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Herbal-supplement liver injuries on the rise for 10 years

VOL. 8 NO. 10 OCTOBER 2014
liver injuries on the
rise for 10 years
Used for bodybuilding and weight loss.
Wally Reeves
Dr. Trevor J. Royce said a “sizable proportion of the U.S. population
who have less than a 9-year life expectancy” had cancer screening.
Unnecessary cancer
screening in U.S.
Frontline Medical News
substantial proportion
of older adults in the
United States undergo unnecessary and even
harmful screening for colon,
prostate, breast, and cervical cancer, contrary to clear
guidelines that are widely
recognized and well publicized, according to two separate studies published online
in JAMA Internal Medicine.
In the case of colon cancer,
most of these unnecessary
screenings can be attributed
to patients getting rescreened
more frequently than at
the 10-year intervals recommended, and continued
screening past the age of 75
years is also a culprit. With
the other cancers, the main
reason for these unnecessary
procedures is continuing
screening in patients who
have a short life expectancy
because of advanced age or
irreversible health problems.
In both reports, the investigators emphasized that
unnecessary cancer screening
not only is inefcient but is
also harmful for individual
patients because it exposes
them to invasive procedures
and complications, impairs
their quality of life, and
sometimes leads to downstream overdiagnosis and
overtreatment of cancers
that would have remained
asymptomatic until the
See Unnecessary В· page 21
GI & HepatoloGy News
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Suite 2,
Plainview, NY 11803-1709
Frontline Medical News
erious liver injury
from herbal and dietary supplements
– including those used by
bodybuilders – has risen
signifcantly over the past
According to fndings
from a review, herbal supplement–related injuries
increased from 2% to 20%
of all nonacetaminophen
drug–related liver injuries.
Injuries from bodybuilding
supplements rose from 2%
to 8%, while those related
to nonbodybuilding supplements increased from 5% to
12%, Dr. Victor J. Navarro,
chair of the hepatology division at the Einstein Medical Center, Philadelphia,
and his coauthors reported
in the September issue of
Hepatology (2014 Aug. 25
[doi: 10.1002/hep.27317]).
The investigators reviewed 839 cases included
in the Drug-Induced Liver
Injury Network (DILIN)
from 2004 to 2013. Of
these, 709 were caused by
nonacetaminophen medications, 85 by nonbodybuilding supplements, and 45 by
bodybuilding supplements.
Overall, the injuries from
supplements rose from 7%
to 20%. Those related to
See Supplement В· page 6
Poor stewardship
Redundant IV antibiotics
found in 80% of
hospitals. • 5
IBD and Intestinal
Freston Conference
Several presentations were
covered; Dr. David T. Rubin,
course director, comments.
• 22
Endoscopy, Pancreas
& Biliary Tract
after RYGB
Overall rates are low; routine
removal not recommended.
• 30
AGA Spring
Postgraduate Course
Learn the latest
Moderators describe this
year’s presentations. • 32
Pill holds promise for C. diffcile
Frontline Medical News
WASHINGTON – A rationally designed microbiome-based pill successfully
eradicated recurrent Clostridium difcile infection in
29 of 30 patients in a study
presented at the annual Interscience Conference on
Antimicrobial Agents and
Preliminary data were presented at the 2014 James W.
Freston Conference sponsored by the American Gastroenterological Association
in August.
The patients in the phase
I/II study were divided into
two separate 15-patient
cohorts and were given
two diferent dose levels of
the therapy, SER-109. The
drug contains spores from
gram-positive bacteria that
are taken from stool and
then purifed to kill the vegetative bacteria, said David
Cook, Ph.D., executive vice
president and chief scientifc ofcer of Cambridge,
Mass.–based Seres Health.
The therapy appears to
See Pill В· page 22
Presorted Standard
U.S. Postage
Permit No. 384
Lebanon Jct. KY
O C TO B ER 2 0 1 4 • G I & HEPATO LO G Y NEW S
What’s your
28-year-old Vietnamese man
without any signifcant past
medical history presented
with 6 months of epigastric pain
without nausea, vomiting, fevers,
weight loss, or other symptoms.
Physical examination was normal,
as were laboratory tests, including a complete blood count, liver
function tests, and chemistry panel.
Proton pump inhibitor therapy was
administered for 2 months without
any improvement in symptoms.
was subsequently performed and
revealed a 3.5 Г— 2.5-cm submucosal
bulge at the gastroesophageal junction (Figure A). Biopsy with cold
forceps elicited persistent extravasation of a thin white fuid (Figure
B). Histology was indeterminate,
and Gram stain, acid-fast bacilli, and
cultures were negative. After endoscopy, computed tomography of the
abdomen/pelvis revealed a 3.6 Г— 2.7
Г— 2.5-cm enhancing perigastric lesion adjacent to a normal-appearing
pancreas without lymphadenopathy
(Figure C).
AGA InstItute
By Dr. Sun-Chuan Dai and Dr.
Audrey Calderwood. Published
previously in Gastroenterology
2012;142:1072, 1258, 1259.
The diagnosis appears on page 30.
[email protected]
Physicians in group practice setting make more
Frontline Medical News
hysicians in medical groups and
other organized systems of care
delivery saw a slight increase in compensation, according to annual survey data released by the American
Medical Group Association.
In general, fndings show average
percentage increases in compensation
in 2013 were slightly higher than
in 2012, with the overall weighted
average increase in 2013 being 2.9%,
up from 1.6% in the previous year.
Results were based on a survey conducted on behalf of the Medical
Group Management Association
(MGMA) by Sullivan, Cotter and
Associates, with 289 medical groups
representing about 73,700 providers
submitting valid survey responses.
Individual specialties showing the
biggest median total compensation
increase year over year include gastroenterology (a 9.0% increase to
in ChiEf
Colin W. Howden, M.D., AGAF
AssoCiAtE Editors
Joel V. Brill, M.D., AGAF
Barbara H. Jung, M.D.
John A. Martin, M.D.
Kevin D. Mullen, M.D., FRCPI
David T. Rubin, M.D., AGAF
Editor EmEritus Charles J. Lightdale, M.D., AGAF
AGA institutE stAff
Managing Editor Brook A. Simpson
Special Content Editor Lindsey M. Brounstein
Publications Coordinator Jillian L. Schweitzer
Vice President of Publications Erin C. Dubnansky
of thE AGA institutE
President John I. Allen, M.D., MBA, AGAF
President-Elect Michael Camilleri, M.D., AGAF
Vice President Timothy C. Wang, M.D., AGAF
Secretary/Treasurer Francis M. Giardiello, M.D., AGAF
AGA Research Foundation Chair Martin Brotman, M.D., AGAF
Past President Anil K. Rustgi, M.D., AGAF
В©2014 by the AGA Institute. All rights reserved. No part of
this publication may be reproduced or transmitted in any
form or by any means, electronic or mechanical, including
photocopy, recording, or any information storage and retrieval
system, without permission in writing from the publisher.
$471,336), cardiac/thoracic surgery
(8.2% to $569,073), emergency medicine (5.2% to $316,739), and neurology
(5.1% to $268,096). Total compensation
includes the total compensation of the
individual provider, including base, variable, and administrative compensation,
plus all voluntary salary reductions.
Four specialties saw compensation
decreases during this time period, including allergy/immunology (a 1.3%
decrease to $267,338), rheumatologic
disease (–0.5% to $239,112), cardiology-
Gi & hEpAtoloGy nEws is the offcial newspaper of the American Gastroenterological
Association (AGA) Institute and provides the gastroenterologist with timely and
relevant news and commentary about clinical developments and about the impact
of health care policy. Content for Gi & hEpAtoloGy nEws is developed through a
partnership of the newspaper’s medical board of editors (Editor in wChief and
Associate Editors), Frontline Medical Communications Inc. and the AGA Institute
Staff. “From the AGA” is provided exclusively by the AGA, AGA Institute, and FDHN.
All content is reviewed by the medical board of editors for accuracy, timeliness,
and pertinence. To add clarity and context to important developments in the feld,
select content is reviewed by and commented on by external experts selected by
the board of editors.
The ideas and opinions expressed in Gi & hEpAtoloGy nEws do not necessarily refect
those of the AGA Institute or the Publisher. The AGA Institute and Frontline Medical
Communications Inc. will not assume responsibility for damages, loss, or claims of
any kind arising from or related to the information contained in this publication,
including any claims related to the products, drugs, or services mentioned herein.
Advertisements do not constitute endorsement of products on the part of the AGA
Institute or Frontline Medical Communications Inc.
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cath lab (–0.4% to $544,733), and endocrinology (–0.2% to $233,769).
Overall, AMGA reported that 68%
of specialties reported increases in
compensation in 2013, with primary
care specialists reporting a 3.8% increase in 2013, up from 2.8% in 2012.
Other specialists saw compensation
increase on average 1.8%, up from
1.6%, and surgical specialists saw an average increase of 3.0%, up from 0.5%.
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GIHEP_3.indd 1
9/12/2013 1:31:52 PM
O C TO B ER 2 0 1 4 • G I & HEPATO LO G Y NEW S
CMS website snafu could lead to penalties for some
Frontline Medical News
irst-time meaningful use participants who are using older technology, but who did not get a hardship
exemption by July 1, will see their
Medicare pay reduced 1% in 2015.
Because of a confuence of factors,
a certain subset of physicians who
engaged in meaningful use for the
frst time this year will not be able
to attest to their participation by the
Oct. 1 deadline set by the Centers for
Medicare & Medicaid Services – and
thus, will be penalized.
“Physicians are not only frustrated,
but perhaps reaching despondency
on the topic,” Dr. Steven J. Stack,
president-elect of the American Medical Association, said in an interview.
Overall, about half of physicians
had not participated in meaningful
use as of the beginning of this year.
Theoretically, all of them could face
the 1% reduction in Medicare pay,
though it’s likely that a smaller subset
will, Dr. Stack said.
Those who did not meet meaningful use criteria in 2013 and who anticipated that they would not do so again
in 2014 could have applied for a hardship exemption by July 1 to avoid a
penalty in 2015. Physicians who were
starting on the meaningful use process
for the frst time in 2014 also had until
July 1 to apply for that exemption.
After determining that many
vendors did not have 2014 software
ready for physicians, CMS proposed
in late May to give all meaningful
users more fexibility. Physicians were
told they could use either a 2011 version, a 2014 version, or some combination, and not be penalized in 2015.
That proposal was made fnal in late
Applying for that fexibility will be
done via the CMS website, which is
slated to be ready a few weeks after
Oct. 1. But frst-time meaningful use
participants must make their attestation to the CMS by Oct. 1.
The bottom line is that frst-time
participants who are using older technology and did not get the exemption will be penalized.
A CMS spokesman said that they
could still receive an incentive payment for 2014 – if they go online in
mid-October and apply for the fexibility option.
But Dr. Stack called that little
consolation. It is as if the CMS took
away $100 of a $1,000 pot and said
that there was still $900 left, he said.
Thom Kuhn, a staf member at the
American College of Physicians, also
said that the CMS explanation was
not good enough.
“Failure to have a system ready
by the time a fnal rule is issued is a
management failure,” said Mr. Kuhn,
in an interview.
Meanwhile, two members of Congress – Rep. Renee Ellmers (R-N.C.)
and Rep. Jim Matheson (D-Utah)
– have called on the CMS to extend
that Oct. 1 deadline. Their legislation
would provide “an administrative
delay” for those attempting to attest
to meaningful use for the frst time
in 2014.
[email protected]
On Twitter @aliciaault
Redundant antibiotics used at 80% of hospitals
Frontline Medical News
edundant combinations of intravenous antibiotics are used
in nearly 8 of 10 hospitals, even
though they are very infrequently
indicated, said a group of researchers
working to promote antimicrobial
stewardship in hospitals.
Leslie Schultz, R.N., Ph.D., of Premier Safety Institute in Charlotte,
N.C., and colleagues reported that a
review of cases from more than 500
U.S. hospitals revealed that about
150,000 days of inappropriate antibiPeople
are not as
aware as they
need to be about
what antibiotics
kill what
otic therapy were prescribed, at an
estimated excess cost of more than
$12 million over the 4-year study
period. Some 78% of hospitals in
the study used the unnecessary drug
combinations, they said.
The combination of metronidazole
and piperacillin-tazobactam accounted
for more than half of the redundant
treatments detected in the study, with
some 32,500 cases receiving this combination for 2 days or more.
Other commonly seen redundant
treatments included metronidazole
and ampicillin-sulbactam, along with
metronidazole and ertapenem, which,
together with the metronidazole and
piperacillin-tazobactam combination,
were seen as responsible for 70% of
redundant treatments administered to
patients (Infect. Control Hosp. Epidemiol. 2014;35:1229-35).
In a telephone press conference,
one of Dr. Schultz’s coauthors on
the paper, Dr. Arjun Srinivasan of
the Centers for Disease Control
and Prevention, Atlanta, said that,
while concerns about antimicrobial
stewardship are not new, the fndings came as a surprise. “We would
expect the use of these combinations
to be vanishingly rare given how often they’re indicated,” Dr. Srinivasan
said, citing a lack of training in antibiotics as a contributing factor.
“We’ve heard from a lot of clinicians that providers don’t know that
piperacillin-tazobactam very efectively kills anaerobic bacteria – but
they do know that metronidazole is
efective,” Dr. Srinivasan said. “Peo-
ple are not as aware as they need to
be about what antibiotics kill what
bacteria, and we need to make sure
people know which antibiotics need
to be combined and when – and that
with some, you don’t gain anything
by adding the second drug. You only
increase the risk of side efects.”
Another physician taking part in
the press conference, Dr. Sara Cosgrove of Johns Hopkins Hospital,
Baltimore, agreed. “We have subopti-
mal training among medical students
and house staf about what antibiotics cover what bugs,” she said. “We
have seen publications suggesting
that medical students and residents
Continued on following page
O C TO B ER 2 0 1 4 • G I & HEPATO LO G Y NEW S
Beware: Labels can lie
Supplement from page 1
nonbodybuilding supplements increased from 5% to 12%, and those
from bodybuilding supplements from
2% to 8%.
There were no transplants or
deaths among those with bodybuilding supplement–related injuries.
These occurred exclusively in men
and were characterized by prolonged
jaundice. Injuries from nonbodybuilding supplements occurred
most often in middle-aged women
(65%). Among these, there were 11
transplants and four deaths; one of
these was a patient who died after
transplant. Two of the other deaths
were related to a cholestatic or mixed
injury, and one resulted from a comContinued from previous page
want more info on antibiotics.”
Dr. Cosgrove also noted
that changes in hospital
work practices may have
contributed to the problem.
“More people are working in hospitals on shorter
shifts, and there are communication issues from one
physician to the next. One
physician may start an antibiotic, and a second physician starts a second. There
are many ways we can
address the problem of unintended duplicate therapy,”
she said, including the use
of alerts generated when the
pharmacy receives a request
for a redundant drug.
Dr. Srinivasan said that
plication of endoscopy.
Most patients were using multiple
supplements, which included multiple ingredients (vitamins, minerals,
and botanical extracts).
The entire group of 130 patients
had taken a total of 217 such products. Among these, 12% of the bodybuilding supplements and 22% of the
nonbodybuilding supplements were
labeled as having a single ingredient.
However, 10% of the bodybuilding
and 13% of the nonbodybuilding
supplements had at least 20 ingredients.
It’s nearly impossible to identify
the specifc culprit ingredients, wrote
Dr. Navarro and his coauthors.
hospitals that have implemented alerts have found
them efective. Still, both
physicians stressed that
whatever the methods
used, dedicated antimicrobial stewardship teams in
hospitals were essential to
ensuring the avoidance of
redundant treatments.
