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Progressnotes
MUSC’s Medical Magazine // July-August 2012
TAVR: A Minimally Invasive
Treatment for Aortic Stenosis
MUSC Ranked #1 Hospital in South Carolina by U.S.
News & World Report
New Legislation Addresses Drug Shortage and
Streamlines Approval for “Breakthrough Drugs”
Autologous Islet Cell Transplantation
Initial Management of Pediatric Burns
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First-in-Human, First-in-Class Phase 1 Clinical Trial
Changing What’s Possible®
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Progressnotes
July-August 2012
Progressnotes Now Offers AMA PRA Category 1 Credit(s)
TM
Progressnotes is now offering AMA PRA Category 1 Credit(s) for one article per issue. You can
complete the steps necessary to receive your AMA PRA Category 1 Credit(s)TM and access all active tests
and associated articles by visiting MUSC Health’s Physician Portal (physicianportal.muschealth.com). For
most articles, the CME activity will remain valid for two years.
TM
This issue’s CME article is dedicated to the initial management of pediatric burns, including the
appropriate referral to a burn center when American Burn Association criteria are met. The subject of the
next issue’s CME article will be the importance of stroke centers (the second half of Progressnotes’ stroke
CME series).
In addition, active CME tests for the following previously published Progressnotes’ articles are still
available on MUSC’s physician portal: “Responding to the Pediatric Obesity Epidemic” and “The
SAMMPRIS Trial: PTAS and Aggressive Medical Management vs Aggressive Medical Management
Alone in Patients with Severe Intracranial Arterial Stenosis.”
Progressnotes CME supplements existing CME activities available through MUSC Health’s Physician
Portal. Currently, CME credit is available for online Medicine and Pediatric Grand Rounds. Other
departments will soon begin offering CME credit for online Grand Rounds as a service to the physicians
of South Carolina.
The following conferences, sponsored by the Medical University of South Carolina, will be held in
Charleston unless otherwise noted. Visit www.musc.edu/cme for a complete list of CME conferences.
September 7– 8, 2012
Southeastern Kidney Disease Consortium Inaugural Meeting
Francis Marion Hotel
September 20 – 22, 2012
Bridge to Success: Acute Pediatric Care from the
Emergency Department to the Intensive Care Unit
Visit Conference Website at http://clinicaldepartments.musc.
edu/pediatrics /conferences /bridgeconference
October 26 – 27, 2012
Thomas Pitts Lectureship in Medical Ethics
Medical University of South Carolina
Executive Editor
Etta D. Pisano, M.D.
Vice President for
Medical Affairs
Dean, College of Medicine
2
In Short
U.S. News & World Report Ranks MUSC #1 Hospital in South Carolina
MUSC’s Stroke Program Recognized for Improved Door-to-Needle Time
Bipartisan Legislation Addresses Drug Shortages
Feature Articles
Editor
Patrick J. Cawley, M.D.
Executive Medical Director,
Medical Center
4
Transcatheter Aortic-Valve Replacement: A Minimally Invasive Treatment for Patients
Managing Editor
Medical Science Writer
Kimberly McGhee, PhD
6
Back From the Abyss : Improved Quality of Life for Patients With Chronic
Please direct all comments, questions or
other feedback to Managing Editor Kimberly
McGhee by emailing [email protected]
or calling 843-792-7877. Well-argued and
well-written letters in reply to articles
are welcome.
9
Into Safe Hands: Appropriately Referring Pediatric Burn Patients to a Regional Burn
14
Unwinding the Maze, Part II: Bringing Promising Preclinical Findings to
20
Welcome
Progressnotes is a publication of the Medical
University of South Carolina
135 Cannon St , Suite 402
MSC 836
Charleston, SC 29425
With Severe Aortic Stenosis Video
Pancreatitis After Pancreatectomy With Autologous Islet Cell Transplantation Video
Center for Improved Outcomes
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Clinical Fruition
Michael B. Lilly, M.D., Associate Director for Translational Research, Hollings Cancer Center
New MUSC Physicians
November 7 – 9, 2012
Neonatal Pharmacology Conference 2012: Incorporating Evidence-
Based Practice into Clinical Decision Making
Doubletree Guest Suites Hotel
November 30 –
15th Annual Frontiers in Pediatrics
December 2, 2012
Francis Marion Hotel
For more information about CME conferences, the Grand Rounds schedule and
online CME courses, visit MUSC’s CME home page at www.musc.edu/cme.
On the cover: Edwards SAPIEN transcatheter heart valve (see “Transcatheter Aortic-Valve Replacement”
on page 4 for more information). Cover image courtesy of Edwards Life Sciences (Irving, CA).
Online edition of Progressnotes available at MUSChealth.com/progressnotes
1
Bipartisan Legislation Addresses Drug Shortages
U.S. News & World Report Ranks MUSC #1 Hospital in South Carolina
and Ranks Six of its Specialties among the Top 50 in Nation
The Medical University of South Carolina (MUSC) is the #1
hospital in South Carolina according to the U.S. News & World
Report released on July 17, 2012. This is the first year the report has
included state rankings.
In addition, four adult and two pediatric specialty programs at
MUSC are ranked among the top 50 in the nation. To be nationally
ranked, a specialty program must not only have a good reputation
but show that it can handle a high volume of the toughest cases and
objectively document the highest-quality care and good outcomes
(eg, survival rates, patient safety), often with data available from the
federal government.
The four nationally ranked adult specialties are cardiology & heart
surgery (#47); ear, nose & throat (#30); gastroenterology (#49) and
nephrology (#44). Nine other adult specialties at MUSC are designated
as “high-performing,” meaning that they are among the top 25% of
programs nationally: cancer, diabetes & endocrinology, geriatrics,
gynecology, neurology & neurosurgery, orthopedics, pulmonology,
rheumatology and urology. Overall, MUSC was recognized for
excellence in 13 of the 16 adult specialty programs assessed.
MUSC has been recognized for excellence by U.S. News & World
Report for more than 15 consecutive years.
The U.S. News Media Group’s 2012-2013 edition of America’s Best
Children’s Hospitals ranks MUSC Children’s Hospital among the top
20 programs for heart (#15 this year), the fourth time it has attained this
distinction. For the first time this year, its pediatric gastroenterology
“MUSC Children’s Hospital was in the best
category of postoperative survival in the survey,
with an overall 30-day survival rate of 99%”
2
program also ranked as one of the top 50 in the nation. MUSC
Children’s Hospital was in the best category of postoperative survival
in the survey, with an overall 30-day survival rate of 99%, including the
most complex surgeries.
“These rankings highlight some of the reasons MUSC has
become a destination medical center,” said Etta Pisano, M.D.,
Dean of the College of Medicine and Vice President for Medical
Affairs. “As an academic medical center with world-class physicians
and ground-breaking research, our patients benefit from the latest
advances in medicine.” According to John R. Feussner, M.D.,
MPH, Executive Senior Associate Dean for Clinical Affairs at
MUSC, ”being named the #1 hospital in the state confirms that we
are fulfilling our clinical mission, just as being ranked among the
top 10 most popular medical schools by U.S. News & World Report
speaks to our commitment to our educational mission.”
This year’s Best Hospitals, the 23rd annual edition, showcases more
than 720 of the nation’s roughly 5,000 hospitals. Fewer than 150 are
nationally ranked in at least one of 16 medical specialties. The rest of the
recognized hospitals are high-performing in one or more specialties.
The rankings were published by U.S. News in collaboration with RTI
International, a research organization based in Research Triangle Park,
N.C. The complete rankings and methodology are available at http://
health.usnews.com/best-hospitals.
In a rare example of bipartisan cooperation, The Food and Drug
Administration Safety and Innovation Act (S. 3187) passed Congress
on June 26, 2012, and was signed by President Obama on July 9,
2012. This legislation, which reauthorizes existing prescription drug
user fees that fund expedited review of new drug applications by the
US Food and Drug Administration (FDA), also streamlines the drug
development pipeline for drugs designated as “breakthrough” agents
(see “Unwinding the Maze, Part II” in this issue of Progressnotes for
more details), takes steps to ensure cutting-edge therapies reach
patients with orphan diseases (those that affect too few patients to
guarantee a profit margin for a pharmaceutical company), authorizes
new user fees for generic drugs and institutes several provisions
meant to ease the current drug shortage and to prevent future ones.
Physicians such as MUSC’s own Michelle Hudspeth, M.D.,
have been urging Congress to act to alleviate current critical drug
shortages, which have hit sterile injectables particularly hard. As
discussed at more length in an earlier Progressnotes article (“Caught
Short: Coping With the Nationwide Drug Shortage Crisis”), causes of
drug shortages include poor communication between manufacturers
and the FDA and between the FDA and the public about impending
shortages; low margins of profitability for generic drugs that lead
many companies to discontinue their manufacture (particularly those,
like sterile injectables, with complicated fabrication requirements);
and outdated manufacturing facilities and increased inspections and
shutdowns of such facilities when violations are found.
The new generic drug user fees will be used to help the FDA
clear its backlog of new generic drug applications and to hire more
inspectors so that it can better monitor conditions of domestic and
international production lines alike. The legislation also mandates that
manufacturers notify the Secretary of Health and Human Services
six months in advance of the closing or suspension of a production
line that could lead to a drug shortage; manufacturers who fail to
comply will receive warning letters from the FDA. Once it knows of a
manufacturing disruption, the FDA must make every effort to inform
the public, patient groups, physicians, and health providers of the
likely shortage, including posting a list of all current drug shortages on
its web site. In coordination as necessary with other agencies involved
in drug regulation, the FDA must consider expediting the review
of new drug applications and/or approval of new production lines
(or reinspection and reauthorization of those closed for violations).
During the time that a drug is in short supply, regulations can be
relaxed for repackaging of that drug by a hospital for use by another
hospital in the same health system (but with no authorization to
repackage for sale or use by an outside hospital). A new mechanism
will also be provided for physicians and health care institutions to
report drug shortages.
The Act also requires that the Secretary of Health and Human
Services provide an annual report that details the numbers of drugs
in shortage, the number of notifications of shortages received and
noncompliance letters sent, and the measures taken to alleviate
those shortages. A study will also be commissioned into the causes
of current drug shortages (particularly sterile injectables), the part
played (if any) in the shortages by current regulatory practice and the
potential benefit (if any) of incentivizing manufacturers to produce
critical medications that are in short supply.1
Reference
1
S. 3187--112th Congress: Food and Drug Administration Safety and Innovation Act. GovTrack.us (database of federal legislation). 2012. Available at http://www.
govtrack.us/congress/bills/ 112/s3187. Accessed June 27, 2012.
