesity is rapidly growing in popularity.

A recent systematic review demonstrated that LSG resulted in a loss of more than 50% of excess weight in the long term (five or more years postoperatively), and a considerable improvement or even remission of comorbidities (Surg Obes Relat Dis 2014;10:177-183).

Current models for estimating the risk for patients undergoing LSG are inadequate, according to Ali Aminian, MD, a bariatric surgeon from the Cleveland Clinic, Ohio, who presented the data at Obesity Week.

For example, the well-known Obesity Surgery Mortality Risk Score is limited because it is based on old data, considers only 12 baseline variables, combines open and laparoscopic procedures and is only applicable to gastric bypass.

Dr. Aminian and his colleagues extracted data on morbidly obese patients undergoing LSG in 2012 from the American College of Surgeons National Surgical Quality Improvement Program database to develop the calculator, which is available online. This database prospectively collects information on more than 150 variables, including demographics, comorbidities, laboratory values and 30-day postoperative mortality and morbidity outcomes for patients undergoing major surgical procedures in the United States.

The investigators included patients who underwent concurrent endoscopy,

liver biopsy, abdominal wall hernia repair, hiatal hernia repair, cholecystectomy and procedures to manage intraoperative complications. They excluded patients who underwent revisional bariatric procedures and cases with unrelated concurrent procedures, such as appendectomy and hysterectomy. Cases of LSG in 2011 were used to examine the validity of the risk model.

The investigators conducted univariate and multivariate analyses on 52 baseline variables to explore risk factors associated with mortality and a 30-day postoperative composite adverse event (AE), including mortality. The composite AE was defined as the presence of any of 14 serious AEs, such as deep vein thrombosis, pulmonary embolism and myocardial infarction (Table).

For the 5,871 patients who underwent LSG in 2012, the composite AE rate was 2.4% and the mortality rate was 0.05%.

“The data point to the overall safety of LSG as a treatment for severe obesity,” Dr. Aminian said. “Incidence of all of the individual complications, except postoperative bleeding, was no greater than 0.5% in this series.”

The researchers identified seven major risk factors for post-LSG serious AEs: history of congestive heart failure, steroid use for chronic conditions, male sex, diabetes, preoperative serum total bilirubin level, body mass index (BMI) and low preoperative hematocrit level.

The risk factors were used to develop a model of estimated risk. Tests showed the model had a good calibration on the Hosmer-Lemeshow goodness-of-fit test with a χ2 of 16.02 (P=0.591) P and a

moderate discrimination (C-statistic, 0.682). The model was then validated on a dataset of patients who underwent LSG in 2011 and showed a relatively similar performance (C-statistic, 0.63).

Dr. Aminian cited several patient examples. The estimated risk in a healthy woman with a BMI of 38 kg/m2 and hematocrit of 42% would be 1%. The estimated risk in a woman with a BMI of 60 kg/m2, with diabetes, history of chronic steroid use (e.g., for asthma or rheumatoid arthritis) and hematocrit of 44% would be 12.6%. “Estimating the risk for postoperative adverse events can improve surgical decision making and informed patient consent,” he said.

Considerable benefit also can be gained by identifying potentially modifiable preoperative factors that are associated with increased risk for postsurgical AEs. “Preoperative optimization of patients with symptomatic heart failure may reduce the risk for elective surgery,” Dr. Aminian said.

“Chronic steroid use can impair the healing process and increase infectious complications. Conservative perioperative and intraoperative measures in such patients with immunosuppression may diminish surgical risk.”

A user-friendly online version of the risk calculator is available at http://rcalc. ccf.org. When the required patient values are entered into the calculator, it estimates the percentage of serious AEs after LSG. Wayne English, MD, a bariatric surgeon at Vanderbilt University Medical Center, in Nashville, Tenn., who served as a discussant of the study after it was presented, said he was a “firm believer”

Table. 30-Day Postoperative Composite Adverse Event 1. Organ/space surgical site infection 2. Stroke 3. Coma 4. Myocardial infarction 5. Cardiac arrest 6. Deep vein thrombosis 7. Pulmonary embolism 8. Reintubation 9. Mechanical ventilation >48 h 10. Sepsis 11. Septic shock 12. Need for transfusion 13. Acute renal failure 14. Death

in using surgical risk-prediction models and was impressed with the new calculator. “This will improve the informed consent process, help to identify high-risk patients and it certainly can help optimize patients prior to surgery. [However], it is unfortunate that [the researchers] didn’t have data to identify what are already well-known risk factors for surgery, such as prior history of VTE [venous thromboembolism] and the breakdown of pulmonary disease, obstructive sleep apnea and procedure time. In addition, surgeon skill factor needs to be taken into consideration as we move forward.”

—Kate O’Rourke Drs. Aminian and English reported no relevant financial conflicts of interest.

Preoperative IV Ibuprofen Improves Recovery After Lap Chole

see Lap Chole, page 29

Placebo Ibuprofen

200

*

190 180 170 160 150

Placebo Ibuprofen

40

MFSS (total score)

optimization of anesthetic management in order to enhance recovery and minimize some postoperative sequelae that occur after surgery,” said Dr. Le, assistant professor of anesthesiology. “So we looked at IV ibuprofen, which we believed would improve postoperative recovery.”

To that end, Dr. Le and her colleagues enrolled 55 individuals undergoing laparoscopic cholecystectomy into the prospective, randomized double-blind study. Each patient received a single preoperative IV dose of either 800 mg of ibuprofen (n=28) or placebo saline (n=27). A number of parameters were measured—including quality of recovery, fatigue, mood and cognitive capacity—at four time points: preoperatively, in the postanesthesia care unit (PACU) and on

Global QoR40

NEW ORLEANS— —To the well-documented analgesic benefits of IV ibuprofen, add this: Preoperative administration of the nonsteroidal anti-inflammatory drug (NSAID) improves the overall quality of recovery. A recent study also revealed that IV ibuprofen also might improve postoperative cognitive recovery.

According to Vanny Le, MD, and a team of researchers from Rutgers New Jersey Medical School, in Newark, the stress response to surgery may lead to a number of postoperative complications, including diminished quality of recovery.

Because NSAIDs may decrease activation of the stress response, the researchers hypothesized that IV ibuprofen might improve recovery characteristics in patients undergoing laparoscopic cholecystectomy.

“Our study specifically looks at the

35 30 25

**

20 15

***

*

10 5 0

Pre-op

POD1

POD3

Pre-Op

PACU

POD1

POD3

Figure 1. Changes in global 40-Item Quality of Recovery questionnaire scores over time.

Figure 2. Changes in the Modified Fatigue Severity Scale over time.

The global QoR40 scores were analyzed using two-way repeated measure ANOVA (analysis of variance) with drug group as the between-subjects factor and period of testing as the within-subjects factor. The main effects of time (P ( <0.001) and drug ( =0.003) were significant. Scores were significantly (P lower in the ibuprofen treatment group than in the placebo treatment group on POD 1 (*P<0.001).

MFSS total scores were analyzed by two-way repeated measure ANOVA with drug group as the between-subjects factor and period of testing as the within-subjects factor. The main effects of time ( <0.001) and drug (P (P ( =0.006) were significant.

Scores were significantly lower in the ibuprofentreatment group versus the placebo-treatment group in the PACU (**P=0.01), POD 1 (***P<0.001) and POD 3 (*P=0.03).

Ibup, ibuprofen; POD, postoperative day; pre-op, preoperatively; QoR40, 40-Item Quality of Recovery questionnaire

MFSS, Modified Fatigue Severity Scale; PACU, postanesthesia care unit; POD, postoperative day; pre-op, preoperatively

29

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Trial Provides Concrete Data for Closing Defects During Gastric Bypass BOSTON—Closing the mesenteric defects in laparoscopic gastric bypass surgery reduces the risk for internal hernias and operation for small bowel obstruction, according to results from a randomized controlled trial. The study, presented at Obesity Week, is the first randomized trial to investigate the issue.

“This is a good paper,” said Alfons Pomp, MD, chief of gastrointestinal metabolic and bariatric surgery and the Leon C. Hirsch Professor of Surgery, NewYork-Presbyterian Hospital/Weill Cornell Medical Center, in New York City, who was not involved with the study. “[Our group] has been talking about this for over a decade and convincing people, gradually, that these defects need to be closed.”

Small bowel obstruction due to internal hernia is a major problem of the laparoscopic Roux-en-Y gastric bypass (RYGBP), occurring in 10% of procedures (Obes Surgg 2011;21:1822-1827).

Many centers close the mesenteric defects routinely at the time of RYGBP, but the evidence for this practice is minimal. The studies suggesting a benefit of this practice are retrospective or noncontrolled trials (Obes Surgg 2006;16:1482-1487; 2007;17:1283-1286; 2009;19:527-530).

A 2013 editorial in Surgery for Obesity and Related Diseasess by Mathew Martin, MD, a surgeon with Madigan Army Hospital, in Tacoma, Wash., pointed out that no high-quality evidence supports closing the mesenteric defects during RYGBP (2013;9:854-855).

In the new study, investigators from 12 bariatric centers in Sweden randomized 2,508 patients undergoing antecolic, antegastric laparoscopic RYGBP to either closure of the mesenteric defects with

Table 1. Operation Rate for Small Bowel Obstruction Time

30 d, %

1 y, %

2 y, %

0.7

1.6

5

1.8

0.9

2.5

open Mesenteric defects closed

Table 2. Cumulative Incidence of Internal Hernia Time

Mesenteric defects closed

30 d, %

1 y, %

2 y, %

0.2

1.1

4.5

0.2

0.8

1.9

‘The benefit of closing the defect comes over time. At two years, there was a markedly reduced risk for operation for bowel obstruction due to internal hernia when the defects were closed.’

—Erik Stenberg, MD

running, nonabsorbable sutures (1,259 patients) or no closure (1,248 patients).

The study monitored patients through the Scandinavian Obesity Surgery Registry database. So far, data have been collected for two years of follow-up and patients will be followed up to five years.

“We compared our data with data from the Swedish National Patient Register, in order to minimize the risk for missing events or serious complications, and bowel obstruction in particular,” said Erik Stenberg, MD, of the Department of Surgery at Örebro University Hospital, in Sweden, who presented the study at Obesity Week.

Approximately 75% of patients were

women. The average age was 41.7 years, and the average body mass index was 42.3 kg/m2. The two trial arms were well balanced in terms of comorbidities such as sleep apnea, hypertension, diabetes, dyslipidemia, depression and previous venous thromboembolism. Patient follow-up was 97.3% at one year and 88.4% at two years.

“If we look at the primary end point in our study, which was reoperation for bowel obstruction, in the early postoperative stage, the first 30 days after the operation, there was an increased risk for reoperation with bowel obstruction when the defects were closed,” said Dr. Stenberg (Table 1). He attributed the higher

whereas there was no change in the ibuprofen group. By postoperative day 3, these scores had returned to baseline for the placebo group.”

