The November 2012 Digital Edition of Gastroenterology and Endoscopy News

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The Independent Monthly Newspaper for Gastroenterologists

Volume 63, Number 11 • November 2012 40th ANNIVERSARY 1972–2012

Barrett’s Consensus Statement Issued

Twitter for Gastros

BY CHRISTINA FRANGOU

BY CHRISTINA FRANGOU

An international group of more than 90 experts has produced a consensus statement that outlines their recommendations for clinical management of early neoplastic Barrett’s esophagus (BE).

Gastroenterologists from 16 countries presented 20 consensus statements to guide clinical care of these

Gastroenterologist Ryan Maadanick, MD, sends his first tweet earlly in the morning to tell his followers about his latest blog post.

A few hours later, Dr. Maadanick, director of the gastroenterologg y/hepatology fellowship program at the University of North Carolina, send ds another tweet, cautioning about a tornaado warning in Chapel Hill. He retweets a message from the university about an upcom ming Facebook chat on pregnancy and depresssion. By the end of the day, he will have tweeted d about the top gastroenterology stories of the dayy, the previous night’s football gamee and his thoughts on using a term liike cirrhoticc instead of “patients with cirrhosis.”

Keeping up his Twitter feed has become as routine to his day as checking email mail and chatting with colleagues in the hallway.

“When I started tweeting two years ago, it was just to try it out, to gain more followers for my blog. I never imagined that it would be such a valuable tool for me,” he said.

see Barrett’s Consensus, page 7

Endoscopic Sedation Guideline Published

BY MONICA J. SMITH Recognizing the need for a comprehensive approach to procedural sedation in endoscopy, the U.S. gastroenterology professional societies and other stakeholders collaborated to write the “Multisociety Sedation Curriculum for Gastrointestinal Endoscopy” (MSCGE), a document intended to serve as a backbone of reference see Sedation Guideline, page 18

Twitter Deconstrructed, in More Than 140 Characters

Heterogeneity of Gastric Cancers Poses Challenges to Physicians

Today, Dr. Today Dr Madanick uses Twitter to network with other physicians, express his opinions on patient care issues—but not, he is clear to stress, on confidential, individual patient care—and communicate with medical students, residents and fellows. In two years, see Twitter, page 19

I N S I D E

EXPERT ROUNDTABLE Watch and Wait for Rectal Cancer?

Ten experts weigh in on the topic:

BY KATE O’ROURKE

Brad Champagne, MD

SAN FRANCISCO—A growing body of evidence demonstrates that stomach cancer is an extremely heterogeneous disease, so much so that researchers are questioning whether clinical trials need to be restructured to reflect the myriad differences.

“Gastric cancer isn’t one disease but many diseases,” said Manish Shah, MD, the director of Gastrointestinal Oncology at Weill Cornell Medical College in New York see Gastric Cancers, page 14

Conor P. Delaney, MD Albert S. DeNittis, MD Richard M. Goldberg, MD Angelita Habr-Gama, MD Gerald Marks, MD John H. Marks, MD

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

3

‘Who Shot J.R.?’

J.R., the Supremes and the PPACA David Cossman, MD Vascular Surgeon Los Angeles, California For those of you in your first few years of practice as an MD, you were being breast-fed in 1980 when “Who shot J.R.?” was the burning question on

the prime-time evening soap, “Dallas.”

Almost half a billion people worldwide tuned in to find out who shot J.R. Ewing, the patriarch of an oil-rich family played

by Larry Hagman (who obviously wasn’t mortally wounded since he’s back, with a new liver, on a “Dallas” remake). A jilted mistress, of course, with family ties to the Barnes, the archenemy of the

Ewings, pulled the trigger. How predictable. And disappointing.

Early this summer, J.R. took center stage again in the form of Chief Justice John G. Roberts, only this time it was “J.R. and the Supremes” who captivated the nation’s attention with the pending decision on the constitutionality of the mandate provision of the Patient

Protection and Affordable Care Act (PPACA) that requires all Americans to buy health insurance. For intrigue and drama, this was true theater. Audience participation through blogs, petitions and talk radio was at a fever pitch. Liberals and conservatives believed everything was on the line, and braced for validation or defeat when decision day came.

This time, however, J.R. turned out to be the shooter and now that his opinion has been read and the smoke is clearing, it’s hard to figure out who won and who lost. Everyone, it seems, got winged.

Let Me Explain

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References: 1. Rex DK, DiPalma JA, Rodriguez g R, McGowan J, Cleveland M. A randomized clinical studyy comparing p g reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage g solution as ppreparation p for colonoscopy. py Gastrointest Endosc. 2010;72:328-336. 2. DiPalma JA, Rodriguez g R, McGowan J, Cleveland MvB. A randomized clinical study evaluatingg the safety and efficacy of a new, reduced-volume, oral sulfate colon-cleansing preparation for colonoscopy. Am J Gastroenteroll. 2009;104:2275-2284. 3. SUPREP Bowel Prep Kit [package insert].

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BRIEF SUMMARY: Before pprescribing, g pplease see full Prescribing Information and Medication Guide for SUPREP® Bowel Prepp Kit (sodium sulfate, ppotassium sulfate and magnesium g sulfate) Oral Solution. INDICATIONS AND USAGE: An osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. CONTRAINDICATIONS: Use is contraindicated in the followingg conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allergies g to components p of the kit. WARNINGS AND PRECAUTIONS: SUPREP Bowel Prepp Kit is an osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. Use is contraindicated in the followingg conditions: ggastrointestinal (GI) obstruction, bowel pperforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allerggies to components of the kit. Use caution when pprescribingg for ppatients with a historyy of seizures, arrhythmias, y impaired p ggagg reflex, regurgitation g g or aspiration p , severe active ulcerative colitis, impaired p renal function or ppatients takingg medications that mayy affect renal function or electrolytes. y Pre-dose and ppost-colonoscopy ECG’s should be considered in ppatients at increased risk of serious cardiac arrhythmias. y Use can cause temporary p y elevations in uric acid. Uric acid fluctuations in ppatients with ggout mayy pprecipitate p an acute flare. Administration of osmotic laxative pproducts mayy pproduce mucosal aphthous p ulcerations, and there have been reports of more serious cases of ischemic colitis requiring q g hospitalization. p Patients with impaired p water handlingg who experience p severe vomitingg should be closelyy monitored includingg measurement of electrolytes. y Advise all patients p to hydrate y adequately q y before, during, g and after use. Each bottle must be dilutted with water to a final volume of 16 ounces and ingestion g of additional water as recommended is important p to ppatient tolerance. Pregnancy: g y Pregnancy g y Category g y C. Animal reproduction p studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive p capacity. p y Pediatric Use: Safetyy and effectiveness in ppediatric ppatients has not been established. Geriatric Use: Of the 375 ppatients who took SUPREP Bowel Prepp Kit in clinical trials, 94 (25%) were 65 years of age g or older, while 25 (7%) were 75 years of age g or older. No overall differences in safety or effectiveness of SUPREP Bowel Prep Kit administered as a split-dose p (2-day) y regimen g were observed between ggeriatric ppatients and yyounger g ppatients. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of SUPREP mayy not be absorbed completely. p y ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal ppain, nausea, vomitingg and headache. Oral Administration: Split-Dose p (Two-Day) y Regimen: g Earlyy in the eveningg pprior to the colonoscopy: ppy Pour the contents of one bottle of SUPREP Bowel Prepp Kit into the mixingg container pprovided.

Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Consume onlyy a light g breakfast or have onlyy clear liquids q on the dayy before colonoscopy. py Dayy of Colonoscopy py (10 to 12 hours after the eveningg dose): Pour the contents of the second SUPREP Bowel Prepp Kit into the mixingg container pprovided. Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Complete all SUPREP Bowel Prep Kit and required water at least one hour prior to colonoscopy.y Consume only clear liquids until after the colonoscopy. STORAGE: Store at 20°-25°C (68°-77°F).

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SU-13280T

January, 2012

Conservatives believed for a variety of reasons that J.R. (Chief Justice John Roberts) and his four reliable conservative allies in the court would shoot the whole law down because there was no precedent for regulating inactivity, such as not buying health insurance. Although Congress could regulate just about anything under the expanded interpretation of the Commerce Clause of the Constitution, it could not compel anyone to engage in commerce. Because PPACA lacked the usual severability clause that protected other provisions of the bill if one was declared unconstitutional, the whole law was vulnerable, unless the court ruled otherwise. In handicapping the decision, conservatives argued that Mr. Roberts and the other conservative justices of the court still held a grudge against President Obama for humiliating them in front of the nation during his State of the Union speech for its decision on corporate campaign financing. No politician had ever reprimanded the court, especially a constitutional lawyer expected to have a profound respect for the separation of powers. In criminal terminology, this very public rebuke was the motivation.

Constitutional justification, one way or the other, can always be found by the creative mind.

Oral arguments for the government by the stammering Solicitor General Donald Verrilli Jr., had conservatives high-fiving like it was all over. He looked like he was taking a dive, whiffing on over-the-plate lobs by the liberal justices who seemed to be coaching more than interrogating.

When asked by Justice Antonin Scalia if there were any constitutional limitations on the prerogatives of the legislative and executive branches in addressing public policy issues, like forcing people to eat broccoli to promote good health, Mr. see PPACA, page 32

4

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

A SCIPpery Slope

Supine ERCP— It’s Easy!

A Philosophical Shift Takes the Individual Out of Medicine Steven S. Kron, MD Anesthesiologist Hartford, Connecticut It began almost imperceptibly with a small Steven S. Kron, regulation here, a comMD ment there. Slowly at first and then with relentless speed and force it grew, and like a tsunami overwhelms anything in its path. By now, every physician who has practiced for more than a few years has noticed the dramatic shifts in the relationship of doctors to the society in which we practice our profession. From relative independence, we are being forced further into group think.

Hardly a day goes by without some new directive from above instructing what and how to perform a task to benefit our patient. Examples abound: The Surgical Care Improvement Project (SCIP) commands us to give a

β-blocker and an antibiotic. Woe to the anesthesiologist who misses the magic hour before incision or without explanation holds metoprolol in a bradycardic patient.

simply achieved by forcing compliance with many relatively small and innocuous requirements. Sounds a lot like the multiplicity of rules and expected behaviors coming down daily from the

small guilds and independent craftsmen to a Hamiltonian recognition of the advantages that size and centralized control can bring.’ —Atul Gawande, MD, The New Yorker, August 11, 2012 Then there is the mandatory computer-based education that instructs us to be caring, do the right thing and dump garbage in the appropriate colorcoded bins—followed by a test. Why bother with medical school and residency? You can’t make this stuff up!

Some centuries ago, Alexis de Tocqueville (or was it Machiavelli) explained how control of a population can be

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STEVEN M. FABER, MD Elizabeth City, North Carolina

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BARBARA B. FRANK, MD Philadelphia, Pennsylvania

FRANK G. GRESS, MD Brooklyn, New York

Comment

‘Essentially, we’re moving from a Jeffersonian ideal of

hospital, insurers, the government and even our own colleagues. A doctor could once choose from multiple diagnostic and therapeutic pathways, like a driver motoring down a wide interstate picking a lane. Now that same physician must navigate a narrowing European cobblestone alley.

In a recent issue of The New Yorker see Individual, page 31

Vol. 63, No. 11

Farmington Hills, Michigan

Re: “Laparoscopic Cholecystectomy/ ERCP One-Step Combo May Result in Better Care, Lower Costs,� by Monica J. Smith. Gastroenterology & Endoscopy News Web August 2012;63:40.

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TARUN MULLICK, MD

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DAVID ROBBINS, MD

I have performed at least 150 ERCP [endoscopic retrograde cholangiopancreatography] procedures for stone removal or stenting, just before, during or immediately after laparoscopic cholecystectomy.

It requires flexibility on the part of endoscopists, since most surgeons don’t do ERCP. It’s really quite easy to carry out supine ERCP, as long as the video monitor is directly across from the endoscopist. I would encourage this efficient modality. It avoids [having] two anesthetic [procedures], and patients are almost always discharged within 24 to 48 hours.

Ronald Feldman, MD Board-certified gastroenterologist Escondido, Calif.

Via website on Aug. 18, 2012

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6

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Radiofrequency Ablation for Barrett’s Esophagus Appears Safe for Older Patients

BY TED BOSWORTH SAN DIEGO—Radiofrequency ablation (RFA) has become the dominant therapy for treating dysplasia related to Barrett’s esophagus (BE), a disease that becomes more prevalent with age. Although RFA is known to be effective and reasonably safe overall, it has only recently been studied as a treatment for older patients.

“Younger patients appear to achieve higher rates of complete eradication of intestinal metaplasia and to do so in a shorter time frame, but older subjects appear to tolerate RFA as well as younger subjects,” said Milli Gupta, MD, Mayo Clinic, Rochester, Minn., one of the authors of a study comparing the efficacy and safety of RFA in older versus younger patients. Dr. Gupta, who conducted the study with senior author, Prasad G. Iyer,

MD, also at Mayo Clinic, noted that the rates of recurrence did not appear to be accelerated in older patients and that the data do not support different patterns of surveillance for BE after RFA, based on age. Dr. Gupta provided the results of this multicenter retrospective study at the 2012 Digestive Disease Week (DDW) meeting.

The study included 529 patients treated with RFA over an eight-year period at three participating centers involved in BE research. Eighty-three percent of patients were younger than age 75 years and 17% were older than age 75 years. The mean follow-up after RFA was approximately two years for both groups. There were no significant differences in baseline characteristics, such as length of BE in centimeters and presence of diaphragmatic hernia. The exception was a greater proportion of older patients

had high-grade dysplasia (38% vs. 32%; P<0.0068).

The difference in the mean time to complete eradication of intestinal metaplasia (1.21 vs. 1.37 years; P<0.0033) and the proportion who achieved this eradication (44% vs. 27%; P<0.0034) favored younger patients, but none of the complications, including bleeding (0.68% vs.

0%) hospitalization (0.68% vs. 0%) or esophageal tears (0.22% vs. 1.1%) were statistically significant when the groups were compared.

These data are useful because they encourage the use of RFA even in older individuals, who may have more complications if their lesions progress to cancer, said Julian Abrams, MD, MPH, assistant professor of medicine, Columbia College of Physicians and Surgeons, New York City.

“The average age of [patients with]

HALO360+ Ablation Catheter Image courtesy of Covidien/BÂRRX Medical

esophageal cancer is over 70 years of age and older patients are frequently poor candidates for surgical resection. As such, we often end up performing endoscopic therapy for Barrett’s esophagus with high-grade dysplasia or intramucosal carcinoma in older patients,” said Dr. Abrams, who was not involved in the study. “It is therefore very reassuring to see that RFA has a comparable safety profile in an older population compared with younger patients.”

■

Benefit of Aspirin as Chemoprevention For Barrett’s May Not Outweigh Risks ‘The big challenge is to see if the 20%

BY CAROLINE HELWICK SAN FRANCISCO—There is no evidence that aspirin is beneficial for preventing esophageal adenocarcinoma in people younger than age 55 years. Even for appropriate patients, the benefits emerge only after many years of use and the related risks remain unclear, said Janusz Jankowski, MD, PhD, the Sir James Black professor at the University of Oxford in the United Kingdom.

Dr. Jankowski is chief investigator of AspECT (Aspirin Esomeprazole Chemoprevention Trial), a randomized trial that is currently evaluating the chemopreventive effect of aspirin in patients with Barrett’s esophagus (BE). Some of the controversy may well be resolved by AspECT, which is one of the largest randomized trials involving the upper gastrointestinal (GI) tract ever. Currently, 2,513 patients are being tested to ascertain whether low-dose aspirin versus no aspirin—both in combination with esomeprazole (20 vs. 80 mg)—can reduce cancer risk. Efficacy results are expected in 2019 (ClinicalTrials.gov Identifier: NCT00357682).

Dr. Jankowski reviewed the available evidence for aspirin’s effect in preventing esophageal adenocarcinoma in a lecture at the American Society for Clinical Oncology 2012 Gastrointestinal Cancers Symposium.

When compared with other chemopreventive agents like cyclooxygenase (COX) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin has shown the greatest efficacy in reducing the risk for cancer (20%30%) and cardiovascular events (25%), at by far the

to 25% of patients who get a cancer prevention benefit are different from the 20% who may get aspirin-induced complications.’

—Janusz Jankowski, MD, PhD

lowest cost (approximately $5 per year), although with a slightly higher risk for upper GI bleeding (2.5%-4% per year).

“Compared with traditional NSAIDs and COX inhibitors, aspirin wins hands down for preventing cancer and cardiovascular disease, but GI bleeds are the biggest side effect,” Dr. Jankowski said. “And this GI bleeding profile is only relevant for aspirin taken alone.

If you take another NSAID, the risk is additive.”

Although rare, aspirin also has been associated with a risk for macular degeneration.

“We have to consider when we look at randomized data, that aspirin could be preventing some p problems but causingg others at a veryy low frequency,” Dr. Jankowski noted.

Preliminary data from the AspECT trial suggest that 5% of individuals are intolerant to aspirin, meaning that one in 20 will discontinue its use due to effects such as GI upset, skin rash or worsening of asthma.

And as patients age, the risk for complications gradually increases and could approach 20% by the age of 70, after 20 years of use, Dr. Jankowski said.

“The big challenge is to see if the 20% to 25% of patients who get a cancer prevention benefit are different from the 20% who may get aspirin-induced complications,” Dr. Jankowski said. “Randomized studies are see Aspirin, page 12

7

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Esophageal Cancer Action Network Warns Patients About Serious Risks of Heartburn

BY MAUREEN SULLIVAN The Esophageal Cancer Action Network (ECAN), a not-for-profit, national organization, has produced a free information pamphlet aimed at educating patients on the potential dangers of heartburn. The guide urges patients to pay attention to symptoms of gastroesophageal reflux disease (GERD) and to initiate a conversation with their doctor to ensure that this condition does not progress to cancer.