“Many hospitals report
that they are thinking about
having an antimicrobial
stewardship program. We’d
like to nudge them into
actually have one,” said Dr.
Cosgrove, who is chair of
the antimicrobial stewardship
committee for the Society for
Healthcare Epidemiology of
America, which publishes Infection Control and Hospital
Though Johns Hopkins
“The numerous products that frequently contain multiple ingredients,
often with unclear chemical descriptors and variable common names,
can confound pinpointing the specifc
toxic agent.
Sometimes, such
supplements are
with microbials,
mycotoxins, and
heavy metals.
Furthermore, some products may
seem quite innocuous, such as multivitamins, making it difcult to conceive of any toxic potential.”
Sometimes, such supplements are
has had an antimicrobial
stewardship team since
2002, most hospitals do not
have formal groups in place,
she said.
The Society for Healthcare Epidemiology of America will publish checklists
and guidelines in 2015 to
help hospitals set up teams,
Dr. Cosgrove said, noting
that California has recently
passed legislation mandating
their creation in all hospitals
in that state.
All the coauthors of Dr.
Schultz’s study except Dr.
Srinivasan are employees of
Premier, which is a for-proft
research corporation. Dr. Srinivasan reported having no
fnancial conficts of interest.
[email protected]
Physician income: Least in the East
Frontline Medical News
oth primary care and
specialty care physicians
in the Eastern United States
had the lowest total compensation of any region in 2013,
the Medical Group Management Association reported.
Specialists in the East
earned $364,000, and primary care physicians earned
$222,000. Compensation
for specialists was highest
in the South, at $434,000,
with primary care physicians
there earning $238,611. Primary care physicians in the
West earned slightly more,
reporting the highest total
at $239,968, with specialists earning an average of
$401,000. In the Midwest,
specialists earned almost
$408,000, and primary care
physicians averaged $236,000,
according to the MGMA.
Nonmetropolitan areas
reported the lowest compensation rates by population,
with primary physicians
earning more than $223,000
and specialists earning
$337,000 in areas with less
than 50,000 residents. The
highest-earning areas by
population were metro-
politan areas of 50,000 to
250,000 people, where primary care physicians earned
$241,000 and specialty physicians earned $422,000. Both
specialists and nonspecialists
in metropolitan areas of
more than 1,000,000 people
averaged marginally more
than physicians in areas
of between 250,001 and
1,000,000 people.
The MGMA data were
collected from almost 4,200
medical groups representing
more than 66,000 providers.
[email protected]
contaminated with microbials, drugs,
mycotoxins, and heavy metals, the
authors noted. “Also, unidentifed
interactions with medications used
concomitantly may be responsible for
toxicity, yet are difcult to establish.”
The authors urged an increased
understanding and sense of responsibility for the issue.
“All stakeholders, including the dietary supplement industry, regulatory
agencies, health care providers, and
consumers must take note of these
fndings if a culture of safety for
herbal dietary supplements use is to
be established.”
Dr. Navarro did not make any fnancial disclosures. Three coauthors
disclosed ties with pharmaceutical
[email protected]
ABIM responds to
�grandfathered’ concerns
Frontline Medical News
hysicians who are grandfathered from maintenance
of certifcation requirements
may soon be listed diferently
on the American
Board of Internal
Medicine website.
The ABIM site
currently reports publicly whether or not
physicians are “Meeting Maintenance of
Certifcation Requirements,” and that
status means grandfathered physicians do not
appear to be meeting MOC
requirements on the American
Board of Medical Specialties’
Certifcation Matters website.
“ �Not meeting MOC requirements’ is, in essence,
a scarlet letter meant to
pressure grandparents into
enrolling in the current
fawed MOC system,” Dr.
Mack Harrell, president of
the American Association
of Clinical Endocrinologists,
said in a June 30 letter to the
ABIM. The Endocrine Society
and AACE have asked that
no information be publicly
reported until the ABIM addresses the MOC concerns of
internal medicine specialists.
At an August meeting,
ABIM agreed that the language “is causing legitimate
confusion.” Grandfathered
physicians are encouraged but
not required to participate in
MOC, yet they are still being
listed as either meeting or not
meeting MOC requirements,
according to an Aug. 15 stateCurrent
reporting is
meant to
grandparents into
enrolling in the
MOC system.
ment from the board.
ABIM is “exploring what
changes to the reporting language can be made,” according to the statement. The issue
is making sure that “reporting
of certifcation status is clear
and consistent across the community of specialty boards.”
The nature and timing of
a change have not yet been
decided by the board, ABIM
spokesperson Lorie Slass
said. “We want to work with
ABMS to make sure there
is consistency and clarity in
web reporting.” Regardless
of whether or not a lifetime
certifcate holder chooses to
enroll in MOC, they will not
lose their certifcation.
[email protected]
On Twitter @aliciaault
GIHEP_7.indd 1
4/22/2014 2:20:38 PM
O C TO B ER 2 0 1 4 • G I & HEPATO LO G Y NEW S
Drug combos increase upper GI bleeding risk
Frontline Medical News
ombining nonsteroidal anti-infammatory drugs
with selective serotonin reuptake inhibitors increased the risk of upper gastrointestinal bleeding by up to 190% beyond the baseline risk found for
NSAID monotherapy, according to researchers.
The report is in the October issue of Gastroenterology.
Patients also faced excess risks of upper GI bleeding
when they took corticosteroids, aldosterone antagonists, or anticoagulants together with low-dose aspirin or nonselective NSAIDs, although the efect was
not seen for COX-2 inhibitors, reported Dr. Gwen
Masclee at Erasmus Medical Center in Rotterdam,
the Netherlands and her associates.
The fndings should help clinicians tailor treat-
astrointestinal toxicity is the major issue
limiting nonsteroidal anti-infammatory use.
The excess annual risk of upper gastrointestinal
bleeding per 1,000 patients is about 1 with lowdose aspirin, about 2 with coxibs, and
about 4-6 with traditional NSAIDs (ibuprofen, naproxen). However, the risk of
upper gastrointestinal bleeding increases
markedly with several factors, including
the use of concomitant medications.
Ideally, large randomized trials comparing NSAIDs with and without a concomitant medication would inform our
assessment of risk. However, few such
trials are available, so we commonly
rely on observational database studies,
such as that of Masclee et al.
These studies have the important beneft of
large sample size and “real world” results, but
also have potential limitations, including reliability of data (for example, accuracy of diagnostic
coding) and potential bias because of unequal
distribution of confounding factors between cases and controls.
Masclee et al. report signifcant synergy (more
than additive risk) of traditional NSAIDs with
ments to minimize upper GI bleeding, particularly
for elderly patients who often take multiple drugs,
the investigators wrote (Gastroenterology 2014
The researchers analyzed 114,835 cases of upper
gastrointestinal bleeding, including all gastroduodenal ulcers and hemorrhages extracted from
seven electronic health record databases from the
Netherlands, Italy, and Denmark. Cases served as
their own controls, they noted.
Monotherapy with prescription nonselective
NSAIDs increased the chances of an upper gastrointestinal bleed by 4.3 times, compared with not
corticosteroids, SSRIs, aldosterone antagonists,
and antithrombotic agents other than low-dose
aspirin (although risk was increased with traditional NSAIDs plus low-dose aspirin). Low-dose
aspirin was synergistic with antithrombotic agents and corticosteroids, while
coxibs were synergistic with low-dose
aspirin and SSRIs.
The results of Masclee et al. support
current North American guidelines,
which suggest use of proton pump inhibitors or misoprostol for traditional
NSAID users taking concomitant medications such as antithrombotics, corticosteroids, or SSRIs, and use of PPIs for
low-dose-aspirin users taking antithrombotics or taking corticosteroids if greater than or
equal to 60 years old. Their results also suggest
further evaluation of aldosterone antagonists is
warranted as another possible risk factor.
Dr. Loren Laine, AGAF, is professor of medicine, Yale
School of Medicine, New Haven, Conn. He is on
Data Safety Monitoring Boards for studies supported
by Eisai, BMS, and Bayer; and is a consultant for
using any of the drugs studied (95% confdence
interval, 4.1-4.4). Bleeding risk from taking either
nonselective NSAIDs or corticosteroids was the
same, the researchers said, adding that studies have
yielded inconsistent fndings on the topic.
The incidence ratios for monotherapy with lowdose aspirin and COX-2 inhibitors were slightly
lower at 3.1 (95% CI, 2.9-3.2) and 2.9 (95% CI, 2.73.2), respectively, they added.
Combining nonselective NSAIDs or COX-2 inhibitors with SSRIs led to excess risks of upper gastrointestinal bleeding of 1.6 (95% CI, 0.5-2.6) and 1.9
(95% CI, 0.2-3.4), respectively. “From a biological
point of view, this interaction seems plausible because SSRIs decrease the serotonin level, resulting in
impaired thrombocyte aggregation and an increased
risk of bleeding in general,” they said.
Corticosteroids combined with nonselective
NSAIDs led to the greatest increases in bleeding risk,
with an incidence ratio of 12.8 (95% CI, 11.1-14.7),
compared with nonuse of any drug studied, and an
excess risk of 5.5 (3.7-7.3), compared with NSAID use
alone, said the researchers.
Adding aldosterone antagonists to nonselective
NSAIDs led to an excess risk of 4.46, compared with
using nonselective NSAIDs alone, they reported (95%
CI, 1.79-7.13).
Because the study did not capture over-the-counter
NSAID prescriptions, it could have underestimated
use of these drugs, the investigators said. Also, changes in health or NSAID use during the study could
have created residual confounding, although sensitivity analyses did not reveal problems, they reported.
Misclassifcation of some data could have led them to
underestimate risks, the researchers noted.
“Finally, we did not take any carryover efect or
dose of drug exposure into account, which potentially limits the generalizability concerning causality of the associations,” they concluded.
Five authors reported employment or other fnancial support from Erasmus University Medical
Center, AstraZeneca, Janssen, PHARMO Institute,
and the European Medicines Agency. The other
authors reported no relevant fnancial conficts of
[email protected]
Pediatric IBD rose by more than 40% in 15 years
Frontline Medical News
ediatric infammatory bowel disease grew by more than 40% in a
15-year period in Ontario, Canada,
according to a retrospective cohort
study published in the October issue
of Gastroenterology.
Although rates of infammatory
bowel disease (IBD) rose in children
and adolescents of all ages, the steepest increase occurred in children with
very-early-onset IBD (VEO-IBD), de-
fned as disease diagnosed before they
were 10 years old, said Dr. Eric Benchimol at the University of Ottawa,
and his associates. But these
patients also tended to use
fewer health services and have
fewer surgeries for IBD, compared with older children with
the disease, the investigators said
(Gastroenterology 2014 October [doi.
The fndings add to research indicating that VEO-IBD is a distinct
form of IBD and indicate the need
to assess subgroups of these patients
to look at phenotype, genotype, intestinal microbiome, and treatment
response, the investigators said.
For the study, researchers created a
cohort based on an algorithm of health
care visits that identifed all children
and adolescents in Ontario diagnosed
with IBD before age 18 years. The anal-
ysis included 7,143 patients with IBD,
among whom about 14% had VEOIBD, the investigators reported.
The overall rate of IBD in children up to 18 years old increased
from 9.4 to 13.2 cases per
100,000 population from 1994
through 2009 (P less than .0001),
the researchers said. And the yearly
increase in VEO-IBD averaged 7.4%
– more than three times greater than
the 2.2% average annual rise among
children diagnosed at 10 years and oldContinued on following page
Continued from previous page
er, the investigators reported.
But health care utilization trends
did not mirror changes in incidence,
Dr. Benchimol and associates reported. For example, children diagnosed
tis were less likely to undergo colectomy than were older girls (HR, 0.88;
95% CI, 0.47-1.63) and boys (HR, 0.42;
95% CI, 0.21-0.85). In contrast, rates of
IBD-related surgery and hospitalization
were similar between children diagnosed at 6-9.9 years of age and those
diagnosed at age 10 up to 18 years, the
investigators said.
A cohort study from the United
States also found a lower likelihood
of surgery in children with VEO-IBD,
the researchers noted. Large-bowel
involvement without ileal disease is
prominent in young children with
IBD, and these patients might be unlikely to undergo resection because
colectomy requires a permanent ostotomy, they added.
[email protected]
Key clinical point: Although the
steepest rise in infammatory bowel
disease occurred in children diagnosed before age 10 years, children
diagnosed before age 6 years had the
lowest rates of IBD-related outpatient
visits, hospitalizations, and surgeries.
Major fnding: Rates of pediatric IBD
increased by more than 40% between
1994 and 2009 in Ontario, Canada.
Rates rose by an average of 7.4%
annually in children diagnosed before
age 10 years, compared with 2.2%
for children diagnosed from 10 years
to before 18 years of age. Rates of
outpatient visits, hospitalizations, and
IBD-related surgeries were signifcantly lower in children diagnosed before
age 6 years, compared with children
diagnosed at 10 years or older.
Data source: Retrospective study of
the Ontario Crohn’s and Colitis Cohort, which included 7,143 children
and adolescents with IBD diagnosed
between 1994 and 2009 in Ontario,
Disclosures: The work was supported
by grants and researcher awards from
the American College of Gastroenterology, the Ontario Ministry of Health
and Long-Term Care, the Canadian
Institutes of Health Research, the
Crohn’s and Colitis Foundation of
Canada, the National Institutes of
Health, the Wolpow Family Chair in
IBD Treatment and Research, the
Ontario Ministry of Research and Innovation, and the Leona M. and Harry
B. Helmsley Charitable Trust. The authors reported no conficts of interest.
before they were 6 years old had
signifcantly fewer outpatient visits
for IBD, compared with children diagnosed at 10 years and older (odds
ratio for girls, 0.67; 95% confdence
interval, 0.58-0.78; OR for boys, 0.86;
95% CI, 0.75-0.98).
Furthermore, patients diagnosed
before age 6 years were less likely to
be hospitalized for IBD than were
older children with the disease (HR
for girls, 0.70; 95% CI, 0.56-0.87; HR
for boys, 1.12; 95% CI, 0.94-1.33), the
investigators said.
The likelihood of undergoing intestinal resection also was lower for children diagnosed before age 6 years with
Crohn’s disease, compared with older
girls (HR, 0.35; 95% CI, 0.16-0.78) and
boys (HR, 0.59; 95% CI, 0.34-0.99), said
the researchers. And patients diagnosed
before age 6 years with ulcerative coli-
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O C TO B ER 2 0 1 4 • G I & HEPATO LO G Y NEW S
Model cut CT scans of Crohn’s patients by 43%
Frontline Medical News
risk stratifcation model that determined whether patients with
Crohn’s disease needed computed
tomography cut scans of these patients in emergency departments by
43%, with a miss rate of only 0.8%,
according to researchers.
The report was published in the
October issue of Clinical Gastroenterology and Hepatology.
Computed tomography scans
yield nonsignificant findings for
almost one-third of patients with
Crohn’s disease (CD) who present
to emergency departments, said
Dr. Shail Govani of the University
of Michigan in Ann Arbor and his
By using their model to identify
patients with serious gastrointestinal complications as opposed to
straightforward intestinal infammation, emergency departments could
prevent more than 250 cancer cases
and save more than $80 million per
decade in the United States, the investigators added.
Patients with CD may be exposed
to increasing cumulative radiation
levels, and 30% of this exposure
occurs in emergency departments,
with 75% due to CT scans, the
researchers said (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.