Similarly, analysis of the nine-item Modified Fatigue Severity Scale revealed that patients in the ibuprofen group had significantly lower scores at every postsurgical evaluation point than their counterparts in the placebo group (Figure 2).

Perhaps not surprisingly, patients in the placebo group experienced significantly more fatigue recorded in the PACU and on POD 1 than before surgery.

Global analyses using the Digits Span Forward and Backward (DSF/DSB) tests revealed the significant effects of time

and ibuprofen, with patients taking ibuprofen having higher DSB scores in the PACU than did patients given placebo (P<0.05).

“There was no significant decline in physical independence in the placebo group on postoperative day 1, but patient support was the same for all time periods after the surgery,” Dr. Le said. “I also think the difference here is that patient support is determined independent of surgical factors and is more dependent on the patient’s social situation.”

Andrea Kurz, MD, professor of anesthesiology at the Cleveland Clinic, in Ohio, called the study interesting, important and promising. “In general, I believe

rate in the closure group to the increased kinking of the jejunojenunostomy in this group (1.4% vs. 0.5%; P P=0.015). “This was directly caused by the suturing of the mesenteric defect,” said Dr. Stenberg.

The incidence of reoperation for bowel obstruction was approximately the same at one year, but after two years, it was more common in the nonclosure group.

“The benefit of closing the defect comes over time. At two years, there was a markedly reduced risk for operation for bowel obstruction due to internal hernia when the defects were closed,” said Dr. Stenberg. The risk for internal hernia rose with time in both groups, but more so when the defects were left open (Table 2).

The average operation time was 14 minutes longer in patients who had their defects closed (83.3 vs. 69.6 minutes; P<0.001), but this did not increase the risk for intraoperative complications such as bowel injuries or bleeding, according to the researchers. There was no difference in hospital stays or complications experienced in the first 30 days postsurgery between the groups.

“By closing the mesenteric defects in laparoscopic gastric bypass surgery, the risk for reoperation for bowel obstruction due to internal hernia can be reduced, the price for doing this is a longer operating time and an increased risk for early bowel obstruction due to kinking jejunojenunostomy,” Dr. Stenberg said. “Further studies are needed to evaluate the optimal method for closure of the mesenteric defects.”

Dr. Pomp said he hoped the researchers continued to follow the patients further, as he expected to see more hernias with longer follow-up.

—Kate O’Rourke

Lap Chole continued from page 28

postoperative days (POD) 1 and 3.

As Dr. Le reported at the 2014 annual meeting of the American Society of Anesthesiologists (abstract 2019), global quality of recovery scores (as measured using the 40-item Quality of Recovery [QoR40] questionnaire) were higher for patients taking ibuprofen than for controls (P<0.001) on POD 1 (Figure 1). Patients in the ibuprofen group also proved superior in the QoR40 domains of comfort, emotion and pain.

“QoR40 scores were the same for both groups preoperatively,” Dr. Le said. “But on postoperative day 1, there was a significant decline in the placebo group,

that any drug that effects perioperative inflammation might be beneficial … as long as we believe that most ‘bad’ postoperative outcomes are related to inflammation, which I do,” Dr. Kurz said.

“My biggest concern with respect to the study is sample size,” Dr. Kurz continued. “In other words, the results are almost too good to be true. Also, their interaction results are interesting, but again, we usually need many more patients for such analyses.”

—Michael Vlessides The study was partly funded by Cumberland Pharmaceuticals, which makes the IV ibuprofen product Caldolor..

30

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Ingest continued from page 1

increasing trend toward serious injury and the manage“There has been a sixfold increase in the frequency ment of ingestions. of a major complication or fatal outcome because of In 2013, poison control centers in the United States the increased sale of lithium button batteries,” which reported 3,366 button-battery ingestions, of which reached 140 million in 2013, Dr. Lito2,227 (66%) were in children under the age of 6 years. ars. vitz it said. id “This is the minimum count; there are certainly many more,” said Toby Litovitz, MD, executive and medical director of the National Capital Poison Center, in Washington, D.C. Battery ingestions led to 37 fatalities and 151 serious complications in 2013, Dr. Litovitz noted.

Peter Koltai, MD, professor of otolaryngology and pediatrics at Stanford University, in California, said that “a large proportion of button-battery injuries have been discovered by gastroenterologists. Often, because of the difficulty accessing and removing these objects, they call us [otolarynTable. Source of Ingested g Batteries gologists] right away, but the diagnosis in the emergency department must Source Child <6 y, % Adult, % be properly made first.”

Kris R. Jatana, MD, an otolarynBattery obtained directly from product 61.8 4.1 gologist at Ohio State Medical Center and Nationwide Children’s Hospital, in Battery is loose or sitting out 29.8 80.8 Columbus, added, “Every three hours, a child presents to an emergency room Battery packaging 8.2 3.0 with a battery-related issue. It can be difficult to make an early diagnosis as Whole hearing aid containing battery 0.2 12.1 it is often an unwitnessed event, or the swallowed patient is asymptomatic or has nonspeFigure. cific symptoms similar to a common Anteroposterior view viral illness.” of a 20 mm lithium Serious complications include esophcoin cell in the upper ageal perforation, tracheoesophageal esophagus of a toddler. fistula, vocal cord paralysis, esophageal Although it’s about the stricture/stenosis, mediastinitis and of a nickel, note size spondylodiscitis, often requiring multhe ring or “halo” at the tiple surgical procedures, prolonged traedge that distinguishes cheotomy and the placement of feeding this button battery tubes. When children put button cells from a coin. in the ear canal or nasal passage, complications may include perforation of Image courtesy of Toby Litovitz, MD the eardrums, hearing loss, facial nerve paralysis, nasal septal perforation and periorbital cellulitis.

“Diameter and voltage are the major predictors of a Although the frequency of ingestion has remained bad outcome,” she said. Lithium cells are usually 3 V, fairly stable, the percentage with a bad outcome has compared with the traditional 1.5 V of smaller button risen dramatically over the past 10 years, Dr. Litovitz cells. The combination of the higher voltage and larger said. Children are most likely to obtain the batteries diameter creates the problem: a battery large enough directly from an electronic device (Table). to get stuck in the esophagus and powerful enough to Last June, the U.S. Consumer Product Safety Commis- generate hydroxide much more rapidly and effectively. sion (CPSC) met with related agencies from 11 countries and the European Union to discuss the issue of button- Management of Battery Ingestions battery ingestion. According to the CPSC, manufacturManagement is based on the age of the patient and ers of the batteries—also called coin cell batteries—have the size of the battery. The first step, in most cases, is taken steps in recent years to reduce the hazard by adding to make sure the patient does not eat or drink until an warnings and making battery packages more secure. esophageal position is ruled out by x-ray. The clinician should examine a companion or replacement battery, Which Batteries Are Most To Blame? then consult the National Battery Ingestion Hotline for Lithium batteries, especially those that are 20 mm in help in identifying battery type and treatment. diameter, midway in size between a nickel and a penny, Patients aged 12 years or younger with any battery are not the most frequently ingested—that title belongs size, or older than age 13 with a battery larger than 12 to 11.6-mm cells. But they are the most damaging mm in diameter, require an immediate x-ray to locate (Figure). the object. Batteries lodged in the esophagus may cause

serious burns within two hours, even without symptoms.

Older patients who have swallowed small batteries do not require x-ray and can be managed at home if they have not developed symptoms, if they have swallowed only one battery, the smaller diameter is certtain and the patient and caregivver are reliable.

“If thee battery has passed beyon nd the esophagus and the patient is assymptomatic, it’s not necessary to remove n it,” Dr. Litovitz said. “An exception is the small child with a big battery in the stomach for four days or more.”

Dr. Jatana added that the clinician removing the battery should assess the location and directioon of the negative polee of the battery to help predict potential complicattions. The rapid rise in pH occurss at the negative terminal and is highest at the junction with positive terminal terminal.

Other diagnostic studies may be done after removal, and patients should be followed after discharge to watch for delayed complications.

Challenges in Treating Battery Ingestions “Injury to the esophagus occurs within two hours and it is challenging to get the battery out in this time period,” Dr. Litovitz said. “Burns can start to occur within minutes.”

Better clinical management is not the answer, she added. “Physicians usually don’t get to the patient fast enough.”

The diagnosis is missed in more than half of fatalities and more than one-fourth of major events, primarily because the ingestion was not witnessed; the patient was not symptomatic; the patient had nonspecific symptoms; or the battery was mistaken for a coin.

These scenarios create “a perfect storm for missing the diagnosis in time to make a difference,” she said.

The best solution is to develop a safer battery, speakers said. “Until then, the single most important intervention is to have secure battery compartments, and to educate the public and parents—don’t leave batteries out!” Dr. Litovitz said.

Collaborations among industry, clinical medicine, public health and government are underway to improve safety.

—Caroline Helwick Dr. Litovitz directs the National Battery Ingestion Hotline at the National Capital Poison Center, which is funded in part by the National Electrical Manufacturers Association.

Drs. Jatana, Jacobs and Koltai reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

The Push Is on for Boosting SP Drug Adherence ‘Optimal’ adherence tools for MS, rheumatoid arthritis and hepatitis C in development PHILADELPHIA— —The Pharmacy Quality Alliance (PQA) is developing new pharmacy quality measures focused on specialty medication adherence, according to Lynn Pezzullo, RPh, CPEHR, PQA’s director of performance measurement.

The two measures currently in draft form are Adherence to Non-Infused Biologic Medications Treating Rheumatoid

Arthritis and Other Inflammatory Conditions and Adherence to Medications Used to Treat Multiple Sclerosis. Hepatitis C and oral oncology adherence measures are also a high priority for PQA, Ms. Pezzullo said recently at the World Congress Summit on Specialty Market Access and Channel Optimization.

The Centers for Medicare & Medicaid

Services (CMS) has announced that three of PQA’s existing adherence measures—on renin–angiotensin system (RAS) antagonists, non-insulin diabetes medications and statins—will be included in the beta-test measure set for qualified health plans participating in the health insurance marketplaces for 2015.

All issuers that offer coverage during the

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

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Real-World Data Mimic Trial Findings For HCV Treatment BOSTON—Drugs often fall short of the expectations set in clinical trials, because the trials often exclude patients with various comorbidities and the sickest of the sick.

This does not seem to be the case with the latest generation of medications to treat hepatitis C virus (HCV) infection, which so far are meeting the high bar they set in pre-approval trials. see Real World, page 28

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

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

M

ore than on ne-third of women with the hepatitis B virus (HBV) are initially diagnoosed with the infection at their first prenatal care visit, but they do not receive follow-up care for the infection after their pregnaancy, researchers have found.

The retrospective stud dy examined the medical records of 243 women with HBV who receiveed prenatal care at facilities under th he umbrella of Massachusetts Gen neral Hospital (MGH).