MUSC’s Stroke Program Recognized for Improved Door-to-Needle Time
MUSC’s Comprehensive Stroke & Cerebrovascular
Center was recognized for Target:Stroke achievement by the
American Heart Association/American Stroke Association in
May 2012 for having increased the percentage of eligible stroke
patients receiving fibrinolytic therapy with tissue plasminogen
activator (tPA) within 60 minutes of their arrival at the hospital
from 33% to well over 50%. Patients receiving tPA (which breaks
up a clot blocking a major artery) within this time window typically have the best outcomes.
Although still short of the 80% target set by the Brain Attack Coalition, which represents the American Heart Association and the American Stroke Association among many other
organizations, the improved door-to-needle times at MUSC’s
Stroke Center outpace those seen at many other stroke centers,
where fewer than a third of patients receive tPA within 60 min-
utes of arrival and where improvements in those times in past years
have been modest (from 19% in 2003 to 29% in 2009).1 This is in line
with a recent study showing greatest improvement at stroke centers
with a high volume of tPA-treated patients, like MUSC.1
To watch a video of Edward C. Jauch, M.D., Interim Director of the Division of Emergency Medicine at MUSC, discussing
improved door-to-needle time at MUSC, visit http://www.youtube.
com/watch?v=DbvexICpJQs&list=UUrLBpAbiF18A6y-HDA1k2w&index=8&feature=plcp
Reference
1
Fonarow GC, Smith EE, Saver JL, et al. Timeliness of tissue-type
plasminogen activator therapy in acute ischemic stroke: patient characteristics,
hospital factors, and outcomes associated with door-to-needle times within
60 minutes. Circulation. 2011;123:750-758.
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 or visit the online edition at MUSChealth.com/progressnotes
3
KEY POINTS
Transcatheter Aortic-Valve Replacement:
• Patients with severe symptomatic aortic stenosis have a survival rate of only 50% at 2 years and 20% at 5 years if the condition
A Minimally Invasive Treatment for Patients with Severe Aortic Stenosis
is left untreated, poorer than that seen in many cancers.
• Surgical aortic replacement is the gold standard for treating patients with severe symptomatic aortic stenosis, but many
patients are not candidates for surgery because of advanced age, frailty, or poor lung function, among other factors.
• Transcatheter aortic-valve replacement (TAVR), a procedure for implanting a heart valve (the Edwards SAPIEN valve; Edwards
Life Sciences; Irving, CA) via a catheter that does not require open heart surgery, offers patients who are poor surgical
candidates a much-needed treatment to prolong survival and improve quality of life.
• In addition to being the first in the state to offer TAVR to inoperable patients, MUSC’s Heart Valve Center has also been
chosen as a site for the PARTNER 2 trial of TAVR using a smaller Edwards heart valve in patients at intermediate surgical risk.
• Already approved for inoperable patients, TAVR has been recommended for approval by a U.S. Food and Drug Administration
FIGURE 1. RetroFlex 3 Delivery
System: balloon-expandable valve
technology. Image courtesy of
Edwards Life Sciences (Irving, CA).
The South Carolina Heart Valve Center (HVC) at MUSC is
the first center in South Carolina and among the first in the nation
to perform transcatheter aortic-valve replacement (TAVR), a cuttingedge procedure for implanting a heart valve that does not require open
heart surgery. Since approval by the US Food and Drug Administration
in November 2011 for TAVR’s use in inoperable patients with severe
aortic stenosis, MUSC’s HVC has performed 6 procedures, with many
more TAVR candidates in the screening process.
Although surgical aortic valve replacement (AVR) remains the gold
standard for treatment of severe aortic stenosis, TAVR makes treatment
available to patients who would otherwise have gone untreated because
they are not suitable candidates for surgery due to advanced age, frailty,
or poor lung function (among other reasons). According to John S.
Ikonomidis, M.D., PhD, Chief of the Division of Cardiothoracic
Surgery at MUSC, “It’s difficult, if you look across the medical
community, to find a single procedure that modifies mortality in the
way this procedure has in medically managed patients.”
Both TAVR and aortic valve replacement are treatments for severe
aortic stenosis, or the obstruction of blood
flow across the aortic valve because of
calcific plaque. An estimated 2% to 9% of
the elderly have aortic stenosis. Although
aortic stenosis can gradually develop
over years without symptoms, once
symptomatic it takes a high toll in terms
of mortality, higher even than a variety of
cancers, including lung cancer. Patients
with severe aortic stenosis have a survival
John S. Ikonomidis, M.D.
of only 50% at 2 years and 20% at 5 years if
the condition is left untreated.
Instead of implanting a replacement heart valve during open heart
surgery, TAVR involves collapsing a bovine heart valve mounted onto a
stainless steel stent (the Edwards SAPIEN valve, Edwards Life Sciences,
Irving, CA) tightly over a balloon (Figure 1), inserting it via a catheter
into the ileofemoral artery and advancing it to the aortic valve. The
procedure is performed twice: on the first pass, the balloon is expanded
to open up the stenosis and on the second pass the Edward SAPIEN
valve is deployed to keep the aortic valve open (Figure 2). The procedure
can also be performed via an apical approach.
Until TAVR, those deemed unsuitable for surgical AVR had to
face the grim survival statistics knowing that no treatments outside
4
of medical management or aortic valvuloplasty (which provided only
temporary symptom relief ) were open to them. It is estimated that 43%
to 74% of patients with severe aortic stenosis never undergo surgery,
either by choice or because it is contraindicated. Preliminary data from
Cohort B of the PARTNER trial (NCT00530894) showing a 20%
to 25% reduction in mortality at 2 years with TAVR versus medical
management alone led to FDA approval of its use in inoperable
patients.1 Patients also reported improved quality of life.
Since FDA approval, TAVR has been much in the news. On May
1, 2012, the Centers for Medicare & Medicaid Services agreed to
reimburse patients for the procedure.2 On June 13, 2012, the FDA’s
Circulatory Systems Devices Panel examining data from Cohort A
of the PARTNER trial recommended approval of its use in high-risk
surgical patients as well.3 The FDA has 100 days to decide whether to
accept the recommendation.
Also in June 2012, MUSC’s HVC was approved as a clinical trial
site for PARTNER 2 (NCT01314313), which will compare the safety
and effectiveness of a smaller version of the SAPIEN (SAPIEN XT)
transcatheter heart valve versus surgical valve replacement in patients
with severe symptomatic aortic stenosis who are at intermediate
surgical risk. The SAPIEN XT treats an annulus size range of 18 mm to
27 mm. MUSC’s HVC plans to enroll its first intermediate-risk patient
in September of this year.
The multidisciplinary HVC at MUSC was created specifically
to leverage these new types of valve technologies that dramatically
alter a patient’s treatment options. Its depth of experience in both
interventional cardiology and cardiac surgery, as well as its expertise
in cardiac imaging and anesthesia, was key to its being approved by
Edwards, the manufacturer of the Edwards SAPIEN heart valve, to
implant the device. These devices can only be implanted once both
an interventional cardiologist and a cardiac surgeon have assessed the
patient (in part by preprocedural imaging) and have agreed that he or
she has a greater than 50% chance of dying or experiencing long-term
complications from surgical aortic valve repair.
Possible complications of TAVR include stroke (some plaque
may be dislodged as the valve is advanced through the vessel) and
vascular damage, both of which can be life-threatening. Careful
patient screening (ie, to ensure that the patient’s vessels are of sufficient
size to allow the device to be implanted via a catheter) should help
to minimize those risks. It is also hoped that the smaller size of the
SAPIEN XT will help minimize these risks.
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 or visit the online edition at MUSChealth.com/progressnotes
(FDA) advisory panel for high-risk surgical patients as well; a final decision by the FDA is expected within 2-3 months.
FIGURE 2. Aortic valve before (left) and after (right) TAVR. Image courtesy of Edwards Life Sciences (Irving, CA).
TAVR is most appropriate in patients with severe aortic stenosis
who are not suitable candidates for surgery and who would stand to
gain considerable quality of life as a result of the procedure. It offers
a treatment option, increased survival and increased quality of life
to a large pool of patients who would otherwise go untreated. If the
FDA decides to follow the recommendation of the advisory panel and
approve TAVR for high-risk patients, then by September MUSC’s
HVC could be treating three distinct populations of patients with
severe aortic stenosis: patients who are inoperable or at high surgical
risk as part of FDA-approved standard of care and intermediate-risk
surgical patients as part of the PARTNER 2 trial.
For a referral to the TAVR program, contact MEDULINE at
1-800-922-5250 or 843-792-2200 and ask to be connected to John
S. Ikonomidis, M.D., PhD, Chief of the
Division of Cardiothoracic Surgery at MUSC;
Daniel H. Steinberg, M.D., the primary
interventional cardiologist at the HVC involved in the TAVR program,
or Suzanne Richardson, RN, the TAVR program coordinator.
References
1
Leon MB, Smith CR, Mack M, et al; for the PARTNER Trial Investigators.
Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot
undergo surgery. N Engl J Med. 2010;363:1597-1607.
2
Centers for Medicare & Medicaid Services. Decision memo for transcatheter
aortic valve replacement (TAVR) (CAG-00430N). Available at http://www.cms.
gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=257&
ver=4&NcaName=Transcatheter+Aortic+Valve+Replacement+(TAVR)&bc=ACA
AAAAAIAAA&. Accessed June 25, 2012.
3
Yu D. FDA panel recommends clinical approval of SAPIEN TAVR device
for high risk surgical aortic valve replacement candidates. The Advisory Board
Company. Available at http://www.advisory.com/Research/Technology-Insights/
The-Pipeline/2012/06/FDA-Panel-Recommends-Clinical-Approval-of-SAPIENDevice-for-High-Risk-Valve-Surgery-Candidates. Accessed June 25, 2012.
To watch a video of Daniel H. Steinberg, M.D., and Dr. Ikonomidis
discussing TAVR, visit MUSChealth.com/TAVRpn.
Daniel H. Steinberg, M.D.