For the study, the investigators
retrospectively reviewed electronic
By using the model to
identify patients with serious
gastrointestinal complications,
emergency departments
could prevent more than
250 cancer cases and save
more than $80 million per
decade in the United States.
medical records from the University
of Michigan from 2000 through 2011,
identifying 613 adults with CD who
made 1,095 visits that included CT
scans within 24 hours of presentation.
The researchers then modeled associations between laboratory values
and perforation, abscess, or other
serious complications as opposed to
intestinal infammation.
Patients averaged 1.8 CT scans
during the decade-long study period, and the overall rate of CT scans
during that time rose from 63% to
87%, the investigators said. Only
16.8% of scans revealed a complication that would change clinical management, they reported.
Only C-reactive protein (CRP)
and erythrocyte sedimentation rate
(ESR) were signifcantly associated
with complications (odds ratio for
CRP, 1.10; 95% confdence interval,
1.05-1.15; P less than .001; odds ratio
for ESR, 1.02; 95% CI, 1.01-1.03; P
less than .001), the researchers said.
Adding ESR to 5 x CRP and not
Continued on following page
Continued from previous page
scanning patients with a resulting value of 10 or
less would avoid CT scans in 18.5% of patients,
they reported. But with use of the more complex
logistic regression model instead of the simpler
equation, scans could be avoided for 43.0% of patients, with a miss rate of 0.8%, they said.
Based on the study, patients assessed as likely to
have complications should undergo a standard CT
scan of the abdomen and pelvis with nonbarium
contrast to avoid barium peritonitis, said Dr. Govani and associates. Other patients should forego CT
scans, have a consult with a gastroenterologist prior
to further imaging, or undergo lower-radiation CT
enterography, depending on presenting signs and
probability of infammation, they added.
The researchers said they were unable to construct good models that included obstruction as
an outcome. Patients with suspected obstructions
should have abdominal x-rays and then CT if an
obstruction remained likely, they said.
“These models are limited in that they are retrospective and represent data from one center,” the
investigators added.
“Although our internal validation with 10-fold
cross-validation shows that these models have
good performance characteristics, further external
validation studies are needed to determine whether these models are generalizable to CD patients
The authors are prospectively testing the algorithms and hope to continue to validate and study
them in emergency departments, they said.
The Infammatory Bowel Disease Working
Group, the Department of Veterans Afairs, and
UCB supported the research. The authors reported
having no conficts of interest.
[email protected]
MicroRNA test improved preop pancreatic cancer diagnosis
Frontline Medical News
ytology and a microRNA-based test identifed
pancreatic cancer 91% of the time in specimens obtained by endoscopic ultrasound-guided
fne-needle aspiration – a substantial improvement,
compared with cytology alone, researchers reported in the October issue of Clinical Gastroenterology and Hepatology.
The microRNA-based test could help reduce
repeated fne-needle aspirations (FNAs) due to
indeterminate cytologies, said Dr. Randall Brand,
AGAF, of the University of Pittsburgh Medical
Center and his associates. Correctly assessing
pancreatic cancer before surgery also could help
patients start neoadjuvant therapy sooner if appropriate, they noted.
Several microRNAs are expressed abnormally in
patients with pancreatic ductal adenocarcinoma.
The new test contains fve of these sequences and
is the frst of its type for pancreatic cancer, the researchers said. To evaluate the assay, they assessed
and compared relative quantitative polymerase
chain reaction and cytology results from 95 formalin-fxed parafn-embedded specimens and 228
endoscopic ultrasound-guided FNAs. Specimens
were collected during routine visits by patients
with solid pancreatic masses, the investigators
said (Clin. Gastroenterol. Hepatol. 2014 Oct. [doi:
The test, used with cytology, correctly identifed
pancreatic cancer in 91% of positive specimens
(95% confdence interval, 85.6%-94.5%), while
cytology alone had a sensitivity of 79% (95% CI,
72.2%-84.5%), the researchers reported. Cytology
and the microRNA test each had positive predictive values greater than 99% (95% CI, 96%-100%),
they added.
When used alone, the microRNA test had a di-
he diagnosis of pancreas cancer is based on
Brand et al. have presented the results of a
the results of clinical presentation, cross-seclarge multicenter 3-year validation trial designed
tional imaging, and endoscopic ultrasound
to determine the performance characteristics of
(EUS)–guided fne-needle aspiration. A defnitive a 5-microRNA-based classifer for the diagnosis
tissue diagnosis is often required beof pancreas cancer on 228 EUS-FNA
fore chemotherapy, radiation therapy,
specimens. In the study, the false-negand surgery. Because of the greater
ative rate for pancreas mass FNA was
sensitivity of EUS over CT scanning,
20%. The results of the miRNA testing
EUS-guided FNA is often the procerevealed a sensitivity of 83% and a
dure of choice. EUS-guided FNA is
false-negative rate of 17%. However,
highly dependent on the identifcation
when both the cytology and the miof malignant cells in the FNA specicroRNA test were used in conjunction,
mens. The presence of a dense perithe sensitivity increased to 91% with a
tumoral stroma containing fbroblasts
specifcity of 96%.
often interferes with the aspiration and DR. BRUGGE
The use of molecular markers in
identifcation of malignant cells.
the management of FNA cytology
The cytological criteria for the diagnosis of
specimens provides an opportunity to objectify
pancreas adenocarcinoma with FNA requires the
the fndings of aspirated tissue analysis. With an
presence of a number of cellular features such as
objective test, the interpretation of specimens is
dark chromatin, large nuclei, and aggregates of
not dependent upon the subjective fndings of a
atypical cells. Not surprisingly, cytologists adhere cytologist. It seems likely that this type of testrigidly to the criteria for the diagnosis of adenoing will gradually improve FNA cytology.
carcinoma resulting in a highly specifc test with
moderately high sensitivity. The sensitivity of EUS Dr. William R. Bruge, AGAF, is director, Pancreas
FNA for the diagnosis of pancreas cancer remains Biliary Center, Massachusetts General Hospital, Bosstubbornly imperfect, between 85% and 95%.
ton. He reported no conficts of interest.
agnostic sensitivity of more than 82% and a specifcity of 96% – better than cytology on the same
specimens, the investigators said. The test correctly found pancreatic cancer in 22 of 39 specimens
previously assessed as benign, indeterminate, or
nondiagnostic by cytology, they said.
The researchers separately assessed 46 specimens
collected percutaneously instead of by EUS-guided FNA and found much lower (58%) diagnostic
MicroRNA sequences can be reliably
recovered from both formalin-fxed
and FNA specimens, making them a
�particularly promising’ class of biomarkers
for pancreatic and other cancers.
sensitivity and a higher rate of technical failures,
although specifcity and predictive value still approached 90%, said the investigators. The percutaneous specimens all were collected from two study
sites outside the United States, so further studies
would need to validate whether a percutaneous approach could replace EUS-guided FNA, they said.
Cytology and microRNA testing also had to be
performed on diferent FNA specimens, a limitation that “could have contributed to some of the
observed discrepancies between cytology and molecular results,” the investigators said.
Pancreatic cancer remains notoriously difcult to
treat, with overall 5-year survival rates of only about
6%. MicroRNA sequences are stable and can be reliably recovered from both formalin-fxed and FNA
specimens, making them a “particularly promising”
class of biomarkers for pancreatic and other cancers,
the researchers said. Based on the study results,
future studies should explore the test’s prognostic
potential, such as for distinguishing patients with resectable tumors that are likely to progress.
The study was supported by Asuragen and a grant
from the German Federal Ministry of Education and
Research. Dr. Brand and another author reported
that they are on the clinical advisory board of Asuragen, and 6 of 27 coauthors reported being employees
of the company. The rest reported no fnancial conficts of interest.
[email protected]
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Impact of the AGA
Research Foundation
Quick Quiz
Q1: Hereditary pancreatitis is NOT:
A. Associated with an increased risk of developing pancreatic cancer.
B. Caused by mutations in cationic
C. Associated with 100% penetrance.
D. An autosomal dominant trait.
Q2: You are seeing a 20-year-old woman
with a history of ulcerative colitis diagnosed at the age of 12. At that time, she
presented with ulcerative proctitis that was
well controlled with mesalamine suppositories. Twelve months ago she developed
worsening symptoms that included bloody
diarrhea; colonoscopy revealed moderate to
severe pancolitis. She was started on AsacolВ®
(mesalamine) 800 mg three times a day and
prednisone. She has been unable to wean
of the steroids without experiencing recurrent symptoms. Six months ago she was
started on azathioprine at 2.5 mg/kg without signifcant response. She is currently
on prednisone 30 mg daily and has 4-5 soft
bowel movements per day.
What would you recommend next?
A. Change the AsacolВ® to ColazalВ® (balsalazide) and follow clinically for the next 4
B. Continue azathioprine and start infiximab 5 mg/kg IV at 0, 2, and 6 weeks.
C. Taper of the prednisone and start Entocort EC (budesonide) 9 mg daily.
D. Stop the azathioprine and start methotrexate at 15 mg IM per week.
E. Continue azathioprine and start tacrolimus at 0.1 mg/kg per day divided twice
Quick Quiz Answers
Hereditary pancreatitis is a distinct clinical
entity inherited as an autosomal dominant
trait with incomplete penetrance and caused
by mutations in cationic trypsinogen (PRSS1).
This process is associated with up to a 60-fold
increased risk of pancreatic cancer.
1. Greer J.B., Whitcomb D.C. Infammation
and pancreatic cancer: an evidence-based
review. Curr. Opin. Pharmacol. 2009;9:411-8.
2. Teich N., Rosendahl J., TГіth M., et al.
Mutations of human cationic trypsinogen
(PRSS1) and chronic pancreatitis. Hum. Mutat. 2006;27:721-30.
3. Whitcomb D.C., Gorry M.C., Preston
R.A., et al. Hereditary pancreatitis is caused
by a mutation in the cationic trypsinogen
gene. Nat. Genet. 1996;14:141-5.
This patient has steroid-dependent ulcerative
colitis. She has not responded to AsacolВ® at
2.4 g daily and azathioprine. Even though
azathioprine has a slow onset of action, therapeutic efcacy should be expected within
3-6 months of initiation of treatment. This
patient should be started on a biologic agent
such as infiximab. If she does not respond
to treatment with infiximab, she should be
considered for colectomy with ileal pouch–
anal anastomosis. Changing the AsacolВ® to
a mesalamine formulation with a diferent
release mechanism – such as balsalazide –
would not likely change this patient’s disease
course but would delay further therapeutic
interventions. Entocort EC (budesonide) is
a glucocorticosteroid with a controlled ileal
release formulation; it undergoes signifcant
frst-pass metabolism in the liver, which
reduces its systemic toxicity compared to
prednisone. It is given to patients with mild
to moderate ileal or ileocecal Crohn’s disease.
However, a new formulation of budesonide
in an MMX release system has recently been
shown to be superior to placebo in ulcerative
colitis, more particularly for left sided colitis.
Nonetheless, the study population did not
include prednisone-resistant or -dependent
patients, and so this strategy of tapering from
prednisone to budesonide in this patient will
be incorrect regardless. Methotrexate is effective in inducing remission in patients with
Crohn’s disease and its efcacy in UC has not
been established. Tacrolimus is an oral calcineurin-inhibitor that is used in transplant patients. Its role in infammatory bowel disease
has not been established.
1. Rutgeerts P., Sandborn W.J., Feagan B.G.,
et al. Infiximab for induction and maintenance therapy for ulcerative colitis. N. Engl.
J. Med. 2005;353:2462-76.
2. Sandborn W.J. A review of immune modifer therapy for infammatory bowel disease:
azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am. J. Gastroenterol. 1996;91:423-33.
[email protected]
he AGA Research
prevention, treatment,
Foundation, the
and cure of digestive
charitable arm of the
diseases has been made
American Gastroin the research
enterological Aslaboratory of a
sociation (AGA),
talented young
plays an importinvestigator.
ant role in medi“This award
cal research.
provided me
The foundation
the support to
provides grants to
examine aspects
young scientists
of colonic stem
at a critical time
cell homeostaDR. POWELL
in their careers.
sis and tumor
The mission of
initiation using
the AGA Research Founsuper resolution microsdation is to raise funds to
copy, perhaps affording a
provide support to young
physical visualization of
researchers in the felds of
colonic cellular processes,
gastroenterology and hepa- which has not been previtology.
ously possible,” said Anne
The research program
E. Powell, Ph.D.
of the AGA has had an imDr. Powell is a Vanderportant impact on digestive bilt University 2014 AGA
disease research for the last Research Scholar Award
30 years in the following
“My long-term aim is to
в–¶ More than $43 million
be an independent inveshas been provided in retigator and a leader in the
search grants.
feld of colonic stem cell
в–¶ More than 780 scientists
biology and this award is
have been awarded rea critical step toward that
search grants.
goal,” said Dr. Powell.
▶ Ninety percent of inves“Undoubtedly, without
tigators who received
the generous support from
an AGA Research Schol- this research scholar award
ar Award (RSA) over
from the AGA Research
the past 10 years have
Foundation, this work
continued to conduct
would not be possible,” she
research in the fields of
gastroenterology and
At a time when funding
from the NIH and other
в–¶ More than 85% of RSA
traditional sources of suprecipients in the past 10
port is in decline, the AGA
years received funding
Research Foundation is
from the National
committed and ready to
Institutes of Health
support young investigasubsequent to their RSAs; tors. The funding provided
more than 50% of these
by the foundation helps to
researchers received $1
launch discoveries that will
million or more in NIH
continue to improve GI
grant support.
practice and better patient
AGA grants have led to
various discoveries. These
The AGA Research
include new approaches
Foundation provides a
to the downregulation of
key source of funding at a
intestinal infammation, a
critical juncture in a young
test for genetic predisposiresearcher’s career. By jointion to colon cancer, and
ing others in donating to
autoimmune liver disease
the AGA Research Foundatreatments.
tion, you will ensure that
The importance of
researchers have opporthese awards is made clear tunities to continue their
by the fact that virtually
life-saving work.
every major advance [email protected].org
ing to the understanding,
GIHEP_20.indd 1
7/28/2014 10:26:17 AM
Screening has risks
from page 1
patient died of other causes.
In one of the studies, researchers analyzed data from the population-based
National Health Interview Survey,
which assesses approximately 90,000
Americans each year to provide health
information representative of the U.S.
population. They focused on 27,404
participants aged 65 years and older
who reported on the cancer screening
they underwent between 2000 and
2010. A validated mortality index was
used to calculate each respondent’s
9-year mortality risk based on factors
such as age, sex, smoking status, body
mass index, comorbidities, hospitalizations, and functional measures, said
Dr. Trevor J. Royce of the departments
of radiation oncology and medicine,
University of North Carolina at Chapel
Hill, and his associates.
They found that contrary to numerous recommendations, “a sizable
proportion of the U.S. population
who have less than a 9-year life expectancy” underwent screening for cancer, including 55% of men who were
screened for prostate cancer, 41% of
people screened for colorectal cancer,
38% of women screened for breast
cancer, and 31% of women screened
for cervical cancer, Dr. Royce and his
associates said ( JAMA Intern. Med.
2014 Aug. 18 [doi:10.1001/jamainternmed.2014.3895]).
Cancer screening was also common in people whose life expectancy
was less than 5 years, or even less
than 3 years. Even though the lack of
net beneft from cancer screening in
such patients “is widely recognized
and publicized in clinical practice
guidelines, important obstacles exist
to reliably applying these guidelines.”