“As a gastroenterologist, I never really had an appreciation of the lack of awareness of GERD in many

people around the country,” said Bruce Greenwald, MD, professor of medicine and gastroenterologist at the University of Maryland Greenebaum Cancer Center and chairman of ECAN. He said the aim of the guide is to be the “very first step—long before the gastroenterologist gets involved—for the person on the street, to help them know that heartburn isn’t normal and to get the appropriate treatment.”

According to statistics from the American Cancer Society, about 17,500 new cases of esophageal cancer will be diagnosed in 2012; only 15% to 20% of patients will

Barrett’s Consensus continued from page 1

patients in the August edition of Gastroenterology (Consensus Statements for Management of Barrett’s Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process. 2012;143:336-346).

“This work represents the most far-reaching, inclusive and informative consensus process on evaluation and management of Barrett’s esophagus with HGD [highgrade dysplasia] or early cancer published to date,” said the authors, led by Cathy Bennett, PhD, researcher from Queens University, Belfast, United Kingdom.

Today, esophageal carcinoma is the fasting growing cause of cancer mortality and it is estimated that patients with BE have at least a 20-fold increased risk for developing esophageal adenocarcinoma. Despite its growing prominence, research into this condition is lacking, leading to a tremendous variation in clinical practice around the world.

Dr. Bennett and her colleagues reviewed more than 11,900 papers on early neoplastic BE, and based on this literature, drafted 91 recommendations for clinical management of patients. The statements then went through a Delphi process in which the experts on the panel voted on the statements anonymously. Four times, the statements were amended to reflect the vote, and the vote was repeated.

In the end, 81 of 91 draft statements achieved consensus. Even so, the authors acknowledged that the quality of the evidence remained generally low. Of 20 statements highlighted in the report, the evidence was classified as very low in 45% of them, low in 30% and moderate in 25%. Although none of the statements was backed by a high level of evidence, all had the approval of at least 80% of the expert panel.

Some of the findings have direct implications for clinical care today, said the authors. These include: • Specimens from endoscopic resection are better than biopsies for staging lesions.

• It is important to carefully map the size of the dysplastic areas to assess the prognosis and risk for progression.

• Patients who receive ablation or surgical therapy require endoscopic follow-up. The authors suggest that, based on available evidence, one strategy

survive for five years or longer after diagnosis.

“People don’t realize how dangerous heartburn can be and making the symptoms go away won’t prevent you from developing cancer,” said Mindy Mintz Mordecai, president and CEO of ECAN, in a statement. “We want people to understand the risks and get screened, so it can be caught early enough to save their lives.”

Supported by a grant of $15,000 from health insurer CareFirst BlueCross BlueShield, the guide eschews medical terminology in favor of more simple language.

The project is the result of a

for post-esophagectomy surveillance is to perform screening endoscopies at two, five and 10 years postsurgery.

• High-resolution endoscopy—at more than 850,000 pixels—is necessary for accurate diagnosis. Highresolution endoscopies and targeted biopsies of every suspicious lesion followed by four-quadrant biopsies every 1 to 2 cm are recommended.

• Endoscopic therapy for HGD is preferred to surveillance. Endoscopic surveillance alone can lead to under-diagnosis of cancer at baseline, said the authors.

• Endoscopic therapy for HGD also is preferred over surgery for management of most patients. HGD in BE is rarely associated with lymph node involvement, provided that deeper invasion has been ruled out by endoscopic mucosal resection, according to the panel. On the rare occasion that endoscopic treatment fails, surgical resection is still possible and generally curative. The operative results are improved if surgery is undertaken in specialist surgical centers.

• The combination of endoscopic resection and radiofrequency ablation (RFA) is the most effective therapy. The authors acknowledge that the evidence for this statement is low but cited one systematic review that suggests that success rates with RFA are superior, with approximately 90% of patients having no HGD after therapy.

Charles J. Lightdale, MD, professor of clinical medicine, Columbia University, New York, said in an email interview that the consensus document is helpful for clinicians because it supports the new management paradigms for early neoplasia in BE that have emerged in recent years.

The highlight of the consensus document is its preference for endoscopic therapy over surveillance or surgical esophagectomy, he said.

“The organ-sparing, minimally invasive endoscopic therapy represents a huge shift in the management of high-grade dysplasia in Barrett’s esophagus. In clear and ringing statements, the consensus group comes down squarely in favor of endoscopic therapy for high-grade dysplasia. This is a game changer.”

In an editorial accompanying the consensus statement, Rebecca C. Fitzgerald, MD, honorary consultant

collaboration between more than 100 doctors, including primary care physicians, gastroenterologists and surgeons from around the United States.

“Because there are currently no clear guidelines about who should be screened for esophageal cancer or Barrett’s esophagus, this is valuable information that patients can use to be advocates for their own health care,” Dr. Greenwald said.

The free brochure, entitled “Reflux Disease (GERD), Barrett’s Esophagus & Esophageal Cancer: A Guide for Patients,” is available to download at www.ecan.org/site/ PageNavigator/Patient_Guide.html.

in gastroenterology and general medicine at Addenbrooke’s Hospital in Cambridge, United Kingdom, and Joel H. Rubenstein, MD, assistant professor of gastroenterology at the University of Michigan, Ann Arbor, called the statements a “commendable effort” at summarizing the best available data.

But they caution the statements need to be viewed against the limited strength of the evidence. “The end result of the consensus document can best be viewed as a synthesis of interpretations of an imperfect knowledge base by a set of experts at a particular point in time.”

The expert panel also highlighted some additional areas that are ready to be applied to clinical management. They called for at least two, experienced, gastrointestinal pathologists to evaluate all BE biopsies when a diagnosis of dysplasia is considered. They found the Prague C&M Endoscopic Grading System is the best available tool for determining the extent of BE and noted that visible lumps in nodules consisting of HGD suggest that a more advanced lesion, with invasion, might be present.

With regard to the at-risk population, the panel said that men have approximately twice the rate of development of HGD and esophageal cancer as women, and non-Hispanic white patients with BE are at higher risk than other racial or ethnic groups. Obesity, they found, is an independent risk factor.

The researchers also said that the consensus process revealed some areas in which urgent research is needed, including the evaluation of genetic markers to determine cancer risk. The identification of such markers could help determine the true risk for progression from dysplasia to early adenocarcinoma and would have implications for surveillance strategies and treatments.

Funding for the research was provided by the International Society of Diseases of the Esophagus, British Society of Gastroenterology, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, Association of Upper Gastrointestinal Surgeons, Fight Oesophageal Reflux Together, German Society of Endoscopy, Netherlands Association of Hepatogastroenterologists and Oesophageal Cancer Fund of Ireland.

Many members of the panel reported relevant disclosures, which are reported in full in the report.

■

References: 1. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syndrome. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.

Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:1559-1574. 2. Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Carcinoid tumour. Lancet. 1998;352(9130):799-805.

What’s behind the symptoms?

Carcinoid Syndrome Can Be Deceptive Early diagnosis of carcinoid syndrome is essential.

The most common symptoms of carcinoid syndrome are severe diarrhea, flushing, abdominal pain, cardiac disease, wheezing, and telangiectasia.1,2 To learn more, visit www.carcinoidfacts.com.

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10

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

EMR Necessary for Accurate Staging of Esophageal Cancer

BY CAROLINE HELWICK SAN FRANCISCO—Distinguishing between the T1a and T1b stages of esophageal carcinoma is critical for appropriate disease management, yet up to 60% of lesions may be incorrectly assessed if the evaluation is based on biopsy or endoscopic ultrasound (EUS), according to Mary P. Bronner, MD, Carl R. Kjeldsberg professor and division chief of anatomic pathology at the University of Utah in Salt Lake City.

Endoscopic mucosal resection (EMR) provides much more accurate staging information and can prevent surgery in many cases, said Dr. Bronner, who gave a lecture at the 2012 Gastrointestinal Cancers Symposium.

“T1a, or intramucosal, cancers are easily cured by EMR and have a risk for metastasis of only 1% to 2%.

But the deeper, submucosal T1b cancers have about a 30 times worse risk. It’s very important to make this distinction,” she said.

EUS and biopsy are “not trustworthy” in assessing early-stage esophageal cancers. “EMR is really the precise approach” for accurate, nonoperative staging, she said.

T1a Versus T1b lesions Depth of invasion is one of the most important prognostic indicators in esophageal adenocarcinoma. T1a cancers are categorized as intramucosal carcinomas because they involve the epithelium, basement membrane and lamina propria, but do not invade farther than the muscularis mucosae, the smooth muscle layer at the base of the mucosa. However, T1b lesions do breach this barrier and extend into the submucosa and thus are labeled submucosal carcinomas.

“While this is a small distance anatomically, the difference is great in terms of metastatic potential, which is only 1% to 2% for intramucosal tumors but rises to about 30% for submucosal cancers,” said Dr. Bronner.

Some classification systems divide T1b tumors further according to their depth within the submucosal space, but this appears to have no significant prognostic significance, she added.

The esophagus in Barrett’s metaplasia frequently develops duplication of the muscularis mucosae, and this is not only underrecognized but creates problems for appropriate staging, Dr. Bronner said. The muscularis mucosae of the esophagus is the thickest of the gastrointestinal tract and becomes even thicker in response to repeated ulcerations in Barrett’s esophagus. Because of this, it can be easily misidentified on EMR specimens as being the much deeper and typically much larger muscularis propria.

Furthermore, when the muscularis mucosae “splits” into superficial and deep layers, the space in between often is misjudged as submucosa, although cancers invading this area actually behave as intramucosal cancer with only a 1% to 2% metastatic risk, as recently documented in a large study of 99 early Barrett’s adenocarcinomas (Estrella JS et al. Am J Surg Patholl 2011; 35:1045).

“It is very easy to over-call T1b cancer on EMR specimens. This is a big source of error,” she said. “As many as 60% of intramucosal lesions are overstaged by EUS and EMR as submucosal cancers. Cancers involving a split muscularis mucosae in actuality are T1a cancers.”

With regard to squamous overgrowth—which occurs as a result of biopsy sites healing, treatment with proton

‘T1a, or intramucosal, cancers are easily cured by EMR and have a risk for metastasis of only 1% to 2%. But the deeper, submucosal

‘Dr Bronner is one of

T1b cancers have

the invaluable GI

about a 30 times worse

[gastrointestinal]

risk. It’s very important

pathologists who

to make this distinction.’

understands both the

—Mary P. Bronner, MD

pathology and biology of Barrett’s esophagus.’

—Richard Sampliner, MD

pump inhibitors and ablative therapy—Dr. Bronner said, “The concern is that squamous epithelium that grows over the Barrett’s mucosa hides it from the endoscopist’s view, but as long as you take sufficient biopsies of the original Barrett’s esophageal segment, dysplasia and cancer will not be missed.” This has been documented in a controlled longitudinal study that reported on more than 30,000 biopsies taken from 208 patients with Barrett’s high-grade dysplasia (HGD) over a five-year time span (Bronner M et al. Gastroenterologyy 2009;136:56-64).

Management of T1a lesions Studies performed over the past decade have demonstrated that, for HGD and intramucosal carcinomas, the complete response rate is about 97% with EMR. The problem, however, is that recurrence or the development of metachronous lesions is fairly significant, Dr. Bronner pointed out. In studies that followed patients for at least one year, recurrence/metachronous rates ranged from 11% to as high as 30%.

“This has been the major problem for EMR as the sole treatment modality,” she pointed out. “The latest approach is to not only resect the lesion using EMR but to do a complete eradication of the Barrett’s segment as well. With the combined approach, the rate is significantly reduced,” she said.

In a single-center study (N=32) with 23 months of follow-up, the recurrence/metachronous rate was only 3%, University of Chicago investigators reported (Chennat J et al. Am J Gastroenteroll 2009;104:2684-2692).

“I think this procedure is going to become very important in the treatment of Barrett’s lesions, dysplasia and cancer,” she predicted.

Management of T1b lesions “Unfortunately, the results are not nearly as good for submucosal cancers,” Dr. Bronner continued. In a recent study from Mayo Clinic, in which 68 patients with T1b tumors were treated with EMR or esophagectomy, mortality rates after long-term follow-up were 38% with EMR and 26% with surgery (Tian J et al. Gastrointest Endoscc 2011;74:1201-1206).

“The interesting observation is that although these patients do not do very well compared with intramucosal

cancer patients, the mortality rates for the two approaches were not significantly different,” she noted. “So, surgery versus EMR is still an open question but it does appear that EMR may be as good for T1b cancers.”

Can Pathologists Tell ‘Bad’ From ‘Worse’?

“Can pathologists and endoscopists using biopsy and endoscopic ultrasound distinguish high-grade dysplasia from intramucosal carcinoma from submucosal carcinoma? When you look at the biopsy alone, without EMR, we cannot,” Dr. Bronner said.

In a study that evaluated agreement among seven expert Barrett’s pathologists at a single high-volume center, interobserver variability was high (Downs-Kelly E et al. Am J Gastroenteroll 2008;103:2333-2340). Agreement was poor overall (κ=0.30) and was moderate (0.47) for HGD, poor for HGD with marked architectural distortion (0.21), poor for intramucosal adenocarcinoma (0.30) and poor for submucosal adenocarcinoma (0.14).

The authors concluded that “the overall, poor, interobserver reproducibility among gastrointestinal pathologists who see a high volume of Barrett’s cases calls into question treatment regimens based on the assumption that high-grade dysplasia, intramucosal adenocarcinoma and submucosal adenocarcinoma can be distinguished reliably in biopsy specimens.”

“So, can we tell bad from worse? No, not on biopsies,” Dr. Bronner reiterated. “If this group of card-carrying Barrett’s pathologists could not reliably tell the difference, I don’t think anyone can. And management of the disease based on the distinction between high-grade dysplasia, intramucosal carcinoma and submucosal carcinoma in biopsies therefore also becomes questionable.”

Discrimination is much better on EMR samples, she said. “Obviously, there is more tissue and we can see the depth of the involvement.”

A study from Massachusetts General Hospital (in which nine pathologists reviewed 25 EMRs and their corresponding biopsies), found that agreement was significantly higher for EMR than for biopsy.

The conclusion from several studies is that EMR provides more accurate information, resulting in alteration of the biopsy diagnosis (up- or downstaging) in 15% to 48% of cases, said Dr. Bronner.

“If you want to appropriately stage early esophageal

11

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Marker for Esophagogastric Cancer Treatment Found Leptin Expression, Along With FDG-PET, May Help Determine Response to Therapy

BY KATE O’ROURKE SAN FRANCISCO—A A new tool to guide treatment decisions in patients with esophagogastric juncttion adenocarcinoma (EGJAc) is on th he horizon.

A study has found d that leptin expression is associated w with chemoresistance and may be a biomarker that can be combined with w fluorodeoxyglucose–positron em mission tomography (FDG-PET T) to determine patient respon nse to chemotherapy.

“Leptin has the potenti tial to be a clinically useful bioomarker,” said Russell Petty, y, MB, PhD, a consultant medical oncologist at the University of Aberdeen in Scotland. He presented thee study at the American Society ty of Clinical Oncology 2012 Gastroointestinal Cancers Symposium.

In the past decade, the incid dence of EGJAc has risen alarmingly, driv driven in i part by the obesity epidemic. The disease has a poor prognosis and for patients with resectable disease, it has been recognized that neoadjuvant treatment is beneficial for some but not all patients.

Studies have shown that a 35% or greater decrease in FDG standard uptake value (SUV) after just 14 days of treatment indicates a metabolic responder to chemotherapy, whereas less than 35% indicates a metabolic non-responder.

Only 50% of patients who are classified as metabolic responders, however, will go on to have a histopathologic response. Of patients who are metabolic

Patients underwent FDGPET computed tomography (PET-CT) scans at baseline and day 14. Chemotherapy continued regardless of radiologic response at day 14. Gene expression profiling with an Affymetrix 1.0 ST Exon GeneChip was performed on tumor biopsies. A tissue microarray comprising an independent set of 154 patients with EGJAc who underwent surgery, with or without neoadjuvant chemotherapy, was used with immunohistochemistry (IHC) for qualification of the gene expression profile results.

The researchers identiffied an 86-gene signature that ccould distinguish patients who had a radiologic response on h CT after completing their full C round of chemotherapy, com‘These data s suggest pared with those who did not respond. Leptin expression was that lepti leptin expression in tumor is a the biggest predictor of radiomarker of chemoresistance.’ logic nonresponse.

“In those FDG-PET meta—Russell Petty, MB, PhD bolic respondent patients who did not have a subsequent radionon-responders, less than 5% will have a logic response, leptin was significantly histopathologic response. overexpressed compared to those patients “There is a need to improve the posi- who had a metabolic response and then tive predictive value,” said Dr. Petty. The went on to have a radiologic response as researchers hypothesized they could com- well,” said Dr. Petty. “These data suggest bine molecular biomarkers with FDG- that leptin expression in tumor is a marker PET to subclassify FDG-PET metabolic of chemoresistance.” responders. They launched a study Somewhat surprisingly, in an IHC that included 28 patients with locally analysis of an independent group of 154 advanced or metastatic EGJAc who patients, high leptin expression was assoreceived platinum-based chemotherapy. ciated with better survival (hazard ratio,

lesions that have high-grade dysplasia or worse, EMR is the way to go,” she emphasized.

Manoop Bhutani, MD, professor of medicine and experimental diagnostic imaging at the University of Texas MD Anderson Cancer Center in Houston, commented on the findings.