5
Back from the Abyss:
Improved Quality of Life for Select Patients with Chronic Pancreatitis after Pancreatectomy with Autologous Islet Cell Transplantation
Minneapolis
Indianapolis
Tennessee
Baylor
Leicester
Cincinnati
MUSC
Alabama
Geneva
Samsung
Patients in whom complete pancreatectomy with islet cell
transplantation should be considered include those with diffuse
small-duct CP, which does not benefit from typical procedures
such as unblocking of the pancreatic duct or partial resection of the
pancreas, and those with hereditary CP, who likely develop the disease
when young and are at increased risk of pancreatic cancer. In all
patients, but particularly in children with hereditary pancreatitis, it is
important to intervene early (after every attempt to save the organ has
been made) to remove the pain stimulus so as to prevent remodeling
of central pain pathways. Once those central pain pathways are
established, they are much harder to break and freeing the patient
of pain becomes much more challenging. MUSC has performed this
procedure in two children with hereditary pancreatitis, one within
the last month, to mitigate pain, improve quality of life and lessen the
risk for cancer.
Islet cell transplantation is currently done at only a handful of
centers because it requires a clean cell facility capable of operating in
accordance with good manufacturing practice (GMP) to ensure the
high degree of sterility needed in cells to be infused back into patients.
Drawing on funds donated by the Abney Foundation, MUSC invested
in such a clean cell facility in 2007 (see “Center for Cellular Therapy”).
MCS at 6 months, respectively, with both percentages increasing to
86% at 1 year. For a healthy individual, the average QOL is about 50.
Patients with chronic pancreatitis have PCS and MCS scores much
lower than for patients of other chronic disease (PCS: 25 vs 37 for
chronic renal failure and 38 for congestive heart failure; MCS: 32
vs 44 for chronic renal failure and 48 for congestive heart failure),
with average PCS increasing to 33 at 6 months and 36 at 1 year and
average MCS increasing to 43 at 6 months and 44 at 1 year.
Such marked and early improvement in QOL scores are especially
notable, according to Dr. Morgan, because “it is hard to demonstrate
changes in quality of life based on any medical intervention … so it
is impressive to see such a clear QOL improvement in these patients.”
Other end points considered in the study included narcotics use
and insulin dependence. Narcotics use increased in the months after
surgery to treat surgery-induced pain but had tapered to less than
preoperative rates in half of patients at 6 months and in two-thirds by
one year, with continued though slow tapering seen. At 6 months after
surgery, 7 of the 33 patients were insulin free and 7 were taking fewer
than 10 units per day. At 1 year, 8 were insulin free and 5 required
fewer than 10 units. Although the remaining patients required higher
doses of insulin, the diabetes was well controlled with the insulin and
FIGURE 1. MUSC is one of the busiest Autologous Islet Cell Transplantation centers, second only to the University of Minnesota, which pioneered the procedure*
Pain isolates. If severe, it can lay waste to a life. Yet it often yields little
outward sign of its presence, sometimes leading others to underestimate
its burden, doubt its existence or even judge the person in pain.
The debilitating pain associated with chronic pancreatitis (CP)
can trap patients in their homes, often leaving them unable to work,
socialize or even maintain relationships.
When a severe bout of pancreatitis sends such patients to an
emergency department, their requests for pain relief may be mistaken
for attempts to obtain narcotics for resale since no biomarker assay
exists to “prove” that they have advanced CP.
Devastated by pain and stigmatized by society, these patients can
at last gain a new lease on life with complete pancreatectomy followed
by autologous transplantation of islet cells, the insulin-producing cells
in the pancreas. MUSC’s Digestive Disease Center, long a center of
excellence in the treatment of pancreatic disease, has performed almost
90 of these procedures since 2009 and is one of the busiest such centers,
second only to the University of Minnesota, which pioneered the
procedure (Figure 1).
According to Katherine A. Morgan, M.D.,
Associate Professor of Surgery and Medical
Director of the Islet Auto-Transplantation
Program at MUSC, offering these patients a
new lease on life is “what makes this surgery
so gratifying. You put someone so sick and
unable to function in life because they’re stuck
on chronic narcotics and unable to hold a job
or interact with community and then you do
this major procedure…and you see them go back to work and have
their relationships reestablished. It’s very gratifying to see patients
come back and say the pain is gone.”
Selecting the patients who would most benefit from this procedure
and helping them to reassemble their shattered lives require the efforts
of a multidisciplinary team. At MUSC, this team comprises surgeons,
anesthesiologists, endocrinologists, interventional radiologists,
nurse pain specialists, physician assistants, research scientists and
technicians, psychologists and social workers, who provide patients
the support they need before, during and after surgery.
Complete pancreatectomy has long been known to provide
pain relief in patients who have not received substantial relief
from or are not suitable candidates for lesser therapies (ie, medical
management with supplemental digestive enzymes, endoscopic
techniques, partial resections of the pancreas—all also available
at MUSC’s Digestive Disease Center). However, it was rarely
performed because the removal of the pancreas resulted in brittle
diabetes, marked by dramatic, recurrent swings in glucose levels
that were very difficult to control. With the advent of autologous
islet cell transplantation, in which islet cells (ie, insulin-producing
cells) are isolated from the patient’s excised pancreas and, a few
hours later, infused back into the patient’s liver via the portal vein,
complete pancreatectomy has become a viable treatment option for
the control of pain in select CP patients (Figure 2). There is no
threat of rejection because the islet cells are derived from the same
patient into whom they are later infused.
Katherine A. Morgan, M.D.
To watch a video interview with Dr. Morgan, visit www.muschealth.com/isletcell
6
*Data on location of centers from Matsumoto S. Clinical allogeneic and autologous islet cell transplantation: update. Diabetes Metab J. 2011;35:199-206
FIGURE 2. Islet cells are isolated from the excised pancreas in a clean cell facility (left) and then reinfused into the patient’s liver via the portal vein (right).
This state-of-the-art facility, capable of handling at least twice the
current volume of cases, positions MUSC as a national referral center
for the treatment of this complicated and devastating disease, offering
patients a chance at a renewed quality of life.
Improved quality of life after complete pancreatectomy with
autologous islet cell transplantation was reported in a recent article
by David Adams, M.D., Professor of Surgery and Head of the
Division of Gastrointestinal and Laparoscopic Surgery at MUSC,
and Dr. Morgan, among others. Study
patients showed significant improvement in
both the physical component score (PCS)
and mental component score (MCS) of the
SF-12 quality of life (QOL) questionnaire.1
Of the 33 patients (25 women; average age,
42 years) undergoing the procedure between
March 2009 and April 2010, 74% and 61%
of patients showed improvement in PCS and
not subject to the radical swings associated with brittle diabetes. Even
patients taking more than 10 units daily of insulin or whose narcotic
use was not drastically reduced reported substantial gains in both the
mental and physical components of QOL.
The autologous islet cell transplantation program at MUSC
dramatically illustrates how close collaboration between clinicians and
research scientists and a commitment to the translation of research
findings into clinical practice can change patients’ lives for the better.
If pain isolates, a community of caring health care professionals
dedicated to relieving the pain of CP can help these patients as they
take the first steps toward resuming a normal life.
Reference
1
Morgan K, Owczarski S, Borckardt J, et al. Pain control and quality of life after
pancreatectomy with islet autotransplantation for chronic pancreatitis.
J Gastrointest Surg. 2012;16(1):129-134. DOI:10.1007/s11605-011-1744-y.
David Adams, M.D.
7
The Center for Cellular Therapy
cme
Date of Release: July 1, 2012
Date of Expiration: July 1, 2014
You can complete the steps necessary to receive your AMA PRA Category 1 Credit(s) TM by visiting MUSC Health’s Physician Portal at
physicianportal.muschealth.com.
Credit Designation: The Medical University of South Carolina designates this enduring material for a maximum of 0.50 AMA PRA Category I Credit(s)TM.
Physicians should only claim the credit commensurate with the extent of their participation in the activity.
Accreditation Statement: The Medical University of South Carolina is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to
provide continuing medical education for physicians.
Disclosure Statement: In accordance with the ACCME Essentials and Standards, anyone involved in planning or presenting this educational activity is required to
disclose any relevant financial relationships with commercial interests in the healthcare industry. Authors who incorporate information about off-label or investigational
use of drugs or devices will be asked to disclose that information at the beginning of the article.
André Hebra, M.D., and Jill Evans, R.N., M.S.N., have no relevant financial relationships to disclose.
Into Safe Hands:
Appropriately Referring Pediatric Burn Patients to a Regional Burn Center for Improved Outcomes
On completion of this article, readers should be able to:
• Outline some of the critical elements of modern burn management and describe the physiologic basis thereof
• Appropriately apply American Burn Association criteria in deciding whether to refer a pediatric burn patient to a burn center
• Accurately calculate the extent of burn injury in a child using a Lund and Browder chart
FIGURE. Clean cell facility staff member working under a laminar flow hood
The success of the autologous islet cell transplantation program
at MUSC would not have been possible without access to a clean
cell facility, where islet cells can be isolated from the pancreas and
processed in accordance with good manufacturing practice for
reinfusion into the patient. The Center for Cellular Therapy (CCT)
at MUSC, directed by David Cole, M.D., Chair of Surgery, houses a
1000 sq. ft., class six clean cell suite with three manufacturing rooms
and a general processing area. The mission of the CCT is to develop
innovative cellular-based treatments such as autologous islet cell
transplantation and to foster a robust translational research program.
Clean rooms, typically used for manufacturing drugs, conducting
scientific research or preparing infusions for cellular-based therapies,
have a low level of environmental contaminants. In comparison with
outdoor urban air, estimated to have 35,000,000 particles per cubic
meter, a class six clean room has 35,000 particles. To maintain these
conditions, rigorous quality control is necessary. According to June
Fried, CLS, MT(ASCP)BB, who coordinates these efforts for the
clean cell facility, quality control is “everything you do to maintain
the integrity of the product and the safety of the patient.” Access
to the clean room is highly restricted, and only staff meticulously
trained in sterile technique and proper gowning are permitted to
enter (Figure). Computers monitor the temperature and other
conditions in the clean room around the clock and notify personnel
by telephone in case of an aberration. Thermometers used to check
the temperature of the pancreas during transport and digestion are
regularly calibrated against national standards. Processed cells are
checked and crosschecked for contamination. Due to these stringent
standards, contamination has never occurred during the processing of
the pancreas and islet cells in the clean cell facility at MUSC.
Hongjun Wang, PhD and Shikhar Mehrotra, PhD, are the
scientific co-directors of the CCT. According to Dr. Wang, the clean
cell facility is “a very unique facility” that is “a treasure for MUSC and
South Carolina.” Indeed, this cutting-edge facility led Dr. Wang, an
islet cell biologist, to leave Harvard University and come to MUSC,
where she can do much more translational research because she can
now extend her study of islet cells from mice into humans.