Chief among these obstacles is
the lack of a simple, reliable tool for
assessing life expectancy in clinical
practice. In addition, physicians may
fnd it difcult to communicate to
patients that they are very likely to
die within the next few years, and
patients may fnd it difcult to accept
that they have a limited life expectancy. Physicians’ fear of litigation further contributes to overscreening, Dr.
Royce and his associates said.
In the other study, researchers used
microsimulation modeling to assess
whether screening more intensively
than recommended for colorectal
cancer would be favorable for individual patients or for society as a
whole. They created two hypothetical
cohorts of 10 million Medicare benefciaries at average risk for the disease:
The frst contained patients who had
a negative screening colonoscopy at
age 55, and the second contained patients who had never been screened
for colorectal cancer, said Dr. Frank
van Hees of the department of public
health, Erasmus University Medical
Center, Rotterdam, the Netherlands,
and his associates.
The model simulated recommended screening (that is, colonoscopy
at ages 65 and 75 years), as well as
several shorter screening intervals,
screening up to age 85 years, and
screening up to age 95 years. It factored into the analyses the sensitivity
rates for colonoscopy for adenomas
or carcinomas at various stages,
age-specifc risks for GI and cardiovascular complications requiring hospitalization, and survival rates after a
variety of possible clinical diagnoses.
“For each scenario of more intensive screening than recommended, we determined the associated
increase in colorectal cancer cases
prevented, colorectal cancer deaths
prevented, life-years gained, life-years
with cancer care prevented, colonoscopies performed, and complications
experienced,” the investigators said.
The balance among benefts, burden,
and harm was unfavorable in almost
every scenario tested, outside the recommended screening scenario.
Similarly, when colonoscopy was
continued to age 85 years instead of
ceasing at age 75 years, “the overall
loss of quality of life exceeded the associated increase in life-years gained.”
Harms were even greater when the
screening interval was reduced to 3
years. “This study provides strong
evidence and a clear rationale for clinicians and policy makers to actively
discourage this practice,” Dr. van
Hees and his associates said ( JAMA Intern. Med. 2014 Aug. 18 [doi:10.1001/
[email protected]
Discuss life expectancy for a change
o reduce unneeded cancer
screening, clinicians must alter
their approach to discussions with
older patients.
Life expectancy should be addressed, because there is substantial
heterogeneity among older persons
in life expectancy and comorbidity
burden. Informational tools should
be developed that can help patients
weigh anticipated benefts and
harms of screening, given their individual risk. It will truly be a new
era when providers will be evaluat-
ed, in part, by their ability to refrain
from ordering cancer screening
tests for some of their patients.
Dr. Cary P. Gross is at the Cancer Outcomes, Public Policy, and Efectiveness
Research Center at Yale University, New
Haven, Conn. He reported having ties
to FAIR Health, Medtronic, Johnson &
Johnson, and 21st Century Oncology.
These remarks were taken from his
invited commentary accompanying the
two reports on cancer screening (JAMA
Intern. Med. 2014 Aug. 18).
Adjuvant S-1 an option for stage III colon cancer
Frontline Medical News
he oral fuoropyrimidine S-1 is efective as
adjuvant chemotherapy for stage III colon cancer, according to fndings from the randomized,
open-label, phase III noninferiority trial in Japan.
Disease-free survival was 75.5% at 3 years in
758 patients with curatively resected stage III colon cancer who were randomized to receive S-1,
compared with 72.5% in 760 such patients who
received tegafur-uracil plus leucovorin (stratifed
hazard ratio for disease-free survival, 0.85), Dr. M.
Yoshida of Osaka Medical College Hospital, Osaka,
Japan, and colleagues reported online in Annals of
Oncology. The fndings were reported on behalf
of the Adjuvant Chemotherapy Trial of TS-1 for
Colon Cancer (ACTS-CC) study group.
The stratifed HR for disease-free survival was
similar even after excluding 14 patients who did
not receive the allocated treatment, and after adjusting for key baseline factors (Ann. Oncol. 2014
Aug. 14 [doi:10.1003/annonc/mdu232]).
The fndings demonstrate the efcacy of S-1 by
confrming its noninferiority to tegafur-uracil plus
leucovorin (UFT/LV), the investigators said.
Postoperative adjuvant chemotherapy for patients with stage III colon cancer is the standard of
care internationally, and Western guidelines call for
frst-line treatment with intravenous 5-fuorouracil
(5-FU) and LV or capecitabine combined with oxaliplatin (the FOLFOX or CapeOX regimens). Fluoropyrimidine monotherapy is also a treatment option.
S-1, which combines tegafur, gimeracil, and
oteracil, has been shown in phase III studies to be
noninferior to conventional 5-FU–based regimens
when used in combination with other cytotoxic
agents for the treatment of advanced gastric cancer
and advanced colorectal cancer. As adjuvant chemotherapy, postoperative S-1 treatment signifcantly
improved survival in patients with gastric cancer
and pancreatic cancer, but its efcacy for colon cancer had not been established, they noted.
Patients included in the current study were
aged 20-80 years (median, 66 years), and 35.3%
were aged 70 or older. Those assigned to the S-1
group received 80-120 mg daily (depending on
body surface area) on days 1-28, every 42 days for
four courses; those assigned to the UFT/LV group
received 300-600 mg of UFT daily (depending on
body surface area) and 75 mg of LV daily on days
1-28, every 35 days for fve courses.
No signifcant diferences were noted between the
S-1 and UFT/LV groups with respect to safety and
feasibility. The fndings suggest that S-1 could be a
new treatment option – with multiple potential advantages over UFT/LV – for adjuvant chemotherapy
in patients with colon cancer, the investigators said.
Among the advantages are lower cost (in Japan, the
cost is half that of UFT/LV), dosing convenience,
and dramatically reduced risk of hand-foot syndrome, compared with capecitabine (1.3% vs. 60%),
they said.
This study was supported by the Foundation for
Biomedical Research and Innovation, Translational
Research Informatics Center, under a funding contract with Taiho Pharmaceutical, Japan. Dr. Yoshida reported receiving honoraria and/or research
funding from Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers
Squibb, Merck Serono, Bayer Yakuhin, Daiichi Sankyo, Sanof, Kyowa Hakko Kirin, Nippon Kayaku,
Ono Pharmaceutical, and Jansen Pharmaceutical.
[email protected]
Encapsulated fecal transplant
Pill from page 1
work by restoring the gut fora to
a normal balance after having been
disrupted by antibiotic treatment.
It is not the frst attempt to encapsulate a fecal transplant; Dr. Thomas
Louie of the University of Calgary (Alberta), presented data on his very effective formulation against C. difcile at
the ID Week annual meeting in 2013.
In the current study, the frst cohort
received a mean dose of 1.5 Г— 109
spores and the second cohort received
a dose of 1 Г— 108 spores. The aim is
to contain the dose in a few tablets for
a commercial product, Dr. Cook said.
All doses were given on 1 or 2 days at
the study’s start.
Patients ranged between 22 and
88 years of age, and all had three or
more laboratory-confrmed C. difcile infections over the previous year.
They had to have a life expectancy
of at least 3 months and be able to
give informed consent. They were
excluded if they had any immunosuppression, a history of irritable
bowel disease, total colectomy, cirrhosis, a need for antibiotics within 6
weeks of baseline, prior fecal transplant, or if they were in intensive
care. There were 10 women and fve
men in each cohort.
After patients stopped taking antibiotics, there was a washout period
after which they took SER-109. Stool
was collected on day 4 and at 1, 2,
4, 8, and 24 weeks. Efcacy was assessed at the 8-week time point.
In the frst group, 13 of the 15 patients achieved the protocol-defned
endpoint: absence of C. difcile over
the 8 weeks.
The two patients who failed had
self-limited, transient diarrhea with a
positive C. difcile test, but neither required antibiotics and both recovered
within 24 hours, so they were considered to not have recurrent C. difcile,
said Dr. Cook. In the second cohort,
14 of the 15 patients were free of C.
difcile at 8 weeks. The patient who
failed had diarrhea and a positive C.
difcile test, and the diarrhea did not
resolve on its own. She required antibiotics to achieve remission.
The company hopes to eventually
conduct a phase III study and seek
Food and Drug Administration approval, but it is too early to say when
that might occur, said Dr. Cook.
[email protected]
Innovations in microbiome research
GA hosted the annual James W.
Freston conference in Chicago
this August, and the topic
was therapeutic innovations in microbiome
research and technology,
with a focus on fecal microbiota transplantation
(FMT). There were over
140 participants from 16
countries present.
The 2-day meeting
opened with lectures highlighting
evolving knowledge about the
human microbiome. These were
followed by additional presentations
about FMT as a treatment for Clostridium difcile, infammatory bowel
disease, and intriguing work on the
role of the gut microbiome in the
metabolic syndrome. Some of the
FMT presentations are summarized
in this issue of GI & Hepatology
The fnal session of the meeting
concerned institutional review board
regulation of trials involving FMT,
and updates from the Food and
Drug Administration.
It is clear that FMT is an efective
treatment for recurrent C. dif. The
short-term safety of FMT in existing trials is reassuring, but
there was consensus at
the meeting that we need
further study of long-term
outcomes of recipients.
Studies of FMT for IBD,
irritable bowel syndrome,
and other conditions are
quite limited at this time,
and it is clear that more
research is needed before we will
understand the associations and
potential causality related to the microbiome. Studies of what additional
viruses, phages, and proteins may be
transferred from a donor to recipient
are desperately needed.
The evidence for safety and efcacy for any conditions beyond C. dif
is lacking. Many attendees emphasized the need for better education
about the potential risks.
Dr. David T. Rubin is Joseph B. Kirsner
Professor of Medicine, section chief of
gastroenterology, hepatology, and nutrition, and co-director of the Digestive
Diseases Center, University of Chicago.
O C TO B ER 2 0 1 4 • G I & HEPATO LO G Y NEW S
Early data on FMT for
severe C. diffcile and IBS
matter of weeks.”
The study followed 13 patients for
Frontline Medical News
an average of 11 months. All had irritable bowel syndrome (IBS) that was
ecal microbiota transplantation
refractory to diet, probiotic, antibiotsuccessfully treated severe and/or ic, and/or antidepressant therapy.
complicated ClostridThe main outcome was
ium difcile infection in a
assessed by a 41-item quesretrospective, multicenter,
tionnaire that evaluated
long-term follow-up study
severity of abdominal pain,
of 17 patients in whom
bloating, fatus, diarrhea,
conventional therapy had
constipation, and overall
failed. Patients had a mean
quality of life.
age of 66 years (ranging
Most of the patients
from 38 to 89 years), and
(7/13) were women.
13 of them were women.
The diagnoses were diDR. ARONIADIS
The 14 inpatients and 3
arrhea-predominant IBS
outpatients were treated for
(nine), constipation-preeither severe or complicated C. difcile
dominant IBS (three), and mixed IBS
infection. They were followed for a
mean of 11 months (ranging from 1 to
The donor pool comprised pa42 months) after FMT.
tients’ relatives, spouses, or close
Diarrhea resolved in 12 patients
friends. The transfusion was delivover an average of 6 days after FMT
ered once by upper endoscopy.
and improved in 4 patients. In 11
There has been speculation about
patients with abdominal pain before
whether a family member, household
transplantation, the pain resolved in
member, or someone else is the ideal
8 patients over a mean of 10 days and donor for fecal transplant; however,
improved in 3 patients, Dr. Olga C.
this study wasn’t powered to address
Aroniadis and her associates reported. this, Dr. Aroniadis said.
Fifteen of 17 patients had no recurPicking the optimal donor probarence of C. difcile infection within 90 bly depends on accurately detailing
days of transplantation, for a primary the microbiome of both donor and
cure rate of 88%. One of the two
recipient. “In the future, we hope
patients with a recurrence within 90
to develop an individual approach
days was treated successfully with
to FMT, but to do this, we need to
a second FMT, for a secondary cure
know which specifc bacterial popularate of 94%, said Dr. Aroniadis of
tions need to be restored in each paMontefore Medical Center, New
tient, and that is several years away.”
York, at the 2014 James W. Freston
Patients responded to FMT regardconference sponsored by the Ameriless of IBS subtype; however, the numcan Gastroenterological Association.
bers of patients in each group were too
Many of the inpatients were hospi- few to perform a statistical comparison.
talized in the ICU and on vasopressor
Dr. Aroniadis and her colleagues
support, she said.
are planning a randomized controlled
“It’s truly a rewarding experience
trial that will enroll only patients
to watch these severely ill patients
with diarrhea-predominant IBS. “We
improve after fecal transplantation,”
will have a much better sense of the
Dr. Aroniadis said. “Fecal transplanta- efcacy of FMT for the treatment of
tion even obviated the need for colec- diarrhea-predominant IBS after we
tomy in one of our patients.”
conduct our clinical trial.” Participants
Fecal microbiota transplant imenrolled in the trial will undergo miproved or alleviated symptoms in 9
crobiome analyses before and after
of 13 of patients with refractory irri- fecal transplant, which she hopes will
table bowel syndrome, a small retroshed some light on how alteration of
spective study also determined.
the intestinal microbiota correlates
A single transfusion of fresh donor
with symptoms.
feces improved abdominal pain, bowel
The present study is the frst to track
habits, dyspepsia, bloating, and fatfecal transplant response exclusively in
ulence, Dr. Aroniadis reported at the
IBS patients, Dr. Aroniadis said.
Dr. Aroniadis had no fnancial disFor some patients, noticeable imclosures.
provement occurred within days, Dr.
[email protected]
Aroniadis said in an interview. “For
On Twitter @sherryboschert
others it took longer, but in those
[email protected]
who felt better, they did so within a
It’s tough to fnd a good fecal donor
Frontline Medical News
inding healthy stool donors for
fecal transplant may be a tough
That’s what Australian researchers have discovered in the course
of the FOCUS trial, which aims to
determine whether fecal microbiota
Key clinical point: Finding fecal
transplant donors is not as simple as
once thought.
Major fnding: Only 10% of people
recruited to be donors for a fecal
microbiota transplant study were
healthy enough to be eligible.
Data source: Donors recruited for the
FOCUS study.
Disclosures: The study is sponsored
by the University of New South
Wales, Sydney. The investigators reported no relevant fnancial conficts.
transplantation (FMT) is safe and effcacious in the treatment of chronic
active ulcerative colitis and in the
induction of remission.
Dr. Sudarshan Paramsothy and his
colleagues at the University of New
After several
rounds of
screening, there
were only 12
healthy donors,
10% of the
starting 116.
South Wales, Sydney, and the University of Melbourne, reported fndings from donor recruitment for the
FOCUS (Faecal Microbiota Transplantation in Ulcerative Colitis) trial
at the American Gastroenterological
Association’s 2014 James W. Freston
Conference in Chicago.
The FOCUS study began enrolling
patients in November, and is continuing to enroll, said Dr. Paramsothy. He and his colleagues also are
continuing to recruit fecal donors.
The data presented in Chicago were
on an initial recruitment efort.
Overall, after screening, only 10%
of recruits were considered eligible
The researchers recruited donors
through letters, newspaper ads, and
online solicitations.
They were told that they would
be reimbursed for their time and for
the transportation of their stool do-
nations to the study site.
After responding, recruits were
told that they would be expected to
make stool donations fve times a
week for a minimum of 6 weeks.
The researchers had 116 potential
donors over a 7-month recruitment
period. Forty-seven declined immediately because of the 5-day-a-week
donation requirement.