“It’s clear from the data that these women are getting lostt to followup or not getting ap ppropriate care to begin with,” saaid Ruma Rajbhandari, MD, MPH, a gastroenterology and hepatology fellow at MGH H, in Boston, who led the sttudy.

“It’s a real shame. It is siimilar to getting diagnosed with HIV and not receiving any follow-up care for it.”

The researchers presented theeir findings at the 2014 Liver Meetin ng of the American Association for th he Study of Liver Diseases (AAS SLD), in Boston (abstract 1552).

In 1990, the Centers for Disease Control and Prevention created the U.S. Perinatal Hep patitis B Prevention Program (P PHBPP) in an effort too reduce perinatal trransmission of the disease.

Under the PHBPP, P pregnantt women are rroutinely screened for H HBV and their inffants are treated an nd monitored approopriately.

The prograam has resulted in a sharp reduction of p perinatal infections with HBV. see Hep B, page 36

I N S I D E

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

W

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

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EDUCATIONAL REVIEW

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

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see insert at page 20

STEPHEN W. LANDRENEAU, MD

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

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

The authors report no relevant financial conflicts of interest.

T

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

Hemorrhoids: Evaluation and Management for the Office-based Clinician

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

Internal hemorrhoidal plexus

normal anatomy and physiology, pathophysiology, and classification of

Dentate line

hemorrhoids, with a particular focus

External hemorrhoidal plexus

on the office-based physician.

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

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

Figure 1. Normal anorectal anatomy.

Courtesy of Iain Cleator MD, Vancouver, BC, Canada

evaluation and treatment of hemorrhoidal disease.

The dentate line represents the junction between the embryologic endoderm and ectoderm and is the point that the mucosa of the anal canal changes from the insensitive columnar epithelium of the rectum to the highly sensitive squamous epithelium of the anoderm.

Found proximally to the dentate line, the internal hemorrhoids are a specialized collection of 3 fibrovascular “cushions” arranged in a left lateral, right anterior, and right posterior configuration.3 They are composed of an arteriovenous plexus where branches of the superior, middle, and, to a lesser extent, inferior hemorrhoidal

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

For iPad

1

2014 coverage year will be required to participate in the beta test of the Quality Rating System in 2015, according to CMS. PQA uses the standard proportion of days covered (PDC) formula to determine adherence. The PDC provides a comprehensive, but conservative, estimate of the adherence rate in situations when the patient switches medications within a class or concurrently uses more than one drug in a class.

Even when using the PDC methodology, developing adherence measures for specialty medications is challenging. Specialty pharmacy adherence measurement—and management—cannot be one size fits all, said Richard Faris, PhD, director of health outcomes and pharmacoeconomics with the pharmaceutical company UCB. “There are issues of loading doses, longer intervals between doses, weekly and monthly and now even dosing that is once or twice a year. How do you measure adherence with these different intervals?

And when you have a drug that’s taken once or twice a year, do you even measure adherence?” he asked.

Some therapeutic classes also include medications that are self-administered and billed under the prescription benefit and others that are infused and billed under the medical benefit. This adds an additional level of complexity, as the two data sets then need to be merged to provide a complete and accurate assessment of adherence across the medication class.

A Vote for Medication Possession Ratio There are also continuing questions about what level of adherence constitutes “optimal.” In January, a CVS Caremark/Brigham and Women’s study published in the American Heart Journal (2014;167[1]:51-58) validated another wide-ly used measure of adherence, the 80% medication possession ratio (MPR) standard, finding that patients with adherence of 80% MPR or greater were 24% more likely than the control group to avoid hospital readmission for another heart-related issue; those with MPR of 79% or less had no significant

33

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

‘We are seeing split fills of a 15-day or 30-day supply [of prescribed medication], because no one wants to pay $84,000 right out of the gate for a full course of Sovaldi, for example.’

—Kelly Pokuta, PharmD

course of Sovaldi [Gilead], for example.”

Catamaran has begun to couple adherence metrics with other measurable outcomes, Dr. Pokuta said, including: • Genotype and subgenotype classification at start of therapy; • Sustained virologic response (SVR) at 12 weeks; • Persistency with therapy; • Patient satisfaction rates; and • Frequency of patient outreach.

Catamaran’s hepatitis C patient outreach program is designed to “touch” patients more frequently than just at the

time of refill and is front-loaded for an increased number of contacts during the early period of therapy. “Our pharmacist and nursing support may reach out every week for the first month, and every two weeks thereafter until done, although the protocol varies according to the patient’s needs,” Dr. Pokuta said. “It’s an opt-out program; patients are in it with the first script being filled, unless they decide not to participate.”

Because of the changing factors surrounding adherence to hepatitis C and other specialty medications, PQA’s

measure concepts, now in development by the Specialty Pharmacy Measures Task Force, would also differ from the draft for rheumatoid arthritis and multiple sclerosis adherence measures, Ms. Pezzullo said. “The task force is considering a set of metrics that in addition to adherence, may assess outcomes (i.e., SVR), outreach program elements, and patient experience and satisfaction.”

—Gina Shaw Dr. Pokuta reports that she has provided consultative service for Biogen IDEC, Gilead and Sanofi. Dr. Faris and Ms. Pezzullo have no relevant disclosures.

for iPad! Download the e app p

st-rea ad from the best-read gastroenterology logy improvement in outcomes over the control group.

But the figure is still rather arbitrary, Dr. Faris said, and can vary significantly by condition and class. “In multiple sclerosis, perhaps 85% is a better number; with HIV, it’s probably 90% to 95%. And then how do you measure adherence in an episodic drug, such as one for bleeding events, versus a prophylactic drug?”

One area of specialty pharmacy where adherence measures are perhaps more important than ever, but also are changing rapidly, is hepatitis C. “Traditional adherence metrics like MPR and PDC may no longer provide value in this space,” said Kelly Pokuta, PharmD, director of specialty pharmacy at Catamaran, a pharmacy benefits management company based in Schaumberg, Ill. With current therapies having a 12-week treatment duration for certain genotypes and with future therapies potentially offering even shorter durations, the time for assessing adherence and persistency is condensed. “That’s wonderful for patients, but what does it do in terms of measurement and monitoring?” asked Dr. Pokuta. “With the minimal side-effect profile and an eight-week regimen in the future, you might expect 100% adherence. But there is still the issue of patient inertia, as well as payor plan designs that can complicate things.

We are seeing split fills of a 15-day or 30-day supply, because no one wants to pay $84,000 right out of the gate for a full

n the publication in s United States

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Mobile App, Cards Aim To Speed Diagnosis of Biliary Atresia Poop app shows parents what’s right–and what’s not–in the diaper

A

mobile application called POOPMD that parents can use to help detect abnormal stools in newborns could lead to earlier diagnosis and treatment of biliary atresia, new research shows.

An early diagnosis of biliary atresia can allow corrective surgery to occur early enough to prevent liver damage.

Yet in the United States, the average child with the condition is not diagnosed until 70 days after birth (Hepatology 2013;58:1724-1731).

These delayed diagnoses lead to worse outcomes for the child and are costly for the health system. Cases of biliary atresia account for half of the cases of pediatric liver failure in the United States and half

of the liver transplants in this age group, according to Douglas Mogul, MD, MPH, assistant professor of pediatric gastroenterology at Johns Hopkins University, in Baltimore. Dr. Mogul and his colleagues at Johns Hopkins are studying ways to increase the chance that U.S. infants are diagnosed early—within 30 to 45 days of birth—such as providing parents with

simple tools they can use to recognize the abnormally pale stools that may indicate a newborn has biliary atresia.

At the 2014 annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), Dr. Mogul received a Clinical Young Investigator Award for his work developing POOPMD, which parents can use to identify the pale or acholic stools of infants with biliary atresia.

Also at the NASPGHAN meeting, another Hopkins investigator, Stefany B. Honigbaum, MD, a fellow in pediatric gastroenterology and nutrition, presented results of her study showing that many mothers in the United States are unable to identify potentially concerning stools (abstract 289).

‘Anything is a normal stool

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color but red, black or white.’

—Douglas Mogul, MD, MPH

Early Recognition Researchers in Taiwan have already demonstrated the value of training parents to recognize acholic stool. In 2004, Taiwan began providing all parents of newborns with a stool color card designed to help them distinguish between healthy newborn stools, which are typically yellow or brown, and the pale or white stools that indicate liver dysfunction.

By 2005, Taiwan saw major improvements in biliary atresia diagnosis (Hepatologyy 2008;47:1233-1240). Before the program began, 72.5% of infants with biliary atresia were identified within 60 days of birth. After the cards were distributed in 2005, 97.1% of the children were diagnosed during this critical window.

To begin to determine if a similar stool card program would be effective in the United States, Dr. Honigbaum and her colleagues assessed the knowledge of 80 mothers of healthy infants at Johns Hopkins Hospital. Mothers were asked about healthy infant stools and tested on their ability to identify unhealthy stools.

“Nearly all mothers recognize that stool color reflects the health of their child, and the majority were confident in their ability to identify normal stool color.” Dr. Honigbaum said. But only 35% of the mothers correctly identified three acholic stool pictures, and only 14% correctly identified descriptions of acholic stool. see Stool, page 38

35

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Study Offers Clues on How Bariatric Surgery Helps Brain Reduction of inflammation and metabolic syndrome BOSTON—For years, clinicians have known that neurocognitive function improves after bariatric surgery, but little has been known about what exactly drives this. Now, a new study presented at Obesity Week 2014 (abstract 1001) provides some clues.

“Weight loss and improvements in inflammation and metabolic syndrome are correlated with improvements in memory and attention,” said lead author of the study John Morton, MD, director of bariatric surgery at Stanford School of Medicine, in Stanford, Calif., and president of the American Society for Metabolic and Bariatric Surgery.

Growing evidence has linked obesity with poor neurocognitive function and risk for developing dementia and Alzheimer’s disease ((J Alzheimers Dis 2012;30:S89-S95). Studies also have shown that individuals who undergo bariatric surgery realize improvements in memory and other cognitive domains ((Am J Surgg 2014;207:870-876).

But what spurs these gains? By undergoing bariatric surgery, individuals not only lose a significant amount of weight, but they also have significant improvements in glycemic control, metabolic syndrome (MetS), depression and daytime sleepiness, all of which could independently improve cognition.

To pinpoint the specific mechanisms involved, Dr. Morton and his colleagues enrolled 47 consecutive bariatric surgery patients. The average preoperative body mass index was 46 kg/m2; the average age was 48.1 years; 32.6% of patients were diabetic; and 43.9% of patients had MetS. Study participants completed a battery of cognitive tests before surgery and then at three, six and 12 months after bariatric surgery. The cognitive tests included the revised Hopkins Verbal Learning Test (HVLT), a brief verbal line learning and memory test with six alternate forms; the Digit Symbol Substitution Test; and Trail Making Tests A and B. Patients also completed the Beck Depression Inventory-II; the Epworth Sleepiness Scale; and the Psychomotor Vigilance Task192, a validated measure of reaction time and psychomotor function.