8
Under the direction of Drs. Wang and Mehrotra, the CCT is
working to continually improve and evolve the islet cell transplantation
process. The more viable islet cells that can be isolated and infused,
the better the likely outcome for the patient. The two critical periods
of islet cell loss are during isolation and shortly after infusion.
To minimize loss of islet cells during isolation, new protocols
are being attempted, including keeping the pancreas at a colder
temperature and using less mechanical shaking to break the pancreas
down. According to Mingli Li, MS, project manager at the CCT,
in the 12 patients who have been treated with islet cells isolated
according to the new protocol, half are insulin-free, a substantial
improvement over the typical 25% to 30%.
Likewise, efforts are under way to improve the viability of islet
cells after infusion, including encapsulating the islet cells using
nanotechnology to protect them from caustic environmental stresses
after infusion and identifying and activating protective genes.
Wang’s laboratory is also working on exposing adipose tissue to
the appropriate transcription factors to induce their differentiation
into β-cells (the primary insulin-producing cells), which can then be
delivered via a bioengineered vehicle into patients.
The research scientists and clinicians working with MUSC’s
autologous islet cell transplantation program collaborate closely
to ensure that research findings are translated quickly into clinical
improvements. They are also collaborating with other high-volume
national and international autologous islet cell transplantation centers
to create a common database of patients for clinical trials of new
protocols.
Although currently all autologous islet cell transplantation is
performed on site with easy access to the clean cell facility, MUSC
hopes to serve as a remote center for islet cell processing within the
next two years. Institutions with no clean cell facility could perform
the complete pancreatectomy and then send the pancreas to MUSC
for the isolation and processing of islet cells, which would then be
sent back to the home institution for reinfusion. New protocols
and techniques will be developed to ensure minimal loss of islet cell
viability during transport.
“Go Tez Go,” read Dortez Gordon’s cake celebrating his discharge
on May 8, 2012, from the Pediatric Burn Center at the Medical
University of South Carolina (MUSC) Children’s Hospital. Although
his survival was in doubt when he and his younger brother were
rushed to MUSC in February after being rescued from an apartment
fire, he is now expected to make a full recovery.
On the day of the apartment fire in February, Dortez’s mother
stood on the second-floor balcony of the burning apartment and
pleaded for someone to save her baby. Hearing her calls, a neighbor
jumped into action, telling her to drop the baby into his waiting
hands. Placing her trust in him, she did so, and then jumped herself
from the balcony. On learning there was another child in the house,
the valiant neighbor made his way into the apartment and carried an
unresponsive Dortez to safety.
Dortez’s mother next entrusted her injured children into the
safe and experienced hands of the pediatric burn team at MUSC.
With burns over 70% of his body and inhalation injury, Dortez was
fortunate to have been brought to a dedicated pediatric burn facility
that practices modern pediatric burn management techniques.
According to a recent article in the Lancet, children with burns over
60% of their total body surface area are at increased risk of mortality
and morbidity and should be treated at such a facility for best chances
of survival.1 Care at a burn center has also been associated with lower
hospital costs and shorter length of stay.2,3
What would have been the outcome if Dortez had been taken to
a non-burn center, as many children are? Could Dortez’s mother have
trusted a physician in the emergency department of a local hospital
to provide the proper initial management, accurately assess the burn
injury and appropriately refer him to a pediatric burn center?
The answer is far from certain. Although estimating the extent of
burn injury (percentage of total body surface area [TBSA]–burned)
is the first step in determining the subsequent treatment course for
a burn patient, a recent Canadian study showed that as many as
70% of physicians did not do so.4 According to a recent 2-year study
of all burn patients admitted to U.S. hospitals participating in the
Healthcare Cost and Utilization Project, almost half of the 29,971
patients treated for a burn of any size who were discharged from
1,376 hospitals located in the 19 included states were treated at non-
André Hebra, M.D.
burn centers although 90% lived in a state with a burn center.5 In a
retrospective, administrative database study of 2036 North Carolina
burn patients, 47% received all of their acute inpatient care at nonburn centers even though almost half of them met criteria for referral
to a burn unit, of which there are two verified ones in the state. All
burn patients who were treated at non-burn centers and subsequently
died met criteria for burn center referral.4
To ensure the best outcomes for pediatric burn patients, first-line
physicians should understand the possible systemic complications of
burn injuries, be versed in initial burn management in children, be
able to appropriately assess the extent of burn injury and be able to
apply criteria sanctioned by the American Burn Association (ABA)
to determine whether the child should be referred to a burn center.
Local and Systemic Complications of Burn Injury
Skin, which bears the initial assault in burn injury, is the portal
between the self and the outside world. It allows us to sense our
environment, controls our interactions with it (eg, regulating heat
loss, water and fluid losses) and protects us against noxious elements
(eg, infectious agents). In all burn patients, the region of localized burn
9
injury to the skin can be divided into three zones:
an innermost zone of irremediable tissue loss, an
intermediate zone of decreased tissue perfusion and
sublethal cell injury that can be remediated with
proper management and the outermost zone that
will spontaneously recover.6 In patients with burns
of 20% or more, systemic complications are likely,
increasing in gravity with the increase in burn
size. Burn injury stimulates the massive release
of inflammatory cytokines (a cytokine storm)
that can increase vascular permeability, result in
capillary leak and lead to systemic inflammatory
response syndrome, an inflammatory state affecting
the entire body that can cause multisystem organ
failure.7 Proper fluid resuscitation is critical in the
first 24 to 48 hours after the burn incident both to
prevent the progression of localized burn damage
and to forestall deadly systemic complications.8
Initial Burn Management
TABLE 1. Lund and Browder Chart
AREA
BIRTH - 1 YR
1 - 4 YR
5 - 9 YR
10 - 14 YR
15 YR
Head
19
17
13
11
9
7
Neck
2
2
2
2
2
2
Ant Trunk
13
13
13
13
13
13
Post Trunk
13
13
13
13
13
13
R Buttock
2.5
2.5
2.5
2.5
2.5
2.5
L Buttock
2.5
2.5
2.5
2.5
2.5
2.5
Genitalia
1
1
1
1
1
1
RU Arm
4
4
4
4
4
4
LU Arm
4
4
4
4
4
4
RL Arm
3
3
3
3
3
3
LL Arm
3
3
3
3
3
3
R Hand
2.5
2.5
2.5
2.5
2.5
2.5
L Hand
2.5
2.5
2.5
2.5
2.5
2.5
R Thigh
5.5
6.5
8
8.5
9
9.5
L Thigh
5.5
6.5
8
8.5
9
9.5
RL Leg
5
5
5.5
6
6.5
7
LL Leg
The immediate response to a burned child should
R Foot
follow the ABCs of trauma care: maintain Airway,
L Foot
assess Breathing, and maintain Circulation. Initial
burn wound care focuses on preventing further
burning and cooling the wound (removing all
clothing, including socks and shoes; applying
saline-soaked towels immediately to the burn surface; continuously
irrigating a chemical burn; avoiding ointments that can retain heat),
maintaining good circulation (removing jewelry, avoiding ice [which
can cause vasoconstriction]) and preventing hypothermia (wrapping
burn surface with clean dry towels and covering child with warm
blankets prior to transfer to a burn center). Inhalation injury, such
as that sustained by survivors of house fires, is the primary cause of
death in pediatric burn patients in the first 48 hours, followed by
hypovolemia and the failure to obtain or maintain a patent airway.
Little can be done to reverse inhalation injury, but proper fluid
resuscitation and airway management can minimize the other two
risks. Although the community physician can take the first steps
toward ensuring a patent airway and adequate fluid administration,
both can be complicated in children and are best performed at a burn
center with pediatric experience.
In cases of children who are obviously severely burned, it is best
to provide basic initial management and refer promptly to a burn
center. According to André Hebra, M.D., Chief of the Division of
Partial
10
ADULT
Full
FIGURE 1. Cross-section of skin showing partial-thickness (left, damage
extending into the dermis) and full-thickness burns (right, damage
extending throughout the dermis).
5
5
5.5
6
6.5
7
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
% BODY SURFACE
AREA (BSA)
3.5
TOTAL %
BSA
Pediatric Surgery and Head of the Pediatric Burn Center at MUSC
Children’s Hospital, “It is better to transfer kids immediately if they
are 10% or more burned. Put a dry blanket on them to prevent
hypothermia and send over right away. If hypoxic, put a breathing tube
in; if you can get an IV in, do; but, if not, send as soon as possible.”
Helicopter transport of pediatric burn patients means they can have
access to a multidisciplinary team of burn professionals within hours
if not minutes.
Estimating the Extent and Severity of Injury
Estimating the extent and severity of burns, the first step in
determining the treatment course of a patient, presents special
challenges in children. The “Rule of Nines,” typically used to assess
the extent of burn injury in adults, is not valid in children younger
than 15 years because their heads are proportionately larger relative
to their extremities than those of adults. In children, a Lund and
Browder chart should be used to map the injured areas, determine
the percentages associated with each mapped area and then total all of
the areas to obtain the total body surface area (TBSA) burned (Figure
1). An accurate assessment of the extent of burn injury is crucial for
determination of fluid resuscitation.8
In addition to the extent, the severity of burn injury must also
be assessed. Skin is composed of three main layers, the epidermis
and the dermis, which together form the cutis, and subcutaneous
tissue. Burns can be classified as superficial (damage to the epidermis
only), partial-thickness (damage extending into the dermis) or fullthickness burns (damage extending throughout the entire dermis)
(Figure 1). Superficial burns are not considered when figuring the
TBSA to calculate fluid volume resuscitation. Partial-thickness burns,
which are extremely painful and characterized by moist blisters, heal
with scarring in three to four weeks. Full-thickness burns, which are
dry and leathery and appear charred, cause little pain because most
nerve endings have been destroyed; these burns never completely
FIGURE 2. Three-year-old boy with burns to over 70% of his body
heal, necessitating a skin graft. Without proper management, major
scarring and contractures can occur during the healing process.
Timely Referral to a Pediatric Burn Center
The ABA has developed a set of criteria for referral to a burn center,
many of which rely on this initial assessment of the extent and severity
of burn injury9 (Table 2). For instance, anyone with greater than 10%
TBSA burned (usually any child with greater than 5% TBSA burned),
with a full-thickness burn, with a circumferential burn or with burns
to the face, genitals, perineum, hands or feet should be transferred
to a burn unit for care. Any burned child should be referred if the
local hospital does not have the qualified personnel and specialized
equipment needed for pediatric burn care.