Twenty-seven had other issues, including medical comorbidities (13),
risk factors for variant Cruetzfeldt-Jakob disease (6), and recent
antibiotic use (1), which disqualifed
them from the study.
Thirty-eight potentially healthy
Continued on following page
Continued from previous page
donors underwent stool and blood
testing; 15 of those donors were
found to have a variety of parasites
or indications of active infection
that excluded them from donation: 5
had Dientamoeba fragilis, 5 had Blastocystis hominis, 1 had B. hominis and
D. fragilis, 1 had Giardia intestinalis
and D. fragilis, 1 had norovirus and
Clostridium difcile toxin, and 2 had
leukocytes or erythrocytes on stool
microscopy. One donor had indeterminate hepatitis C serology.
While it is not uncommon for
people to have asymptomatic parasite carriage in the gastrointestinal
O C TO B ER 2 0 1 4 • G I & HEPATO LO G Y NEW S
tract, “we did not expect it in such a
high proportion,” said Dr. Paramsothy. “Our screened donor population
was not an at-risk group,” he said,
adding that they were otherwise
healthy and had no risk factors or
gastrointestinal symptoms.
“Our detection rates may have
been slightly higher as donor stool
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return within a few months despite anti-infammatory
medicine. At UPMC, our multidisciplinary team developed
a new post-op treatment approach that has reduced
the recurrence of Crohn’s disease by nearly three
fourths. And now many other hospitals are adopting
this novel approach. Because when you make patients
feel better, it’s normal to want them to stay that way.
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UPMC is affliated with the University of Pittsburgh School of Medicine.
samples were sent to a pathology center with expert, specialized
GI parasitologists for review,” Dr.
Paramsothy said.
There’s also some question as to
whether some parasites, such as
Blastocystis and Dientamoeba, “are
truly pathogenic or rather commensal organisms,” he said, adding that
it was thought better to exclude
patients with these parasites if there
were any doubt.
That left 22 potential donors. Further questioning found that two had
used antibiotics in between recruitment and stool testing, and one was
living with a household member
The donor results �suggest
that, while FMT is an exciting
new therapy, it is diffcult
to identify appropriate and
willing anonymous donors,’
Dr. Paramsothy said. But that
should not have an overall
impact on FMT as a therapy.
who was positive for D. fragilis.
Of the 19 remaining, 1 dropped out
and 18 were screened again. Three
were excluded because of a body
mass index over 30 kg/m2, 1 because
of illicit drug use, 1 because of irregular bowel movements after starting
a new medication, and 1 because of
uncontrolled anxiety and depression.
Dr. Paramsothy said that highBMI donors were excluded because
some studies have shown that gut
microbiota potentially infuence insulin sensitivity and obesity.
Illicit drug use is a red fag because it is potentially associated with
blood-borne disease acquisition, he
At the end, there were only 12
healthy donors, 10% of the starting
116. Dr. Paramsothy said that it was
not necessary to have a single donor
for every single patient in the trial.
He said he could not disclose currently the number needed for the
study, however.
The donor results “suggest that,
while FMT is an exciting new
therapy, it is difcult to identify appropriate and willing anonymous
donors,” Dr. Paramsothy said. But
that should not have an overall impact on FMT as a therapy, he said
– rather, it might just make it harder
for a small practice to establish an
in-house FMT program.
Dr. Paramsothy reported no relevant fnancial conficts of interest.
[email protected]
On Twitter @aliciaault
Diabetes develops from liver grafts donated after DCD
Frontline Medical News
SAN FRANCISCO – The type of liver graft used
in transplantation plays a large role in early development of new-onset diabetes, according to a
retrospective study of 430 patients from the United
A team led by Dr. Hermien Hartog, an honorary
clinical fellow in the Liver Unit, Queen Elizabeth
Hospital, Birmingham, England, studied patients
undergoing primary liver transplant between 2008
and 2012. Patients were excluded from the study if
they had preexisting diabetes, had died, or had undergone retransplantation within 90 days.
The investigators assessed both the development
of new-onset diabetes after transplant (NODAT),
using criteria adapted from a published article
�Our study confrms known associations
with NODAT after liver transplantation
but identifes DCD graft as a novel
risk factor. ... We hypothesize that
hyperglycemia may be related to liver graft
function through ischemia-reperfusion–
induced hepatic insulin resistance.’
(Transplantation 2013;96:58-64), and its resolution,
defned as the date of cessation of antihyperglycemic therapy or the last episode of hyperglycemia.
Seventy-nine percent of the patients received
grafts donated after brain death (DBD), Dr. Hartog
reported at the annual meeting of the 2014 World
Transplant Congress. Among the recipients of
grafts donated after circulatory death (DCD), the
mean warm ischemic time was 21 minutes.
With a median follow-up of 2.5 years, the cumulative 1-year incidence of NODAT was 19%
in the entire cohort, with a median time to onset
of 30 days. In the 44% of afected patients whose
NODAT resolved, the median time to resolution
help inform new approaches
was 150 days post transplanVITALS
for graft optimization and setation, Dr. Hartog reported at
Key clinical point: Recipients of liver
the congress, which was spongrafts donated after circulatory death
Session cochair Darius Mirsored by the American Society
are at a slightly higher risk for postza, also of the University of
of Transplant Surgeons.
transplant new-onset diabetes.
Birmingham, asked, “Why
The cumulative 1-year inMajor fnding: The risk of new-onset
does the pattern of recovery
cidence of NODAT was 23%
diabetes within 90 days of transseem to be diferent in the
in DCD graft recipients and
plantation was 1.8-fold higher for
DCDs versus the DBDs? Also,
18% in DBD graft recipients, a
patients who received a DCD graft
why are the cumulative incinonsignifcant diference. But
than for peers who received a DBD
dence and the time frame so
when patients were stratifed
by graft type, “we saw an earData source: A retrospective cohort
“Actually, in the literature,
ly occurrence and high peak
study of 430 primary liver transplant
I have not seen any reports
incidence of NODAT in DCD
looking at the early postgraft recipients. Also, a larger
Disclosures: Dr. Hartog disclosed no
relevant conficts of interest.
transplant period. So most
proportion of these patients
reports look at one time point,
resolved their NODAT over
normally 1 year,” Dr. Hartog
time,” she commented.
The overall temporal pattern suggested that “the replied.
“What I think is that there is an early peak
efect that we see of graft type seems to be temporary and [lessens] over time when multifactorial caused by DCD grafts that would explain why
there is an early peak, but also why those patients
factors come into play,” according to Dr. Hartog.
recover later on. I think this peak is a bit obscure
In multivariate analyses, the risk of NODAT
because there are also other factors that come into
within 90 days of transplantation was higher for
play, maybe after a while, that will obscure that
patients who received a DCD graft (hazard ratio,
frst peak. If you would take those other factors
1.8). More detailed analysis showed that the elevaout of the equation, I think you would just see a
tion of risk was greatest within the frst 15 days.
peak in the early period.”
“Our study confrms known associations with
Dr. Mirza also wondered about the role of using
NODAT after liver transplantation but identifes
DCD grafts that are accepted under extended criteDCD graft as a novel risk factor. This causes a
temporary efect in the early posttransplant period ria. “So you start of using mainly young, ft DCD
livers. Now, the vast majority are extended-criteria
that is independent from known risk factors,” Dr.
DCD livers. Do you think that plays a role, or is it
Hartog commented.
“Based on our observations, we hypothesize that too early to say?”
“Yes, I think so,” Dr. Hartog said, while adding
hyperglycemia may be related to liver graft function through ischemia-reperfusion–induced hepatic that this phenomenon is likely not restricted to
DCD grafts.
insulin resistance,” she added.
“From earlier literature, there is a clear difer“We are currently trying to confrm our data in
ence between a living donated graft and deceased
an independent data set, which will also include
postreperfusion glucose levels and correlation with donation. And it might also be that the extended
grafts or the more steatotic grafts may exhibit this
the insulin receptor pathway in time-zero liver biefect more than the better grafts.”
“The clinical relevance of our fndings is as yet
[email protected]
unknown,” she acknowledged. However, they may
Statins linked to lower hepatocellular carcinoma risk
Frontline Medical News
se of statins for any duration of
time is associated with a significant reduction in the risk of hepatocellular carcinoma in a low-risk
population, according to researchers.
In a nested case-control study, re-
searchers matched 94 cases of
hepatocellular carcinoma to 468 controls by using pharmacy records of
a health maintenance organization
between 1999 and 2010.
The study showed a 68% decrease
in the risk of hepatocellular carcinoma among patients who were
using statins for less than 2 years
Key clinical point: Statin use may signifcantly reduce the risk of hepatocellular carcinoma.
Major fnding: Statin use for less than
2 years is associated with a signifcant
68% decrease in the risk of hepatocellular carcinoma, and a 69% decrease
among patients using them for more
than 2 years, compared with nonusers.
Data source: A nested case-control
study among 94 cases of hepatocellular
carcinoma matched to 468 controls.
Disclosures: No conficts of interest
were declared.
and a 69% decrease among patients
who were using statins for more
than 2 years, compared with nonusers, according to the investigators.
The study was published online
Aug. 8 in the journal Cancer Epidemiology (
[email protected]
пЃ‡пЃ‰пЃ€пЃ…пЃђпЃџпЂІпЂёпЂ®пЃ©пЃ®пЃ¤пЃ¤ пЂ±
пЂ№пЂЇпЂ±пЂІпЂЇпЂІпЂ°пЂ±пЂґ пЂІпЂєпЂµпЂ±пЂєпЂ°пЂі пЃђпЃЌ
TURQUOISE regimen active against HCV+HIV
Frontline Medical News
WASHINGTON – Early studies
show that a new, combined antiviral
regimen seems to suppress hepatitis
C viremia while keeping HIV viremia
stable in coinfected patients.
Dr. Joseph Eron presented phase
II data from 63 patients who were
enrolled in TURQUOISE-I. A total
of 94% (59/63) of patients achieved
a sustained virologic response (SVR)
12 weeks after completing 12 weeks
of therapy, and 61 of 63 patients
achieved an SVR 4 weeks after completing 12 or 24 weeks of therapy, Dr.
Eron reported at the annual Interscience Conference on Antimicrobial
Agents and Chemotherapy.
The regimen included ABT-450 (an
NS3-4A protease inhibitor that was
identifed by AbbVie and Enanta),
which was combined with ritonavir
and ombitasvir (another AbbVie
drug, also known as ABT-267) into
a single tablet, plus dasabuvir (ABT333) and ribavirin. Ombitasvir is an
NS5A inhibitor and dasabuvir is a
nonnucleoside NS5B polymerase inhibitor.
To be included in TURQUOISE-I,
patients have to be aged 18-70 years;
be treatment naive or have previous
pegylated interferon/ribavirin treatment experience; have hepatitis C
virus (HCV) genotype 1 infection;
have plasma HIV-1 RNA less than 40
copies/mL; and be taking a stable,
qualifying HIV-1 antiretroviral therapy regimen, said Dr. Eron, a professor of medicine at the University of
North Carolina, Chapel Hill.
Patients with cirrhosis are not excluded, but will not be enrolled if
they have had prior therapy with direct-acting antivirals for HCV, or any
current or past clinical evidence of
liver decompensation.
All patients will be followed for 48
weeks after therapy is stopped. Thirty-one patients were given therapy
for 12 weeks and then assessed for
SVR at 12 weeks. Thirty-two patients
were given therapy for 24 weeks and
assessed 4 weeks later. Patients also
were evaluated for end-of-treatment
response, on-treatment virologic
failure, and posttreatment HCV viral
At baseline, 59 patients in each
arm were male, and 16 were African
American. The mean age was 51
years. Six patients in each arm (19%)
Key clinical point: A new therapy
is on the horizon for HCV-HIV coinfected patients that achieves high
virologic response with few severe
side effects.
Major fnding: A three-drug regimen
that includes ABT-450 and ombitasvir in one pill, plus dasabuvir
and ribavirin, achieved high SVR in
patients coinfected with HCV GT1
and HIV.
Data source: A 63-patient, two-arm,
open-label prospective study.
Disclosures: The study was sponsored by AbbVie. Dr. Eron received
grant and research support from,
and/or served as a consultant to,
AbbVie, Bristol-Myers Squibb, and
other companies. Other authors had
numerous additional disclosures.
had cirrhosis. A high proportion in
each arm (53/63 in the 12-week and
49/63 in the 24-week arm) had the
interleukin-28B genotype, which is
known to indicate a much harder-totreat disease, Dr. Eron said.
At the end of treatment, only one
patient in each arm was not responsive. Four weeks post therapy, 29 of
31 patients in the 12-week arm and
31 of 32 patients in the 24-week arm
had an SVR.
Two patients had virologic failure.
Both had been unresponsive to previous therapies, and both had the
IL-28B genotype and resistance-associated variants at the time of failure.
No patient withdrew because
of adverse events, but about 90%
(57/63) experienced some side efect,
with the most common being fatigue
and insomnia.
Six patients had to reduce their
ribavirin dose because of a drop in
hemoglobin levels, but they were still
responsive to therapy. Five patients
had a confrmed increase in HIV
RNA higher than 40 copies/mL, but
not above 200 copies/mL, said Dr.
Eron. And all the patients remained
suppressed on the same HIV regimen
and without interrupting their HCV
therapy, he said.
Soon, a cohort of patients on stable
darunavir antiretroviral therapy will
be enrolled and given the three-drug
HCV regimen for 12 weeks. The full
global TURQUOISE study will begin
later in 2014, Dr. Eron said.
[email protected]
On Twitter @aliciaault
O C TO B ER 2 0 1 4 • G I & HEPATO LO G Y NEW S
Post–LRYGB cholecystectomy most common
Frontline Medical News
he overall rate of cholecystectomy after weight-loss surgery
is low, but it is more likely to
occur among patients who experience
excessive weight loss following their
procedure and those who undergo
laparoscopic Roux-en-Y gastric bypass.
Analysis of prospective data from
1,398 patients undergoing bariatric
surgery showed an overall cholecystectomy rate of 7.8% over a median
follow-up of 49 months, with the
frequency higher in the frst 6 months,
according to data published in Surgery
for Obesity and Related Diseases.
Cholecystectomy rates were signifcantly higher among individuals who
underwent laparoscopic Roux-en-Y
gastric bypass (LRYGB), compared
with those who received a laparoscopic adjustable gastric band (LAGB) or
laparoscopic sleeve gastrectomy (LSG)
(10.6% vs. 2.9% vs. 3.5%, P = .001).
“Although the LRYGB was the procedure associated with the highest
rate of cholecystectomy, the present
study found that this relationship was
due to the superior %EWL [percent
excess weight loss] associated with
this procedure, compared with the
LAGB and LSG procedures,” wrote
the late Dr. Victor B. Tsirline of
Northwestern Memorial Hospital,
and his colleagues.
Patients who lost more than a
quarter of their weight within 3
months of surgery showed signifcantly higher rates of cholecystectomy, and there was a 25% increase in
cholecystectomy per 10% of excess
weight loss within the frst 3 months
after weight-loss surgery, although
this association was signifcant only
among patients treated with gastric bypass (Surg. Obes. Relat. Dis.
There were statistically signifcant
diferences in cholecystectomy rates
performed by the three surgeons
involved, although again, this was
only in patients who had undergone
gastric bypass, and researchers said
this could be partly attributed to the
fact that one surgeon saw a greater
proportion of revision patients.
Researchers also noted an interaction with race, as black patients had
signifcantly lower rates of cholecystectomy, compared with white patients (2.2% vs. 8.9%, P = .0001), and
Native American patients showed the
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highest rates of all (65%).