“We have recently performed and published a metaanalysis of 19 international studies on EUS for superficial esophageal cancer. Although overall, EUS had a good accuracy (area under the curve, 0.93), heterogeneity among the included studies suggested that multiple factors, including the location and type of lesion, method and frequency of EUS probe and the experience of the endosonographer, can affect the diagnostic accuracy of EUS (Thosani et al. Gastrointest Endoscc 2012;75:242-253),” Dr. Bhutani said. “Therefore from a clinical standpoint, I agree with Dr. Bronner that EMR with pathologic examination is more precise and accurate in differentiation of

T1a and T1b esophageal cancers, the clinical implications of which, for the patient, are enormous.”

Richard Sampliner, MD, of University Medical Center in Tucson, added, “Dr. Bronner is one of the invaluable GI [gastrointestinal] pathologists who understands both the pathology and biology of Barrett’s esophagus.

She clearly points out the accuracy and clinical utility of endoscopic [mucosal] resection because the depth of resection is beneath the superficial mucosa.”

Dr. Sampliner emphasized the key issues brought forth by Dr. Bronner: 1. T1a (intramucosal) cancers have a low frequency of lymph node metastasis—less than 2%, similar to the operative mortality of a high-volume surgical institution. The muscularis mucosa is the key separation level of T1a versus T1b—a low- versus highfrequency metastasis lesion.

2. EMR provides accurate staging on a pathologic

0.85; P P=0.04). But when the investigators conducted a stratified analysis, they found that patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, and those with leptin-negative tumors fared better if they received chemotherapy.

A variety of data supports leptin’s pathogenic role in EGJAc. It is produced by adipocytes and a strong epidemiologic link between obesity and EGJAc exists. High serum and gastric fundus leptin levels have been associated with an increase in Barrett’s esophagus. Leptin receptors are expressed in more than 90% of esophageal adenocarcinomas, and in vitro studies show that leptin stimulates esophagogastric cancer cell proliferation and can inhibit apoptosis.

According to Dr. Petty, his study suggests that leptin expression has value as a predictive biomarker and also as a therapy-independent prognostic marker as well.

“I would suggest that the paradigm of combining molecular biomarkers and FDG-PET appears to be valuable to predict therapy response, and perhaps should be further investigated,” Dr. Petty said.

Karyn Goodman, MD, a radiation oncologist at Memorial Sloan-Kettering Cancer Center, in New York City, said the study was hypothesis-generating, but not ready for prime time.

“This is not something that will be incorporated into clinical practice, until the results have been validated with further studies,” she said.

■ Drs. Petty and Goodman reported no conflicts of interest.

basis. This is in contrast to EUS and routine biopsy.

The EMR finding of limitation to the muscularis mucosa defines the appropriateness of endoscopic therapy, avoiding the need for surgical intervention.

3. The recognition of reduplication of muscularis mucosa in Barrett’s is necessary for the correct interpretation of staging.

4. The problem of squamous overgrowth of intestinal metaplasia can be avoided by an adequate biopsy protocol including biopsies 1 cm above the endoscopic squamocolumnar margin.

“Dr. Bronner highlights the accurate histologic staging of dysplastic Barrett’s. This aids in the separation of patients who can be treated with endoscopic rather than surgical therapy,” he concluded.

■ Drs. Bronner, Bhutani and Sampliner reported no conflicts of interest.

Q & A

12

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

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In a meta-analysis of randomized controlled trials involving 100,000 participants followed for a period of six years (Seshasai SR et al. Arch Intern Med. 2012;172:209-216), it was found that aspirin treatment reduced total cardiovascular events by a modest 10%, did not prevent cardiovascular deaths and was associated with a 31% increased risk for nontrivial bleeding events.

The investigators concluded that routine use of aspirin for primary prevention is not warranted.

“So, should one take low-dose aspirin?” Dr. Jankowski asked. “At this time, the answer is indefatigably ‘No, you should not,’ unless you have secondary risk factors for cardiac or GI conditions.”

The international Consensus Statements for Management of Barrett’s Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process (BADCAT, Gastroenterology, 2012;143:336-346) confirmed Dr. Jankowski’s conclusions. The group’s consensus is that it is not currently known whether aspirin can prevent the progression of BE and that the inherited genetics of BE has not been clarified. These topics should be a research focus, the group stated.

Early data from the AspECT trial, however, have offered encouraging signs that four years of aspirin treatment may be protective.

“There are not enough data to determine if it prevents cancer, but we see new squamous islands appearing where Barrett’s esophagus was,” said Dr. Jankowski.

“We may have a recommendation regarding aspirin use within the next two years,” he added. “Meanwhile, there is no evidence whatsoever, even with risk factors for cancer or cardiac disease, that a person should take aspirin before the age of 55 years. And we don’t think

that taking aspirin after the age of 75 makes sense, based on the need to take it for 10 years to achieve a benefit, and because of the high incidence of side effects at this age. Between the ages of 55 and 75, a patient could take aspirin, but there are still risk–benefit issues and we don’t know who will respond. We need to deal with these issues urgently.”

Prateek Sharma, MD, professor of medicine at the University of Kansas School of Medicine, Kansas City, commented on the findings.

“The majority of esophageal adenocarcinomas originate in patients with Barrett’s esophagus. These patients progress to low-grade dysplasia, high-grade dysplasia, intramucosal carcinoma and finally to invasive carcinoma,” he noted. “Currently, we survey patients with Barrett’s esophagus to detect high-grade dysplasia and early cancer, which can then be treated for cure. We could achieve substantial health care savings if we had an agent that would prevent these conditions.

Although observational studies have generated preliminary data on the ability of certain agents such as aspirin, sulindac and DFMO [difluoromethylornithine) to prevent esophageal cancer, their broad clinical applicability is limited due to their toxicity,” he added.

“Further research is needed to identify which subset of patients would benefit from chemoprevention and the dose required, duration of treatment and toxicity.” ■

Aspirin continued from page 6

the only way to fully answer the questions related to the risks and benefits of aspirin as chemoprevention.”

An analysis of individual patient data from randomized trials (Rothwell PM et al. Lancet 2011;377:31-41) concluded that taking aspirin daily (≥75 mg) reduced deaths due to common cancers, during and after the trials, in 20% to 25% of subjects. The effect was most pronounced for GI tumors; it was apparent after four years and became significant after 10 years.

“One-fifth to one-quarter of patients taking aspirin for cardiac reasons got a secondary benefit in terms of cancer prevention,” Dr. Jankowski observed. “But, based on the data, you may have to take aspirin for at least 10 years, and maybe 20, to get this benefit, so the sideeffect frequency needs to be exceptionally low. And as good as aspirin is, the response rate is just 20% and we still don’t know who the responders will be.”

It also is possible that the preventive effect is smaller, he added, based on his reanalysis of the Rothwell data.

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From cardiology data it is clear that aspirin use affects cardiovascular events only in persons already at high risk (i.e., the secondary prevention population). A recent paper recapitulated this finding in cancer as well as cardiac disease, Dr. Jankowski noted.

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2. Based on colony-forming unit count: Information Resources, Inc., (IRI) retail data for 52 weeks, ending December 25, 2011.

Dr. Jankowski has served as a consultant and has received honoraria and research funding from AstraZeneca.

Dr. Sharma reported no conflicts of interest.

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14

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Gastric Cancers continued from page 1

City, speaking at the American Society of Clinical Oncology 2012 Gastrointestinal Cancers Symposium (ASCO-GI).

“This is supported by epidemiology, risk factors, response to therapy and even molecular analyses.”

Teasing Out the Differences Although gastric cancer is more prevalent in Asia, there is more advanced disease in the United States and the West in general.

“Then there is the question of whether there is different underlying biology. That has been a prevalent topic of research over the past five or 10 years,” said Dr. Shah.

The main risk factors for gastric cancer are Helicobacter pylori, whose rates vary worldwide, tobacco use and family history. Several genetic syndromes predispose individuals to the disease (Table 1). Gastric cancer also has different histologic patterns—intestinal versus diffuse—and is found in different digestive locations, such as the gastroesophageal (GE) junction and the pyloric antrum.

A recent study compared a database of gastric cancer patients from Memorial Sloan-Kettering Cancer Center in New York City (n=711) with data from a hospital in Korea (n=1,646) from 1995 to 2005 (Strong VE et al. Ann Surgg 2010;251:640-646).

“In the U.S., and certainly in the Northeast and probably the West, proximal tumors, GE junction, distal esophagus and cardia tumors are much more prevalent than they are in Asia, about 40% of the population here versus 10% in Korea, whereas middle and lower tumors of the stomach are more prevalent in Korea,” said Dr. Shah (Table 2).

This study also showed a difference in tumor stage at diagnosis. Nearly half (42%) of the patients in Korea had stage Ia, the earliest tumor stage, and more than half (60%) were stage I. In the United States, there was more of an even split by tumor stage: Ia (28%), Ib (21%), II (20%), IIIa (16%) and IIIb (8%).

Thirty-day postoperative mortality was higher in the United States (2%) than in Korea (0.2%), a difference that could not be explained by differences in surgical volume or quality of surgical care, said Dr. Shah. Patients in Korea had higher overall survival (OS; 81% vs.

58%; P<0.0001) and disease-specific survival (DSS; 82% vs. 74%; P<0.0001) than patients in the United States. After adjusting for all known confounding risk factors, the DSS for Korean gastric cancer patients remained significantly better than that for U.S. patients by roughly 30% (hazard ratio [HR], 1.3; P=0.05).

P

“The study cannot exclude inherent biologic differences between gastric cancer in the United States and Korea that accounts for superior survival in Korean patients,” said Dr. Shah.

In areas where gastric cancer is most prevalent, such as in China and Japan, intestinal gastric cancer, which has a glandular appearance and spreads through the stomach wall as part of a tumor mass,

Canc Netw 2010;8:437-447). The first type, non-cardia gastric cancer, is linked to environmental factors such as high dietary salt, tobacco use and increasing age; clinical factors such as H. pylori infection and use of nonsteroidal antiinflammatory drugs; and genetic factors including immune regulatory single nucleotide polymorphisms. A second type, diffuse gastric cancer, is associated with CDH1 mutation and family history and has no known environmental or clinical factors. The third type, proxi‘Upper GI cancers are complex mal gastric cancer, is caused by tobacco with multiple genetic and and alcohol use; has no known genetic link; and is associated with obesity, high epigenetic alterations. The body mass index and gastroesophageal complexity of signaling reflux disease.

networks in cancer cells is allenge in developing a challenge essful therapeutics.’ successful —Wael El-Rifai, MD, PhD

‘Not only do we have epidemiologic evidence that there are different subtypes of is the most common type. There is no regional variation in diffuse gastric cancer, which spreads as discohesive individual cells throughout the stomach wall and is less common than the intestinal type.

Dr. Shah pointed out that proximal and distal gastric cancers have two distinct epidemiologies. Cardia and GE junction cancers are five times more common in men than in women, twice as common in blacks as in whites, occur in a wide range of ages and are common in industrialized nations. Non-cardia cancers (distal), which are more frequent in Korea, are twice as prevalent in males as in females, four times more common in blacks than in whites, and the incidence increases with age.

In 2010, investigators devised a classification system for gastric cancer that divided the disease into three types (Shah MA, Kelsen DP. J Natl Compr

gastric cancer, we now have [gene] expression evidence that there are different subtypes of gastric cancer as well.’

—Manish Shah, MD

Probing the Genes The classification system suggested genetic differences between the disease types, said Dr. Shah.

“If you have clinical criteria that define three different diseases, they should have different molecular signatures as well,” he said.

Dr. Shah analyzed gene expression profiles from the primary tumors of 36 patients with gastric cancer and identified gene signatures that could discriminate three types of gastric tumors—proximal GE junction tumors, diffuse gastric tumors and distal intestinal type tumors— with 85% accuracy (Shah MA et al. Clin Cancer Ress 2011;17:2693-2701).

“Not only do we have epidemiologic evidence that there are different subtypes of gastric cancer, we now have [gene] expression evidence that there are different subtypes of gastric cancer as well,” Dr. Shah said.

Additional evidence for diverse genetics comes from a Nature Genetics study in which researchers performed exome sequencing with 22 gastric cancer samples (Wang K et al. 2011;43:1219-1223).

They found that 59% of gastric cancers had an error in chromatin modification; 59% had an error in cell junction organization; and 77% had an error in cell cycle regulation.

In 2011, researchers also published a study analyzing gene expression profiles for 37 gastric cancer cell lines and identified two intrinsic subtypes, intestinal (G-INT) or diffuse (G-DIF), that they then validated in the primary tumors of 521 patients (Tan IB et al. Gastroenterology 2011;141:476-485). They identified a 171-gene set that robustly classifies tumors into the two subtypes. In univariate and multivariate analyses, these intrinsic subtypes, but not subtypes based on Lauren’s histopathologic classification, were prognostic of survival.

The G-INT cell lines were significantly more sensitive to 5-fluorouracil (5-FU) and oxaliplatin, but more resistant to cisplatin, than the G-DIF cell lines.

The subtypes were also linked with survival following adjuvant, 5-FU–based therapy.

Table 1. Genetic G i Syndromes S d That Th Predispose P di Patients P i To Gastric Cancer Hereditary diffuse gastric cancer syndrome (3%-5% of gastric cancers) Lynch syndrome (1%-2%) Familial adenomatous polyposis (1%) Li-Fraumeni syndrome (<1%) Peutz-Jeghers syndrome (<1%)

15

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

From the Literature

Genetic Prediction of Disease Development Still Has ‘A Long Way To Go’

BY ROSEMARY FREI, MSC The ability to scan an individual’s DNA and determine the precise risk he or she has for developing a given disease is still far closer to science fiction than fact.

A recently published analysis showed that most people would test negative for the genetic underpinnings of many common diseases— including several types of cancer—even when they actually have at least one of the diseases (Roberts NJ et al. Sci Transl Med d 2012;4:133ra58).

“A fortune-teller with this crystal ball would soon go out of business,” said investigator Bert Vogelstein, MD, professor of oncology at Johns Hopkins Kimmel Cancer Center in Baltimore, at the American Association for Cancer Research’s 2012 annual meeting, where he released results of the study.

However, there also was good news: Based on studies of genotyping and disease risk in monozygotic twins, the analysis indicated that more than 90% of people would test positive for a clinically meaningful genetic susceptibility to at least one disease, allowing them to take preventive health and lifestyle measures.

The results underscore the complex nature of disease development.

“I thought it was quite a good paper, in that they

Restructuring Clinical Trials “The implication of all this is that gastric cancer is not one disease. There are subtypes of gastric cancer and these subtypes may explain the differences in response to therapy and the differences in prognosis,” said Dr. Shah. “If you accept that there are subtypes of gastric cancer, then you must accept that they might have different molecular drivers and therefore they may respond to different molecular targets, and I think that is the future of gastric cancer.”

According to Wael El-Rifai, MD, PhD, professor of surgery at Vanderbilt University Medical Center in Nashville, Tenn., a wide range of therapeutic drugs are in the pipeline in Phase I/II clinical trials for upper gastrointestinal (GI)

formalize something we knew informally before— that in cancers and most other prevalent diseases, genetics alone is a minor component,” said Tom Curran, PhD, deputy scientific director at The Children’s Hospital of Philadelphia Research Institute and associate director of translational genomics at the University of Pennsylvania in Philadelphia.

“Moving forward, one would like to take full advantage of personal genome sequencing, including sequencing of methylation patterns in conjunction with analyses of other components of the epigenome that form the interface between the genome and the environment.”

The paper was an ambitious genetic and mathematical analysis of information from 53,666 monozygotic twin pairs. Dr. Vogelstein’s team gathered the data from registries in the United States, Finland, Denmark, Norway and Sweden.

They calculated the greatest theoretical ability of whole genome sequencing to determine risk for 27 diseases, including cancers and autoimmune and cardiovascular diseases.

More than 50% of patients who had one of the 13 diseases would not test positive on a genetic assay. Among the cancers included in the analysis, prostate cancer was the least likely to produce a false-negative genetic test result, with about 53% of individuals with this disease testing genetically negative. The best result was for coronary heart disease in men, with just over 90% of men with this

cancer. These include inhibitors of crucial molecular targets and cancer signaling pathways such as EGFR, VEGFR, HER2, HER3, aurora kinases, MET, BCL2, DNA methyltransferases, histone deacetylases, heat shock proteins, AKT, mTOR and MEK. “Upper GI cancers are complex with multiple genetic and epigenetic alterations. The complexity of signaling networks in cancer cells is a challenge in developing successful therapeutics,” said Dr. El-Rifai.

Genetic approaches, he argued, are powerful in identifying novel targets that could modulate response to therapy, but given the complexity of signaling networks in cancer cells, single-agent therapies may not work for

Table 2. Differences Diff iin P Pathologic h l i Characteristics Ch i i Of Gastric Cancers Korea, %

United States, %

Gastroesophageal junction

0.4

18

Upper

9

21

Middle

36

27

Lower

54

33

Whole

0.4

2

Unknown

1

0

Adapted from Strong VE et al. Comparison of gastric cancer survival following R0 resection in the United States and Korea using g an internationallyy validated va alidated nomogram. g Ann Surg.

Surg g. 2010;251:640-646.

2010;251:640 ; 646.

condition likely to test positive for it. Alzheimer’s disease, thyroid autoimmunity and type 1 diabetes also were associated with high percentages of positive testing.

The researchers also found that the maximum fraction of individuals with or without each disease who would receive a positive test for that disease—indicating a clinically meaningful risk— was very low. Among the cancers, prostate cancer had the highest percentage of positive test results, at about 7%. Leukemia had the lowest, at around 1%. Risk for coronary heart disease death was associated with the highest percentage, at approximately 81%.

Overall, the investigators determined that more than 95% of men and more than 90% of women would receive at least one positive test result, assuming risk alleles are distributed in real life in a way that would produce maximum sensitivity for testing.

Dr. Curran said that prediction of disease development has “a long way to go.