With burns to more than 70% TBSA, including full-thickness
burns, circumferential burns, and burns to the head and hands, as well
as inhalation injury, Dortez Gordon’s best chances for survival and a
good outcome were at a pediatric burn center because, in addition
to management of the burn itself, pediatric specialists would be on
hand to handle systemic complications as they arose. According to Dr.
Hebra, “once patients survive the first 24 to 48 hours, the burn is
secondary. What will threaten their life are pulmonary complications
(pneumonia), infections and unexpected events. They are no longer
pediatric burn patients but pediatric critical care patients with
multisystem organ failure. A multidisciplinary team effort is required
because every system is involved.” The case of Dortez Gordon,
summarized below, illustrates the importance of a multidisciplinary
team effort by a group of pediatric specialists in an institution with a
high volume of pediatric critical care cases.
Report of a Case
A previously healthy 3-year-old male became trapped inside a house
on fire in North Charleston, SC. He was rescued by volunteers and taken
by Emergency Medical Services to the MUSC Children’s Hospital. At
the time of his initial assessment in the emergency department, he was
awake, alert, anxious and breathing fast with a respiratory rate of 35
breaths/min. Initial estimation of the TBSA burn injury was 70% fullthickness (third degree) burns based on the Lund and Browder chart
(Figure 2). He also had significant inhalation injury.
Initial management included endotracheal intubation and
mechanical ventilation. Central venous access was obtained using the
right and left femoral vessels (through nonburned skin). The patient was
admitted to the Pediatric Critical Care and Burn service at the MUSC
Children’s Hospital. Fluid resuscitation based on the Parkland formula
was initiated. Burns to both upper extremities were full thickness
and circumferential. Escharotomy was performed in both arms and
forearms, extending into both hands. Despite the escharotomy, no
radial/ulnar Doppler signal was detected in either wrist.
Initial debridement of the burned tissue was performed and
Silvadene dressing was applied. Within 24 hours, a tissue sample of
normal skin was obtained from the groin and axillary region and sent
to Boston for cultured epidermal cell growth. After the first 48 hours,
the patient developed signs of worsening respiratory distress syndrome
and required significant ventilatory support with oscillator ventilation.
Within the first week after injury, the patient underwent surgical
debridement and grafting of one of the upper extremities. Blood
transfusion was necessary due to blood loss. He developed postoperative
abdominal compartment syndrome with fulminant respiratory failure
and inability to oxygenate and required urgent laparotomy as a lifesaving measure. The abdomen was packed open and a wound-vac was
placed over the abdominal viscera. The patient developed sepsis and
signs of multiorgan failure syndrome. Wound care was continued
with Silvadene, the abdomen was re-explored and the viscera were
inspected. Abdomen closure was achieved within one week, and the
temporary abdominal wall silo was removed. The patient’s ventilatory
status improved, but he required a tracheostomy.
Over the course of the first 4 weeks, the patient underwent
sequential debridement of the burn tissues with placement of
homograft (cadaver donor skin) for temporary coverage. Nutritional
support was maintained by jejunal tube feeds. The patient developed
several episodes of bacteremia/sepsis/ funguemia, successfully treated
with antibiotics and antifungal agents.
After 4 weeks, cultured epidermal skin cells (epicell) became
available and lots were shipped from the laboratory in Boston for
grafting. The patient underwent a total of 19 operative procedures
with complete skin grafting of all burned tissue. A combination of
autografts and epicell allowed for successful coverage of the burned
skin, including face, upper and lower extremities, trunk and hands.
The patient lost a total of 4 digits, but most of the hand and fingers
were preserved. The patient also developed deep vein thrombosis of
femoral vessels and required anti-coagulation therapy.
His respiratory status improved and he was weaned off mechanical
ventilation 12 weeks after admission. Minor upper airway obstruction
developed but the tracheostomy tube was successfully removed.
The patient was discharged home 3 months after hospital admission
and is currently undergoing outpatient rehabilitation therapy with the
MUSC pediatric burn team.
TABLE 2. Burn Center Referral Criteria for
Pediatric Patients
•
•
•
•
•
•
•
•
•
Burn injuries of greater than 10% TBSA
All full-thickness burns
Inhalation injury
Burns involving the hands, feet, face, perineum, genitalia, or
major joints
Electrical or chemical burns
Circumferential burns
Burns accompanied by significant associated trauma/ injury,
preexisting disease, or suspected child abuse or neglect
(report to local child and youth agency)
Burned children in hospitals without qualified personnel or
equipment for the care of children
Injury of a patient that will require special social, emotional,
or rehabilitative intervention
11
FIGURE 3. Members of the pediatric burn team with Dortez and his mother on the
day of his release from the hospital
Discussion
The case of Dortez Gordon illustrates that severely burned pediatric
patients achieve better outcomes when treated in a regional burn
center with strong experience in pediatric critical care and the
specialized equipment needed to treat children. Pediatric surgeons at
such centers have the burn care experience and knowledge of pediatric
physiology and anatomy needed to confidently perform escharatomy
and to successfully execute the many skin graft operations that will be
needed. Access to a variety of pediatric specialists also improves the
burned child’s chances of surviving the two main killers of postburn
patients: respiratory distress and infection.
Dortez had circumferential, full-thickness burns to the upper
extremities, putting him at risk for compartment syndrome. Eschar,
a leathery inelastic mass of burned tissue associated with full-thickness
burns, can act almost like a tourniquet when the burn extends all the
way around a body part, causing a buildup of pressure in the affected
body compartment that in turn collapses the vascular and lymphatic
structures and causes tissue death. The pressure must be relieved by
making an incision through the burn eschar. This procedure is best
performed at a burn center by a surgeon familiar with pediatric anatomy
and experienced with burn care. Although compartment syndrome
is most often associated with the extremities, it can also occur in the
abdomen, as it did in Dortez’s case, although this is rare. Had pediatric
surgeons and pediatric intensivists not been on hand to treat this lifethreatening condition, Dortez would likely not have survived.
After the first 48 hours, Dortez developed severe respiratory
distress, which was treated with the use of an oscillator. Unlike a
traditional ventilator that inflates and deflates the child’s lungs and
could cause damage, the oscillator maintains the lungs open with
positive end-expiratory pressure (PEEP) and vibrates the air to help
diffuse the gases. Without access to such specialized equipment and
physicians experienced in managing respiratory failure in children,
Dortez may not have survived.
In the burn patient, the skin, which is the primary barrier against
invading pathogens, is severely compromised. As a result, the burn
patient is prey to a large number of fungal and bacterial infections,
some of them otherwise quite rare. Debridement of wounds and
removal of scar tissue helps reduce infection, as do specialized
dressings (eg, Silvadene and silver-based dressings). Ultimately,
however, a patient’s ability to fend off pathogen challenge will be
restored by the grafting of new skin on all of the exposed sites.
However, obtaining enough skin to cover the burn wounds can be
challenging in a pediatric patient, especially in a patient as severely
burned as this one. In this case, cadaver skin was used initially while
Dortez’s own skin was harvested and sent to an ancillary laboratory
for the culture of amplified epithelial cells. While waiting on the
12
cells to grow, Dortez had to be maintained as infection free as
possible. Although he developed fungal and bacterial infections,
these infections were successfully managed by pediatric infectious
diseases specialists and intensivists familiar with both common and
uncommon pathogens and adept in the dosing of antibacterial and
antifungal agents in children.
Risk of infection can also be reduced by proper nutrition. Severe
burns elicit a hypermetabolic response, in which the body’s core
temperature is raised, more oxygen is consumed, more nitrogen is
excreted and more carbohydrates, proteins and triglycerides are
catabolized to meet the increased metabolic demands.8 The intensity
of this response increases with the extent of the burn. It can lead
to body wasting and poor wound healing. A recent study provides
evidence that the initiation of enteral feeding within the first 24 hours
decreases the length of stay in the intensive care unit and reduces the
risk of wound infection.10 Proper management of Dortez’s nutrition
contributed to his positive outcome.
This case report demonstrates that outcomes of pediatric burn
patients depend on the early initiation of modern burn management
techniques and the availability of a wide range of pediatric specialists
ready to take on any complication that might arise from the burn
(eg, pediatric critical care specialists for respiratory distress; pediatric
surgeons for abdominal compartment syndrome, escharatomy, and
skin grafting; pediatric infectious diseases specialists and pharmacists
for proper antifungal and antibiotic dosing; nurse burn specialists
for wound care and support). It is also important to note that the
patient and the family received dedicated care by child life specialists
(see “More Than Child’s Play” on page 13), social workers, nurse case
managers, and physical and occupational therapists (Figure 3).
In the words of Dr. Hebra, “I am convinced that if this patient had
been in any other environment, even an adult burn center, he would
not have made it, not just because of the care of the burns but the overall
care of the patient, including surgery, fluid resuscitation, medication
management, critical care interventions, ventilator breathing machine
management, sepsis treatment and antibiotic coverage.”
Fortunately for Tez, he had been delivered into safe and very
experienced hands. Three months later, the pediatric burn team
returned him to the arms of his mother.
References
1
Kraft R, Herndon DN, Al-Mousawi AM, et al. Burn size and survival probability
in paediatric patients in modern burn care: a prospective observational cohort
study. Lancet. 2012; 379: 1013–1021.
2
Sheridan RL. Burn care: results of technical and organizational process. JAMA.
2003;290(6):719-722.
3
Sheridan R, Weber J, Prelack K, et al. Early burn center transfer shortens the
length of hospitalization and reduces complications in children with serious burn
injuries. J Burn Care Rehabil. 1999 Sep-Oct;20(5):347-50.
4
Carter JE, Neff LP, Holmes JH. Adherence to burn center referral criteria: are
patients appropriately being referred? J Burn Care Res. 2010;31:26-30.
5
Zonies D, Mack C, Kramer B, et al. Verified centers, nonverified centers or
other facilities: a national analysis of burn patient treatment location. J Am Coll
Surg. 2010 March; 210(3): 299-305. doi:10.1016/j.jamcollsurg.2009.11.008.
6
Cox S and Rode H. Modern management of pediatric burns. AJOL. 2010;
28(3):113-118.
7
Yarrow J, Moiemen N, Gulhane S. Early management of burns in children.
Paediatrics and Child Health. 2009; 19(11):509-516.