This study found no diference in
cholecystectomy rates between patients taking ursodiol and those who
Rapid weight loss after bariatric
surgery is associated with an increased risk of gallstones, and routine cholecystectomy at the time of
bariatric surgery has been the subject
of considerable debate.
Those in favor argue that it prevents the morbidity of symptomatic
cholelithiasis and avoids the risk of
duct stones which can be difcult to
treat after gastric bypass.
However opponents say routine
cholecystectomy would prolong hospital stays, lengthen operating times,
and potentially increase complication
rates, when the use of ursodiol after
weight-loss surgery has been shown to
decrease the frequency of gallstones.
“The fndings of the present study
indicate that a conservative approach
to cholecystectomy ... is warranted, because only 7.8% of patients developed
symptomatic gallbladder disease within
4 years on average,” researchers wrote.
“Furthermore, there are technical
advantages of delayed cholecystectomy that stem from reduced intra-abdominal fat content and decreased
liver size secondary to weight loss.”
There were no conficts of interest
[email protected]
The diagnosis
Answer to “What’s your
diagnosis?” on page 2:
Tuberculosis diagnosed by
endoscopic ultrasonography with
fne-needle aspirate
ndoscopic ultrasonography
visualized a heterogeneous perigastric mass abutting the gastric
cardia and extending down to, but
not invading, a normal-appearing
pancreas. Fine-needle aspiration
of the mass demonstrated necrotizing granulomas with acid-fast
bacilli. A chest x-ray was negative
for any cavitary lesions.
The patient was started on
antituberculosis therapy with resolution of his pain shortly afterward.
Six months later, repeat computed
tomography of the abdomen and
pelvis showed an interval decrease
in size of the perigastric mass (2.6
Г— 2.0 Г— 1.6 cm). He has since then
completed a total of 9 months of
medical therapy and remains asymptomatic.
This is an unusual presentation
of tuberculosis as an isolated
perigastric mass. The presence
of gastric acid and the paucity of
lymphoid tissue make the stomach
the least likely area of the gastrointestinal tract to be afected by
Gastroduodenal tuberculosis is
thought to present in three ways:
most commonly gastric outlet
obstruction, upper gastrointestinal
hemorrhage from a tubercular
ulcer, and more rarely as a gastric
or periampullary mass. Complications such as fstulae formation
may also arise. Our patient presented with epigastric discomfort,
and this can be the initial presenting symptom in up to 56.5% of
Conventional endoscopic biopsy
has poor diagnostic yield,2 although fne-needle aspiration
guided by either computed tomography or endoscopic ultrasonography may produce better results.
We suspect local extension from
regional lymph nodes to be the
cause of the perigastric mass,
but hematogenous spread and
swallowing of organisms may also
precipitate gastric tuberculosis.
Perforation has been reported
rarely,3 and treatment entails conventional tuberculosis therapy, as
our patient received. In cases of
obstruction, fstulae, or persistent
ulceration, surgical management
may be considered.
1. Tromba, J.L., Inglese, R.,
Reiders, B., et al. Primary gastric tuberculosis presenting as
pyloric outlet obstruction. Am.
J. Gastroenterol. 1991;86:1820-2.
2. Rao, Y.G., Pande, G.K., Sahni,
P., et al. Gastroduodenal management guidelines, based on a
large experience and a review
of the literature. Can. J. Surg.
3. Sharma, D., Gupta, A., Jain,
B.K., et al. Tuberculosis gastric
perforation: report of a case.
Surg. Today 2004;34:537-41.
[email protected]
After 3-year stumble, new weight-loss drug wins
Frontline Medical News
fter a delay of more than 3
years, the Food and Drug Administration has approved the
nation’s third weight-loss drug, a combination of naltrexone and bupropion.
The extended release tablets (Contrave; Orexigen and Takeda) are approved for use in adults who have a
body mass index of at least 30 kg/m2, or
those with a BMI of at least 27 kg/m2
and at least one additional weight-related condition such as hypertension, type
2 diabetes, or dyslipidemia. The agency
recommended that Contrave be used
in addition to caloric restriction and increased physical activity.
Dr. Timothy Garvey, chair of the
American Association of Clinical Endocrinologists’ scientifc committee,
lauded the approval. He said Contrave
will be a valuable addition to the existing weight-loss medications: the phentermine/topiramate combo (Qsymia;
Vivus) and lorcaserin (Belviq; Arena).
“There are no head-to-head trials
with the other drugs, so we really can’t
say much about relative efcacy,” said
Dr. Garvey who is also chair of the
department of nutrition at the Univer-
sity of Alabama at Birmingham, “But
when you look at the placebo-subtracted weight loss in all the phase III data,
it looks like Contrave is in the middle,
with about a 6% loss over lifestyle
interventions alone. So it’s not as efective as the topiramate combination, but
more efective than lorcaserin.”
In the pivotal, 56-week phase III
trials, those taking Contrave lost 5%8% of their baseline body weight, compared with a loss of 1%-2% in those on
placebo. The proportion of those who
lost at least 5% of their baseline body
weight ranged from 45% to 56% of
those on the proposed dose, compared
with 16%-43% of those on placebo.
FDA guidance on weight-loss drugs
suggests a 12-week efcacy evaluation – if the patient has not lost at
least 5% of total body weight by
then, the drug should be discontinued and another started.
Because it contains bupropion, an antidepressant linked to suicidal risk, the
drug carries a black box warning. Bupropion is also known to lower seizure
threshold, so the drug should not be
used in patients with seizure disorders.
If a seizure occurs while taking the
medication, it should be permanently
Orexigen and Takeda originally
brought the drug forward in December 2011. It was not approved at that
time because of concerns about its
efect on blood pressure – an unexpected move, and one that Orexigen
management called “a big setback.”
About a quarter of those in the
56-week pivotal phase III trial experienced signifcant blood pressure
increases of at least 10% above their
baseline, compared with about 20%
of those in the control arm. Increases
of diastolic blood pressure of at least 5
mm Hg over baseline occurred in 37%
of those on the combination, compared with 29% of those on placebo.
About a quarter in the active arm also
had heart rate increases of at least 10
beats per minute, compared with 19%
of those taking placebo.
Because of these concerns, the
FDA required the companies to
conduct a large, double-blinded randomized, placebo-controlled trial to
investigate the risk of major cardiovascular events. Takeda and Orexigen then launched the 4-year, 8,900
patient Light study, which is still ongoing. Endpoints are major adverse
cardiovascular events (cardiovascular
death, nonfatal myocardial infarction,
and nonfatal stroke) in overweight
and obese subjects who have concomitant diabetes and/or other cardiovascular risk factors.
In June, citing encouraging preliminary results, Takeda and Orexigen
brought Contrave to the FDA once
more – only to be shot down again,
at least temporarily. The agency required a review extension in order to
come to agreement on the fnal form
of postmarketing surveillance, said
Denise Powell, a spokeswoman for
Orexigen. “At that time, FDA said
the data looked good,” she said in
an interview. “We just needed more
time to work out the postmarketing
requirements.” These will include a
cardiovascular outcomes trial, studies
in pediatric patients, and clinical trials
to evaluate dosing in patients with
hepatic or renal impairment.
Dr. Garvey is a consultant for Daiichi Sankyo, LipoScience, Takeda,
Vivus, Boehringer Ingelheim, Janssen,
Eisai, and Novo Nordisk. He has received research funding from Merck,
AstraZeneca, Weight Watchers, Eisai,
and Sanof.
[email protected]
On Twitter @alz_gal
May 16–19, 2015
Exhibit Dates: May 17–19, 2015
Washington, DC
Walter E. Washington
Convention Center
Get Noticed.
Join the effort in providing the latest research to health-care
professionals in gastroenterology, hepatology, GI endoscopy
and GI surgery. Share your work at the world’s largest gathering of
leaders in the п¬Ѓeld of digestive diseases.
DDWВ® is the premier educational forum for digestive disease
professionals. Year after year, thousands of GI academicians, clinicians,
researchers and students attend the meeting to witness innovative
advances in basic, clinical and translational research.
Accepted abstracts will be published in the April 2015 online
supplement to GIE: Gastrointestinal Endoscopy or the April 2015 online
supplement to Gastroenterology.
To submit your abstract, view informational videos, read submission
guidelines and get answers to frequently asked questions,
Submit your abstract at
BEGINS: Tuesday, Oct. 21, 2014 at 9 a.m. ET
ENDS: Tuesday, Dec. 2, 2014 at 9 p.m. ET
O C TO B ER 2 0 1 4 • G I & HEPATO LO G Y NEW S
These presentations were given at Digestive Disease WeekВ® 2014 in Chicago
Colon section
prep completion and performance of colonoscopy
improves bowel prep quality. Dr. Sameer Saini rehe colon course brought us numerous pearls, viewed additional system-level factors to improve
from how to perform quality endoscopy safe- ADRs, such as high-defnition and wide-angle
ly, to providing updates on genetic
colonoscopes, high-quality withdrawal
screening for colon cancer syndromes
techniques, and colonoscope adjuncts
and fecal microbiota transplant.
such as caps, chromoendoscopy, and narQuality colonoscopy is not just an
row-band imaging.
efort to provide the best care to our
A quality endoscopy is also a safe enpatients; it will become a barometer
doscopy, and Dr. Neena Abraham providfor not only government and private
ed numerous “cardiogastroenterology”
payers, but also patients looking for toppearls to help guide care of patients with
notch care. Adenoma detection rate is
gastrointestinal diseases requiring endosan objective parameter that we should
copy during anticoagulant and antiplateDR. EARLY
monitor regularly and strive to meet or
let therapy. If you remember one key
exceed national benchmarks.
point from her talk, it should be: Do not
We learned from Dr. Thomas Imperiale that
stop aspirin for endoscopy.
advances in bowel preparation have led to resulA major goal of colonoscopy is adenoma detectant improvements in adenoma detection rate
tion and removal, and Dr. Joseph Elmunzer guided
(ADR). We now know that split preparations are
us through techniques to tackle the “defant polmost efective, and minimizing the time between
yp,” including submucosal injection, proper coloBY DAYNA EARLY, M.D.
noscope positioning, clip closure of defects, and
the importance of complete adenoma resection.
When we fnd adenomas and cancers, we should
be vigilant in inquiring about the patient’s family
history, and be mindful of patterns suggestive of a
hereditary cancer syndrome such as a large number
of adenomas, right-sided sessile serrated adenomas,
and family members with colorectal neoplasia at a
young age. Dr. Elena Stofel reviewed clinical features of common hereditary syndromes.
Dr. Lawrence Brandt reviewed treatment of refractory or recurrent Clostridium difcile infection.
He discussed therapy with fdaxomicin, which has
been shown to be superior to vancomycin for C.
difcile recurrence, and provided an overview of the
process of fecal microbiota transplant.
Dr. Early is professor of medicine, Washington University, St. Louis.
[email protected]
Esophagus/upper GI section
ne highlight of the AGA Postgraduate Course was the
esophageal disease session.
The presentation by Dr. Michael B.
Wallace summarized recent studies
using advanced imaging modalities
in patients with Barrett’s esophagus.
Studies using chromoscopy and virtual chromoscopy techniques such as
narrow-band imaging have increased
the detection of dysplasia in BE patients. These are so-called red fag
techniques that image large areas of
mucosa to detect mucosal abnormalities suspicious for the presence of
dysplasia or neoplasia.
Endomicroscopy describes the use
of real-time, targeted endoscopic imaging modalities that are capable of
producing histologic-like images of
mucosa at depths up to 200 microns.
Confocal laser endomicroscopy (CLE)
uses a blue light laser (405 nm) and
collimated light detection and analysis
to produce 1,000-fold magnifed images. When used with a fuorescent
contrast agent such as fuorescein or
acrifavin dye, these systems produce
cellular-level images that are comparable to those images seen with optical
microscopy. Further, a multicenter
study will soon begin using a tethered-capsule (nonendoscopic) form of
volumetric laser endomicroscopy as a
method to screen for BE.
Dr. Amitabh Chak expanded on
doscopic testing was reviewed, inthese issues and reviewed those surcluding the diferential diagnosis of
rounding screening and surveillance
lymphocytic duodenosis with use of
of BE patients for the early detecnonsteroidal anti-infammatory drugs
tion and treatment of esophageal
(NSAIDs), Helicobacter pylori infecadenocarcinoma. This presentation
tion, Crohn’s disease, and Sjogren’s
suggested that necessary future imsyndrome. Proper duodenal biopsy
provements include cost-eftechnique was emphasized
fective advanced imaging
with two forceps biopsy
techniques optimized for
samples obtained from the
use in clinical practice, moduodenal bulb and four
lecular biomarker panels
biopsy samples obtained
for prediction of which
from the second portion
patients may progress to
of the duodenum. Also
dysplasia and neoplasia,
discussed was the utility
and high-quality intensive
of HLA typing for DQ2/8
endoscopic surveillance for
in patients currently using
high-risk BE patients.
a gluten-free diet, patients
Dr. Joe Murray’s comprewith negative serology rehensive presentation of celiac disease
sults but abnormal duodenal biopsy
described the protean clinical presenfndings, and those with negative
tations of this disease as well as optiserology results who are at increased
mal use of serologic and endoscopic
genetic risk.
testing. Celiac disease is increasingly
Dr. James Scheiman discussed manidentifed in middle-aged patients
agement of the complex interaction
(median 45 years) without diarrhea.
and risks associated with the use of
Classic malabsorption symptoms of
NSAIDs, aspirin, clopidogrel, and
diarrhea, weight loss, steatorrhea,
proton pump inhibitors in the setting
and nutritional defciencies are found
of previous ulcer disease, gastrointesin 25% of patients. Half of celiac
tinal bleeding, and H. pylori infection.
patients will have only one symptom
Results from randomized controlled
such as anemia, diarrhea, lactose
studies and observational studies
intolerance, or weight loss. Nongaswere the basis for the Consensus
trointestinal symptoms are present in
Group to recommend the use of PPI
another 25% of patients such as infer- therapy as the GI bleeding protective
tility, bone disease, chronic fatigue, or strategy of choice. PPI therapy was
abnormal liver enzyme test results.
also recommended as cost-efective
Optimal use of serologic and entreatment for aspirin-using patients,
although the risks and benefts of
long-term PPI treatment require patient education and individualization.
Finally, Dr. Rhonda Souza discussed
eosinophilic esophagitis, a chronic immune/antigen-mediated esophageal
disease characterized by symptoms
related to esophageal dysfunction
associated with eosinophil-predominant infammation such as dysphagia,
food impaction, chest pain, heartburn,
abdominal pain, and refractory refux
dyspepsia. Endoscopic features include
the ringed esophagus, white specks,
linear furrows, and stricture.
Histologic features of EoE are eosinophilia (more than 15 intraepithelial eosinophils per high-power feld),
basal zone hyperplasia, and dilated
intercellular spaces. These eosinophils
are activated via T-helper 2 immune
system via interleukins-4, -5, and -13.
Treatment of EoE usually requires
use of PPIs. The use of topical corticosteroids and endoscopic dilation
for symptomatic strictures may also
be necessary. Nondrug treatment
approaches such as the six food elimination diet of the most common food
allergens such as milk, soy, eggs, wheat,
nuts, and seafood have also been successful.
Dr. Wolfsen is in the division of gastroenterology and hepatology, Mayo Clinic,
Jacksonville, Fla.