“We expect there will be successes along the way with individual rare diseases. I don’t think there’s going to be a big, blinding flash of insight—it is more likely that the knowledge is going to accrue incrementally.”

every patient.

“Combined strategies that take into account the molecular and biological features of tumors are the future of personalized medicine in cancer therapy,” said Dr. El-Rifai.

He added that clinical trials need to consider the molecular defects in cancer cells of each patient to allow matching patients to therapies that are likely to block the effects of those specific molecular alterations. However, because of the complexity of the cancer genome, treatment response could vary from one patient to another.

In a recently reported Phase II trial, Dr. Shah and colleagues tested a modified docetaxel, cisplatin, 5-FU and bevacizumab (Avastin, Genentech) regimen in patients with metastatic gastroesophageal adenocarcinoma (Shah MA et al. J Clin Oncoll 2011;29:868-874). The data were encouraging with a six-month progression-free survival (PFS) of 79%, a median PFS of 12 months and a median OS of 16.3 months.

The results were more intriguing, however, when researchers looked more closely at subtypes.

“If you divide by the subtypes we defined—proximal tumors, distal tumors and diffuse tumors—we see quite significant differences,” Dr. Shah said. The response rate was 85% in patients with

Drs. Vogelstein and Curran reported no conflicts of interest.

proximal/GE junction tumors, 38% in diffuse tumors and 56% in patients with distal/intestinal tumors.

According to Dr. Shah, investigators testing agents such as cetuximab (Erbitux, Bristol-Myers Squibb), panitumumab (Vectibix, Amgen), sorafenib (Nexavar, Bayer Healthcare Pharmaceuticals) and trastuzumab (Herceptin, Genentech) have not examined the effectiveness of these agents by subtypes of gastric cancer.

“Many of these [agents] have been studied in gastric cancer, but virtually none have actually defined the diseases they have studied. They [the researchers] have grouped them all together,” said Dr. Shah. He thinks clinical trials should be designed to address or account for disease heterogeneity that occurs within a disease and also globally.

“Understand your target. Understand your disease,” he said. “I think we are approaching that in gastrointestinal malignancies, and therefore the future is bright.”

■ Dr. Shah has received research funding from Genentech and Sanofi.

Dr. El-Rifai reported no conflicts of interest.

16

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Classification of, Risk for Cholangiocarcinoma Reviewed

BY CAROLINE HELWICK SAN FRANCISCO—For patients with cholangiocarcinoma (CCA), the distinction between intrahepatic and extrahepatic cholangiocarcinoma (IH-CCA and EH-CCA, respectively) has become increasingly important, as epidemiologic features, biologic and pathologic characteristics and clinical course are different,

according to Domenico Alvaro, MD, of the Sapienza University of Rome, in Italy.

CCA is a cancer arising from the neoplastic transformation of the biliary epithelium. Its incidence is increasing worldwide, as is associated mortality. IHCCA and EH-CCA are the two classifications of CCA, with the second-order bile ducts acting as the separation point.

Dr. Alvaro described the differences in etiology between the two types of CCA

in an invited lecture at the American Society of Clinical Oncology 2012 Gastrointestinal Cancers Symposium.

The incidence of CCA varies globally, with very high rates being observed in Asia. In northeast Thailand, CCA represents about 90% of total primitive liver cancers. In contrast, in Australia, CCA represents less than 3% of total primitive liver cancers.

Temporal trends in incidence of

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IH-CCA and EH-CCA also vary by country. In many Western countries, the incidence of IH-CCA progressively increased between 1980 and 2000, while during the same period of time, the incidence of EH-CCA was stable or slightly decreasing. Epidemiologic data from 2000 to 2007 show that the incidence of IH-CCA has increased in Korea, has been stable in Italy, France, Germany, England–Wales, and the United States, and is declining in Denmark; in all of these countries, the incidence of EHCCA is stable or slightly decreasing, even in more recent determinations.

It is important for clinicians to understand that risk factors for the two classifications of CCA are different, Dr. Alvaro said.

Hepatic infection by liver flukes (e.g., Clonorchis sinensis, Opisthorchis viverrini) and hepatolithiasis are associated with the high incidence of CCA in Asian countries.

A recent meta-analysis of risk factors for CCA, based on 10 published studies, revealed an odds ratio of 4.84 for infection with liver flukes (Shin HR et al.

Cancer Sci 2010;101:579-585). The study found that in the presence of O. viverrini infection, the incidence ratio of CCA to hepatocellular carcinoma (HCC) is 8:1; in the absence of such infection, CCA is outnumbered by HCC by a ratio of 1:8.

“This is important, as more than 25 million persons worldwide are infected with these organisms,” Dr. Alvaro noted.

“Untreated liver flukes are the main reason for IH-CCA in many countries.

The implementation of a more intensive preventive and treatment program may reduce the incidence rates of CCA in endemic areas.”

In Western countries, hepatitis C virus

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Table. Risk Factors For Cholangiocarcinoma Abnormal pancreaticobiliary junction with bile duct dilatation Alcohol use Caroli’s disease Cholangitis Cholecystectomy Choledocholithiasis Cholelithiasis

toxins. Risk factors for CCA are outlined in the Table.

All risk factors for CCA share chronic inflammation of the bile duct, cholestasis, and cholangiocyte damage and proliferation as common features.

In this regard, “CCA could be considered a prototype of inflammation-associated cancer,” Dr. Alvaro said. “However, in more than 60% of cases, no putative risk factor is detectable.”

Tushar Patel, MD, professor of medicine at Mayo Clinic, Jacksonville, Fla., who moderated the session where this lecture was presented, commented that although CCA is not common, it is still a significant problem for gastroenterologists, as the risk factors are often “underrecognized.”

“We are now identifying more risk factors for cholangiocarcinoma than we previously appreciated, especially HBV,

HCV and cirrhosis,” Dr. Patel said.

Because the intrahepatic and extrahepatic forms of the disease are very different, it is important for clinicians to appreciate that they have different etiologies, Dr. Patel stressed.

■

Dr. Alvaro has received research funding from Karo Bio. Dr. Patel reported no conflicts of interest.

Diabetes Genetic polymorphisms Hepatic schistosomiasis Hepatitis B virus infection Hepatitis C virus infection Hepatolithiasis Inflammatory bowel disease Liver cirrhosis Liver flukes Obesity Primary sclerosing cholangitis Surgical biliary–enteric drainage Tobacco use Toxins (e.g., Thorotrast, dioxins, asbestos)

(HCV) infection is the most robust risk factor for CCA. “The burden of HCV could explain the increased incidence of CCA registered in the period 1980 to 2000, in these countries.”

In the meta-analysis by Shin et al, infection with HCV carried an odds ratio of 1.8, whereas hepatitis B virus (HBV) infection had an odds ratio of 4.8.

HCV is a definite risk factor only for IH-CCA. “The more advanced the liver disease, the more significant the association,” Dr. Alvaro said. Similarly, HBV seems to be associated only with IHCCA. “In general, the higher the HBV prevalence, the greater the significance of the association with CCA,” he said.

Risk factors exclusive for IH-CCA include hepatolithiasis and HCV infection, among the definite risk factors, and hepatic schistosomiasis, liver cirrhosis and HBV infection are probable risk factors. The only definite risk factor exclusive for EH-CCA is an abnormal pancreaticobiliary junction with bile duct dilatation; the two probable risk factors include cholelithiasis and cholecystectomy. The most important risk factors shared by both forms of CCA include hepatic infection by liver flukes, primary sclerosing cholangitis, choledochal cysts and exposure to Thorotrast (a radiocontrast agent, now abandoned) and other

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18

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Sedation Guideline continued from page 1

for gastroenterology fellows, fellowship directors and established gastroenterologists.

“One of the main reasons for developing the curriculum was that we felt, as a group, that developing a reference guide to procedural sedation training was necessary,” said lead author and editor of the guideline, John Vargo, MD, who is vice chairman of the Digestive Disease Institute and chairman of Gastroenterology and Hepatology at Cleveland Clinic, in Ohio.

“We attempted at the outset to include experts from various specialties and make the document as broad as possible,” Dr. Vargo said.

The document, published jointly in The American Journal of Gastroenterology, Gastroenterology, Gastrointestinal Endoscopy, Hepatology and Gastroenterology Nursing was a collaborative effort between the American College of Gastroenterology (ACG), the American Gastroenterological Association (AGA), American Society for Gastrointestinal Endoscopy (ASGE), the American Association for the Study of Liver Diseases (AASLD) and the Society of Gastroenterology Nurses and Associates (SGNA). It is available in full on the ASGE website at www.asge.org/WorkArea/showcontent.aspx?id=15396.

Professional non-GI societies and regulatory organizations also were invited to the table. The American Association of Nurse Anesthetists (AANA) did not respond to the invitation, and the Centers for Medicare & Medicaid Services (CMS) declined the request to participate, but the American Society of Anesthesiologists (ASA) did send a nonvoting observer who participated in the developmental process.

“Our goal was to supply GI fellows as well as GI fellowship training directors with comprehensive training resources for procedural sedation. The document includes an entire spectrum of topics from preprocedural assessment, basic pharmacology, airway management and informed consent, right up to how we assess our trainees for competency in each area,” Dr. Vargo said, noting that they used the standard GI core curriculum as a benchmark for development of the document.

“Another important piece of this was to develop the curriculum for the practicing gastroenterologist as a reference guide, or to provide an update to newer techniques in procedural sedation,” he added. “It was meant to be comprehensive. I think we really achieved a balance of covering the bandwidth of the training in procedural sedation while making it not an unwieldy document.”

The document is divided into 11 sections, which the participants recognized as essential for the practice of procedural sedation in GI endoscopy, with the importance of each topic described in full, and a description of the goals of training, the training process, and an assessment of competence in each area.

Those areas include sedation pharmacology, informed consent for endoscopic sedation, periprocedural assessment for endoscopic procedures, levels of sedation, training in the administration of specific agents for moderate sedation, training in airway/rescue techniques and management of complications, intraprocedural monitoring, postprocedural assessment training, endoscopy in pregnant and lactating women and assessment of competency in endoscopic sedation.

The MSCGE is in no way meant to be a static document and Dr. Vargo anticipates that it will be revised every three to five years to reflect major developments

in endoscopic sedation. “We really see it as a living document that will be reviewed and revised as further developments in pharmacology as well as the science of competency-based training evolves,” he said.

Douglas Rex, MD, professor, Department of Medicine, Indiana University School of Medicine; director of Endoscopy, Indiana University Hospital, Indianapolis; and a co-author of the MSCGE, anticipates future changes to the document will hinge to some extent on changes in the regulatory and political environments surrounding endoscopy-driven propofol, a topic touched on only briefly in the document.

‘One of the main reasons for developing the curriculum was that we felt, as a group, that developing a reference guide to procedural sedation training was necessary.’

—John Vargo, MD

‘We attempted at the he outset to incl include lude experts from various specialties and make the document as broad as possible.’

—John Vargo, MD

“To the extent that regulatory issues from CMS or FDA change, the specific aspects [of MSCGE] with regard to the pharmacology of different drugs or methods of delivery will need to be updated, and the relative importance of different sections will change, too,” Dr. Rex said.

“But it’s really hard to predict what will happen. The current environment has been influenced by many factors—it’s not just the evidence or science, but the opinions of regulatory groups as to whether evidence created by expert gastroenterologists interested in sedation can transition safely into community practice,” said Dr. Rex. “Further, it’s clear that financial incentives are part of the politics.

“That said, I think it was important to establish a curriculum, that it’s a good curriculum, and that Dr. Vargo’s point about it being a living document means that, as things change, we’ll hopefully need to update the document to reflect changes in the regulations regarding what gastroenterologists can do in sedation,” Dr. Rex concluded.

Lawrence B. Cohen, MD, clinical professor of

medicine, Mount Sinai School of Medicine, New York City, considers MSCGE quite similar to position statements on sedation published by the AGA and ASGE in recent years, but suggested that the lack of discussion of propofol use represents a sea change in the stance of GI societies on the topic.

“The statement is as important in what it doesn’t say as in what it does,” Dr. Cohen said.

“I think there is general acknowledgment, No. 1, that the idea of non-anesthesiologists training in and using propofol has become rather unpopular, and second, that some of the regulatory statements that came out recently—particularly the clarification statement issued

by CMS—seemed to put that issue pretty much out of the reach of most of us in gastroenterology,” Dr. Cohen said. “So I think the societies decided not to broach the subject.”

John Tetzlaff, MD, professor of anesthesiology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, in Ohio, who was not involved in MSCGE, was impressed by the document’s comprehensiveness.

“Frankly, if I were writing a protocol for anesthesia residents about to have their first experience giving resi aneesthesia for gastroenterology procedures, I couldn’t imaagine a better document,” said Dr. Tetzlaff. “Given thaat none of the authors are anesthesiologists, that’s quiite remarkable.” q He does wonder, however, how MSCGE will actually H be used. “It is not at all clear to me how this document willl become a course that will be a regular part of GI felllowship, but ultimately, that is the responsibility of thee GI world,” he said.

Dr. Tetzlaff was pleased to note recognition of the D rolee of emergency support for endoscopy sedation perform med by non-anesthesiologists. “The section for indications for using anesthesia team members is very lucid cat and, in a lot of places, matches the expectations of the anesthesia groups.”

He also noted that the design of the comprehensive bibliography, which is divided into segments by subject, makes it easy for readers to research key articles for more information. “A lot of consensus documents conclude with 300 references and you’re left to wonder what they’re about or you have to dig them out of the article,” he said.

The one area Dr. Tetzlaff felt needed a bit more exploration was the role of capnography. “Evidencewise, I agree with their statement that there is currently no data showing the benefits of capnography in adults undergoing upper endoscopy or colonoscopy,” he said.

“But many things in the article are expert opinions of the authors, and I think if the panel had been broadened to include an equal number of endoscopists and people who provide anesthesia for endoscopists, capnography would have been more strongly advocated.”

Dr. Tetzlaff also acknowledged that any discussion of propofol in endoscopic sedation is touchy. “When you say the words sedation, propofol and gastroenterologists, there is immediately controversy and a lot of different opinions on that subject,” he said. “I’m sure that’s partly why this document was built.”

The MSCGE is published in Gastroenterology, American Journal of Gastroenterology, Gastrointestinal Endoscopy, Hepatology and Gastroenterology Nursing and is available in full on the ASGE’s website.

■

19

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Twitter continued from page 1

‘When I started tweeting

he’s put out more than 20,000 tweets and racked up 3,433 foollowers, giving him one of the larggest followings on Twitter for a sellf-identified gastroenterologist.

He calls Twitter “useeful, helpful, informative for physiciaans.”

two years ago, it was just to try it out, to gain more followers for my blog. I never imagined that it would be such a valuable tool for me.’

—Ryan Madanick, MD

Twitter Basics One doesn’t have to have a Twitter account to know thaat this social media platform, based on messages sent in a 140-characteer format, is revolutionizing the waay information is spread. By doing so, it’s opening up a new style of conversaations about health care, one in which everr y player—patients, physicians, policymakkers—can connect summarily, albeit superrficially.

Today, more than 200 million Twitter accounts exist. Accord ding to the Pew Internet and American Life Prooject, 13% of U.S. Internet users have used or curreently use Twitter. One-third of U.S. consumers have used sociial media to find health-related d consumer reviews of treatments orr doctors; one in three have sought inforrmation related to other patients’ experiences wiith their disease; and one in four have posted comments about their health experience.

As for physicians on Twitter, no one has an exact figure; some studies are currently under way that will examine physician and subspecialty participation in social media. Notably, not all physicians self-identify as physicians on Twitter; some use it anonymously, or for strictly personal purposes. Some physicians are represented by their hospital or department tweets. Then, there are the self-identified physicians. As of September 2012, approximately 1,200 physicians were registered with the Directory of Twitter Doctors. But it is believed that this number represents only a proportion of the physicians on Twitter.

Whatever the actual figure, there’s no question that only a small minority of physicians tweet.

“When I joined, I thought I was already the second

As of September 2012, approximately 1,200 physicians were registered with the Directory of Twitter Doctors. But it’s believed that this number represents only a proportion of the physicians on Twitter.

wave of physicians p y on Twitter,” , said Dr. Madanick.

“We’re still barely in the first wave—maybe 0.05% of physicians are on Twitter. It’s probably less.”

Bryan Vartabedian, MD, pediatric gastroenterologist at Texas Children’s Hospital, Baylor College of Medicine, in Houston, is one of the more prolific gastroenterologists on Twitter. Dr. Vartabedian has sent out more than 15,700 tweets and amassed more than 10,500 followers. He also writes about the intersection of medicine, social media and technology on his blog, 33charts.com.

“Gastroenterologists are not heavily represented in the public space,” said Dr. Vartabedian. “We see a fair number of pediatricians, OB/GYNs and orthopedic surgeons, but not gastroenterologists.”

Most gastroenterologists who spoke with

A Twitter Primer

BY CHRISTINA FRANGOU Twitter Defined Twitter is a free social networking site. Users may post messages up to 140 characters in length, called “tweets,” to their followers.

Getting Started Register online at www.twitter. com. There, set up a username

and password. You can choose to add a photo and brief description to your profile page. You also may select to protect your tweets so that only approved followers can read your posts.

Once you’re established, you can select the Twitter accounts that you would like to follow.

(See “Who To Follow,” for some

Gastroenterology & Endoscopy N News said that they do not use Twitter.

Said one: “I do NOT tweet. I have little interest in others’ moment-to-moment thoughts, and really don’t want to share my thoughts or daily activities.”

Tailoring Twitter to Your Needs Plenty of gastroenterology, endoscopy and general health care information is being called out in 140-character bits on Twitter—some of it helpful, some not. For a physician, plucking out the useful information can be difficult, but also beneficial. For example, Twitter can be a great way to network. It’s a way to meet other researchers, to advertise upcoming events or to discuss issues in patient care.