8
Young AE. The management of severe burns in children. Current Paediatrics.
2004; 14: 202–207.
9
American Burn Association. Burn center referral criteria. Available at http://
www.ameriburn.org/ BurnCenterReferralCriteria.pdf. Accessed June 4, 2012.
10
Mosier MJ, Pham TN, Klein MB, et al. Early enteral nutrition in burns:
compliance with guidelines and associated outcomes in a multicenter study. J
Burn Care Res. 2011 Jan-Feb;32(1):104-109.
More Than Child’s Play: Helping Pediatric Burn Patients Be Kids Again
For children with severe burns, their world seems to have spun
out of control. They have endured the trauma of the injury itself, been
ripped from their familiar surroundings and placed in an unknown
environment where they must undergo sometimes painful procedures
(eg, debridements, dressing changes) associated with burn care.
Even after recovery, they bear physical and emotional scars that
impair self-esteem, complicate family life and make social interactions
challenging. They can no longer trust that the world is a safe place.
Adults might cope by talking through their feelings of helplessness
and isolation. Young children are less likely to do so. Play offers them
a way to reassert control over their environment and vent their pentup feelings.
With one touch of his finger, the car spun out of control and then went
whirling out of his room into the hall outside. For Dortez, this was the
first step in reclaiming a life that had itself momentarily spun out of
control, the first sign that good times would once again return.
Camp Can Do
MUSC’s Child Life Services
MUSC’s Child Life
Services,
which
is staffed by a
dozen
child
life
specialists, tends to
the emotional needs
of children as they
receive medical care,
offering
support
to
families
and
opportunities for play
FIGURE 1. Child life specialists use play to help
to children. Betsy
children cope with their injuries and treatment.
McMillan, MA, a
senior child life specialist at MUSC who has worked with pediatric
burn patients for almost 16 years, believes that play can bolster the
spirits of a child recovering from a trauma because “play is normal
and natural to a child in an environment where nothing else is.”
To encourage recovering children to play, a light and colorful
atrium near the inpatient pediatric units at MUSC Children’s
Hospital has been turned into a play area, complete with a wealth
of age-appropriate toys, board and video games, DVDs and reading
materials. The atrium offers a safe haven for children, a place of fun
and relaxation where medical procedures never occur. According
to McMillan, play has an almost magical effect upon the children,
whose injuries may have left them emotionally withdrawn: “When
children start to play, their personalities come back really quickly.”
Play can also be used to help children make sense of their injuries
and teach them about the medical procedures they must undergo
(Figure 1). Their injuries can be reproduced on simple stuffed dolls
by putting bandages where the child’s bandages are. Betsy McMillan
regularly puts tracheostomies in these dolls and even has tiny pressure
garments for them, identical to those that children must wear for up
to a year after skin grafting is complete.
Children should be allowed to play freely with the dolls
because, according to Betsy McMillan, “Children can be very exact
at recreating their experiences when they are in the driver’s seat.”
They may use the doll to represent how their own injury occurred or
reproduce a recent blood stick or dressing change.
Above all, open-ended play allows children to reassert a sense of
control.
While he lay in bed recovering from his burn wounds at MUSC, his
fingers splinted to help prevent contractures, Dortez Gordon relished
the remote control car that Child Life Services brought to his room.
FIGURE 2. Summer 2012 Camp Can Do Campers and Counselors
Once they leave the hospital, children face a different set of
emotional challenges. Anxious over their scars and with a sometimes
impaired self-esteem, they must return to school, where stares, teasing
and a constant barrage of questions likely await them. Camp Can Do instills in them the confidence that they “can”
meet these challenges and lead a fulfilling life (Figure 2).
Cosponsored by MUSC’s Pediatric Burn Center and the Burned
Children’s Fund, the weeklong camp designed especially for burn
survivors is held each summer at Camp St. Christopher on Seabrook
Island, South Carolina. The Burned Children’s Fund is a collaboration
of MUSC Children’s Hospital and South Carolina Firefighters,
and most of its monies come from the collection and recycling of
aluminum cans by firefighters statewide.
Jill Evans, R.N., M.S.N., a burn nurse with more than 20 years of
experience, is the Coordinator of Pediatric Burn Services for MUSC
Children’s Hospital and the Burned Children’s Fund and is the
Administrative Director of Camp Can Do. According to Evans, the
camp has a “a very comfortable, accepting atmosphere” and provides
kids a break, a place where “they get to feel accepted and know no
one’s going to be asking them a lot of questions.”
Camp Can Do offers pediatric burn survivors all the fun of a
regular summer camp. They can swim in the ocean, play on the
beach, fish, play in the mud, dance, do arts and crafts, play basketball
and eat grilled food. They can do so in a protected environment, with
peers who have experiences similar to their own. They can share their
stories easily with others who truly understand what they have been
through. They can let their guards down and be kids again.
Campers return year after year, building strong friendships. They
also build confidence, as they realize they are not alone. The kids say
it best themselves: “Whenever I go to camp, I can always count on
not getting teased and not feeling left out about anything and just
fitting in. I build confidence in myself. It’s a good feeling.”
13
KEY POINTS
Unwinding the Maze:
•
Successfully Navigating the Drug Discovery and Development Pathway
Part II: Bringing Promising Preclinical Findings to Clinical Fruition
MUSC’s Hollings Cancer Center has succeeded in bringing an anticancer compound (a sphingosine kinase inhibitor) on which
several laboratories at MUSC conducted mechanism of action studies to a first-in-class, first-in-human clinical trial (the Apogee
trial), a rare feat even among National Cancer Institute–designated cancer centers.
• Hollings Cancer Center is fully engaged in all phases of clinical research, with 219 clinical trials (127 of which are therapeutic)
currently open and an additional 55 in the activation process; many of these trials are of innovative targeted therapies.
increase the clinician’s anticancer armamentarium, particularly when it
comes to inflammation-associated cancers like pancreatic and hepatic
cancer (for more information on the sphingosine kinase pathway, see
“The Spingosine Kinase Pathway,” page 17).
A True Team Sport
Melanie Thomas, M.D.,
“For cancer centers, it’s the holy grail,” notes Melanie Thomas,
M.D., Associate Director of Clinical Investigations at MUSC’s
Hollings Cancer Center, speaking of a cancer center developing a new
drug from a concept, through extensive research and testing, to an
actual first-in-human clinical trial. Hollings Cancer Center, the only
National Cancer Institute–designated cancer center in South Carolina
and one of only 66 in the country, has recently done just that with
the Apogee trial, a first-in-human, first-in-class phase 1 clinical trial
of a sphingosine kinase inhibitor. As Dr. Thomas notes, “Not all 66
cancer centers do first-in-human trials; lots of times researchers go
with a contract research organization and the trials go offshore to
Russia or elsewhere. For someone to stay here and trust us, it’s a vote
of confidence.”
The Apogee Trial: First-in-Human, First-in-Class
The Apogee trial (“ABC294640 in Treating Patients With Advanced
Solid Tumors” [ABC-101; NCT01488513]) is a phase 1 trial of a
sphingosine kinase inhibitor in patients with solid tumors who have
not received benefit from standard-of-care chemotherapy. This trial is
the first of a new category of drugs that act on a novel, lipid-based
signaling pathway—the sphingomyelin degradative pathway. The
research of Charles D. Smith, PhD, Professor of Pharmaceutical
and Biomedical Sciences and Director of the Drug Discovery Shared
Resource at MUSC, and others has shown the importance of this
pathway in regulating cancer cell death and survival and thereby
in supporting the development of resistance to chemotherapy and
radiation by cancer cells. Dr. Smith hypothesizes that cancer cells could
be made more sensitive and less resistant to chemotherapy and radiation
treatment through inhibition of sphingosine kinase, a key player in
this pathway and one that tilts it toward cancer cell survival and away
from apoptosis (ie, programmed cell death). If proven efficacious and
safe in clinical trials, sphingosine kinase inhibitors could substantially
14
The Apogee trial would not have been possible had not basic
scientists and clinicians stretched beyond their comfort zones to
communicate and collaborate together. Taking advantage of retreats
sponsored by Hollings Cancer Center and the South Carolina Clinical
and Translation Research Institute (SCTR), Dr. Smith informed
clinicians of the promising new compound, and the prospect of
launching a trial of a compound for which MUSC investigators had
done some of the basic science research kept everyone motivated.
According to Dr. Thomas, “Everybody kept the foot on the gas pedal.
As a group, people were really motivated to keep this going.”
Their motivation helped the study clear any number of hurdles that
could have slowed momentum. For example, the investigational new
drug application (IND) that must be submitted to the FDA to gain
approval for a clinical trial can be a quagmire for many investigators.
The IND for the Apogee trial, on which Dr. Smith (whose laboratory
investigated the mechanism of action of the compound) and Dr. Thomas
(who serves as the trial’s principal investigator) both collaborated, won
speedy approval. Likewise, once the trial was approved, Stephen M.
Lanier, PhD, Professor of Pharmacology and Associate Provost for
Research, the clinical trials office and the institutional review board
ensured that the proper boundaries were in place between Dr. Smith,
the compound’s sponsor (he owns the startup company Apogee), and
Dr. Thomas. Dr. Thomas is completely responsible for the conduct
of the trial and the selection of patients; Dr. Smith has no direct
involvement in the trial.
Why Aren’t There More Success Stories?
Sadly, such stories of the successful translation of promising new
compounds from the laboratory into clinical trial through close
collaboration between basic scientists and clinicians are too rare
nationwide. Studies confirm that, despite substantial investment
in biomedical research by both the government and especially the
pharmaceutical industry, the number of new cancer drugs making
it to the clinic has been disappointing. 1 Kathleen T. Brady, M.D.,
PhD, Director of SCTR and Associate Dean for Clinical Research
in MUSC’s College of Medicine, echoes this concern: “Our advances
in the health of the nation have not paralleled the big investment in
research.”
Many investigators falter as they attempt to make the transition
from preclinical study to clinical trial, the so-called “valley of death.”
According to Dr. Thomas, “the landscape is littered with drugs that
got as far as animals and didn’t get any further.” Even after IND
• Nationwide, the number of new cancer drugs reaching the market is disappointing given the level of funding by industry
and government, leading some to criticize the current drug development process as antiquated (based on an outdated
understanding of and therapeutic approach to cancer) and overly cumbersome.