Preoperative test scores showed that patients were well below population averages in HVLT immediate recall (T score 38.3) and HVLT delayed recall (T score 41.4), and had slower mean response speeds on the Psychomotor Vigilance Task-192 (norms 2.48 seconds vs. patients 3.63 seconds; P<0.05).

Diabetes was the single biggest factor found to affect cognitive scores, according

to the researchers. Patients without preoperative diabetes had significantly faster times on Trail Making Test B (diabetes 90.4 seconds vs. no diabetes 63.1 seconds; P P=0.039).

“The brain is a big consumer of glucose for its size,” Dr. Morton said. “It consumes a lot more glucose than your heart or your muscles. It really needs it,

and when there are derangements in the glucose metabolism, some of the brain chemistry doesn’t work as well. The actual synaptic firings across neurons are impeded.”

At 12 months postsurgery, patients had improved memory and attention, as measured by the HVLT immediate recall (+2.63; P P=0.004), the HVLT

delayed recall (+1.04; P P=0.003) and the Trail Making Test A (–7.25 seconds; P<0.001). Changes in sleepiness and depression did not correlate with changes in cognitive function. Patients without preoperative MetS had significantly greater three-month improvements in HVLT immediate recall (MetS +0.50 vs. see Bariatric Brain, page 37

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Study Identifies Factors for Hospital Readmission After Bariatric Surgery BOSTON—Roughly 5% of hospital inpatient readmissions after bariatric surgery are potentially avoidable, according to an analysis of 2012 data from New York hospitals. The new report also identified factors, such as type of surgery and patient characteristics, that are associated with higher rates of readmissions.

“Our potentially preventable readmission rate was 5.3%,” said Wendy Patterson, MPH, of the New York State Department of Health, in Albany, who presented the research at 2014 Obesity Week (abstract A203). “There is a lot of room to decrease the potentially preventable readmission rate.”

The Statewide Planning and Research

Cooperative System (SPARCS) database allows researchers to track patients over time. In their analysis of this database, the researchers included adult inpatient bariatric surgical discharges from all hospitals in New York between Jan. 1, 2012 and Dec. 31, 2012. Patients were defined by an International Classification of Diseases-9-CM principal diagnosis code for

Cases in Hyponatremia

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Michael L. Moritz, MD

The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD Ron and Nancy McFarlane Distinguished Professor and Chair Division of Practice Advancement and Clinical Education UNC Eshelman School of Pharmacy Chapel Hill, North Carolina

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia.

2 Describe the comorbidities and causes commonly associated with hyponatremia and their significance in treatment.

3 Summarize current evidence and best practices in the management of hyponatremia.

4 Explain how to mitigate adverse events secondary to treatment of hyponatremia.

5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

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overweight or obese and a principal procedure code for bariatric surgery.

The investigators used the potentially preventable readmission (PPR) logic developed by 3M Health Information Systems to identify readmissions that were clinically related to previous hospitalizations and therefore may have been preventable.

“The 3M software excludes most types of admissions related to cancer, traumas and burns; ob-gyn patients; and any patient whose care ended abruptly: left against medical advice or were transferred to another hospital,” Ms. Patterson said. A logistic model was used to analyze the data by sex, age, race/ethnicity, payor, body mass index (BMI), surgical approach, complications and comorbidities.

Patients were mainly female (80%), more than 40 years old, white nonHispanic, and covered by commercial insurance. “Roughly 45% of them had a BMI of 45 or greater,” Ms. Patterson said. “Only about 5% had a complication during their original surgery; 50% had hypertension; 30% had diabetes without complications; and 20% had chronic pulmonary disease.”

The statewide PPR rate was 5.3%, and the all-cause readmission rate was 5.9%. “Of the 10,448 bariatric surgeries performed in 2012, 552 were followed by at least one PPR. Those 552 surgeries actually had 711 readmissions. So, of all the patients who had a readmission after surgery, on average they had 1.3 readmissions,” Ms. Patterson said. “Roughly 69% only had one readmission; 20% had two; and 11% had three or more.”

The most common bariatric surgical approach was laparoscopic gastric bypass (46%), followed by sleeve gastrectomy (41%), laparoscopic banding (8%) and open gastric bypass (5%). Open gastric bypass surgeries had the highest PPR rate per 100 surgeries (8.8), followed by laparoscopic bypass (6.1), sleeve gastrectomy (4.3) and laparoscopic banding (3.3).

Patients who underwent open gastric bypass surgery were 2.4 times more likely to have a PPR than those undergoing laparoscopic banding (P<0.05). Patients who underwent laparoscopic bypass were 1.8 times more likely to have a PPR than laparoscopic banding (P<0.05).

“It would be expected that laparoscopic banding, a minimally invasive procedure, would result in a lower PPR rate and that open bypass, a more invasive procedure, would have a higher PPR rate,” Ms. Patterson said.

Other factors that increased the risk

37

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

for a PPR were black non-Hispanic ethnicity rather than white non-Hispanic (odds ratio [OR], 2.0), complications during surgery (OR, 1.9), chronic pulmonary disease (OR, 1.5), diabetes with chronic complications (OR, 1.9), diabetes without chronic complications (OR, 1.3) and rheumatoid arthritis/collagen disease (OR, 1.8; P<0.05 for all).

“While it is not always appropriate to select a less effective procedure based solely on readmission rate, we do feel that it is something that should be considered,” Ms. Patterson said.

John Morton, MD, president of the American Society for Metabolic and Bariatric Surgery and director of bariatric

‘There is a lot of room to decrease the potentially preventable readmission rate’ —Wendy Patterson, MPH surgery at Stanford School of Medicine, in Stanford, Calif., said his group presented a similar paper at a meeting of the American College of Surgeons (ACS) that identified an all-cause readmission rate of 5.22% among patients who had bariatric surgery. His study was based

on the ACS National Surgical Quality Improvement Program. Studies appear to be providing consistent results, he said.

“Readmissions are becoming an increasingly important metric to look at. In regard to some of the risk factors you presented, I was taken by the chronic

pulmonary disease and rheumatoid arthritis as risk factors. They are comorbidities that might be affected by steroid use, and that is a potentially modifiable risk factor,” Dr. Morton said. “In addition, increasing pre-op ambulation and incentive spirometer use may also help [decrease readmission rates].”

—Kate O’Rourke Ms. Patterson reported no relevant financial conflicts of interest. Dr. Morton is a consultant for Covidien and a speaker for Ethicon.

Bariatric Brain continued from page 35

no MetS +4.14; P P=0.024). Improvements in HVLT immediate recall were strongly correlated with improvements in inflammatory markers at three months, triglyceride/high-density lipoprotein (HDL) ratio (r=0.603; P P=0.006) and C-reactive protein (r=0.538; P P=0.021), as well as the percentage excess weight lost (r=0.452; P=0.035) at three months.

P “All of the patients lost weight at the usual rate that we expect, roughly about 70% of their excess weight in one year,” said Dr. Morton. “Triglycerides and HDL are markers for metabolic syndrome. Think of a lot of these [neural] pathways as being like highways. When you have all that inflammation, you have a clogged highway, and the normal processes are just slower,” Dr. Morton said.

“The neurons are preoccupied with inflammatory markers and aren’t doing their usual job.”

The bottom line, Dr. Morton said, is that before bariatric surgery, patients scored well below the national norms on cognitive tests, and after surgery, they normalized or scored similarly to their nonobese peers. These improvements were tied to inflammation and MetS. John Gunstad, PhD, associate professor in the Department of Psychological Sciences at Kent State University, in, Ohio, has been studying neurocognitive function as it relates to cardiovascular disease and obesity for the past 10 years.

“Although obesity is bad for your brain, losing weight can help improve your memory and other mental abilities,” Dr. Gunstad said. “This study provides another clue toward understanding how the weight loss following bariatric surgery helps to improve brain function.”

—Kate O’Rourke

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Stool continued from page 34

Defining Normal To help more mothers and fathers identify acholic stools, Dr. Mogul created a mobile application for Android and Apple phones based on the stool card program in Taiwan.

Like the earlier version, the app has photos depicting normal and acholic stool. Parents also can take a photo of their child’s stool and use the app’s color

recognition software to analyze whether it is normal. The application can email the result to the infant’s pediatrician. The app also automatically reminds parents to check their infant’s stool.

“We hope that this is something that will be helpful to parents,” Dr. Mogul said. “Most parents come to understand that stool shades of yellow or brown are normal.” Dr. Mogul said he’d like to see

the phrase “Anything is a normal stool color but red, black or white,” become as common as “breast is best” or “back to sleep.”

Dr. Mogul and his colleagues presented data from the pilot study of the app at the NASPGHAN meeting (abstract 331).

They found that the application was able to correctly identify 100% of pale stool samples and 90% of normal stool

samples. The application identified 10% of normal stools as being indeterminate.

The POOPMD app has been downloaded more than 1,000 times, Dr. Mogul said. An easier-to-use update was scheduled for release in January, he added.

Johns Hopkins also is working with Procter & Gamble, the maker of Pampers diapers, to distribute traditional stool cards to U.S. hospitals. Dr. Mogul said that so far about 40 hospitals with a total of 45,000 births a year have signed up to participate. Procter & Gamble also will make the cards available to pediatricians to distribute to parents.

Only 35% of the mothers correctly identified three acholic stool pictures, and only 14% correctly identified descriptions of acholic stool.

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A similar stool card distribution program has been launched in British Columbia, Canada. Richard A. Schreiber, MD, professor of pediatrics at the University of British Columbia, conducted a cost-effectiveness analysis of distributing stool cards to parents as a means of boosting early recognition of biliary atresia ((J Med Screen 2014;21:126132). He calculated that the screening card program had an incremental costeffectiveness ratio of $21,000. And in a recently published study, Dr. Mogul and his colleagues also found the intervention to be cost-effective ((J Pediatr Gastroenterol Nutrr 2014 Sep 11. [Epub ahead of print]). The program was rolled out to the whole province in August and data about its effectiveness are expected in the spring.

Dr. Schreiber noted that one potential downside of an app-based program is that the color quality of the pictures taken by the app may vary depending on the resolution of the image—one reason British Columbia cards include the validated color photos used in Taiwan. He also cautioned that printing the stool card photos from a website may distort the color and should be avoided. Dr. Mogul said, however, that the app was tested under different lighting conditions, with different phones and users, and produced consistent results.

“I think what they are doing is great,” Dr. Schreiber said. “Whatever work is done to raise awareness about biliary atresia is very important.”