[email protected]
These presentations were given at Digestive Disease WeekВ® 2014 in Chicago
Pancreatic-biliary section
n the frst presentation, on benign
biliary strictures, Dr. Greg Cote
divided etiologies into extrinsic vs.
intrinsic and noted which ones require
only bridging plastic stents while treating the underlying cause. The etiologies that require endoscopic therapy
include chronic pancreatitis, postoperative (both postcholecystectomy and
posttransplant), primary sclerosing
cholangitis, and the rare common bile
duct stone–induced stricture. For primary sclerosing cholangitis, dilation
alone is usually sufcient and safer
than dilation plus stenting. Strictures
that are postoperative or due to chron-
ic pancreatitis require endotherapy
combining dilation and placement of
the maximal number of
plastic stents possible.
Dr. David Lichtenstein
gave a talk on bile duct
strictures. He discussed the
multiple diagnostic methods needed to determine
whether a stricture is benign
or malignant. At endoscopic
retrograde cholangiopanDR. ELTA
creatography it is useful to
combine both brush cytology (+/– FISH) and intraductal biopsy.
Higher sensitivities are obtained by
utilizing endoscopic ultrasound (EUS)/
fne-needle aspiration (FNA), although
Hepatology section
alcoholic steatohepatitis. By careful
estimates, he predicts that there may
he hepatology session had a
be as many as 25 million patients in
range of excellent topics for the the U.S. with NASH. New treatments
practicing gastroenterologist/
are being developed, but we are
hepatologist. Perhaps the area chang- still a long way from having reliable
ing most rapidly is that of
treatments for this disease.
treatment of hepatitis C.
Thus, lifestyle modifcations
Dr. Jordan Feld presented
with judicious weight loss
“Choosing the optimal
and exercise regimens reHCV regimen.” He highmain the most important
lighted the recent approval
treatments available for
of simeprevir and sofosNASH/NAFLD. Dr. Harbuvir both with pegylated
rison also highlighted the
interferon and ribavirin for
recent studies that demontreatment of chronic hepstrate that regular cofee
atitis C genotype 1. HCV
consumption may be helpcure rates of 80%-90%
ful for reducing fbrosis in
were described. He also told us about patients with NAFLD.
exciting developments with interferDr. Jorge Marrero presented data
on-free regimens that will be availon kidney injury in cirrhosis and how
able in October/November of 2014.
to diferentiate acute kidney injury
The combination of sofosbuvir
from hepatorenal syndrome. Finally,
and ledipasvir and the combination
Dr. Sam Lee taught us to recognize
of three direct-acting antiviral agents that cirrhosis is not a hypocoagulable
with or without ribavirin will revostate and that there are situations
lutionize our care of hepatitis C pawhere anticoagulant therapy in cirtients from now on. Many clinicians
rhosis is defnitely a beneft. The idea
have already been using interferof using anticoagulation in patients
on-free regimens by combining sime- with cirrhosis is counterintuitive to
previr and sofosbuvir for 12 weeks
many of us, but Dr. Lee presented
with excellent results.
data to endorse this approach.
Dr. Michael Lucey from the University of Wisconsin School of Medicine
Dr. Bacon is the James F. King MD Enand Public Health talked about the
dowed Chair in Gastroenterology, profesmanagement of alcoholic hepatitis.
sor of internal medicine, and director of
Dr. Stephen Harrison from Brooke
abdominal transplantation at Saint Louis
Army Medical Center presented imUniversity School of Medicine, division of
pressive data on the huge number of
gastroenterology and hepatology, St. Louis.
patients that we will be seeing with
[email protected]
nonalcoholic fatty liver disease/nonBY BRUCE R. BACON, M.D., AGAF
if the patient is a resection or transplant candidate, some surgeons are
fearful of tumor seeding
with FNA.
Other techniques discussed included cholangioscopy and probe-based
confocal microscopy. The
pros and cons of various
palliative stents were
also discussed, as were
experimental endoscopic
therapies including photodynamic therapy and
endobiliary radiofrequency ablation.
Dr. Robert Hawes discussed the
management of chronic pancreatitis
pain with medical, endoscopic, and
surgical therapy. He reviewed the
causes of pain in chronic pancreatitis, the variable clinical presentations
(due to main pancreatic duct obstruction or ongoing infammation),
and the fact that placebo response
rates are high. Medical therapies,
including pancreatic enzymes, antioxidants, and octreotide are not
well proven although often tried.
Celiac axis blockade has at best a
short-lived, 50% chance of beneft.
Endoscopic therapy (often combined
with extracorporeal shock wave
lithotripsy has some efcacy for
obstructive disease. Surgery is most
efective for obstructive disease, but
resection carries the risk of insulin
Dr. Martin Freeman discussed
acute idiopathic recurrent pancreatitis and its likely multifactorial causes
with interaction of genetic, anatomic, and environmental factors.
He noted the overlap presentation
of acute pancreatitis with chronic pancreatitis. He said EUS has a
key diagnostic role, as does secretin-stimulated magnetic resonance
cholangiopancreatography. The controversial role of endoscopic therapy
was discussed.
Dr. Elta is professor of internal medicine, University of Michigan, Ann Arbor.
[email protected]
O C TO B ER 2 0 1 4 • G I & HEPATO LO G Y NEW S
AMA calls on vendors, feds to improve EHRs
Frontline Medical News
ith more physicians reporting
that electronic health records
are more of a hindrance than
a help, the American Medical Association is calling on vendors and federal health ofcials to make changes
that will improve the usability of
electronic systems.
The AMA released eight priorities for
improving physician usability of EHRs.
But Dr. Steven J. Stack, the AMA’s
president-elect, who is an emergency
physician in Lexington, Ky., said the
most helpful frst step would be for federal ofcials to add more fexibility to
the so-called meaningful use program,
which requires physicians to meet requirements for the clinical use of their
EHRs, such as meeting benchmarks for
electronic prescribing or communicating with patients via an online portal.
The AMA is asking the Centers
for Medicare & Medicaid Services,
which oversees the meaningful use
program, to lower the thresholds for
earning incentives and penalties. Currently, physicians must meet 100% of
the meaningful use standards to earn
The most helpful
frst step would
be for federal
offcials to add
more fexibility to
the meaningful
use program.
the bonus payment and avoid a penalty. The AMA wants physicians to
be able to avoid penalties by meeting
half of the requirements.
But vendors also have a role to play,
according to the AMA. Dr. Stack said
during a Sept. 16 news conference to
announce the new AMA framework
that most currently available systems
aren’t customized with displays for individual specialties, ask for too much
data entry from physicians, and require excessive scrolling and clicking.
The AMA has set eight priorities
for improving EHR usability, developed by an advisory committee of
physicians, experts, researchers, and
health IT executives. The priorities
▶ Enhancing physicians’ ability to
provide high-quality patient care.
в–¶ Supporting team-based care.
в–¶ Promoting care coordination.
в–¶ Ofering product modularity and
в–¶ Reducing cognitive workload.
в–¶ Promoting data liquidity by allowing data to be shared between diferent settings.
в–¶ Facilitating digital and mobile engagement.
в–¶ Expediting user input into produce
design and postimplementation feedback.
The AMA’s call to action comes in
the midst of National Health IT week,
which features a week of events with
IT vendors, federal ofcials, health
care providers, and other groups focused on advancing health through
the use of electronic systems.
[email protected]
On Twitter @maryellenny
This month we continue last month’s
theme that focused on the role of pathology in the care of our GI patients.
Many gastroenterologists have successfully incorporated pathology into their
core practices either within a business
infrastructure or as part of a larger
health care system. Dr. Gibson and her
colleagues at Yale University School of
Medicine have helped inform us about a
particularly difcult management problem: how to handle the genetically highrisk patients we see frequently in our
hospitals and endoscopy units. New comprehensive practice guidelines concerning
management of hereditary colon cancer
syndromes are in development, but this
article provides a clear and concise guide
for the practicing gastroenterologist.
John I. Allen, MD, MBA, AGAF,
Special Section Editor
s health care reform progresses,
the pressure to more closely integrate clinical service lines such
as colorectal cancer management has
intensifed. The practicing gastroenterologist may fnd that they are not
equipped to understand pathology
information required for coordinated
team-based care of their patients. This
is especially true in the case of molecular classifcation of CRC, something
that has become a standard component of comprehensive oncologic care
and has been incorporated into many
gastroenterology practice pathology
services. Molecular characterization
not only provides insight into the
pathogenesis of cancer but has prognostic and therapeutic implications.
This review is a practical guide to the
most common molecular tests used
in what has become standard GI practice.
Molecular classifcation
of colorectal cancer
The molecular classifcation of colon
cancer is based on the cumulative
study of precursor lesions (such
Microsatellite instability testing
as adenomas and sessile serrated
polyps), inherited colon cancer
syndromes (such as familial adenomatous polyposis syndrome and
Lynch syndrome/hereditary nonpol-
sporadic dMMR/MSI cancers is believed to be the sessile serrated polyp,
an epithelial proliferation characterized by the V600E BRAF mutation.
Therefore, sporadic dMMR/MSI
yposis colon cancer), and molecular
profling of colorectal cancers. Broadly, colorectal cancers are divided into
two general groups based on genomic diferences: chromosomal instability, accounting for 75%-80% of all
colorectal cancers, and microsatellite
instability (MSI), accounting for
15%-20% of all colorectal cancers.1,2
Inherited colorectal susceptibility
syndromes are estimated to account
for approximately 1%-2% of the MSI
cancers and less than 1% of chromosomal instability cancers.
Microsatellite instability pathway
MSI is defned by changes of microsatellite length (repetitive noncoding
DNA sequences) resulting from
defcient mismatch repair (dMMR)
during DNA replication.1,3,4 The
protein complex responsible for mismatch repair function is a tetramer
composed of two heterodimers:
MLH1/PMS2 and MSH2/MSH6.4
The expression of each protein in
a heterodimer is dependent on its
partner, such that if one protein is
absent, the partner protein consequently is degraded. When this occurs, the heterodimer is not available
to form a functional tetramer and
dMMR, as manifested by MSI, is the
Most dMMR/MSI cancers occur
sporadically and are associated with
the loss of MLH1 expression owing
to epigenetic silencing of the MLH1
gene promoter via CpG island methylation.1,2 The precursor lesion of
Content from this column was originally published in the “Practice Management: The Road Ahead” section of Clinical Gastroenterology and Hepatology
“Practice Management Toolbox” provides key information and resources necessary for facing the unique challenges of today’s clinical practices.
Resources for Practical Application: To view additional online resources about
this topic and to access our Coding Corner, visit, www/
cancers also frequently harbor the
V600E BRAF mutation.5
Approximately 1%-2% of dMMR/
MSI cancers occur in the setting
of Lynch syndrome as a result of
a hereditary gene defect in one of
the four MMR genes.6,7 The most
frequently mutated gene in Lynch
syndrome patients is MSH2 (40%),
followed by MLH1 (30%). MSH6 and
PMS2 are mutated at lesser frequencies, approximately 15% each. In contrast to the sporadic setting, dMMR/
MSI cancer in Lynch syndrome patients arises from adenomas without
BRAF mutations. Therefore, cancers
in Lynch syndrome patients will have
a wild-type BRAF gene.5
Methods of dMMR/MSI detection
dMMR is detected by immunohistochemistry (IHC) and MSI is detected by polymerase chain reaction
(PCR).3,8 PCR involves extraction
of DNA from a tumor followed by
DNA amplifcation of microsatellite
markers, and determination of the
amplifed microsatellite lengths as
compared with nontumor DNA from
the same patient. Although laboratories vary with regard to the number
of microsatellites tested, most use
a standard set of fve microsatellite
markers. A tumor is classifed as MSIhigh if two or more of the fve microsatellite markers show instability,
as MSI-low if only one of fve markers is unstable, and as microsatellite
stable (MSS) if the microsatellite
markers show no expansion.3,8
The IHC method uses antibodies
directed against each MMR protein to
detect the expression of the proteins
in the tumor cells.3 In cancers with
dMMR/MSI, loss of nuclear expression of MMR proteins is seen in the
cancer cells. In contrast, nonneoplastic
cells, such as lymphocytes or adjacent colonic mucosa, show preserved
nuclear expression of the MMR proteins, irrespective of the hereditary or
sporadic setting. The nonneoplastic
cells therefore serve as an important
internal control for the IHC procedure. Most laboratories test each of
the four MMR proteins. The majority
of dMMR/MSI cancers show loss of
expression of both MMR proteins in
a heterodimer (either MLH1/PMS2
or MSH2/MSH6) in the cancer cells,
with preserved expression of the other heterodimer. In sporadic dMMR/
MSI cancers, loss of MLH1/PMS2
expression is characteristic, whereas in
Lynch syndrome either heterodimer
may be lost.3,6 Occasionally, unusual
IHC patterns exist, usually in the setting of Lynch syndrome, such as isolated loss of MSH6 in 10% of cancers
or isolated loss of PMS2 in approximately 5% of cancers.6
Polymerase chain reaction
vs. immunohistochemistry
The results obtained from PCR and
IHC studies are complementary but
provide diferent information.3,7 The
PCR method does not detect which
protein in the mismatch repair tetramer is defcient. Therefore, PCR
cannot distinguish between sporadic or Lynch syndrome associated
dMMR/MSI cancer. IHC, on the other hand, provides specifc mismatch
repair protein expression data and
can suggest etiology. Loss of MSH2/
MSH6 suggests Lynch syndrome,
whereas loss of MLH1/PMS2, although seen in Lynch syndrome, is
characteristic of the more common
sporadic dMMR/MSI cancer.6 When
present, abnormal IHC results also
can be used to guide gene sequencing
in patients with a high risk of Lynch
syndrome. If the nuclear protein
expression of all four MMR proteins
is intact, the tumor is assumed to be
MSS, with rare exceptions, and PCR
may not be needed except in patients
at high risk for Lynch syndrome.
IHC is inexpensive, is widely available in most pathology laboratories,
and can be performed on both biopsy
specimens and resection specimens,
usually within 1-2 days. In the majority of cases, interpretation of IHC
expression is straightforward and
requires little training. False-negative
results occur in less than 10% of
Lynch syndrome patients with mutations that lead to protein dysfunction
with preserved immunoreactivity.4
PCR analysis is performed on tissue removed from a tissue block containing an adequate tumor sample
(at least 30% of the tissue within the
block consisting of tumor) for DNA
extraction, as well as accompanying
Continued on following page
Continued from previous page
normal tissue for comparison. Biopsy
samples may not contain sufcient
tumor volume for PCR, whereas
most resections are sufcient. The
turnaround time for PCR is 5 days to
2 weeks.
When to test and which specimen
It now generally is accepted that all
patients with colorectal cancer should
be tested for MSI/dMMR using either
IHC, PCR, or both at some point
during the evaluation and treatment
of their cancer, regardless of their
age.3,9 Published guidelines, such as
the 2004 Revised Bethesda guidelines
and the Revised American College of
Gastroenterology 2008 guidelines, are
aimed at detecting Lynch syndrome
patients postoperatively.7,10 However,
testing of biopsy material before surgical resection has been advocated by
some and has become standard practice in many institutions. At least two
updated guidelines are in process, one
by the U.S. Multi-Society Task Force
on Colorectal Cancer and one by the
American Gastroenterological Association Institute ( John I. Allen, MD,
personal communication).
Testing of cancer in the setting of
neoadjuvant chemoradiation treatment can be challenging because
O C TO B ER 2 0 1 4 • G I & HEPATO LO G Y NEW S
marked therapy responses
limit the amount of cancerous tissue available for
DNA extraction. Residual
tumor volume may be
sufcient for IHC analysis.