• Barriers preventing more rapid availability of innovative new drug therapies to cancer patients include the high cost of all
clinical trials, particularly the very large phase 3 trials needed to provide evidence of efficacy (ie, survival benefit versus standard
therapy) to the US Food and Drug Administration; low participation rates by patients in clinical trials; and inadequate
communication among basic scientists, academic clinicians and community physicians at critical junctures in the pathway.
• Legislation recently passed by the U.S. Congress and signed into law by President Obama will streamline the approval process
for “breakthrough drugs,” defined as those that are intended to treat serious or life-threatening disease and that have strong
preliminary evidence of efficacy, as demonstrated by a clinically relevant end point.
approval, only 1 in 20 drugs for which an application is filed makes
it to market.2
Why is the track record for new drug approvals so poor? Why
does it take so long for the drugs that do gain approval to make it
to market and become available to cancer patients who desperately
need them?
What We Have Here Is a Failure to Communicate
Poor communication between basic scientists and clinicians,
between investigators and regulatory agencies, and between academic
clinicians and community physicians can prevent or delay the arrival
of promising new therapies in the clinic. Too often, according to Dr.
Thomas, “clinicians and scientists live in parallel universes,” siloed
into their own specialties with little time to communicate across
the translational divide. Without communication, clinicians will
never learn of promising new compounds in the laboratory and basic
scientists will not be familiar with the clinical context in which such
compounds might one day be used. More dialogue early in the design
process between investigators and regulators could improve study
design and increase the chances that a drug will be approved. All of the
effort, dedication and monies needed to bring a drug through the four
phases of clinical trials (see “The Four Phases of Clinical Research,”
page 18) and into commercialization mean little if these novel
therapies do not reach the patients who need them. Despite strong
evidence of efficacy and safety from clinical trials, new therapies are
sometimes not adopted by community physicians. Complicated drug
regimens and dosing schedules that may be handled easily at academic
medical centers where clinical trials are run may not be feasible in
busy private practices. With feedback from physicians in private
practice or at local hospitals, treatment regimens could be adjusted to
maximize their practicality.
The High Costs of Clinical Trials
Many investigators simply run out of money to pay for the
exorbitantly expensive clinical trials, particularly the large, complex,
multisite phase 3 trials. Drugs that can show a statistically significant
survival benefit versus available therapies stand the best chance for
approval. Reaching sufficient power for statistical significance requires
the recruitment of a large number of study participants, difficult
at a time when only 2% to 3% of patients enroll in clinical trials.2
Establishing statistically significant survival benefit often entails
waiting for enough patients in the control group to die, considerably
prolonging the trial and delaying the drug’s entry into the clinic.2 This
time-consuming and resource-draining process will inflate the price
of any drug that is eventually approved, putting it outside the reach
of many patients, particularly when reimbursement by Centers for
Medicare & Medicaid Services and private insurers remains in doubt.2
An Antiquated Drug Approval Process?
Of course, ensuring safety and efficacy trumps concerns of cost
effectiveness. However, some have questioned whether the current
parameters for efficacy and safety set by regulatory agencies have
become obsolete as our understanding of and approaches to treating
cancer have changed.3 We once knew little about the underlying
mechanisms of cancer and most anticancer agents were highly
cytotoxic agents that were lethal to cancerous and healthy cell alike.
However, much has changed in our understanding of cancer and
how to treat it, as Dr. Harold Varmus, Director of the National
Cancer Center, made clear in a visit to MUSC in June of 2012: “We
have gone from a time when cancer was a complete mystery to a
time now, just 20 or 30 years later, when we understand exactly the
kinds of changes that occur in our chromosomes that turn a normal
cell into a cancer cell and that has had profound implications for
prevention, diagnosis and treatment.”
15
a redundant prosurvival or prometastatic pathway. A shorter-term
clinical trial looking only at tumor responsiveness might miss the
resurgence of cancer after the trial is over. Many proponents of the
new end points think that increased vigilance during postmarketing
surveillance could help address this potential shortcoming.
“Breakthrough” Legislation
Charles D. Smith, PhD
We know, for example, that cancer is not a single monolithic entity
but a plurality of diseases. It is now classified not only by the organ it
affects (eg, breast cancer) but by the genetic marker(s) with which it
is associated (Her2+). Targeted therapy, in which an anticancer agent
targeting a specific mutation is given to patients specifically with
that mutation, is slowly replacing the blunt instrument of broadly
cytotoxic agents. More broadly defined, targeted therapies can
include those that knock out signaling pathways known to be linked
to tumor growth and metastasis. Because of their precise aim, these
agents are thought to cause less collateral damage to healthy cells and
so, in the opinion of some, do not require the extensive and expensive
studies in large animals currently required to identify a safe starting
dose for phase 1 clinical trials. Likewise, the large phase 3 trials
needed to establish survival benefit do not lend themselves easily to
these targeted therapies and their more defined patient populations
(patients with a cancer bearing a specific mutation). However, when
tested in the target population, these drugs can have very high
response rates.
Despite their promise, these drugs are slow to come to market
as they attempt to meet antiquated criteria. Using a clinical end
point other than overall survival could help break this log jam.
Tumor response and disease-free progression have been suggested
as possible surrogates of efficacy; clinical trials with such end points
could be of substantially shorter duration. These suggested clinical
end points have their drawbacks. Cancer is notorious for developing
drug resistance; if one signaling pathway is blocked, it simply uses
16
Spurred in part by the outcry over recent severe drug shortages
(see April/May issue of Progressnotes and page 3 of this issue for
more on the recent drug shortages and how this legislation addresses
them) and by continuing criticism of the cumbersome drug approval
process, the U.S. Congress, in a rare show of bipartisan cooperation,
passed the Food and Drug Administration Safety and Innovation
Act (S. 3187), on June 26, 2012. President Obama signed it into
law on July 9, 2012. This legislation proposes streamlining the drug
development pathway for “breakthrough drugs,” defined as those
that are intended to treat serious or life-threatening disease and that
have strong preliminary evidence of efficacy, as demonstrated by a
clinically relevant end point.4
The definition of “a breakthrough drug” is key in this legislation.
To be so designated, a drug does not have to demonstrate improved
overall survival versus currently available therapy, the gold standard
for approval until now. It must only show efficacy in improving one
or more end points, such as tumor responsiveness or progressionfree survival.
In addition to relaxing its definition of efficacy for these drugs,
many of which are targeted therapies, the legislation also mandates
frequent communication between regulators and investigators to
ensure proper study design and efficient conduct of the trial.
This legislation represents the first reform of the FDA’s drug
approval process for innovative therapies in more than 15 years
(since 1997, when Fast Track was instituted). It addresses many of
the obstacles that have slowed the flow of new drugs to the clinic,
meaning that innovative new therapies could reach patients far more
quickly and at a lower cost. Although cancers that initially respond
well to such breakthrough drugs could develop resistance to them,
the increased number of clinically available drugs will provide the
building blocks of new combination regimens that could help prevent
recurrence by blocking multiple pathways.
The result of all these changes could be a more nimble approval
process that will allow the promise of personalized medicine and
targeted therapies for cancer patients to become clinical realities.
References
1
Dorsey ER, Thompson JP, Carrasco M, et al. Financing of U.S. biomedical
research and new drug approvals across therapeutic areas. PLoS ONE.
2009;4(9): e7015. doi:10.1371/journal.pone.0007015.
2
Schein PS, Scheffler B. Barriers to efficient development of cancer therapeutics.
Clin Cancer Res. 2006; Jun 1;12(11 Pt 1):3243-3248.
3
Wagstaff A. Beyond survival – what should new cancer drugs have to prove
and how? Cancer World. July/August 2011; 22-29.
4
S.3187--112th Congress: Food and Drug Administration Safety and
Innovation Act. GovTrack.us (database of federal legislation). 2012. June 25,
2012 Available at http://www.govtrack.us/congress /bills/112/s3187
The Sphingosine Kinase Pathway
Once thought to merely serve as structural components of the plasma
membrane, sphingolipids are major actors in pathways that lead
to angiogenesis, inflammation, as well as cancer development and
resistance to chemotherapy and radiation.1,2
Through a series of enzyme reactions, sphingomyelin, a phospholipid
found in animal membranes (especially of nerve tissue), is catalyzed
first to ceramide and then to sphingosine. Sphingosine then picks
up a phosphate group from either sphingosine kinase 1 or 2 to form
sphingosine 1-phosphate (S1P), which has been implicated in cancer
cell survival and resistance (Figure).
Ceramide, sphingosine and S1P constitute a rheostat (ie, a sort
of control mechanism) that regulates apoptosis (ie, programmed cell
death). Ceramide and sphingosine encourage apoptosis of cancer cells,
whereas S1P encourages cancer cell survival.2
This is in essence a recycling pathway. Ceramide is lysed into
sphingosine that is then phosphorylated into S1P. However, various
phosphatases can in turn remove the phosphate and turn the prosurvival
S1P back into the proapoptotic sphingosine. Sphingosine can in turn be
converted back into ceramide by ceramide synthase. This system tilts
toward cell survival or cell death depending on the ratio of ceramide
and sphingosine to S1P.
This rheostat is thought to play a role in resistance of cancer cells to
chemotherapy. Chemotherapy triggers apoptosis, but it is thought that
the system compensates by producing more S1P to promote survival.
The question is how to tip this regulatory pathway toward apoptosis
without triggering compensatory survival pathways. Knocking
out sphingosine kinase, which is responsible for the production of
prosurvival S1P, with an SKI could tilt the system toward apoptosis.3
If this ability to tilt the system is borne out in clinical trials, then SKIs
like ABC294640 could be used in combination regimens along with
chemotherapy to potentiate its therapeutic effects.4,5
Sphingolipids are also thought to play a role in inflammation.1
Inflammatory cytokines activate sphingosine kinase 1 and 2, which in
turn can lead to inflammation by the downstream induction of cyclooxygenase (COX2) and the induction of adhesion molecules important
in the inflammatory response (sticky molecules that encourage the
infiltration of leukoyctes). Inhibiting sphingosine kinase could then
reduce the inflammation associated with some cancers (ie, pancreatic,
hepatic), perhaps making them more responsive to chemotherapy and
radiation, and could also have a role to play in chronic inflammatory
diseases. According to Dr. Thomas, who is the principal investigator on
the trial of the SKI, “pancreatic tumors are desmoplastic tumors—there
is a great deal of stroma and inflammatory reaction between cells—and
so are chemorefractory tumors; if an SKI can change the milieu and
clear up the inflammation, then gemcitabine, the only drug with a long
history of efficacy, could be used to greater effect.”