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Carrel continued from page 9

at the University of Chicago. There, Dr. Carrel became immersed in organ transplantation, publishing some of his first work with Dr. Guthrie in 1905, called “Functions of a Transplanted Kidney.” In it, they described successfully transplanting a kidney from a dog’s abdomen to its neck. Although the dog died a few days later, the transplanted kidney produced urine. He and Dr. Guthrie also transplanted kidneys and ovaries, and even a heart, from one dog to another. These experiments paved the way for clinical organ transplantation in the 1950s.

In 1906, Dr. Carrel accepted an inv invitation to join The Rockefeller In Institute for Medical Research (today, The Rockefeller Ro University) in New York City, the first institution in the United States devoted solely to medical research.

The culmination of his work at Rockefeller ultimately earned him the Nobel Prize.

At Rockefeller, Dr. Carrel continued his transplantation and suturing work, performing saphenous vein bypasses, coronary artery grafting and vascular prosthesis as well as blood transfusions and limb replantation, in which he transplanted the thigh from one dog to another.

In 1908, Dr. Carrel also began to work on wound d healing, an endeavor that proved instrumental during World War I. He experimented on guinea pigs, creating wounds on the skin, dressing them and measuring the healing process, and by 1913, he tried treating leg ulcers.

Dr. Carrel was rewarded for his groundbreaking work, receiving the Nobel Prize in Physiology or Medicine in 1912. Commenting on Dr. Carrel’s legacy, surgeon Julius Comroe Jr., MD, wrote: “Between 1901 and 1910, Alexis Carrel, using experimental animals, performed every feat and developed every technique known to vascular surgery today” (Cardiovasc Diss 1979;6:251-270).

Antisepsis and World War I When World War I broke out in 1914, Dr. Carrel served as a major in the French Army Medical Corps, stationed in Lyon. “During this time, he got the idea that contaminated wounds should be treated with antiseptics,” Dr. Walker said.

Dr. Carrel reached out to chemist Henry Drysdale Dakin, who also worked in New York City. The duo met in Paris, and with funding from the Rockefeller Institute to establish a research hospital, they devised a new way to treat war wounds called the Carrel–Dakin method. The duo tested more than 200 solutions before settling on sodium hypochlorite—what we know today as Clorox—as an antiseptic that would not harm tissue.

Dr. Carrel also developed a delivery system, configured with tubes to irrigate the wounds on a precise two-hour schedule.

“This method of wound healing marked quite an advance,” Dr. Walker said. “Dr. Carrel showed that by using a solution of sodium hypochlorite, buffered to make it almost neutral, he could decrease the bacterial contamination of wounds.”

Such treatment was crucial given that antibiotics had not been discovered yet and that the battles of World War I were fought in cow pastures in France, where massive wound contamination from organisms occurred, Dr. Walker noted.

‘Between 1901 and 1910, Alexis Carrel, using experimental animals, performed every feat and developed every technique known to vascular surgery today.’

—Julius Comroe Jr., MD

“While it was not a major medical advance in itself, the glass perfusion pump encouraged people to think about bypassing the heart, which was later done by John Gibbon, MD, in 1953, with the first heart–lung machine,” Dr. Walker said.

A Controversial Figure

Drs. Carrel and Dakin’s trreat-ment sparked a huge debate amongg British physiologists and bacteriologistss w h o felt that antiseptics did not work in wounds.

However, the success of the Carrel–Dakin method spoke for itself. Deaths and amputations decreased significantly after its implementation.

“The Carrel–Dakin solution was used after the war to treat industrial wounds and trauma in general, but with the development of antibiotics, it has become less important over time,” Dr. Walker said.

Perhaps more notable than the method was Dr. Carrel’s overall efforts to improve wartime care, which included blood transfusions, hemorrhagic shock treatments and other elements of day-to-day patient care.

Dr. Carrel received the Legion of Honor from France for this work.

Before the war, he met his future wife, Anne de La Motte, who was working as a nurse in Paris. “Anne worked with Dr. Carrel closely in his World War I hospitals, and she was described as a tyrant and boss of the hospital,” Dr. Walker said, citing an account by Harvey Cushing, MD. In 1930, Dr. Carrel forged an important collaboration and friendship with the American aviator Charles Lindbergh, which led to the development of a perfusion system in 1935 that permitted living organs to exist outside the body for a period of time. Lindbergh had approached Dr. Carrel about helping his sister-in-law, who had developed heart failure from mitral stenosis.

Lindbergh proposed devising a technique to operate on the bloodless heart, but Dr. Carrel dismissed this idea in favor of developing the first perfusion pump, which could maintain the heart and other organs outside the body by circulating fluids through them.

According to Richard J. Bing, MD, director of experimental cardiology, Huntington Medical Research Institutes, in Pasadena, Calif., if Dr. Carrel had followed Lindbergh’s suggestion, he could have advanced the future of cardiac surgery by many years. Still, the perfusion pump marked a step forward. Lindbergh and Dr. Carrel published “The Culture of Organs” in 1938, describing their work.

Along with his important work in suturing and wound healing, Dr. Carrel is also associated with more contentious ideas about eugenics. g In 1935, Dr. Carrel published “Man, the Unknown,” in which he explored creating a genetically superior race of intellectuals to improve p mankind and espoused p ridding humanity of deviants, those “who have killed, committed armed robbery, kidnapped children, robbed the poor or seriously i l b betrayed t d public bli confidence,” fid ” he h wrote. t The book, both praised and panned by critics, became a bestseller.

Tired of his sensational reports in the press, The Rockefeller Institute mandated Dr. Carrel’s retirement in 1938. In retirement, Dr. Carrel’s ultimate goal was to remake humanity by studying humankind with the scientific precision he gave to his suturing technique. During World War II, with France under the Nazi regime, Dr. Carrel became the director of the Carrel Foundation for the Study of Human Problems, an institution established by the Vichy government.

Dr. Carrel’s persistence and ego may have blinded him to the reality of what was happening. “It likely didn’t occur to him that the Vichy government was anything but a patriotic group trying to save France, when in fact the reality was far different,” Dr. Walker said.

Dr. Carrel’s relationship with the Nazi-supported Vichy regime sullied his reputation. He was considered by many to be a Nazi collaborator, and when France was liberated in 1944, he was placed under house arrest and charged with cooperating with the Nazis.

Perhaps spurred by the stress of these accusations and his fall from public grace, Dr. Carrel suffered a heart attack and then a stroke, which led to his death in November 1944, before going on trial.

According to Dr. Bing, who worked with Dr. Carrel in the 1930s, “most of the descriptions of Carrel that you read about are wrong. Some people make him out to have been a diabolical scientist with a Nazi connection,” Dr. Bing wrote in an article ((JAMA A 1983;250:32973298). “But to me, a young kid, he was wonderful. …

Carrel showed me only interest and affection.”

Dr. Walker said Dr. Carrel’s career was marked by unusual highs—and lows. “During the first [world] war, Dr. Carrel was called a hero, and by the second, he was considered a traitor,” he said. “His early work was brilliant, unbelievably advanced for the time, but in his own hubris, he may have sealed his fate.”

—Victoria Stern

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Operative Report—the Annotated Version Preoperative1 diagnosis2: Carcinoma3 of the Right Colon4 Postoperative5 diagnosis: Carcinoma of the Right Colon 6

Procedure: Right Colectomy

Surgeon7: Leo A. Gordon,8 MD9 Estimated blood10 loss: 25011 cc Intraoperative12 Complications: None Indications: This 6813 y/o W14 F15 presented with anemia.16 A barium enema17 revealed a cecal18 lesion.

Findings: A bulky, transmural19 cecal carcinoma was found.

References [To the Politically Correct Operative Report]

few years. I do not mean to discount or to impugn these accomplishments.

1.

3.

I mean no disrespect to any other type of diagnosis. The postoperative diagnosis is particularly sensitive to this. The use of “preoperative” is a necessary descriptive term and implies no lack of respect for the operative or postoperative diagnosis.

It is unfortunate that other disease states could not be given credit in this operative report. The entire sarcoma family (leiomyo-, rhabdo- and carcino-), not to mention the colitides (infectious and ischemic) are all reputable and earnest diseases.

2.

4.

No snub or prejudice is intended by using the term “diagnosis.” “Prognosis” has made great strides over the past

Although the transverse and left colons are honest and reputable organs and have made great embryologic

strides, they could not be mentioned in this report. I do not mean to impugn their abilities or strengths, nor do I mean any disrespect or offense.

5.

The postoperative state is equal to the preoperative state under the Constitution of the United States.

6.

There are many operative procedures, each of which has its own strengths. These procedures are equal.

I mean no prejudice against the left see Report, page 42

Procedure:

With the patient in the supine20 position, the abdomen21 was prepared and draped in the usual22 fashion. A right mid-abdominal transverse incision23 was made, dividing the subcutaneous tissues.24 The fascia of the right rectus muscle was identified and divided. The rectus and lateral body wall muscles25 were divided.

The peritoneal cavity was entered. A bulky cecal carcinoma was found. There was no evidence of liver metastases, peritoneal seeding or ascites.26 The peritoneal attachments of the right colon were taken down. The hepatic flexure was mobilized, identifying the duodenum27 and dissecting it inferiorly.

After mobilizing the terminal ileum,28 proximal and distal transection points29 were identified.

The terminal ileum was divided, as was the right transverse colon. This was done with the stapling device.30 The mesentery of the right colon was then divided, identifying the ileocolic vessels31 and doubly ligating them with 2-0 silk.

A side-to-side ileo-colostomy32 was then performed using a posterior row of 3-0 silk33 and an inner-running34 suture of 3-0 chromic.35 The inner layer was continued anteriorly in a Connell36 fashion. The anterior outer layer of the anastomosis was completed with interrupted 3-0 silk in a Lembert37 fashion.

The resultant mesenteric defect38 was closed with a running suture of 3-0 chromic.

The abdomen was irrigated with saline.39 There was no evidence of bleeding in any areas of dissection. The abdomen was closed with a running No. 240 monofilament41 suture to the anterior and posterior fascial layers.42 The skin was closed with the skin-stapling device.43 A dryy44 sterile45 pressure dressing was applied.

The sponge and needle counts46 were reported as correct.

The patient was transferred to the recovery room47 in stable condition.48 Leo A. Gordon, MD D: 2/14/14 T: 2/15/14 #78882577/op900056

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

Report continued from page 41

colectomy, the gastrectomy or the Nissen fundoplication. Only mentioning the right colectomy may be construed in some quarters as an unfair advantage to the right side of the colon. This is unintentional.

7.

The use of the term “surgeon” does not intend to discriminate against any other group. It is an unfortunate custom that this restrictive and culturally insensitive term is perpetuated in formal documents such as operative reports.

8.

Separating an individual by name should not be construed as unfair to other people who are not Gordons. All Gordons are equal under the law, even my lazy uncle Phil who, although last employed in 1981, still refers to himself as “between jobs.”

9.