GI-friendly ideas.) In turn, you’ll be able to track who is following your tweets. You also can block specific individuals from following you.

Twitter has a help site to assist new users in setting up their account and finding followers (http://support.twitter.com/ groups/31-twitter-basics).

The Lingo A few common Twitter terms are: • Retweet: reposting another person’s tweet • Tweeps: Twitter followers

see Twitter, page 20

• @: used to call out user names in tweets; for example, to address Gastroenterology & Endoscopy News, you’d start the message with @gastroendonews.

• Hashtag: used to mark keywords or topics within a tweet; common hashtags used by physicians include #hcsm (health care social media) and #meded (medical education).

• Direct messages: Private tweets between the sender and recipient • Lists: Curated groups of other Twitter users. (Lists are a good way to find physicians).

20

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Who To Follow COMPILED BY CHRISTINA FRANGOU Gastroenterologists and Other Physicians @Atul_Gawande, Atul Gawande, MD: surgeon and writer @Doctor_V, Bryan Vartabedian, MD: pediatric gastroenterologist and blogger (www.33charts.com) from Texas Children’s Hospital, Baylor College of Medicine, Houston; leader in the health care/social media space @DonaldJensenMD, Donald Jensen, MD: hepatologist specializing in liver disease, viral hepatitis and cirrhosis at the University of Chicago Medical Center @ericbenchimol, Eric Benchimol, MD, PhD: pediatric gastroenterologist and clinical researcher in inflammatory bowel diseases, based in Ottawa, Ontario, Canada @gastrodocmattar, Mark C. Mattar, MD: gastroenterologist and hepatologist at MedStar Georgetown University Hospital, Washington, D.C. @gastromom, Meenakshi Budhraja, MD: Arkansas gastroenterologist @GlassHospital, John Schumann, MD: general internist and medical educator at the University of Oklahoma School of Community Medicine, Tulsa; blogs about the workings of medical practice and how to improve the health care experience for patients (www.glasshospital. com) @hjluks, Howard Luks, MD: orthopedic surgeon, blogger (www.howardluksmd.com) and advocate for patient-centered care @kevinmd, Kevin Pho, MD: writer (www.kevinmd.com) and internal medicine physician; leader in health care social media @RyanMadanickMD, Ryan Madanick, MD: assistant professor of medicine, University of North Carolina at Chapel Hill School of Medicine @SkepticalScalpel: surgeon who tweets and blogs about medicine at

Twitter continued from page 19

Also, Twitter is a very targeted way to get up-to-the-minute news about things that affect your practice and patients. For instance, organizations like the Centers for Disease Control and Prevention and the FDA use their Twitter feeds to send out real-time updates on things like pandemics, emergencies and drug approvals. All of the major gastroenterology professional societies also are on Twitter, tweeting about things like annual meetings, publication of major studies and member-related news. Additionally, every major gastroenterology/hepatology and medical journal has a Twitter presence. When used in this way, Twitter can serve as a highly personalized, continuously updating news feed of a physician’s most valued interests.

Twitter also has the potential as a resource to help grow the size of one’s practice and/or to find patients for clinical trials. Donald M. Jensen, MD, professor of medicine and director of the University of Chicago’s Center for Liver Diseases, joined Twitter three years ago to find patients for hepatitis C trials.

“I thought it might be an easy starting point. I don’t check Twitter very often so it hasn’t been terribly helpful for clinical trials so far. But you never know where this will lead.”

Dr. Vartabedian said that physicians can tailor how they use Twitter to get the results they want. For example, if a physician is interested in only one type of information—say, updates on new drugs—he or she can follow only users who send out information relevant to that topic.

“If you follow 20 to 30 really smart people—people who are part of a conversation that you are interested in, be it endoscopy, interventional endoscopy, whatever—you can get a really great signal or feed that will provide you with remarkable information.”

Dr. Vartabedian stressed that physicians can control what they want to say, if indeed, they want to say anything at all.

“I use Twitter more for listening than for speaking, for following than for driving the conversation,” he said.

For individuals who want to use Twitter without being “seen,” that’s also possible. One simply locks the account so that only your “Tweeps” (i.e., Twitter

www.skepticalscalpel.blogspot.com @tauseefalimd, Tauseef Ali, MD: assistant professor of medicine and director, Inflammatory Bowel Center, University of Oklahoma College of Medicine, Oklahoma City @thefoodgutdoc, Scot Lewey, DO: gastroenterologist and blogger (www.thefooddoc.com) in Colorado Springs, Colorado Professional Societies @AASLDNews: American Association for the Study of Liver Diseases @AmCollegeGastro: American College of Gastroenterology @AmerGastroAssn: American Gastroenterological Association @ASGEendoscopy: American Society for Gastrointestinal Endoscopy @CCFA: Crohn’s & Colitis Foundation of America @cdchep: CDC’s Division of Viral Hepatitis @DDWMeeting: Digestive Disease Week meeting @IFFGD: International Foundation for Functional Gastrointestinal Disorders @NASPGHAN: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Publications @AnnalsofIM: Annals of Internal Medicine @ArchInternMed: Archives of Internal Medicine @gastroendonews: Gastroenterology & Endoscopy News @GIE_Journal: Gastrointestinal Endoscopy @Gut_BMJ: Gut @JAMA_current: Journal of the American Medical Association @JCGjournal: Journal of Clinical Gastroenterology @JPGNonline: Journal of Pediatric Gastroenterology and Nutrition @NEJM: The New England Journal of Medicine @TheLancet: The Lancet

followers who you have approved) can see the account.

Importantly, Twitter is a good way for physicians to be a part of a dynamic conversation that is already happening among physicians, patients and policymakers.

“We cannot work in a very isolated way, in little silos,” Dr. Vartabedian said.

“We need to be part of a broader conversation, a broader knowledge base, for us to remain relevant as a profession.”

Twitter Faux Pas Physicians generally are able to maintain a high degree of professionalism and steer clear of privacy violations on Twitter. This has been shown in a small study published last year in which a group of physicians from the VA Medical Center in Washington, D.C., studied 260 self-identified physicians with 500 or more Twitter followers (Chretien KC et al. JAMA A 2011;305:566-568). The investigators tracked physician tweets over a one-month period and coded the results, looking for potentially unprofessional tweets. Of 5,5156 tweets analyzed, 49% were health- or medical-related, 21% were personal communications,

14% were retweets and 58% contained hyperlinks. Of the tweets, 3% (144 of 5,5156) were categorized as unprofessional: 0.7% of tweets represented potential patient privacy violations, 0.6% contained profanity, 0.3% included sexually explicit material and 0.1% included discriminatory statements. Nine of 10 of physicians who sent tweets that included potential privacy violations were identifiable by a full listed name on their profile, profile photograph or full listed name on a linked website.

The investigators concluded that Twitter might be enormously beneficial, but that health professionals could benefit from education and guidelines about use of social media.

Self-identified physicians on Twitter share medical information with the public, with the potential to positively affect health, wrote Katherine C. Chretien, MD, and colleagues. “Accountability for health professionals, in addition to greater education and guidelines, may be needed to maximize potential society and professional benefit through engagement with social media.”

Medical schools are getting on board with the idea that educating physicians

21

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Follow us on twitter

@

gastroendonews

and aspiring physicians about social media is critical. This year, four medical schools were awarded two-year grants to help educate faculty members and medical students on use of social media. The project aims to teach faculty, who can then instruct students, on how to use social media sites like Twitter and Facebook to benefit patient care while maintaining professional standards.

“The next generation of doctors needs to understand how social media can be a double-edged sword,” said principal investigator Elizabeth Kitsis, MD, director of bioethics education and assistant professor of epidemiology, population health and medicine at Albert Einstein College of Medicine in New York City, in a statement. “It can be a great way to provide personalized medical education for patients. However, great attention must be paid to maintaining the principles of professionalism, such as privacy and confidentiality of the physician–patient relationship.”

In 2010, the American Medical Association issued a policy statement to help physicians keep their online experiences positive and preserve the integrity of the

patient–physician relationship, including the following recommendations: • Use privacy settings to safeguard personal information.

• Routinely monitor your own Internet presence to ensure that online personal and professional information is accurate and that content posted by others is accurate and appropriate.

• Maintain appropriate boundaries of the patient–physician relationship online and ensure patient privacy and confidentiality is

maintained.

• Consider separating personal and professional content online.

• Recognize that actions online can negatively affect your reputation among patients and colleagues.

Dr. Vartabedian said that adhering to professional standards and preventing privacy violations comes down to two simple rules: 1) Never post anything online that you wouldn’t want disseminated among your colleagues, and 2) avoid any mention of specific patient information.

So, Is It Time To Start Tweeting?

Social media experts suggest that it is certainly not a bad time to check out Twitter. Dr. Madanick recommends: “When people ask me about Twitter, I say that you don’t need to do it unless you are really interested in it. Twitter is very good for some people, particularly those who can listen and respond succinctly to information.”

“It’s certainly worth checking out. If you want to be involved, if you’re interested, try it. Sign up. If you sign up and don’t like it, you haven’t lost anything.” ■

BRIEF SUMMARY: Consult the Full Prescribing Information for complete product information.

LIALDAÂŽ (mesalamine) Delayed-Release Tablets

Rx only

INDICATIONS AND USAGE LIALDA is indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis and for the maintenance of remission of ulcerative colitis.

CONTRAINDICATIONS LIALDA is contraindicated in patients with known hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of LIALDA. [See Warnings and Precautions, Description and Adverse Reactions in the Prescribing Information] WARNINGS AND PRECAUTIONS Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as LIALDA that contain mesalamine or are converted to mesalamine.

It is recommended that patients have an evaluation of renal function prior to initiation of LIALDA therapy and periodically while on therapy. Exercise caution when using LIALDA in patients with known renal dysfunction or a history of renal disease.

In animal studies, the kidney was the principal organ for toxicity. [See Drug Interactions and Nonclinical Toxicology in the Prescribing Information] Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difďŹ cult to distinguish from an exacerbation of ulcerative colitis. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, and sometimes fever, headache, and rash. Observe patients closely for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with LIALDA. Hypersensitivity Reactions Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to LIALDA tablets or to other compounds that contain or are converted to mesalamine.

Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported with LIALDA and other mesalamine medications. Caution should be taken in prescribing this medicine to patients with conditions predisposing them to the development of myocarditis or pericarditis.

Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering LIALDA to patients with liver disease.

Upper GI Tract Obstruction Pyloric stenosis or other organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastric retention of LIALDA which would delay mesalamine release in the colon.

ADVERSE REACTIONS The most serious adverse reactions seen in Lialda clinical trials or with other products that contain or are metabolized to mesalamine are: s 2ENAL IMPAIRMENT INCLUDING RENAL FAILURE [See Warnings and Precautions (5.1)] s -ESALAMINE INDUCED ACUTE INTOLERANCE SYNDROME [See Warnings and Precautions (5.2)] s (YPERSENSITIVITY REACTIONS [See Warnings and Precautions (5.3)] s (EPATIC IMPAIRMENT INCLUDING HEPATIC FAILURE [See Warnings and Precautions (5.4)] Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reďŹ&#x201A;ect the rates observed in practice. LIALDA has been evaluated in 1368 ulcerative colitis patients in controlled and open-label trials.

Induction of Remission In two 8-week placebo-controlled clinical trials involving 535 ulcerative colitis patients, 356 received 2.4 g/day or 4.8 g/day LIALDA tablets and 179 received placebo. The most frequent adverse reaction leading to discontinuation from LIALDA therapy was exacerbation of ulcerative colitis (0.8%).

Pancreatitis occurred in less than 1% of patients during clinical trials and resulted in discontinuation of therapy with LIALDA in patients experiencing this event. Adverse reactions occurring in LIALDA or placebo groups at a frequency of at least 1% in two 8-week, double blind, placebo-controlled trials are listed in Table 1. The most common adverse reactions with LIALDA 2.4 g/day and 4.8 g/day were headache (5.6%and 3.4%, respectively) and ďŹ&#x201A;atulence (4% and 2.8%, respectively).

Table 1: Adverse Events in Two Eight-Week Placebo-Controlled Trials Experienced by at Least 1% of the LIALDA Group and at a Rate Greater than Placeboa,b

The following adverse reactions, presented by body system, were reported infrequently (less than 1%) by LIALDA-treated ulcerative colitis patients in the two controlled trials.

Cardiac Disorder:: tachycardia Vascular Disorders:: hypertension, hypotension Skin and Subcutaneous Tissue Disorders: acne, prurigo, rash, urticaria Gastrointestinal Disorders:: abdominal distention, colitis, diarrhea, pancreatitis, rectal polyp, vomiting Investigations:: decreased platelet count Musculoskeletal and Connective Tissue Disorders:: arthralgia, back pain Nervous System Disorders:: somnolence, tremor Respiratory, Thoracic and Mediastinal Disorders:: pharyngolaryngeal pain General Disorders and Administrative Site Disorders:: asthenia, face edema, fatigue, pyrexia Ear and Labyrinth Disorders:: ear pain Maintenance of Remission of Ulcerative Colitis The dose evaluated in three studies of LIALDA given for the maintenance of remission in patients with ulcerative colitis was 1.2 g twice daily or 2.4 g/once daily. One of these studies was a 6-month double-blind comparator study while two were 12- to 14-month open-label studies.

The most common adverse reactions with LIALDA in the maintenance arms of long-term trials were colitis ulcerative (5.8%), headache (2.9%), liver function test abnormal (2.3%), and abdominal pain (2.2%). Of the 1082 subjects in the all maintenance studies pooled, 1.9% had severe adverse reactions. The most common severe adverse reactions were gastrointestinal disorders; these were mainly symptoms associated with ulcerative colitis.

Table 2: Adverse Reactions in Three Maintenance Trials Experienced by at Least 1% of the LIALDA Group (maintenance phases of trials)

The following adverse reactions, presented by body system, were reported infrequently (less than 1%) by LIALDA-treated ulcerative colitis patients in the three long-term maintenance trials (maintenance phases of these trials): Cardiac Disorder:: tachycardia Skin and Subcutaneous Tissue Disorders:: acne, alopecia, pruritis, urticaria Gastrointestinal Disorders:: colitis, ďŹ&#x201A;atulence, nausea, pancreatitis, rectal polyp, vomiting Nervous System Disorders:: dizziness Respiratory, Thoracic and Mediastinal Disorders:: pharyngolaryngeal pain General Disorders and Administrative Site Disorders:: asthenia, pyrexia Ear and Labyrinth Disorders:: ear pain Postmarketing Experience In addition to the adverse reactions reported above in clinical trials involving LIALDA, the adverse reactions listed below have been identiďŹ ed during post-approval use of LIALDA and other mesalamine-containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole:: lupus-like syndrome, drug fever Cardiac Disorders:: pericarditis, pericardial effusion, myocarditis Gastrointestinal: pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer Hepatic:: jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, Kawasaki-like syndrome including changes in liver enzymes Hematologic:: agranulocytosis, aplastic anemia Neurological/Psychiatric:: peripheral neuropathy, Guillain-Barre syndrome, transverse myelitis Renal Disorders:: interstitial nephritis Respiratory, Thoracic and Mediastinal Disorders:: hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis) Skin:: psoriasis, pyoderma gangrenosum, erythema nodosum Urogenital:: reversible oligospermia DRUG INTERACTIONS .O INVESTIGATIONS OF INTERACTION BETWEEN ,)!,$! AND OTHER DRUGS HAVE BEEN PERFORMED (OWEVER

the following interactions between mesalamine medications and other drugs have been reported.

Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal antiinďŹ&#x201A;ammatory drugs (NSAIDs) may increase the risk of renal reactions.

Azathioprine or 6-mercaptopurine The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood disorders.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats at doses up to 1000 mg/kg/day (1.8 times the maximum recommended human dose based on a body surface area comparison) and rabbits at doses up to 800 mg/kg/day (2.9 times the maximum recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Mesalamine is known to cross the placental barrier.

Nursing Mothers Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. The clinical signiďŹ cance of this has not been determined and there is limited experience of nursing women using mesalamine. Caution should be exercised if LIALDA is administered to a nursing woman.

Pediatric Use Safety and effectiveness of LIALDA in pediatric patients have not been established.

Geriatric Use Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia and pancytopenia in patients who were 65 years or older who were taking mesalamine-containing products such as LIALDA. Caution should be taken to closely monitor blood cell counts during mesalamine therapy.

Clinical trials of LIALDA did not include sufďŹ cient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients. Systemic exposures are increased in elderly subjects. [see Clinical Pharmacology in the Prescribing Information]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reďŹ&#x201A;ecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients.

OVERDOSAGE LIALDA is an aminosalicylate, and symptoms of salicylate toxicity may include tinnitus, vertigo, headache, confusion, drowsiness, sweating, seizures, hyperventilation, dyspnea, vomiting, AND DIARRHEA 3EVERE INTOXICATION MAY LEAD TO DISRUPTION OF ELECTROLYTE BALANCE AND BLOOD P(

hyperthermia, dehydration, and end organ damage.

There is no speciďŹ c known antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may be beneďŹ cial in the event of acute overdosage. Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy. Adequate renal function should be maintained.

Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087, USA

by Cosmo S.p.A., Milan, Italy. By license of Giuliani S.p.A., Milan, Italy.

U.S. Patent No. 6,773,720 Š 2011 Shire US Inc. Rev. 08/11 LIA-02667

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER NOVE 2012

23

Watch and Wait for Rectal Cancer?