Pitfalls exist; neoadjuvant
therapy has been reported
to induce MSH6 loss in
20% of colon cancers.11 In
this setting, comparison
with PCR results or prior
biopsy samples may be
In addition to testing
cancer tissue, dMMR/MSI
testing also can be performed on adenomatous
tissue in patients with a
high risk of having Lynch
syndrome based on clinical
criteria.12 However, in this
setting, the interpretation
of intact MMR expression
by IHC should not be
used as evidence against
the possibility of Lynch
syndrome because MMR
Figure 1. Mismatch repair immunohistochemistry algorithm.
loss is speculated to occur
as a late event in the adenoma-carcinoma sequence. Initiation of genetic counselors. Decisions regard- 1), the patient most likely does not
ing which test to use (IHC, PCR, or
dMMR/MSI testing is best achieved
have Lynch syndrome. Outside of
through a coordinated efort between both) are center dependent. There is
this scenario, patients whose tumors
clinicians (gastroenterologists, oncol- a trend at many centers to begin with are MSI-high and/or show abnormal
IHC for dMMR, reserving PCR anal- IHC should be referred to a certifed
ogists, surgeons), pathologists, and
ysis for specifc situations (Figure 1).
genetic counselor for informed consent to undergo diagnostic germline
Indications for dMMR/MSI testing
testing for mutations in the Lynch
Tissue testing for dMMR/MSI serves genes (Figure 1). I
two clinically important functions:
Informed consent before tumor
to screen for Lynch syndrome and
testing has been raised as an ethical
to provide prognostic information
issue15; however, it is not currently
regardless of syndrome status. In
required because tumor testing is
addition, although beyond the scope
simply a screen for Lynch syndrome.
of this review, MSI testing is also inIt is advised that clinicians prepare
creasingly used in other investigative
patients for the possibility that if
contexts, such as to predict theratheir tumor screen is positive, they
peutic response to 5-fuorouracil. For then will be referred for genetic
these reasons, and because the Amcounseling and testing.
sterdam and Bethesda criteria have
Tumor screening and genetic testfailed to serve as efective screens for ing for Lynch syndrome is critical in
Lynch syndrome, determination of
preventing additional primary maligdMMR/MSI now is recommended in nancies in the patient, and in testing
all colorectal tumors.13
and providing appropriate surveillance and risk reduction to family
Relevance to Lynch syndrome
members. However, a recent study
dMMR/MSI detection serves solely
showed that surgeons referred fewer
as a screen for Lynch syndrome, and
than half of their patients with highare not by themselves diagnostic.
risk tumors for genetic testing.6
This represents not only a subIn addition, each test will miss 5%15% of all cases of Lynch syndrome. stantial liability risk for clinicians
and their institutions, but a waste
Therefore, a negative tumor screen
of health care dollars and a potenshould not negate a referral to genetic counseling if the personal and/ tially life-saving lost opportunity for
patients and their families. At some
or family history is suggestive of
centers genetic counselors review
a hereditary cancer syndrome.14 If
IHC shows loss of MLH1 and PMS2
all MSI testing, including follow-up
expression, BRAF analysis should be
methylation/BRAF testing, to ensure
performed. If a V600E BRAF mutacorrect interpretation and to increase
tion is present and there are no other the likelihood that patients will rerisk factors (Supplementary Table
Continued on following page
AGA InstItItute
Continued from previous page
ceive the necessary genetic counseling and testing they need.9,16
The cost of dMMR/MSI testing
is variable and depends on methods
used (IHC and/or PCR). With the
decreasing prices of germline gene
panels that include not only Lynch
syndrome genes but many other
genes associated with hereditary
cancer syndromes, it soon may be
less expensive and more accurate
to ofer all patients diagnosed with
CRC at age 50 years or younger,
and those with a personal or family
history suggestive of a hereditary
cancer syndrome, genetic counseling
and testing. We may reserve routine
tumor testing for those diagnosed
with CRC at older than age 50 with
no risk factors. In fact, with the cost
of genome-wide analysis expected to
decrease to less than $1,000 within
a few years, gastroenterologists may
be increasingly confronted with a patient who brings their tumor analysis,
showing an alteration in MMR genes.
Relevance of dMMR/MSI
testing to prognosis
The diagnosis of dMMR/MSI colorectal cancer has important clinical
implications regarding prognosis,
and has emerged as an essential component of the evaluation and management of patients with colorectal
cancer, especially those with stage II
colon cancer.
Retrospective studies have shown
that dMMR/MSI colorectal cancer is
associated with a favorable prognosis
independent of classic clinical prognostic factors, including stage.17,18 Patients with dMMR/MSI tumors are
less likely to have lymph node and
1. Molecular characterization
of colorectal cancer is a vital
component of comprehensive
oncologic care.
2. Testing for microsatellite instability (MSI) in colorectal
cancer is performed in the
pathology lab using immunohistochemistry and/or PCR
3. Detection of MSI colorectal
cancers serves as a screening
tool for identifcation of possible Lynch syndrome.
4. Patients who have MSI
colorectal cancer have a
better prognosis independent
of stage.
distant metastatic disease than patients with MMR-profcient tumors,
and the prevalence of the dMMR/
MSI phenotype decreases with advancing stage at diagnosis from more
than 20% in stage II to less than 4%
in stage IV.
In one of the largest pooled analyses of more than 7,600 colorectal
cancer cases, of which 16.7% were
dMMR/MSI, the hazard ratio for
overall survival associated with
dMMR/MSI was 0.65.17 In patients
with stage II and III colon cancer,
recurrence-free survival and overall
survival are increased signifcantly
in patients with dMMR/MSI tumors
compared with those with MMR-profcient/MSS tumors.19,20 These observations, in the aggregate, support the
hypothesis that dMMR/MSI tumors
have reduced metastatic potential and
a favorable biology compared with
MMR-profcient/MSS tumors.
Despite its prognostic value, MMR
status is not incorporated into widely
used calculators for the assessment of
risk of recurrence in stage II and III
colorectal cancer and does not fgure
into colonoscopy surveillance recommendations after cancer resection.
Nonetheless, MMR/MSI status should
be assessed routinely and considered
in risk assessment in all patients with
stage II colon cancer because the favorable prognosis of the dMMR/MSI
phenotype is a key determinant in the
decision to use adjuvant chemotherapy in these patients.
Although BRAF mutation confers a
worse prognosis compared with BRAF
wild type in dMMR/MSI colorectal
cancer, the prognosis of dMMR/MSI
colorectal cancer remains superior
to MMR-profcient/MSS colorectal
cancer, irrespective of BRAF status.5
However, BRAF status in dMMR/MSI
colorectal cancer is not yet incorporated routinely into risk assessment or
treatment decisions.
In a previous article in this “Practice
Management: The Road Ahead” section, the authors described how gastroenterologists might develop a seamless
CRC clinical service line including risk
assessment for hereditary CRC syndromes.21 In addition, with rapid movement to value-based reimbursement
and the potential to create a bundled
colonoscopy payment methodology,22
careful consideration of how molecular
testing and analysis will be incorporated into our standard CRC prevention
practice will be important.
The authors acknowledge the help of
Dr. Pei Hui for his assistance with the
Supplementary Table 1: Risk
factors for Lynch syndrome
в–¶ CRC diagnosed at age less than 50
в–¶ Multiple CRC primaries
в–¶ A personal and/or family history
of the following cancers: uterine,
ovarian, colon-rectal, pancreatic,
endometrial, gastric, ureter, renal
pelvis, biliary tract, brain, small
intestine, sebaceous adenoma, and/
or carcinoma, especially in families
with a history of CRC
в–¶ Multiple family members in the
same bloodline with CRC
в–¶ Abnormal MSI and/or IHC testing
в–¶ Known familial mutation for hereditary colon cancer
Supplementary material
Note: To access the supplementary
material accompanying this article,
visit the online version of Clinical
Gastroenterology and Hepatology at, and at http://
1. Markowitz, S.D., Bertagnolli, M.M. Molecular origins of cancer: molecular basis
of colorectal cancer. N. Engl. J. Med.
2. Al-Sohaily, S., Biankin, A., Leong, R., et al.
Molecular pathways in colorectal cancer.
J. Gastroenterol. Hepatol. 2012;27:142331.
3. Zhang, X., Li, J. Era of universal testing
of microsatellite instability in colorectal
cancer. World J. Gastrointest. Oncol.
4. Zaanan, A., Meunier, K., Sangar, F. et
al. Microsatellite instability in colorectal
cancer: from molecular oncogenic mechanisms to clinical implications. Cell Oncol.
(Dordr). 2011;34:155-76.
5. Lochhead, P., Kuchiba, A., Imamura, Y.,
et al. Microsatellite instability and BRAF
mutation testing in colorectal cancer
prognostication. J. Natl. Cancer Inst.
6. Ward, R.L., Hicks, S., Hawkins, N.J.
Population-based molecular screening
for Lynch syndrome: implications for
personalized medicine. J. Clin. Oncol.
7. Umar, A., Boland, C.R., Terdiman, J.P.,
et al. Revised Bethesda Guidelines for
hereditary nonpolyposis colorectal cancer
(Lynch syndrome) and microsatellite instability. J. Natl. Cancer Inst. 2004;96:2618.
8. Laghi, L., Bianchi, P., Malesci, A. Diferences and evolution of the methods for
the assessment of microsatellite instability. Oncogene 2008;27:6313-21.
9. Ngeow, J. Eng, C. Population-based
universal screening for Lynch syndrome: ready, set ... how? J. Clin. Oncol.
10. Rex, D.K., Johnson, D.A., Anderson,
J.C., et al. American College of Gastroenterology guidelines for colorectal cancer
screening 2009 [corrected]. Am. J. Gastro-
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enterol. 2009;104:739-50.
11. Bao, F., Panarelli, N.C., Rennert, H., et
al. Neoadjuvant therapy induces loss of
MSH6 expression in colorectal carcinoma.
Am. J. Surg. Pathol. 2010;34:1798-804.
12. Pino, M.S., Mino-Kenudson, M.,
Wildemore, B.M. et al. Defcient DNA
mismatch repair is common in Lynch syndrome-associated colorectal adenomas. J.
Mol. Diagn. 2009;11:238-47.
13. Palomaki, G.E., McClain, M.R., Melillo, S., et
al. EGAPP supplementary evidence review:
DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome.
Genet. Med. 2009;11:42-65.
14. Overview of testing for Lynch syn-
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drome/HNPCC. Updated 2012. Available at:
php?option=com_docman&task=cat_view&gid=58&Itemid=. Accessed
October 2013.
15. Chubak, B., Heald, B., Sharp, R.R.
Informed consent to microsatellite instability and immunohistochemistry screening for Lynch syndrome. Genet. Med.
16. Lynch, P.M. Tumor-based screening for
hereditary nonpolyposis colorectal cancer:
does age-based selection optimize yield? J.
Oncol. Pract. 2013;9:180-1.
17. Popat, S., Hubner, R., Houlston, R.S.
Systematic review of microsatellite instability and colorectal cancer prognosis. J.
Clin. Oncol. 2005;23:609-18.
18. Gryfe, R., Kim, H., Hsieh, E.T. et al.
Tumor microsatellite instability and
clinical outcome in young patients
with colorectal cancer. N. Engl. J. Med.
19. Sargent, D.J., Marsoni, S., Monges, G.,
et al. Defective mismatch repair as a predictive marker for lack of efcacy of fuorouracil-based adjuvant therapy in colon
cancer. J. Clin. Oncol. 2010;28:3219-26.
20. Sinicrope, F.A., Foster, N.R., Thibodeau,
S.N., et al. DNA mismatch repair status
and colon cancer recurrence and survival
in clinical trials of 5-fuorouracil-based
adjuvant therapy. J. Natl. Cancer Inst.
21. Braden, G.L. Allen, J.I. Organizing your
clinical service line: colon cancer pre-
vention. Clin. Gastroenterol. Hepatol.
22. Ketover, S.R. Bundled payment for colonoscopy. Clin. Gastroenterol. Hepatol.
Dr. Gibson, Ph.D. is assistant professor of
pathology, Yale School of Medicine, New
Haven, Conn; Dr. Robert is professor of
pathology, Yale School of Medicine; Dr.
Lacy is associate professor of medicine
(medical oncology), Yale School of Medicine; and Ms. Matlof, MS, CGC, is CEO
[email protected]
Also available at
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Albuquerque, NM
Presbyterian Healthcare Services is seeking Board Certified Gastroenterology trained
physicians to join our established practice of 11 physicians, 2 Gastroenterology
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EHRs rob physicians of 4 hours of free time per week
Frontline Medical News
sing an electronic health
records eats 48 minutes of
doctors’ free time daily – or 4
hours per week – according to a survey of family physicians.
At least one data management
Key clinical point: Physicians may
balk at using EHR systems because
they consume rather than save time.
Major fnding: EHR usage is accounting for 48 minutes of lost free
time per day.
Data source: An analysis of 411 responses to a survey.
Disclosures: The study was funded
by the National Library of Medicine
and the American College of Physicians. The authors reported no conficts of interest.
function took more time when using an EHR than when using a paper-based system, according to 411
family physicians who responded to
a survey conducted by the National
Functions that took longer with
an EHR included returning
telephone calls. Nearly
64% of respondents, all of
whom were experienced
EHR users, reported that
�note writing took longer.’
Library of Medicine (NLM) and the
American College of Physicians.
The results were published
Sept. 8 in JAMA Internal Medicine
(2014 Sept. 8 [doi:10.1001/jamainternmed.2014.4506]).
Functions that took longer with an
EHR included returning telephone calls;
managing messages, refll requests, or
new test results; writing visit notes; ordering and scheduling tests; fnding and
reviewing medical records; writing prescriptions; and reading colleagues’ notes.
Nearly 64% of respondents, all of
whom were experienced EHR users,
reported that “note writing took longer,” according to Dr. Clement McDonald of NLM and his associates.
“Surprisingly, a third (34%) reported
that it took longer to fnd and review
medical record data with the [EHR]
than without, and a similar proportion, 32%, [reported] that it was slower to read other clinicians’ notes.”
Respondents reported using a wide
variety of systems, with 61 distinct
EHR systems being identifed.
However, nine systems were used
by 20 or more respondents and accounted for 79% (324) of all users
responding to the survey. Of these
nine, the Veterans Afairs’ Computer
Patient Record System was associated
with lowest amount of free time loss
at less than 20 minutes per day.
“The loss of free time that our
respondents reported was large and
pervasive and could decrease access
or increase the cost of care” Dr.
McDonald wrote. “Policy makers
should consider these time costs in
future [EHR] mandates.”
[email protected]
†Over a 6-month period; P
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to
fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which
may lead to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing
antibiotic use not directed against C. difficile may need to be discontinued.
There is increased systemic exposure in patients with more severe hepatic
dysfunction. The clinical trials were limited to patients with MELD scores < 25.
Therefore, caution should be exercised when administering XIFAXAN to patients with
severe hepatic impairment (Child-Pugh C).
incidence than placebo in the clinical study were peripheral edema (15%), nausea (14%),
dizziness (13%), fatigue (12%), and ascites (11%).
Xifaxan 550 mg is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc.
Please see brief summary on reverse.
References: 1. Khungar V, Poordad F. Management of overt hepatic encephalopathy. Clin Liver Dis.
2012;16(1):73-89. 2. Xifaxan [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc; 2014.
3. Bajaj JS, Sanyal, AJ, Bell D, et al. Predictors of the recurrence of hepatic encephalopathy in
lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):1012-1017.
Web site:
8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597)
В©2014 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. XIFH70-0414
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