Separating people by abbreviations and degrees may be construed as elitist. The use of this term is required by state law to show that a licensed physician performed the surgery. I apologize for any perceived slight to non-MDs.

10.

11.

I mean no disrespect to any other body fluid.

All integers deserve equal protection under the law. The use of the integer 250 should not upset 111, 238 or even 457. These are fine and able numbers.

12.

The intraoperative state has not received any unfair advantage in this report.

13.

The use of the number 68 should not be construed as “ageism.” The patient was, in fact, 68 years old. Despite many attempts to broaden the concept of “68” so as not to prejudice any member of the health care team, its use was unavoidable. Nevertheless, I have received many complaints from the AARP insisting that the term 68 led to preconceived notions that, with reasonable legal probability, might prejudice youth-oriented operating room personnel.

14.

Many attempts at multicultural enhancement and sensitivity were made preoperatively. It was just impossible to convince the patient that she was anything but a Caucasian female.

15.

The Preoperative Gender Awareness representative from the hospital visited the patient and counseled her that her gender would not work against her in the face of a male surgeon.

All OR staff members were required to attend a gender awareness seminar before the performance of this case.

16.

Polycythemia is good too. I mean no disrespect to pancytopenia or leukopenia.

17.

No prejudice is to be implied by the use of this term. Colonoscopy is a good, honorable and committed procedure.

18.

The cecum was the site of this lesion. I recognize the importance and contributions made by the splenic flexure, the hepatic flexure and the sigmoid. They are honest, hardworking colonic segments.

19.

20.

I mean no prejudice against flat, noninvasive lesions.

Prone is good. Left-lateral decubitus is good. Jackknife is good. I also want to mention Trendelenberg, reverse Trendelenberg, lithotomy, Simms and semi-Fowlers. These positions are good too.

21.

Over the years, all body cavities have become important. I do not mean to denigrate the thorax or the cranium.

22.

The unusual fashion is perfectly acceptable. I fully recognize the contributions of the unusual fashion and do not mean to relegate the unusual fashion to a subordinate status.

23.

Incision choice is rife with prejudice and preconceived notions of superiority. Choosing a right midabdominal transverse incision was done only after recognizing the place of other incisions in a historical-surgical context.

The many contributions to society by the midline incision were acknowledged, as were the contributions of the paramedian, Rocky-Davis and the chevron.

that they could not be involved in a meaningful way in this operation.

29.

Equal time was given to assessing both the proximal and distal transection points.

30.

The contributions of any member of the American labor force engaged in nonstapling device production are recognized, appreciated and admired.

31.

“Why the ileo-colics?” I am asked. Why not a specific mention of each vessel to the right colon, such as arterioles to the cecum or marginal arteries? How about the submucosal vessels? Each of these vessels is important. Each, in an embryologic-sociologichistorical context deserves mention and adulation, although they were not specifically identified in this case.

32.

I received an angry letter from the American End-to-End Lobbying Coalition in Washington decrying my use of this method. There is a rich cultural history to the end-to-end that I overlooked. My sincerest apologies to them. End-to-ends will be given preference from now on.

33.

34.

35.

Rayon, dacron, velcro and polyester are good too.

No disrespect is intended toward interrupted suturing.

Molybdenum, titanium, lead and the entire periodic table of the elements should have been mentioned. I just ran out of trace elements.

36.

Loose areolar tissue has always been low on the list. It should be higher. Regrettably, there was no way to weave it into this operative report.

24.

The McArdles, O’Flahertys and MacDougalls had their own fashion. Each was proper, honest, hardworking and has made meaningful contributions to American surgery.

25.

37.

A vicious letter to the OME (Office of Muscle Equality) was forwarded to me. It was written by the left trapezius alleging preferential treatment for the body wall musculature.

26.

Metastases, seeding and ascites have all formed political action committees to further their cause. The fact that there was “no evidence” of these groups does not imply a lack of respect or admiration for their many fine accomplishments.

27.

The specific identification of the duodenum should not be interpreted as prejudice against the right lobe of the liver, the head of the pancreas or the right kidney.

28.

The proximal and mid-ileum have made significant contributions to the ileum. It is unfortunate

The Cocteaus, Rouleauxs, Flamberts and other French surgeons all made great contributions.

I mean no disrespect, despite a vitriolic editorial against me in the Journal Lycee De Churgirie de France De Allemaigne.

38.

Although “defect” has a negative connotation, it is used here to describe a hole resulting from the surgery. It is unfortunate that the Latin root of defect is defectus meaning “to fail or to be wanting.” I mean no implied failure or lack of achievement of any group of organs or systems in using the term in this operative report.

39.

Ringers lactate is fine. Water is good. It is incredibly unfair that the term saline is still used. I am waiting for a better word to describe the original solution from which we all arose.

40.

41.

No. 3 is fine. No. 8 is great. All integers are equal.

Braided sutures deserve special consideration and must be viewed in a historical-societal context to bring them into mainstream surgery.

The braideds have been paid less than the monofilaments. They, as immigrants, were discriminated against in the early part of the century. Using the term “monofilament” is a cultural judgment made by the operating surgeon, who must ultimately bear the responsibility of his suture selection.

42.

Equal time and attention was given to both anterior and posterior layers.

43.

The American suture worker is strong, talented and productive.

The use of the stapling device should not be construed as reverse Luddism.

44.

45.

Wet is good too.

Partisan groups fostering the cause of germs ask, “What’s wrong with unsterile dressings?” They raise a good point. I will try, and will encourage my colleagues to try to incorporate more unsterile activities in the operating room to balance this obvious injustice.

46.

Why are only sponges and needles important? Letters poured in from instruments, light fixtures, IV tubing, drapes, mops and Mayo stands (even a telegram from a towel clip) all wanting to know why they were not counted in this report. They all are important and will be incorporated via a three-year preferential phase into the counting process.

47.

In America, all rooms are equal.

Those rooms that feel they are not equal, or have been dealt some injustice in the past will be receiving patients in the future. I am having a bit of trouble suggesting the boiler room as an acceptable recovery room alternative.

48.

Unstable and critical conditions have always been upset with the use of this term. When we refer to a condition, we use it as a descriptive, not historical term. “Critical” and “unstable” had their heyday in the past and quite frankly now begrudge “stable.”

The professors of American surgery will lead us into the 21st century holding high the banner of critical and unstable conditions.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

High-Protein Spurs Metabolism, but Effect Is Fleeting BOSTON—A high-protein diet may spark a person’s metabolism, causing it to burn more calories in the process of digestion than it would with a standard diet, and may result in enhanced storage of lean muscle tissue. But, this effect disappears immediately once a person resumes a normal diet, according to new research presented at Obesity Week 2014.

“This study is one more nail in the coffin for the magic bullet for eating everything we want without gaining weight,” said Dale Schoeller, MD, professor emeritus of nutritional sciences at the University of Wisconsin, in Madison. “It’s the holy grail of metabolism research, but it’s always come up negative.”

To investigate the thermic effect of food (TEF) on metabolism, researchers at the Pennington Biomedical Research Center, in Baton Rouge, La., conducted a post hoc analysis of an overfeeding study that investigated the composition of weight gain in individuals fed low-, normal or high-protein diets ((JAMA 2012;307:47-55).

“It was an inset study, very expensive and highly controlled, so it gave us an opportunity to examine the question of whether there is a difference between the diets’ effect on metabolism,” said lead researcher Elizabeth Frost, a PhD candidate at Pennington.

In the original research, participants consumed a weight-stabilizing diet for 13 to 25 days and were then randomized to eight weeks of low-, normal or highprotein diets (containing 5%, 15% and 25% protein, respectively), with an excess caloric intake 40% greater than their maintenance diet.

Protein Calories More Likely To Be Stored as Lean Mass All participants gained weight, but the composition of weight gain varied considerably across the three groups.

Those who were fed the low-protein diet stored 95% of their excess calories as fat, whereas those who consumed the highprotein diet stored 50% of their excess calories as fat. The researchers concluded

that calories alone increased body fat, whereas protein increased lean body mass and energy expenditure.

Ms. Frost and her colleagues were interested in the possibility of nutritional programming in adults—whether a high- or low-protein diet could influence metabolic inefficiency or metabolic efficiency. “We wanted to see if the metabolic increase you’d normally see with a high-protein diet—the TEF—had residual effects after you return to a normal diet. Can we program our metabolism to maintain that energy expenditure when it’s breaking down food?”

To investigate their hypothesis that the TEF is elevated following high-protein intake and to further determine whether that elevation is short-lived or prolonged, the researchers evaluated the JAMA A study

data on the participants’ TEF, which was captured by indirect calorimeter for a four-hour period after meals.

In the first two to four weeks of the assigned diets, resting energy expenditure did not change in the low-protein group, but increased significantly in the normal and high-protein groups. At six weeks, participants were fed a standard meal, similar to what they had eaten at baseline. All reverted to their baseline resting energy expenditure. “We found that there was no difference at all in the thermic effect of food,” Ms. Frost said.

On the final day of overfeeding, measurements were taken once more. “But instead of challenging them with a standard meal, we gave them their study diet—so if they were on the low-protein diet, they got a low-protein meal; if they

‘The evidence is that it works, that you can achieve energy expenditure not only by exercising but by increasing the amount of protein in your diet.’

were on the high-protein diet, they had a high-protein meal that morning,” Ms. Frost said. “We found that, as the literature supports, those who were on the high-protein diet experienced a doubling of the thermic effect of food.

“We showed acutely that if you eat a high-protein diet, you have an elevated thermic effect of food. If you prolong that diet, you maintain the increased effect.

But as soon as you revert to a normal diet, the increased expenditure goes away. Your body doesn’t save that elevation.”

Ms. Frost and her colleagues concluded that although TEF is influenced by protein intake, prolonged exposure to a high-protein diet does not alter the body’s response to a standard meal.

Therefore, TEF is probably very tightly regulated and cannot be reprogrammed.

As for the study’s applicability, Ms. Frost pointed out that although the JAMA A study used an overfeeding model, it supports something many Atkins diet followers have experienced. “The evidence is that it works, that you can achieve energy expenditure not only by exercising but by increasing the amount of protein in your diet,” Ms. Frost said.

“But it’s important to know that the positive effects of a high-protein diet are not saved by your body, and that if you want to maintain the benefits, you have to maintain the diet.”

The study’s findings were not surprising to Lee M. Kaplan, MD, PhD, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital, in Boston.

“The belief that you could change your diet for a finite period of time and reprogram the human body is not a realistic strategy,” Dr. Kaplan said. “But this paper, on the background of a great deal of previous research, provides important new information that helps us define the physiologic response of the body to different diets. If it were as simple as shifting to a high-protein diet for a brief period, we would have been a lot more successful in the last 40 years than we have been.”

—Monica J. Smith

—Elizabeth Frost

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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 GIspecific physician assistants and nurse practitioners (as reported to BPA Worldwide, Publishers Audit, based on circulation data as of July 2013).