Wat Watch Brad Champagne, MD

Conor P. Delaney, MD

Albert S. DeNittis, MD

Associate Professor of Surgery Division of Colorectal Surgery Case Western Reserve Medical Center and University Hospitals of Cleveland Program Director, Accreditation Council for Graduate Medical Education Colorectal Residency Surgical Director Community Center of Excellence Digestive Health Institute

Chief, Division of Colorectal Surgery Surgical Director, Digestive Health Institute Vice Chairman, Department of Surgery University Hospitals Case Medical Center, Professor of Surgery Director, Center for Surgery and Simulation Case Western Reserve University Cleveland, Ohio

Clinical Associate Professor Lankenau Institute for Medical Research Chief of Rradiation Oncology Lankenau Medical Center Wynnewood, Pennsylvania

Richard M. Goldberg, MD

Angelita Habr-Gama, MD

Gerald Marks, MD

Klotz Family Professor of Medicine Physician in Chief Arthur G. James Cancer Hospital Wexner Ohio State Medical Center Associate Director Ohio State University Comprehensive Cancer Center Columbus, Ohio

Professor of Surgery University of Sao Paulo School of Medicine Sao Paulo, Brazil

Professor of Surgery Colorectal Surgeon Lankenau Medical Center Wynnewood, Pennsylvania

John H. Marks, MD

Tim Nguyen, MD

Rodrigo Perez, MD

Chief, Section of Colorectal Surgery Main Line Health Program Director Fellowship in Minimally Invasive Surgery and Rectal Cancer Management Lankenau Medical Center Wynnewood, Pennsylvania

Gastrointestinal Medical Oncologist Cleveland Clinic Weston, Florida

Professor of Surgery University of Sao Paulo School of Medicine Sao Paulo, Brazil

Theodore Saclarides, MD Director, Division of Colorectal Surgery Loyola University Health System Professor of Surgery Loyola University Chicago Stritch School of Medicine Chicago, Illinois

COMPILED AND WRITTEN BY COLLEEN HUTCHINSON

W

riting this column on the eve of the World Congress of Endoscopic Surgery in Puerto Vallarta, I am reminded of

The past decade has given witness to a sea change in the manage-

how dedicated these colorectal surgeons and oncologists

ment of the patient with rectal cancer. As new approaches evolve,

are to research, education and surgical and oncological advancement.

each apparent discovery brings with it new and unexpected ques-

Some of the contributors to this column stayed at work late to provide

tions. Proper consideration of these questions and the formulation

their heir responses; some wrote theirs over their weekend weekend, carving out time

of personalized patient care guidelines aimed at providing the high-

that they share with their families; and some did it on the plane to Puerto

est quality of life while maximizing cure demand a multidisciplinary

Vallarta. I even had one person send his from an airport in Asia during

approach by dedicated experts. This roundtable, by providing a

a layover.

forum for airing some of the many penetrating issues with commentary by the experts, offers an opportunity to sensitize and enlighten

Thank you to all of this month’s contributors for their candid beliefs, opinions and observations, and most importantly for the time it took to share them. Where would we be without the thought leaders who operate, innovate and educate in their own operating rooms and across the globe? This roundtable centers on innovative approaches in colorectal surgery and highlights topics that develop at the intersection of colorectal surgery and colorectal oncology—including neoadjuvant therapy, transanal endoscopic microsurgery, watch and wait, and what the colorectal surgery patient deserves to know. All of these areas of debate were covered at the Eighth International Rectal Cancer Consensus Conference at Lankenau Medical Center. Also at that meeting, the formation of the new Multidisciplinary International Rectal Cancer Society was announced, and here we have a message from its founders:

readers of the need to remain alert to evolving data that shift treatment paradigms. The members of the recently organized Multidisciplinary International Rectal Cancer Society wish to express their appreciation to the editors of Gastroenterology & Endoscopy News for permitting this timely and important dialogue.

So read on for some illuminating perspectives on the topics that colorectal surgeons should keep abreast of to best serve their patients. A special thank you goes out to Dr. Gerald Marks, a true pioneer in colorectal surgery, for being a shining beacon of innovation and patient advocacy in a distinguished career that continues today. see Rectal Cancer, page 24

24

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Rectal Cancer continued from page 23

Agree or disagree: Patients deserving radical rectal resection should always be informed of the laparoscopic option.

Dr. Goldberg: The current ACOSOG (American College of Surgeons Oncology Group) trial is evaluating the relative risks and benefits of laparoscopic versus open rectal surgery. In the COST (Clinical Outcomes of Surgical Therapy) trial run by the ACOSOG and the North Central Cancer Treatment Group (NCCTG) in the 1990s (Clinical Outcomes of Surgical Therapy Study Group. N Engl J Medd 2004;350:2050-2059), this technique was proven to be both safe and effective for colon cancer resection. A cautious approach to the integration of this technique in patients who are not enrolled in clinical trials is prudent until data becomes available from the studies under way.

surgeons and patients need to remember that an operation is not laparoscopic simply because it is called laparoscopic. For rectal cancer surgery, specimen extraction sites—the largest incision—have been as large as Pfannenstiel or lower midline incisions for laparoscopic-assisted surgery, or as small as transanal or transostomy site extraction. In my own practice, most patients with rectal cancer have the specimen removed through the ileostomy site, and go home on acetaminophen for analgesia, with three other 5-mm port sites. I believe these outcomes and potential for recovery need to be discussed with patients who have rectal cancer.

‘Standard treatment for T1 rectal cancer should be total mesorectal excision. Local excision should be considered an alternative treatment strategy, particularly for frail patients unable to undergo major abdominal surgery or for those who refuse abdominal perineal excision when this treatment is the primary surgical alternative.’

—Angelita Habr-Gama, MD, and Rodrigo Perez, MD

Dr. J. Marks: On the fence. For colon cancer I would give an unqualified “agree”! The data are overDr. Champagne: I disagree. For colon cancer, whelming in favor of laparoscopy. In fact, if open surhowever, they should always be informed. gery was somehow the new procedure it would never be allowed to be adopted, Dr. Saclarides: Patients based on all the studshould be informed about lapaies. For rectal cancer, ‘Patients should be informed roscopy, and included in the disthere are very promcussion should be the fact that a ising individual and about laparoscopy, and prospective, randomized, nationspecialized center data, included in the discussion wide multi-institutional but this hasn’t been valtrial is under way in the idated yet in a prospecshould be the fact that a United States to determine tive randomized trial. prospective, randomized, its efficacy compared with open The ACOSOG Z6501 surgery. Until these data are availtrial is under way and nationwide multi-institutional able, the surgeon should do his should address this trial is under way in the United or her best operation that follows issue. With a personal States to determine its efficacy the basic principles of obtaining experience of more negative margins and doing the than 300 laparoscopic compared with open surgery.’ level-appropriate mesorectal excitransanal endoscopic —Theodore Saclarides, MD sion for lymph node clearance. microsurgery (TEM) resections and a local Dr. Nguyen: Agree. In a recurrence rate of less retrospective study, disease-free than 5%, I am confiand overall survival seem to be comparable with open dent of what the outcome will be, and I believe it will surgery but with less postoperative complications and favor the laparoscopic approach. shorter hospital stay.

Drs. Habr-Gama and Perez: Definitely!

Dr. Delaney: I agree that laparoscopy almost always should be discussed for radical rectal cancer surgery. Dr. DeNittis: Agree. Surgical ability, however, plays Although there are some patients who are not candidates a role here. Laparoscopic resections are limited by the because of morbid obesity, multiple prior operations or number of surgeons who can perform them. If not perrequirements for multivisceral resection, the majority formed properly, the patient can be at risk for increased of patients are candidates for a laparoscopic approach. recurrence rates with increased local quality-of-life issues.

Many randomized controlled trials and meta-analyses have clearly shown that patients with colon cancer have Dr. G. Marks: Agree, with hesitancy. Just as colon better outcomes with laparoscopy—at least equivalent cancer is effectively and advantageously managed lapaoncological outcomes, with lower complication rates, less roscopically, it appears that surgery for rectal cancer may pain and earlier recovery. Fewer studies have been per- enjoy the same benefits. Although I am inclined to say formed for rectal cancer, but these studies now include that patients should be informed of the option as a matseveral randomized trials and many large comparative ter of informed consent, we probably are not there yet series by experienced surgeons. Not surprisingly, laparos- because the conclusive data are not in hand. copy has again shown equivalent oncological outcomes to open surgery. Short-term benefits for rectal cancer have Agree or disagree: been similar to colon surgery. Knowing the variability of methods and incisions used for laparoscopy, and espe- Local excision without neoadjuvant cially laparoscopy for rectal cancer, it is no surprise that therapy should be the standard for T1 short-term benefits have been called into question. I think rectal cancer.

Drs. Habr-Gama and Perez: No! Standard treatment for T1 rectal cancer should be total mesorectal excision. Local excision should be considered an alternative treatment strategy, particularly for frail patients unable to undergo major abdominal surgery or for those who refuse abdominal perineal excision when this treatment is the primary surgical alternative. There is hope that neoadjuvant chemoradiotherapy (CRT) followed by local excision will be a valid and appropriate treatment strategy in the future for these patients.

Dr. Champagne: I agree as long as there are no high-risk features and the risk for recurrence is well explained to the patient who would otherwise tolerate a formal resection. The patient can then make an educated decision about surveillance or more surgery.

Dr. G. Marks: Disagree. A treatment failure for a T1 cancer in my mind is unpardonable, and the reported local failure rates for local excision alone are unacceptably high. Radical resection with sphincter preservation or full-thickness local excision (FTLE) after neoadjuvant CRT is preferable.

Dr. Goldberg: In the hands of expert surgeons and with compulsive visual follow-up, the outcomes for local excision with T1 lesions are excellent and avoid the need for more aggressive therapy and the potential long-term complications of radiation or more extensive surgery. It is critical to scope patients regularly to permit early detection and definitive management of local recurrence.

Dr. J. Marks: Disagree. The results to date, from major centers, show failure rates anywhere from 5% to 19% with T1 cancers treated by local excision alone.

This is unacceptable for a group of patients who should have the best results, and the local recurrence rate for unfavorable cancers at our institution and other places is only 3%. For selected cancers (SM1 or very small foci of cancers), as with medically compromised patients, it is an excellent option.

Dr. Nguyen: Agree. For T1 disease, local control and survival are not improved by addition of neoadjuvant CRT. Dr. DeNittis: Disagree. Due to the high local see Rectal Cancer, page 26

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EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Rectal Cancer continued from page 24

failure rates and possibility of lymph node metastases, Dr. Saclarides: Even if downstaging has occurred I don’t know why with neoadjuvant therapy, one wouldn’t radical surgery is still the consider neoadsurgical option of choice ‘Even if downstaging has occurred with juvant therapy. because residual cancer may neoadjuvant therapy, radical surgery is It seems we have be present in endoscopically a chance here to normal areas far removed still the surgical option of choice because cure this subfrom the post-treatment residual cancer may be present in group of patients scar or ulcer. TEM/FTLE but offer them in this setting is an option, endoscopically normal areas far removed suboptimal therhowever, for elderly from the post-treatment scar or ulcer.’ apy. If neoadjupatients, patients —Theodore Saclarides, MD vant CRT is not with comorbid conconsidered, then ditions that render radical radical resection surgery risky or for patients should be performed. In our experience with high-dose who absolutely refuse to have a stoma for life. radiation to 5,580 cGy prior to surgery, patients do extremely well.

Dr. DeNittis: Agree. Determining the type of surgery on a patient-by-patient basis in this subgroup of Dr. Saclarides: This statement may apply for downstaged patients is critical. The timing of the type of most T1 rectal cancers; however, the surgeon needs to surgical procedure should be eight to 10 weeks post-therreview the slides with a pathologist who has a dedicated apy. There are tumors that respond slowly and the patience interest in gastrointestinal cancers. If there is deep pen- to wait for that response is very important. We are finding etration into the submucosa, or the lesion is poorly dif- that some patients can be long-term survivors with local ferentiated or has lymphovascular invasion, then radical surgery alone. surgery is probably preferable. If local excision is chosen, the patient must be informed about recurrence rates of Dr. Nguyen: On the fence. Although few retroabout 10% and should undergo close periodic follow-up spective studies suggest TEM/FTLE is safe for T3 so that recurrences can be salvaged. downstaged to T0 to T1 after neoadjuvant CRT, no randomized study has been conducted to answer this question. Having a complete responder of the rectal lesion on Agree or disagree: TEM/FTLE is not equal to no residual disease in the Selective transanal endoscopic lymph node or mesorectum.

microsurgery/full-thickness local excision (TEM/FTLE) is acceptable for the downstaged distal rectal cancer.

Dr. G. Marks: Agree. Selective TEM/FTLE is an acceptable option in the downstaged rectal cancer, particularly when the surgeon cannot technically offer sphincter preservation. Secondary determinants come into play and radical restorative resection for the young, fit patient offers a statistical advantage. Reading between the lines, the issue of the timing of surgical decision making is the pivotal point. The state of the cancer after neoadjuvant therapy and a suitable interval should determine the surgical decision.

Dr. Goldberg: Most patients should be enrolled in trials to help to better define the relative outcomes of these approaches compared with standard abdominal perineal resection or low anterior resection. In selected cases where patients refuse definitive surgery or are too high-risk medically for surgery due to comorbid medical conditions, this approach can be considered with careful review of the risks and benefits. Compulsory screening for local recurrence, as well as systemic imaging, should be a part of any post-procedure surveillance plan.

Drs. Habr-Gama and Perez: Despite this treatment strategy sounding appropriate, long-term oncological outcomes are yet unavailable. Considering that the risk for nodal metastases is closely related to final pathologic ypT status, TEM/FTLE may be acceptable for ypT0 and ypT1.

Dr. J. Marks: Agree. This is an excellent option, especially when the other alternative is an abdominoperineal resection (APR). Pathologic ypT3 or node-positive disease should be followed then by a radical resection.

The decision should be based on the characteristics of the cancer after therapy. The lesion should be nonulcerated and less than 4 cm. All of the mural induration with a 1-cm margin must be excised. Using this approach, we have had a 4% local recurrence, but longer follow-up is needed.

Dr. Champagne: Disagree. This may become standard in the next decade as we become more adept at determining which tumors are amenable to this approach. However, for now, it is only acceptable in patients who cannot tolerate formal resection.

Agree or disagree: Selective TEM/FTLE for the downstaged rectal cancer should not be limited to the distal rectum.

Dr. Saclarides: My response is the same as for the preceding statement. TEM, however, does provide longer reach and improved access to lesions in the mid and upper rectum.

Dr. G. Marks: Agree. TEM in the hands of the proficient surgeon permits safe sphincter-preserving FTLE for cancers in the mid and upper rectum when

general and local factors indicate the advisability of FTLE. Drs. Habr-Gama and Perez: Selective TEM/FTLE for the downstaged rectal cancer shouldd be limited to the distal rectum.

Dr. J. Marks: Agree. TEM gives the ability to extend local excision into the proximal rectum. With pathologic complete response ranging up to 30%, this approach offers an excellent option. Of course, the challenge remaining for all local therapy is to predict which rectal cancers will have lymph node involvement. Armed with this knowledge, I would advocate TEM much more aggressively, but unfortunately we are still grappling with this issue.

‘TEM gives the ability to extend local excision into the proximal rectum.

With pathologic complete response ranging up to 30%, this approach offers an excellent option.’

—John Marks, MD

Dr. Goldberg: If the experienced surgeon is confident that higher rectal tumors can be excised transanally and pathologic review is favorable for clear margins, this approach can be considered in tumors that are not in the distal rectum and that have been downstaged by preoperative neoadjuvant therapy. This is not a standard approach at this time, however.

Dr. DeNittis: Agree. When selecting the patient appropriately, FTLE is an excellent option for the mid to upper rectum, provided the surgeon has the proper technical expertise and is fully knowledgeable from the oncologic standpoint.

Dr. Nguyen: Agree, TEM for the downstaged rectal cancer can be performed for mid and upper rectal cancers.

Agree or disagree: Watchful waiting for the complete responder should be restricted to institutional review board (IRB)-approved study programs.

Dr. Saclarides: This statement is absolutely true and the patient should be informed that watchful waiting is not the standard of care in the United States.

Drs. Habr-Gama and Perez: Watchful waiting should be restricted to centers with expertise in rectal cancer management and multidisciplinary settings.

Dr. Goldberg: It is clear that complete response is a favorable predictor for a good long-term outcome.

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

In practice, it is sometimes necessary due to patient preference or risk of definitive surgery to individualize care.

Restricting this to research patients in unusual circumstances does not seem reasonable, provided the patient is informed of risks and follow-up is individualized to fit the circumstances.

Dr. Champagne: It also can be considered in elderly high-risk patients as long as they are compliant with aggressive surveillance.

Dr. Nguyen: Agree. We do not yet have the modality that can evaluate with reasonable certainty a clinical complete response that correlates with pathologic complete response.

‘Tumor assessment is critical to developing the proper strategy for managing patients after neoadjuvant

Dr. J. Marks: Agree! This is a very exciting development and has real promise. That said, there is still a great deal to learn in its applicability. The major concern that I have is that this is being inappropriately applied to patients who are significant operative challenges. There is mucosal regression, but still a sizable cancer left in the wall and these patients are just being followed. We have seen too many patients who have had their treatment inappropriately delayed, with persistent, unrecognized cancer. I think this would be minimized if this was only done under protocol.

therapy.’

—Richard M. Goldberg, MD

Agree or disagree: Surgical decision making should always await tumor assessment following neoadjuvant therapy and a suitable interval.

Dr. G. Marks: Agree. Following the published results of watchful waiting for the complete responder Dr. Champagne: Disagree. There are many by the Habr-Gama group, there was a rush to embrace cases when the appropriate surgical procedure (APR this revolutionary concept. I fear that this is driven by vs. colo-anal) can be determined after the office visit surgeons unable or disinclined to and pelvic magperform sphincter-presnetic resonance ervation surgery for lowimaging. How‘Watchful waiting should be limited lying lesions. Recognizing ever, there also to IRB-approved study programs in the complete responder with any are some patients degree of certainty requires excepwho are “bordercenters with high volume.’ tional experience and advanced line” and their —Gerald Marks, MD knowledge of the appearance of ultimate fate can the neoadjuvant-treated rectal be better assessed cancer. Accordingly, watchful after neoadjuvant waiting should be limited to IRBtherapy. approved study programs in centers with high volume.

Dr. J. Marks: Agree. This is the only way the Dr. DeNittis: Agree. Although there appears to patient and surgeon can enjoy the full benefit of tumor be data supporting this approach, it certainly is not the downstaging. Although I would never advocate a ministandard of care. Clinical trials will ensure the proper mal margin for a mid to upper rectal cancer after treatsimilarities in patient selection and treatment techniques. ment, in the distal rectum, where sphincter preservation

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hangs in the balance, the advantages to this approach are obvious. Using this mindset, many centers, including our own, have been able to show a decrease in permanent colostomy rate from 25% to 40% to 10% or less.

Dr. Goldberg: Tumor assessment is critical to developing the proper strategy for managing patients after neoadjuvant therapy.

Dr. G. Marks: Agree emphatically. A small body of latecomers to neoadjuvant therapy, perhaps borrowing a page from the treatment of head and neck cancers, advocated that the selection of the surgical procedure be determined by the original presentation of the tumor rather than after neoadjuvant therapy. Nothing speaks so loudly as the strikingly improved results of local or radical sphincter-preserving surgery following neoadjuvant therapy where otherwise APR would be indicated.

Dr. Saclarides: This statement is false for most patients who have acceptable operative risks.

The decision as to which operation is best for such patients should be based on pretreatment tumor size, location and distance from the anus. Until more data are available, the decision should not be based on how much downstaging occurs with radiation and chemotherapy.

Drs. Habr-Gama and Perez: Definitely.

Dr. DeNittis: Agree. There is a significant amount of new evidence to suggest that surgical decision making should be based on the neoadjuvant tumor response and not the pretreatment staging. The response may be predictive of outcome and patient-by-patient decision making is crucial. The patient who would otherwise be considered only a candidate for APR would frequently be considered for low anterior resection.

Dr. Nguyen: Agree. Regression of a large tumor that would have required an APR can be evident in four to 12 weeks following neoadjuvant therapy, possibly allowing for conversion to sphincter-sparing surgery.

■

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OPINION

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31

Individual continued from page 4

magazine, Atul Gawande, a Harvard surgeon, wrote about the efficiencies, quality and cost control of the Cheesecake Factory restaurant chain as a model for improvements in medical care delivery.

Airline pilots no longer our role models in anesthesiology, our new role models deliver crab cakes and teriyaki chicken … but, oh so efficiently.

A Postmodern Philosophy We have all heard about the advantages of replacing the individualistic phyp y sician making clinical decisions based d on his judgment, education and experieence with uniform algorithm-driven mediccine.

Minimizing variation and increasing predictability, we are told, will improve care and decrease costs. But, in addition n to those practical reasons, I believe deeep structural changes must have occurreed to allow this viewpoint, unthinkablee a generation ago, to become an everyday reality.

I believe the answer lies in th he migration of postmodern conttinental philosophy to the elite bastions of American education. Tod day’s

medico-political-educational opinion leaders, Boomers and Gen Xers, alumni of Ivy League schools—the best of the “best of the best”—came of age in an atmosphere steeped in the words of Derrida, Lyotard, Foucault, Baudrillard and other intellectuals whose thoughts and writings became voguish in the 1970s. These ideas subsequently penetrated state universities and community colleges, became part of the standard curriculum and spread mimetically

throughout the culture. Today art, architecture, critical theory, science, medicine, psychiatry and, in many ways life in general, are viewed through the postmodern lens.

A cornerstone concept of postmodern philosophy is the importance of the collective over the individual. (Incidentally, this is curious since postmodernism developed out of existentialism, in which individual responsibility was paramount).

As reported by Roger Kimball in his

book, “Tenured Radicals: How Politics Has Corrupted Our Higher Education” (Ivan R. Dee), a 1984 Stanford University conference of “formidable scholars” essentially declared the death of the concept of the individual as defined by classic liberal Enlightenment thinking, the American Declaration of Independence and the U.S. Constitution. In its place was an ill-defined “reconstructed postcultural entity,” whatever that means.

The postmodern generation is obsessed with the idea that we are all in th his together. This is so obvious a truism aas to be banal, but do they take it too far?

Does this approach translate to remote D ccontrol of medical decision making by aanonymous experts, far removed from a particular doctor–patient interaction?

In Dr. Gawande’s view, at least, such a syystem deserves a chance—indeed, he aargues, it’s the future for many hospitals.

Our leaders may not deliberately have decided to deconstruct Marcus Welby, d M.D. and his weekly TV struggles M aagainst medical conformity. But trapped in n their postmodern Weltanschauung, they simply could not help themselves.

■

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

PPACA continued from page 3

Even a strict constructionist Verrilli froze. He couldn’t think of any. It was the “if the glove doesn’t fit you must acquit” moment for the anti-mandate side. New York’s Mayor Michael Bloomberg’s assault on 32-ounce colas was still months away, so there was still a belief among rational people in the gallery that somewhere, boundaries separating our private lives from the expanding domain of the nanny state would be found and enforced by the

court’s decision in this case when the mandate was overturned.

Then the president weighed in with his now infamous warning that it would be “unprecedented” for the court to strike down a law duly passed by an elected majority of both houses of Congress. The characterization of Obamacare as a bipartisan bill aside, the only thing unprecedented about the president’s statement was

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the failure by a constitutional lawyer to recognize that striking down bills passed by elected officials is in fact the only business the court is in. Surely the president, even though he was in fact not a constitutional law professor at the University of Chicago Law School as advertised, but a paid “senior lecturer,” knew that. The only way to make sense of his comment was that he expected defeat, and was setting the stage for a

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with a grudge couldn't force himself to rule that it was the court’s business to run health care. Good for him.

full frontal attack on the conservative court for judicial activism in thwarting the will of the people and depriving them of all the benefits of PPACA. Given the disastrous results of the 2010 interim elections for Democrats who had to run on the newly minted health care law, many pundits thought that the politically savvy president secretly preferred to run as a victim of the conservative court’s misanthropy rather than as a defender of a bill that was becoming increasing unpopular as voters were beginning to understand the president’s quaint pledge that no one happy with their current insurance would be affected by this bill. It also didn’t help that Europe was imploding; crushed by entitlements they couldn’t afford, and California was doing a credible imitation of Greece. The markets were queasy, and the Office of Management and Budget had revised upward the cost of the bill, and reminded everyone it could be even worse if the assumptions provided by the current administration proved inaccurate. For a president who seemed to value getting re-elected above all else, getting out from beneath this bill by a court decision he could vilify didn’t seem like a bad way to go.

For their part, liberals yearning for the fulfillment of the 100-year quest for socialized medicine believed that at least one conservative justice, probably Anthony Kennedy, would split from the pack and rule that the prohibition against regulating “inactivity” was too soft an argument to thwart Congress’ will. Although the concept of there being no constitutional basis to compel activity was clever, the court would not recognize “inactivity” as

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

for political reasons he was trying to snatch defeat from the jaws of victory.

Whatever. The intrigue was over.

Even a strict constructionist with a grudge couldn’t force himself to rule that it was the court’s business to run health care. Good for him.

The postmortem began and we learned that Mr. Roberts initially sided with the other four conservative justices to strike down the mandate, but then

changed his mind. We don’t know why and it certainly wasn’t because the solicitor general dazzled him. His conservative colleagues were sliding him messages under his door inquiring if he really believed Congress should regulate a Kansas farmer who grew corn for his own consumption. Despite the cajoling, the chief justice was immovable in his basic premise that government has a duty to tend to the nation’s business.

33

Perhaps Mr. Roberts saw this as an opportunity to restore the nonpartisan reputation of a court that had been injured by the Bush v. Gore (2000) decision that left a big ideological cleavage in the country.

My own belief is that although the issue of the mandate was brought to the court by conservatives, the chief justice could never convince himself see PPACA, page 34

New

a constitutionally protected right like freedom of speech, religion and congregation.

Liberals also pointed to legal precedent for regulating inactivity under the Commerce Clause. In the famous Wickard v. Filburn (1942) case, the court ruled that Congress had jurisdiction over a Kansas corn farmer who grew corn only for his own consumption under the theory that anything that affects the supply of corn by dumping or withholding affects the price and is therefore interstate commerce, even if a single ear never left the farm, no less crossed the state line. Because the price of insurance is affected by the number of policy holders, not buying insurance affects the price and not buying it is therefore “commerce” and therefore is subject to regulation by Congress. Clear as a bell, no?

With a 5-4 conservative majority in the court, handicappers were predicting that, short of a defection, PPACA would be struck down.

The Decision and Postmortem When the decision was announced, you could hear the agonized ululations of conservatives everywhere from Fox News to Rush Limbaugh to the Drudge Report and Breitbart. Almost as divesting as the decision was the unexpected betrayal of the dependable conservative chief justice, who not only sided with the liberal majority, but also wrote the opinion that simply stated, it’s the job of Congress and not the Supreme Court to manage health care. When stated this way, it seems so irrefutable and makes one wonder why the president had framed his statement in a manner sure to antagonize, unless

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OPINION

34

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

PPACA continued from page 33

that being compelled to buy health insurance violated any true sensibility of conservative doctrine that purports to put a premium on personal responsibility and accountability for one’s actions.

I think he believed that the mandate issue was merely the best legal pretext for overturning a law that conservatives found objectionable for a host of other reasons and a legal challenge is always the quickest way to expedite repeal.

Live Free or Die The problem with all these bold proclamations about not buying insurance is that everyone knows despite all the rhetoric about the ‘uninsured,’ that everyone is covered. Go to any hospital with an emergency room and at least 10% of the beds will be filled with the homeless, the indigent and the uninsured.

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Full disclosure. I’m also conservative by nature, but in the past I have advocated forcing everyone to buy health insurance, especially young adults who were making BMW payments instead of paying for premiums. I found nothing about mandatory health insurance that violated any of my conservative beliefs. I saw not buying health insurance as unrealistic and irresponsible, and not a noble expression of one’s commitment to the concepts of personal freedom and liberty.

I got angry letters from people who said it was like forcing people who don’t own a car to buy auto insurance. The analogy does not hold because people who do not drive do not need auto insurance. People without health insurance get sick. When I see a guy on TV with the “Live Free or Die” t-shirt saying he doesn’t want the government telling him he has to buy health insurance (or wear a helmet) because it’s an infringement on his liberty, I know he knows that when his Harley skids off the road and hits a tree, he’s not going to be left for road kill. He’s going to be scooped up and helicoptered to a Level 1 trauma center where $1 million are going to be spent putting Humpty Dumpty back together again.

I’ll take these Don’t-Tread-on-Me types seriously when I see a signed advance directive pinned to their shirts declining any care at the public’s expense when they get sick or injured. Those people don’t have to buy insurance. If there are a dozen of them, I’d be surprised.

The problem with all these bold proclamations about not buying insurance is that everyone knows despite all the rhetoric about the “uninsured,” that everyone is covered. Go to any hospital with an emergency room and at least 10% of the beds will be filled with the homeless, the indigent and the uninsured. EMTALA [Emergency Medical Treatment & Labor Act] is the name of their insurance company.

Those “conservatives” who refuse to recognize that they might get sick or hurt, and that when they do they’ll get free care at their neighbor’s expense are really camouflaged liberals who expect and demand free treatment as a “right.”

Strip off the philosophical varnish of the conservative about “freedom” and the net result to society is the same. They are all “takers” who will never understand that they are taking from people, not the government. The government doesn’t come in the middle of the night to sew them up; a person does. The government doesn’t appear in court as a defendant when they’re not happy with how their scar looks; a person does. It’s not even

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

the government that pays for them. The government is a conduit from our pockets to theirs. Loud antigovernment rhetoric should not be permitted to disguise the real intentions of people who are takers, regardless of whom they vote for and what side of the aisle they sit on.

Constitutionality My guess is that Mr. Roberts never believed the mandate was a fundamental conservative issue, and that the court didn’t need to extend itself to protect the phony prerogatives of people too dense to understand and provide for the vagaries and inevitabilities of the human condition.

The chief justice’s opinion could have stopped with the affirmation of the right of Congress to deal with health care.

President Obama and the Democrats would have been a lot happier if it did.

But Mr. Roberts, knowing he would face violent criticism from the right, went on to opine that the reason why the mandate was constitutional was because it was a tax and not a penalty for inactivity, despite what Minority Speaker Nancy Pelosi and Majority Speaker Harry Reid called it during the legislative process. OMG. A TAX. And not even on the 1-percenters, because they’ve all got health insurance. No one disputes the right of Congress to tax, and that is exactly what it’s doing. A tax on the middle class doesn’t play well in Peoria on the campaign trail.

And Mr. Roberts didn’t stop there.

The mandate derived its authority

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from the power to tax and not from the Commerce Clause, that infinitely elastic regulator of interstate commerce that provided the pretext for virtually everything Congress wanted to do for the past 50 years. The Wickard v.

Filburn decision allowed Congress to bulldoze its way into every nook and cranny of American life, including onto the private cornfields of a Kansas farmer minding his own business. By shunning

this decision that liberals wanted to use as the pretext to regulate inactivity, the chief justice put a gigantic stop sign in front of the bulldozer.

And Mr. Roberts could have stopped there. But he didn’t. He further opined that members of Congress had every right to impose socialized medicine on the people for exactly the reason stated

by President Obama when he allegedly was jawboning the court to uphold the

35

mandate. Congress is a duly elected body voted into office for the purpose of representing the people and giving them what they want and need. If for any reason people don’t like how the president or Congress interprets exactly what it is they need, then they should use, as Justice Ruth Bader Ginsberg stated, “deferred settlement of the issue.”

Translation: Vote for someone else. see PPACA, page 38

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Indication and Important Safety Information Prepopikâ&#x201E;¢ for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. r 1SFQPQJL JT DPOUSBJOEJDBUFE JO UIF GPMMPXJOH DPOEJUJPOT QBUJFOUT XJUI TFWFSFMZ SFEVDFE SFOBM GVODUJPO HBTUSPJOUFTUJOBM PCTUSVDUJPO PS JMFVT CPXFM perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should CF BEWJTFE PO UIF JNQPSUBODF PG BEFRVBUF IZESBUJPO BOE QPTU DPMPOPTDPQZ MBC UFTUT TIPVME CF DPOTJEFSFE JG B QBUJFOU EFWFMPQT TJHOJGJDBOU WPNJUJOH or signs of dehydration after taking Prepopik r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r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r 1SFQPQJL TIPVME OPU CF VTFE JG HBTUSPJOUFTUJOBM PCTUSVDUJPO PS QFSGPSBUJPO JT TVTQFDUFE 1SFQPQJL JT OPU GPS EJSFDU JOHFTUJPO &BDI QBDLFU NVTU CF EJTTPMWFE JO PVODFT PG DPME XBUFS BOE BENJOJTUFSFE BU TFQBSBUF UJNFT JO BEEJUJPO UP BEEJUJPOBM DMFBS GMVJET BDDPSEJOH UP UIF EPTJOH SFHJNFO *O SBOEPNJ[FE NVMUJDFOUFS DPOUSPMMFE DMJOJDBM USJBMT OBVTFB IFBEBDIF BOE WPNJUJOH XFSF UIF NPTU DPNNPO USFBUNFOU FNFSHFOU BEWFSTF SFBDUJPOT (>1%) following Prepopik administration 1MFBTF TFF CSJFG TVNNBSZ PG 1SFTDSJCJOH *OGPSNBUJPO GPMMPXJOH UIJT BEWFSUJTFNFOU

New Prepopik helps patients arrive ready with: t Lowest volume of active prep solution and a flexible hydration schedule1 t Demonstrated non-inferiority, with both split-dose and day-before regimen1 t Superior cleansing efficacy with ACG-recommended split-dose vs day-before regimen comparator*1 – 84% vs 74%, respectively, achieving “excellent or good” visualization, validated per the Aronchick scale* t A dual mechanism that stimulates peristalsis and produces osmotic water retention1 *Evaluated in a randomized trial. The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efficacy endpoint was the proportion of patients with successful colon cleansing defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists.1

To learn more, scan this code with your smartphone, or go to www.prepopik.com.

Reference: 1. Prepopik™ Prescribing Information, July 2012.

Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

© 2012 Ferring B.V. PREPOPIKTM is a trademark of Ferring B.V. PREP_LJAD_001_0912

38

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ NOVEMBER 2012

PPACA continued from page 35

The Fallout No wonder that although President Obama â&#x20AC;&#x153;won,â&#x20AC;? he looked like he had lost all 32 games in the opening bracket of the NCAA tournament. Although conservatives were wailing in self-pity and rancor, apparently incapable of understanding that they had truly won, the president seemed to immediately understand the court was doing him no favors. He tried to pretend he was

happy, but really was at a loss for words to express his joy. He knew Mr. Roberts had yoked him with PPACA for the coming campaign season and by this time he probably rues the day he didnâ&#x20AC;&#x2122;t take former president Bill Clintonâ&#x20AC;&#x2122;s advice to stay away from health care.

Itâ&#x20AC;&#x2122;s a monster that will consume those that try to control it. Better to nibble around the edges with incremental reforms that are affordable. He looked

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Information for complete product information.

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INDICATIONS AND USAGE PREPOPIKâ&#x201E;˘ (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults.

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The uninsured hoard of 30 million faceless people who had been the abstract representation of the liberalsâ&#x20AC;&#x2122; love for mankind was suddenly coming to life and competing with them for their doctorsâ&#x20AC;&#x2122; attention.