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45

GASTROENTEROLOGY & ENDOSCOPY NEWS • FEBRUARY 2015

C. diff continued from page 1

“The conundrum of this infection is that treatment is based on severity,” said Sahil Khanna, MD, assistant professor of medicine at Mayo Clinic in Rochester, Minn. “If you have mild or moderate disease, you get treated with metronidazole.

If you have severe disease, you get treated with vancomycin.”

The American College of Gastroenterology (ACG) defines severe disease as CDI in patients with albumin below 3 g/dL, and either white blood count of at least 15,000 cells/mm3 or abdominal tenderness.

‘On univariate analysis, not considering other factors, people who were older had a threefold higher risk for dying of CDI than younger people. That was striking.’

“On univariate analysis, not considering other factors, people who were older had a threefold higher risk for dying of CDI than younger people. That was striking.”

Several other factors stood out as well, such as undergoing colectomy, and certain comorbidities—congestive heart failure, pulmonary circulation disorders, metastatic cancer, electrolyte disorders and weight loss—were associated with a significantly higher risk for death.

“Our conclusion is that age should be factored into assessment of severity, and people older than 65 should be considered

when trying to predict disease severity and therapy.

“However, I would be more forward regarding the implications of the study results,” Dr. Gupta added. “This study actually adds to a growing body of literature showing that older age is associated with higher mortality in patients with CDI. As a result, this study confirms the results of prior studies, and clinicians should start considering patient age when managing CDI if they are not doing so already.”

—Monica J. Smith

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

The Independent Monthly Newspaper for Gastroenterologists

Real-World Data Mimic Trial Findings For HCV Treatment BOSTON—Drugs often fall short of the expectations set in clinical trials, because the trials often exclude patients with various comorbidities and the sickest of the sick.

This does not seem to be the case with the latest generation of medications to treat hepatitis C virus (HCV) infection, which so far are meeting the high bar they set in pre-approval trials.

—Sahil Khanna, MD “We wanted to see if there were other markers that could [identify] severity, and the first step in doing that was to study an end point for severe infection, which in our study was mortality,” Dr. Khanna said. “We wanted to evaluate what predicts mortality in patients with CDI, and whether some factors are more predictive than others.”

Dr. Khanna and his colleague, Darrell Pardi, MD, professor of medicine at Mayo, evaluated data from the National Hospital Discharge Survey. “We looked at all the hospitalized patients with CDI and compared CDI patients who died with those who didn’t die, and tried to identify factors that predict in-hospital mortality in hospitalized CDI patients,” Dr. Khanna said.

The survey included an estimated 162 million adults between 2005 and 2009, of whom 1.26 million had CDI. All-cause mortality of hospitalized patients with CDI was 6.9% compared with 2.2% for hospitalized patients without CDI. “We can’t say they died of CDI, just that they had CDI and also died in the hospital,” Dr. Khanna noted.

The most prominent factor the researchers observed associated with CDI and mortality was increased age. “The older people were, the more likely their chance of dying. So we dichotomized people into two age groups: from 18 to 64 and 65 and older,” Dr. Khanna said.

to have severe disease and possibly managed with vancomycin rather than metronidazole. Of course, future studies will need to investigate this in clinical practice; this was a retrospective study and mostly hypothesis-generating.”

Dr. Khanna presented the research at the ACG’s 2014 annual meeting (poster P1644).

Neil Gupta, MD, MPH, assistant professor of medicine and director of interventional endoscopy at Loyola University Medical Center, in Maywood, Ill., agreed that age should be considered

see Real World, page 28

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

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

M

ore than on ne-third of women with the hepatitis B virus (HBV) are initially diagnoosed with the infection at their first prenatal care visit, but they do not receive follow-up care for the infection after their pregnaancy, researchers have found.

The retrospective stud dy examined the medical records of 243 women with HBV who receiveed prenatal care at facilities under th he umbrella of Massachusetts Gen neral Hospital (MGH).

“It’s clear from the data that these women are getting lostt to followup or not getting ap ppropriate care to begin with,” saaid Ruma Rajbhandari, MD, MPH, a gastroenterology and hepatology fellow at MGH H, in Boston, who led the sttudy.

“It’s a real shame. It is siimilar to getting diagnosed with HIV and not receiving any follow-up care for it.”

The researchers presented theeir findings at the 2014 Liver Meetin ng of the American Association for th he Study of Liver Diseases (AAS SLD), in Boston (abstract 1552).

In 1990, the Centers for Disease Control and Prevention created the U.S. Perinatal Hep patitis B Prevention Program (P PHBPP) in an effort too reduce perinatal trransmission of the disease.

Under the P PHBPP, pregnantt women are rroutinely screened for H HBV and their inffants are treated an nd monitored approopriately.

The prograam has resulted in a sharp reduction of p perinatal infections with HBV. see Hep B, page 36

I N S I D E

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

W

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

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

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

see insert at page 20

STEPHEN W. LANDRENEAU, MD

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

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

The authors report no relevant financial conflicts of interest.

T

Hemorrhoids: Evaluation and Management for the Office-based Clinician

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

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

Internal hemorrhoidal plexus

normal anatomy and physiology, pathophysiology, and classification of

Dentate line

hemorrhoids, with a particular focus

External hemorrhoidal plexus

on the office-based physician.

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

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

Figure 1. Normal anorectal anatomy.

Courtesy of Iain Cleator MD, Vancouver, BC, Canada

evaluation and treatment of hemorrhoidal disease.

The dentate line represents the junction between the embryologic endoderm and ectoderm and is the point that the mucosa of the anal canal changes from the insensitive columnar epithelium of the rectum to the highly sensitive squamous epithelium of the anoderm.

Found proximally to the dentate line, the internal hemorrhoids are a specialized collection of 3 fibrovascular “cushions” arranged in a left lateral, right anterior, and right posterior configuration.3 They are composed of an arteriovenous plexus where branches of the superior, middle, and, to a lesser extent, inferior hemorrhoidal

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Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection?

MOHAMMAD TITI, MD

NEIL GUPTA, MD

PRATEEK SHARMA, MD

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

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

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.

C

olorectal

cancer

(CRC) is the second leading cause of

cancer-related in

the

mortality

Western

world.1

Screening colonoscopy and polypectomy have become widely accepted as the mostt effective available methods for early detection and preve ention of CRC and have shown a reduction d ti in i mortality in 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 in the screened population.4 Improving detection of adenomas during colonoscopy therefore may be the key to more effective screening.

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1

Several elements can influence the detection of adenomas during colonoscopy, including improving the quality of bowel preparation to facilitate visualization of the mucosa and enhancing the endoscopistâ&#x20AC;&#x2122;s skills to perform the procedure. For the latter, careful inspection behind the folds, mucosal washing, adequate insufflation, and recognition of subtle mucosal changes or flat polyps are critical factors. These factors are of particular importance when dealing with flat polyps, especially those in the right colon, which may harbor a higher risk for colon cancer.5 The recent recognition of sessile serrated polyps as precursors to right-sided colon cancer emphasizes that these polyps usually are subtle and flat and can easily be missed or incompletely resected, resulting in the risk for an interval colon cancer.5-7 Standard-definition white-light (SDWL) colonoscopy has shown limitations in recognizing such subtle or flat changes and in detecting small polyps behind the folds. Accordingly,

the past several years have witnessed a growing interest in enhancing the imaging and endoscopic technology used during colonoscopy beyond SDWL and traditional forward-viewing angles. This article summarizes the advances made so far in the colonoscopy technology used during screening for CRC and the clinical evidence for their efficacy in improving adenoma detection (Table).

High-Definition Endoscopy And Wide-Angle Views

Chromoendoscopy

The higher resolution provided with the high-definition white-light (HDWL) scopes allows for more detailed imaging of the colonic mucosa. This feature, along with the fact that some HDWL scopes provide wider-angle views (170 degrees; OLYMPUS CF-HQ190) compared with 140 degrees with older scopes, suggest that these new devices may improve the detection of neoplasias. However, studies using HDWL scopes have found a small increase in the adenoma detection rate (ADR) compared with SDWL, mainly by improving the detection of small polyps with no benefit in the detection of large or advanced lesions.8-10 Three randomized trials comparing HDWLs with SDWLs found a small trend toward greater adenoma detection with HDWL scopes that did not reach statistical significance.8-10 The majority of published data comes from nonrandomized trials that involved sufficiently large sample sizes and comparable groups of patients. These studies found a small increase in ADRs with HDWL scopes.11-13 A recent metaanalysis found that HDWL colonoscopy has improved the ADR by 3.5% (95% confidence interval [CI], 0.9%6.1%), largely as a result of increased detection of diminutive adenomas.14

Methylene blueâ&#x20AC;&#x201C;assisted colonoscopy

Water-Infused Colonoscopy

Table.

Advances in Colonoscopy White-light endoscopy Fuse High-definition colonoscopy Standard-definition colonoscopy Water-immersion colonoscopy Dye-based endoscopy (white light)

Virtual chromoendoscopy Autofluorescence imaging Blue light imaging i-SCAN Narrow band imaging Accessory-assisted endoscopy Balloon-assisted colonoscopy Cap colonoscopy Endocuff-assisted colonoscopy Third Eye Retroscope colonoscopy

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The initial goal of using water infusion instead of air insufflation during colonoscopy was to facilitate cecal intubation and reduce patient discomfort.15,16 Early attempts at the water-immersion method combined water infusion and air insufflation during insertion. In this technique, infused water and any residual stool material are suctioned during withdrawal but the contaminated water obscures visibility and raises concern about reducing polyp detection. A recent systematic review, however, reported no differences in ADR between waterimmersion and air-insufflation colonoscopy.17 An alternative technique, the water-exchange method, has emerged. Air insufflation during insertion is replaced completely by water infusion with the contaminated water suctioned and exchanged for clean water. This approach results in a cleaner colon during withdrawal, facilitating mucosal inspection, and is proposed to increase ADR. Initial nonrandomized data do

indicate a significant increase in ADR, by 11% to 15% over air-insufflation colonoscopy.18-20 The 2 published randomized controlled trials (RCTs) showed a higher ADR with the water-exchange method, but this difference was not statistically significant.21,22 In an attempt to further improve the water-exchange method, an observational study added indigo carmine to the infused water during colonoscopy. The ADR was significantly higher in the indigo carmine group than in a historical cohort of patients who had undergone standard water-exchange (62% vs 40%; P<0.05) or air-insufflation colonoscopy (62% vs 36%; P<0.05).23 In another attempt to improve the water-exchange method, a pilot study compared the water-exchange technique plus cap-assisted colonoscopy (CAC) with air-insufflation colonoscopy alone. The mean number of adenomas was higher with the water-exchange CAC method (n=50) than in the group that received air-insufflation colonoscopy (n=101), although the ADR was not statistically significantly higher (70% vs 59.4%; P=0.22).24

Full-Spectrum Endoscopy The recently developed Fuse system (EndoChoice) allows for full-spectrum views of the colon lumen, comprising 330 degrees. The colonoscope in the Fuse system has 2 additional cameras, one on each side of the scope’s tip, to supplement the front camera. The video images transmitted from the cameras are displayed on 3 contiguous monitors corresponding to each camera. This array provides a comprehensive view of the total colonic lumen, including imaging of the traditionally encountered blind spots at the flexures or proximal edges of the mucosal folds.