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dour and thin-lipped when he gave his usual perfunctory salute to the 2 million young adults now able to enjoy extended adolescence by staying on their parentsâ&#x20AC;&#x2122; insurance policy until 26 years of age, thanks to the law; as if extending dependency nearly into middle age were a good thing. He seemed disinclined to discuss much of anything else in the 3,500-page law that the court had salvaged, especially the mandate that

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was now officially a new tax on the middle class. There was the obligatory mention of the 30 million uninsured and those with preexisting conditions, but people were on to the fact that their care was going to be paid for by new taxes on the middle class. The uninsured hoard of 30 million faceless people who had been the abstract representation of the liberalsâ&#x20AC;&#x2122; love for mankind was suddenly coming to life and competing with them for their doctorsâ&#x20AC;&#x2122; attention.

The decision could not have come at a worse time. One hundred and thirty million people with employersponsored insurance had just received premium increases of between 10% and 25% with explanations from the carriers that the increase was in anticipation of underwriting losses due to 30 million new customers with unmet health needs flooding the system. Someone also was going to have to pay the expense of insuring those with preexisting illnesses who had been denied coverage. And all those wonderful â&#x20AC;&#x153;freeâ&#x20AC;? benefits mandated by the law? Turns out they are actually not free. They too will be paid for. The insurance companies are not in business to lose money.

At least the premium notices didnâ&#x20AC;&#x2122;t say at the bottom, â&#x20AC;&#x153;If youâ&#x20AC;&#x2122;re happy with your insurance and care, nothing will change.â&#x20AC;? That would be cruel. Little

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

wonder the president chose not to go there, sticking with the 26-year-olds who can now continue to sponge off Mommy and Daddy until they find a real job, as if that is something that they might be able to do in today’s economy.

So, Who Shot J.R.?

Who shot J.R.? That was easy.

The mistress, who else? Who won the mandate war? Well, that’s about as clear and easy to understand as the

going to do with health care from either candidate has been deeply distressing.

We just spent one full year on an idiotic, meaningless debate about whether or not compelling someone to buy health insurance is constitutional. J.R. says it is, so it is. We should have just called him a year ago and saved ourselves all the trouble. We could have spent the time and energy picking over the 3,500 pages of PPACA to find some stuff

worth salvaging that most could agree on, and unloading all the crap that really needs to go, like the Independent Payment Advisory Board and worthless bureaucracies that will have the entire medical profession as card-carrying members of the Service Employees International Union within a decade, which I’m sure is the ultimate intent of the law.

The great health care debate with the

denouement in the Supreme Court had the original “Who Shot J.R.” beat by a mile for complexity and intrigue. So much so that now that the smoke has cleared, you can’t even tell the winners from the losers. How great is that?

And they said “Who shot J.R.?” was much ado about nothing.

■

Think of Enterography as a GPS for Crohn’s disease.

presidential candidates’ positions on health care issues when either can pull themselves away from discussing Bain Capital and Barack Obama’s Columbia and Harvard transcripts.

In a nutshell, President Obama supports the mandate that he violently opposed and called unconstitutional when he ran against Hillary Clinton in the 2008 presidential Democratic primary. Now that it passed, he’s really happy. Not. Mitt Romney is against the same mandate that he imposed in Massachusetts that nearly ate the state treasury and demoralized the medical profession. He was proud of it then and disavows it now. He claims that that mandate was different from the one he now opposes, but other than one was state and the other federal, they’re identical twins. When you ask the candidates about health care, they both squirm and look like you’re about to produce an embarrassing picture from a college frat party. For the tumult that led up to decision day, health care fell off the public’s radar like an expensive Hollywood blockbuster that gets bad word of mouth on opening weekend and winds up on DVD in two weeks.

As a doctor, taxpayer, patient and voter, the lack of even a semblance of intelligent discussion on what we’re

Image shows not only thickening of the bowel wall, but also the increased attenuation of the mucosa compatible with active Crohn’s disease.*

Enterography gives you a highly effective diagnostic tool for evaluating and managing treatment of small bowel disorders like Crohn’s disease.1 By producing abdominal images that provide clear visualization of the small bowel wall and lumen,2 enterography shows the degree, extent and location of Crohn’s disease3 and is quickly becoming a first-line exam in leading IBD Centers for the evaluation of small bowel disorders.2 For more information about the benefits of enterography for small bowel diagnostics, please contact Bracco Professional Services at 1-800-257-5181, option 1. * Representational image, individual results may vary. Image courtesy of Alec Megibow, MD, NYU REFERENCES: 1. Bruining DH, Siddiki HA, Fletcher JG, et al. Benefit of computed tomography enterography in Crohn’s disease: Effects on patient management and physician level of confidence. Inflamm Bowel Dis. 2012;18(2):219-225. 2. Fletcher JG. CT enterography technique: theme and variations. Abdom Imaging. 2009;34(3):283-288. 3. MDCT and 3D imaging of the small bowel and mesentery.

Mahmoud M. Al-Hawary, MD, Ravi K. Kaza, MD, and Joel F. Platt, MD, University of Michigan Health System, Ann Arbor, MI. Applied Radiology. 2011 Nov;40(11). ©2012 Bracco Diagnostics Inc. All Rights Reserved.

39

40

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

New Software Introduced To Track Residents’ Performance For Future ACGME Accreditation Requirements A provider of information and management systems for medical training institutions, MyEvaluations.com has recently launched new software that addresses the requirements of the Accreditation Council for Graduate Medical Education (ACGME) for residency programs.

In February of this year, the ACGME announced its Next

Accreditation System (NAS) that will be rolled out at the beginning of July 2013, with full implementation expected in July 2014. The new NAS requires each medical residency program accredited by the ACGME (more than 9,000 programs) to provide evidence that its residents have learned the necessary skills for patient care, including

medical knowledge, professionalism, practice-based learning and i m p ro v e m e n t , s y s t e m s - b a s e d practice and interpersonal communication skills. Teaching institutions also are required to publish the specific learning objectives they have developed for their students as benchmarks of progress. They must submit biannual reports to ACGME

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that track each resident’s performance against these benchmarks.

“The introduction of the new NAS performance-based reporting has residency programs scrambling to implement evaluation tools that capture new variables required for accreditation,” said David P. Melamed, MD, MSc, founder and CEO of MyEvaluations.com in a statement. “Our new software tools are designed to meet reporting needs efficiently and automatically. Institutions and programs can develop streamlined tools that connect their evaluations, milestones, competencies and outcomes in a single data stream.”

In a statement, Melvin Blanchard, MD, associate professor of medicine and chief of medical education at Washington University, St. Louis, said, “As one of the largest academic medical centers in the country, our immediate priority following release of NAS was how to operationalize the requirements across our residency and fellowship programs without disrupting our curriculum. MyEvaluations.com is working with us to create a customized solution that meets all of our needs.”

ACGME will update the accreditation status of each program on an annual basis, based on key performance indicators.

For more information about the software application, visit www. myevaluations.com.

—Based on a press release from MyEvaluations.com

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Norton Greenberger; Richard Blumberg; Robert Burakoff September 20, 2011 Striking the perfect balance between comprehensiveness and ease of use, this book is essential for gastroenterologists, general internists, family physicians and surgeons.The second edition has been updated to reflect the latest advances in diagnostic and therapeutic endoscopy.

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F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2012

Ethicon Launches New Endocutter for Use in Laparoscopic Surgery According to Ethicon, the new 45mm device reduces the risk for potential tissue trauma during laparoscopic surgery and extends the technology platform to include more procedures in multiple surgical specialties, including thoracic, bariatric and colorectal surgery. Compared with traditional, lever-based, two-handed endocutters, Ethicon’s new product provides easier access to transection sites that are difficult to reach and has the ability

Photo courtesy of Ethicon Endo-Surgery, Inc.

Ethicon Endo-Surgery, Inc., recently launched a new innovation in its line of powered endocutters—a 45mm version of the Powered Echelon Flex Endopath Stapler. The product was unveiled at the American College of Surgeons meeting in Chicago in October. It is the company’s second offering in this product line, following the introduction of the 60mm Powered Echelon Flex.

“Our powered Echelon Flex endocutters have been used in nearly 50,000 cases worldwide since they were launched in 2011,” Tim Schmid, president of Ethicon, said in a statement. “With the launch of the new 45mm stapler, we are excited to bring the benefits of this innovative technology across the range of surgical specialties, where stability and control are critical to positive patient outcomes.”

to grasp, hold and manipulate tissue without the use of a second device, the company said.

Advanced features of the stapler include system-wide compression that delivers consistent, properly formed staples; one-handed operation that minimizes movement of the distal tip for enhanced stability and surgeon-centered power that allows for manual override and the ability to pause or reverse the stapling process.

For more information about the 45mm Powered Echelon Flex, visit www.ees.com/clinicians/products/staplers/endocutters/powered-echelon-flex.

Statement of Ownership This document is a copy of the Statement of Ownership, Management and Circulation of Gastroenterology & Endoscopy News. A copy of this document must be published in Gastroenterology & Endoscopy News once per year, as required by the United States Postal Service.

—Based on a press release from Ethicon Endo-Surgery, Inc.

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43

Humira Receives Indication for Ulcerative Colitis In September, the FDA expanded its approval of Humira (adalimumab) to include the treatment of moderate to severe ulcerative colitis (UC) in adults. Combined with its 2007 approval for Crohn’s disease, Humira is now positioned to treat the two primary forms of inflammatory bowel disease.

Classified as a tumor necrosis factor (TNF) blocker, Humira may be used to control UC in the event that immunosuppressant medications such as corticosteroids, azathioprine and 6-mercaptopurine have not been effective.

“Each patient with ulcerative colitis experiences the disease differently, and treatment must be adjusted to meet each individual’s needs,” according to Donna Griebel, MD, director of the Division of Gastroenterology and Inborn Errors Products in the FDA’s Center for Drug Evaluation and Research. “[This] approval provides an important new treatment option for patients who have had an inadequate response to conventional therapy.”

Two clinical trials were conducted to establish Humira as a treatment for ulcerative colitis. In both trials, investigators used the Mayo scoring system to determine participants’ degree of UC by measuring stool frequency, rectal bleeding and endoscopy. The studies aimed to determine the number of patients whose Mayo score decreased to a value of 2 or lower after an eight-week treatment period.

The study included 908 patients

who had never been treated with a TNF blocker or who had lost response to or were intolerant of TNF blockers. At the start of the trial, all of the patients had a Mayo score of 6 to 12, with an endoscopy subscore of 2 to 3. Patients were assigned to take Humira or a placebo based on a random selection.

Results from both studies showed that a far greater percentage of patients treated with Humira achieved

clinical remission (16.5%-18.5%) compared with those on placebo (9.2%-9.3%); one of the studies also showed that the number of patients who sustained remission was twice as high in patients taking Humira as in the group on placebo (8.4% vs.

4.1%).

The studies were unable to establish the effectiveness of Humira in treating patients who had become intolerant of, or lost response to, TNF

—Based on a press release from the FDA and Abbott Laboratories

MoviPrep®

USE IN SPECIFIC POPULATIONS

(PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid for oral solution) The following is a brief summary only; see full Prescribing Information for complete product information.

Pregnancy: Pregnancy Category C. Animal reproduction studies have not been performed with MoviPrep. It is also not known if MoviPrep can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MoviPrep should be given to a pregnant woman only if clearly needed.

INDICATIONS AND USAGE MoviPrep is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older.

CONTRAINDICATIONS

MoviPrep is contraindicated in patients with the following conditions: gastrointestinal (GI) obstruction, bowel perforation, gastric retention, ileus, toxic colitis or toxic megacolon, or hypersensitivity to any components of MoviPrep.

WARNINGS AND PRECAUTIONS Use with caution in patients using concomitant medications that increase the risk of electrolyte abnormalities (such as diuretics, angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs), patients with known or suspected hyponatremia), patients at increased risk of cardiac arrhythmias, patients with a history of seizures or at increased risk of seizures such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with impaired renal function or patients taking concomitant medications that affect renal function (such as diuretics, ACE inhibitors, ARBs, or non-steroidal anti-inflammatory drugs), patients with severe ulcerative colitis or inflammatory bowel disease, patients with impaired gag reflex or patients prone to regurgitation or aspiration, patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization.

Concurrent use of stimulant laxatives and MoviPrep may increase the risk and is not recommended. The potential for mucosal ulcerations resulting from the bowel preparation should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease.

If gastrointestinal obstruction or perforation is suspected, appropriate diagnostic studies should be performed to rule out these conditions before administering MoviPrep. If a patient experiences severe bloating, abdominal distension, or abdominal pain, administration should be slowed or temporarily discontinued until symptoms abate.

Patients with electrolyte abnormalities should have them corrected before treatment with MoviPrep. Patients should be advised to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep post-colonoscopy lab tests (electrolytes, creatinine, and BUN) should be considered. Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment.

MoviPrep contains phenylalanine (233 mg per treatment).

ADVERSE REACTIONS

In clinical trials, the most common adverse reactions for split dosing regimen (incidence 5%) were malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing regimen (incidence 5%) were abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness.

Isolated cases of urticaria, rhinorrhea, dermatitis, and anaphylactic reaction have been reported with PEG-based products and may represent allergic reactions.

Published literature contains isolated reports of serious adverse events following the administration of PEG-based products in patients over 60 years of age.

These adverse events included upper gastrointestinal bleeding from a MalloryWeis tear, esophageal perforation, asystole, and acute pulmonary edema after aspirating PEG-based preparation.

In addition to adverse reactions reported from clinical trials, the following adverse events have been identified during post-approval use of MoviPrep: hypersensitivity reactions including anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritis, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness. Fever, chills and dehydration.

DRUG INTERACTIONS Use caution when prescribing MoviPrep for patients with conditions, or who are using medications that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and prolonged QT in the setting of fluid and electrolyte abnormalities. Consider additional patient evaluations as appropriate.

Photo courtesy of Abbott Laboratories

blockers. No new side effects were established apart from those already identified, which included infections, headache and rash.

For the treatment of UC, Humira is approved for an initial dose of 160 mg, a second dose of 80 mg two weeks after the initial dose and a 40-mg maintenance dose every other week thereafter.

Oral medication administered within 1 hour of the start of administration of MoviPrep may be flushed from the gastrointestinal tract and the medication may not be absorbed.

Nursing Mothers: Because many drugs are excreted in human milk, caution should be exercised when MoviPrep is administered to a nursing woman.

Pediatric Use: The safety and effectiveness of MoviPrep in pediatric patients has not been established.

Geriatric Use: Of the 413 patients in clinical studies receiving MoviPrep, 91 (22%) patients were aged 65 or older, while 25 (6%) patients were over 75 years of age. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in responses between geriatric patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

OVERDOSAGE There have been no reported cases of overdose with MoviPrep. Purposeful or gross accidental ingestion of more than the recommended dose of MoviPrep might be expected to lead to severe electrolyte disturbances, including hyponatremia and/or hypokalemia, as well as dehydration and hypovolemia, with signs and symptoms of these disturbances. The patient who has taken an overdose should be monitored carefully, and treated symptomatically for complications.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Long-term studies in animals to evaluate the carcinogenic potential have not been performed with MoviPrep. Studies to evaluate potential for impairment of fertility or mutagenic potential have not been performed with MoviPrep.

STORAGE Store carton/container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

When reconstituted, store upright and keep solution refrigerated. Use within 24 hours.

PATIENT COUNSELING INFORMATION s Advise patients to read the Medication Guide included in the full prescribing information. s Advise patients who require a diet low in phenylalanine that MoviPrep contains phenylalanine. s Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration. s Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquid (e.g., water, clear soup, fruit juice without pulp, soft drinks, tea and/or coffee without milk) according to instructions. s Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep. s Tell patients not to take other laxatives while they are taking MoviPrep. s Tell patients that MoviPrep produces a watery stool (diarrhea) which cleanses the colon before colonoscopy. Advise patients receiving MoviPrep to adequately hydrate before, during, and after the use of MoviPrep. Patients may have clear soup and/or plain yogurt for dinner, finishing the evening meal at least one hour prior to the start of MoviPrep treatment. No solid food should be taken from the start of MoviPrep treatment until after the colonoscopy. s Tell patients that the first bowel movement may occur approximately 1 hour after the start of MoviPrep administration. Abdominal bloating and distention may occur before the first bowel movement. If severe abdominal discomfort or distention occurs, stop drinking MoviPrep temporarily or drink each portion at longer intervals until these symptoms diminish. If severe symptoms persist, notify your health provider.

Rx only

Manufactured by: Norgine B.V. Hogehilweg 7 1101 CA Amsterdam Zuidoost Netherlands For: Salix Pharmaceuticals, Inc. Raleigh, NC 27615 © 2012 Salix Pharmaceuticals Inc. Feb 12

Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive Raleigh, NC 27615 Tel. 866-669-SLXP (7597) All rights reserved.

MoviPrep® #1 prescribed branded purgative in the United States

1

Seeing is believing MoviPrep has proven 89% excellent or good cleansing when used as a split dose2 ° Low-volume PEG-3350 provides consistent, clear visibility of the entire colon ° FDA approved for PM|AM Split Dosing™ ° Osmotic laxative with electrolytes ° In clinical trials, no differences in safety and tolerability between younger and geriatric patients -Most common adverse reactions for split dosing (incidence ⱖ5%) are malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing (incidence ⱖ5%) are abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness.

Please see Brief Summary of full Prescribing Information on reverse.

References: 1. Medi-Span® Price Rx® [database online]. Indianapolis, IN: Wolters Kluwer Health. http://www.medispan.com/drug-pricing-analysis-pricerx.aspx. Accessed July 13, 2012. 2. MoviPrep [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012.

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel·866.669.SLXP (7597) MoviPrep® is a registered trademark and PM | AM Split Dosing™ is a trademark of Salix Pharmaceuticals, Inc. © 2012 Salix Pharmaceuticals, Inc. All rights reserved. MOV11/41-3

www.MoviPrep.com