The Fuse system was first studied in a model of simulated colonic polyps. Thirty-seven endoscopists performed colonoscopies with a forward-viewing colonoscope followed by the Fuse system. The investigators found a significant increase in polyp detection with Fuse: 85.7% versus 52.9% with the conventional scope (P<0.0001). The difference was particularly pronounced for detection of polyps at flexures or behind folds.25 The safety and feasibility of the Fuse system was reported in a pilot study of 50 patients. The investigators found a rate of cecal intubation of 100% with a mean time of 3.1 minutes (SD=1.5 minutes).26 A randomized, multicenter, back-to-back study with sameday colonoscopies using Fuse and forward-viewing colonoscopy was performed in 185 patients.27 In those who underwent standard colonoscopy first (n=88), the Fuse system detected 39 additional polyps, including 20 adenomas, corresponding to an increase in detection of polyps and adenomas of 78% and 71.4%, respectively. In those patients who underwent screening with the Fuse system first (n=97), standard forward-viewing

colonoscopy detected 11 additional polyps, including 5 adenomas, corresponding to an increase in detection of polyps and adenomas of 10.8% and 8.2%, respectively (P<0.01). The adenoma miss rate with Fuse was considerably lower than with forward-viewing colonoscopy (7.5% vs 40.8%; P<0.0001). However, the median withdrawal time was approximately 30 seconds longer with Fuse colonoscopy (5.6 vs 6.2 minutes; P<0.01), a difference that may have biased the results. More studies are required before definitive conclusions can be made.

Chromoendoscopy Dye-spray chromoendoscopy (CE) has shown some benefit in increasing detection of neoplastic lesions in high-risk populations, such as patients with inflammatory bowel disease or hereditary syndromes that cause colonic polyps.28 However, the yield of such techniques in populations with average risk for colon cancer is uncertain; some small randomized trials found a higher ADR,29 whereas a large randomized trial comparing CE plus HDWL with HDWL colonoscopy found only a marginal increase in ADR (patients with at least 1 adenoma: 55.5% vs 48.4%, respectively; absolute difference: 7.1%; 95% CI, 0.5%-14.7%; P=0.07) and the number of adenomas per patient: 1.3±2.4 versus 1.1±1.8, respectively (P=0.07).30 These discouraging results, along with the fact that dye-spray CE is time-consuming and carries a prolonged withdrawal time, have limited the adoption of this technique in routine screening of patients at average risk for colon cancer. However, a new technique has been described in which the dye is incorporated within the bowel preparation using methylene blue (MB). MB MMX (Cosmo Technologies) tablets are an oral modified-release formulation manufactured using a multimatrix structure that ensures colonic drug delivery. MB tends to be absorbed by the normal columnar epithelial cells of the colonic mucosa, which results in mucosal staining, but is less absorbed by neoplastic lesions, resulting in unstained areas when these lesions are present. A preliminary study on the efficacy of MB MMX 25 mg for the detection of polyps involved 96 patients undergoing routine colonoscopy. Polyps were detected in 61 patients, resulting in a 63.5% polyp detection rate.31 More clinical trials are needed to evaluate this technique.

Virtual Chromoendoscopy Several systems have been developed that can enhance the contrast of the image by selecting specific light wavelength. The Narrow Band Imaging (NBI) system (Olympus Medical Systems) filters light before image processing to the narrow bands of the blue and green wavelengths (Figure 1). In contrast, the Fujinon Intelligence Chromoendoscopy (FICE, Fujinon Inc) and i-Scan (Pentax) systems manipulate light using post-processing

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Figure 1. Narrow band imaging of a tubular adenoma in the colon.

computer algorithms. These selective demonstrations of specific wavelengths result in a different color image resembling CE. The Autofluorescence Imaging (AFI) system (Olympus Medical Systems) is based on the fact that tissue has naturally fluorescent molecules that, upon activation by the absorbed light energy, emit different light wavelengths depending on characteristics such as thickness, glandular density, and distribution of collagen.

Endoscopes that are capable of recognizing autofluorescence can produce a different colored image resembling CE; colorectal neoplastic lesions usually are shown as purple in contrast to normal colonic mucosa, which appears green.

Studies of virtual CEâ&#x20AC;&#x201D;chiefly NBIâ&#x20AC;&#x201D;overall found limited benefit of virtual CE in improving ADR compared with HDWL colonoscopy.32 More than 11 RCTs evaluated

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NBI and ADR in a screening population of average- and higher-risk individuals and found limited benefit compared with HDWL colonoscopy. These results were supported by a recent Cochrane review of 3,673 patients in 8 randomized trials (relative risk [RR], 0.94; 95% CI, 0.87-1.02). However, on pooled analysis, HDWL and NBI had higher ADRs than SDWL colonoscopy alone (RR, 0.87; 95% CI, 0.78-0.97).32-35 Three large RCTs comparing FICE with HDWL colonoscopy found that the techniques appear to have virtually identical ADRs.36,37 The published RCTs comparing HDWL with i-SCAN38,39 or AFI40-42 had small sample sizes and showed conflicting results. No final conclusion on these modalities can be made at this point. Although larger trials may provide more accurate information, the lack of substantial benefit with

Figure 2. Recognition of colon polyp using cap-assisted colonoscopy.

virtual CE devices makes it less likely that the technology in its current form improves the detection of adenomas.

Technical issues inherent to virtual CE likely are responsible for the disappointing results. Insufficient brightness of the virtual CE image during colonoscopy produces suboptimal visualization of the colonic mucosa when used in a large-diameter colon lumen.

Furthermore, inadequate preparation of the colon leaves behind residual fluid or stool that appears red and dark in virtual CE images, hindering an optimal view of the mucosa.

Cap-Assisted Colonoscopy Putting a 4-mm clear cap on the end of the colonoscope was intended to improve visualization during

mucosal resection procedures by flattening the mucosal folds (Figure 2). However, randomized trials of CAC versus conventional colonoscopy have produced conflicting results. Although CAC may shorten cecal intubation time, it appears to have limited or no benefit in improving the ADR.43-45 A meta-analysis of 16 RCTs found a marginal increase in the number of individuals with polyps detected (RR, 1.08; 95% CI, 1.00-1.17) but no statistically significant difference in ADR.46

Third Eye Retroscope The Third Eye Retroscope (Avantis Medical Systems) has a 3.5-mm flexible single-use catheter with a camera and light source at the tip that is retroflexed 180 degrees after being advanced through the working channel of the colonoscope to provide a 135-degree

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retrograde view of the colon. Investigators who studied the device said the Third Eye Retroscope improves visualization of the colonic surface area from 87% with standard 140-degree view colonoscopes to 99%.47 Two nonrandomized studies evaluated the additional diagnostic yield of the Third Eye Retroscope and found an approximately 14% increase in polyp detection and an 11% to 16% increase in ADR.48,49 In the only randomized trial, the TERRACE (Third Eye Retroscope Randomized Clinical Evaluation) study, investigators reported net additional polyp and adenoma detection rates with the device of 29.8% and 23.2%, respectively.50 Although withdrawal time was nearly 2 minutes longer for patients in the Third Eye Retroscope group, post hoc analysis showed this did not significantly affect polyp detection.

Despite the reported increase in polyp detection, the Third Eye Retroscope system has several limitations that may hinder widespread adoption. In addition to costing more than conventional colonoscopy, reduced suction while using the scope means residual materials must be suctioned during insertion or the device must be removed intermittently during withdrawal. Furthermore, the scope must be removed from the working channel if any device, such as forceps or a snare, is needed for polyp removal. These factors may prolong withdrawal time and limit the use of this device in daily practice. Modifications that leave the suction channel free may help resolve some of the difficulties associated with this system.

Balloon- and Endocuff-Assisted Colonoscopy A new endoscopic cuff (EndoCuff AEC120 or AEC140; Arc Medical; distributed in the United States by Medivators) has been introduced as a means of enhancing visualization and scope stability during endoscopic mucosal resection of large or flat polyps of the sigmoid colon.51 The EndoCuff (EC) is a 2-cm long, flexible cuff with 2 rows of small flexible, hinged wings that help flatten large mucosal folds during withdrawal of the instrument (Figure 3). Because the wings fall flush with the colonoscope, they do not interfere during insertion.

EC-assisted colonoscopy was found to have good procedural success rates in terms of cecal intubation and time, as well as a good safety profile, with no associated complications.52 A prospective randomized trial in 498 patients undergoing screening colonoscopy in Germany showed EC-assisted colonoscopy increased the absolute rate of polyp detection by 14% over unassisted colonoscopy from 42% to 56% (P=0.001). The increase was particularly marked for polyps in the sigmoid colon—32% versus 15% (P<0.0001), and cecum— 14% versus 7% (P=0.019).53 Balloon-assisted colonoscopy is similar in concept to the endoscopic cuff. The NaviAid G-EYE colonoscope

6

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Figure 3. The EndoCuff slips over the ti th tip off an endoscope; d d during i withdrawal, its flexible arms open the bowel for inspection to improve views of mucosa previously difficult to visualize.

(SMART Medical Systems) permanently integrates an inflatable, reusable balloon onto the flexible tip of a standard colonoscope. The balloon can be reprocessed and reinflated by the endoscopist upon withdrawal of the scope. The mechanical flattening and straightening of haustral folds with the inflated balloon permit visualization of hidden anatomic areas, thus increasing the ADR. In a prospective cohort study, 50 gastroenterologists performed back-to-back conventional (non–balloon-assisted) colonoscopy followed by balloon-assisted colonoscopy in a model of simulated colonic polyps. The median rate of polyp detection for all simulated polyps was significantly higher with balloon-assisted colonoscopy than with unassisted colonoscopy: 91.7% versus 45.8%, respectively (P<0.0001).54 The significantly higher rate of polyp detection with balloon-assisted colonoscopy was observed for both nonobscured and obscured lesions (P<0.0001 for both). Clinical studies in humans are needed to further evaluate this new technology.

Conclusion One of the major advances in colonoscopy in recent years has been the development and adoption of HDWL. However, new technologies are still being investigated, and one of these approaches may increase adenoma detection to a degree that would result in reductions in the rate of interval cancers for all endoscopists and at a negligible incremental cost. Until then, endoscopists with low ADRs should review the existing technologies and consider whether and to what extent these devices may help their clinical practice.

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