By tipping the ceramide-sphingosine-S1P rheostat toward
apoptosis, an SKI could also act as a radiosensitizer, rendering cancer
cells more susceptible to radiation and thus lowering the total amount
of radiation needed and minimizing the consequent ill effects.6
A sphingosine kinase inhibitor such as ABC294640 could then be
used as a monotherapy, as an adjuvant to chemotherapy to help reduce
resistance or as a radiosensitizing agent. Although their signaling
role in a number of cancers has been established, they show the most
promise in cancers characterized by significant inflammation.
References
1
Snider AJ, K. Gandy AO, Obeid LM. Sphingosine kinase: role in regulation
of bioactive sphingolipid mediators in inflammation. Biochimie. 2010; 92(6):
707–715. doi:10.1016/j.biochi.2010.02.008.
2
Pyne NJ, Pyne S. Sphingosine 1-phosphate and cancer. Nat Rev Cancer. 2010
Jul;10(7):489-503. Epub 2010 Jun 17. Review. doi: 10.1038/nrc2875.
3
Beljanski B, Lewis CS, Smith CD. Antitumor activity of sphingosine kinase
2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts.
Cancer Biology & Therapy. 2011;11(5):524-534.
4
Antoon JW, White MD, Slaughter EM, et al. Targeting NF-κB mediated
breast cancer chemoresistance through selective inhibition of sphingosine
kinase-2. Cancer Biol Ther. 2011 April 1; 11(7): 678–689.
5
Guillermet-Guibert J, Davenne L, Pchejetski D, et al. Targeting the
sphingolipid metabolism to defeat pancreatic cancer cell resistance to the
chemotherapeutic gemcitabine drug. Mol Cancer Ther. 2009 Apr;8(4):809-820.
6
Mahdy AE, Cheng JC, Li J, Elojeimy S, et al.Acid ceramidase upregulation in
prostate cancer cells confers resistance to radiation: AC inhibition, a potential
radiosensitizer. Mol Ther. 2009 Mar;17(3):430-8.
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 or visit the online edition at MUSChealth.com/progressnotes
17
The Four Phases of Clinical Research for Drug Development
Clinical Trials at MUSC’s Hollings Cancer Center
Once the IND application has been approved by the FDA, clinical research is scaled up in phases, with
data from the previous phase needed for approval of the next.
According to Terri Matson, CCRP, Director for Research Administration at MUSC’s Hollings Cancer Center, 219 clinical trials (127 of which are
therapeutic) are open, with 55 more in the activation process. If trials that are complete but continue to follow up patients are included, that number
increases to 458 (299 of which are therapeutic). This wealth of clinical trials offers residents of the region a unique resource, an opportunity to benefit
from cutting-edge anticancer regimens while they are still in their infancy. A few are summarized below to illustrate each of the phases of clinical
research. For more information on these trials, call MEDULINE at 1-800-922-5250 or 843-792-2200 and ask for Susan Shannon, CCRC,Clinical
1
Operations Manager at Hollings Cancer Center, or visit http://hcc.musc.edu/clinicaltrials
Phase 1 Trial: Finding a Safe Dose in Humans
The main purpose of a phase 1 trial is to establish a safe dose for a phase 2 trial. The initial dose is very low and is based on data from large
animal studies. Because safety and not efficacy is being tested, enrollment can be less restrictive in these studies. For example, a patient with
any solid tumor could be enrolled in the Apogee trial; it did not have to be a tumor of a particular type. Typically, a cohort of three patients
is administered each dose. If a dose-limiting effect (as defined by the protocol) develops in any of the patients, an additional three patients are
added at the same dose to further explore it. If no toxicity develops, a higher dose is explored in another three patients. If, however, a second
dose-limiting toxicity develops in any of those patients, then it is judged that the maximum tolerated dose has been reached and more dose
exploration is done at the previous dose.
Phase 1: ABC294640 in Treating Patients With Advanced Solid Tumors (ABC-101; NCT01488513)
Principal Investigator: Melanie Thomas, M.D.
The Apogee trial is seeking to establish a safe dose for a sphingosine kinase inhibitor, a new class of anticancer drugs and one being tried for
the first time in humans. Knowing that poor patient selection can lead to the demise of a potential new therapy, Dr. Thomas set up a phase 1
committee that meets regularly to discuss patient enrollment and to make other decisions regarding Apogee and other phase 1 trials. For the
Apogee trial, a team of three clinicians selects patients, each contributing patients from his or her specialty: Dr. Thomas, liver cancer; Steven
Chin, M.D., cancers of pancreas and the upper gastrointestinal tract; and Keisuke Shirai, M.D., MSCR, melanomas and cancers of the lung,
head and neck. To date, the study has enrolled 10 patients. Once a safe dose has been established, Dr. Thomas plans to expand the phase 1 trial
to an additional cohort of patients with pancreatic cancer, because this type of cancer, heavily associated with inflammation, is postulated to
respond well to a sphingosine kinase inhibitor.
Phase 2 Trial: Establishing Efficacy and Short-Term Adverse Effects in a Defined Population
Once a safe dose for a drug has been established in a phase 1 trial, its efficacy for a particular indication in a given population of patients can
be assessed in a phase 2 trial, which typically enrolls fewer than 100 participants. Because efficacy is at stake, patient populations must be well
defined. For example, a phase 2 trial might be in patients with advanced breast cancer. If the drug was thought to also have efficacy in another
tumor type, then a separate phase 2 study would be needed. Likewise, each combination of the study drug with another medication would
require a separate phase 2 trial. Phase 2 trials are crucial because they provide initial evidence of efficacy or lack thereof in given diseases and so
provide guidance as to whether to proceed to the far more costly and complicated phase 3 trials. The transfer of a compound from a university
or a startup to a pharmaceutical company most typically occurs once strong phase 2 evidence is in place to justify the investment needed for
phase 3 trials and commercial rollout.
Phase 2: A Treatment Trial Comparing Gemcitabine and Pazopanib Versus Gemcitabine and Docetaxel for Patients With Advanced
Soft Tissue Sarcoma (NCT01593748)
Principal Investigator: Andrew S. Kraft, M.D.
This phase 2 trial currently under way at Hollings Cancer Center assesses the efficacy of pazopanib, a multitarget, small molecule
angiogenesis inhibitor being developed by GlaxoSmithKline for the treatment of renal carcinoma, as part of a combination chemotherapeutic
regimen to treat advanced soft tissue sarcoma. This trial was investigator initiated, meaning that its principal investigator, Andrew S. Kraft,
M.D., Director of MUSC’s Hollings Cancer Center, approached GlaxoSmithKline about studying pazopanib, which has shown efficacy in
renal cell carcinoma, in a new patient population. As opposed to docetaxel, which interferes with cell division, angiogenesis inhibitors like pazopanib seek to starve the tumor by preventing the
growth of new blood vessels needed to supply it with nutrients and oxygen. If this phase 2 trial shows efficacy for pazopanib, GlaxoSmithKline
could decide to pursue a phase 3 trial for this new indication.
2
3
4
18
Phase 3 Trial: Establishing Survival Benefit and Safety in Larger Population Samples
After phase 2 trials have established some clinical efficacy for a drug in a given patient population, phase 3 trials, which enroll far more
patients (approximately 2000 vs <100) and often involve multiple (sometimes well over 100) sites, further establish the benefit/risk profile of
the drug. To maximize chances for FDA approval of the drug under study, these complicated, randomized, controlled trials must demonstrate
statistically significant survival benefit (P<.05) versus currently available therapy. To reach sufficient power to demonstrate such survival
benefit, a large number of patients must be enrolled and the trial must continue until enough of the control patients have died to demonstrate a
statistically significant survival benefit for the study drug. Because of their complexity, duration and size, such trials are exorbitantly expensive
and out of reach of most academic institutions without outside pharmaceutical support. On the basis of strong evidence of survival benefit
and an acceptable safety profile from phase 3 trials, sponsors of a developmental drug can submit a new drug application and, if it is approved,
begin to commercialize the drug.
Phase 3: A Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of Pazopanib as Adjuvant Therapy for
Localized or Locally Advanced Renal Cell Carcinoma After Nephrectomy (NCT01235962)
Principal Investigator: Harry A. Drabkin, M.D.
On the basis of the findings of increased progression-free survival in a previous phase 3 trial, pazopanib is approved for treatment of patients
with end-stage (metastatic) renal cell carcinoma. In patients with localized or locally advanced renal cell carcinoma, the treatment of choice is
resection via partial or radical nephrectomy. Unfortunately, however, 20% to 40% of patients will experience a local recurrence or metastasis
after nephrectomy and no adjuvant treatments have been available to lessen this risk. The study under way at Hollings, which was initiated
by GlaxoSmithKline, is seeking to determine whether pazopanib, with proven efficacy against metastatic disease, can also lessen the risk of
localized progression or metastasis when given as an adjuvant therapy to patients with localized or locally advanced disease after nephrectomy.
Phase 4 Trial: Further Understanding a Drug’s Benefits and Risks in a Real-World Setting Through Postmarketing Surveillance
Although the FDA approves the commercialization of new drugs on the basis of phase 3 findings, further elucidation of the drug’s benefit/
risk profile is needed once it is used in more real-world populations without the tight controls (ie, detailed inclusion and exclusion criteria)
that characterize clinical trials. Phase 4 trials, or postmarketing surveillance, are meant to capture this important postrelease data and provide
an extra measure of protection for patients. Dosing may need to be adjusted based on real-world findings. The cost-effectiveness of the new
compound vs existing drugs is also evaluated. Some adverse effects may only reveal themselves in the longer time frame of the phase 4 trial. If
the long-term adverse effect profile for a drug is concerning, the FDA may issue a black box warning or request the pharmaceutical company
to withdraw the drug from the market or the pharmaceutical company may elect to do so itself.
Phase 4: A Phase 4, Multicenter, Randomized, Comparator, Parallel Trial of a Weight-Based Dose (240-g/kg) Versus a Fixed Dose
(20mg) of Plerixafor Injection to Mobilize and Collect ≥ 5x106 CD34+ cells/kg in 4 Days in Patients with non-Hodgkin’s Lymphoma
Weighing ≤70kg
Principal Investigator: Luciano Costa, M.D., PhD
Patients with non-Hodgkin’s lymphoma (NHL) can be treated with high-dose chemotherapy followed by autologous transplantation of
hematopoietic stem cells. Plerixafor, a small molecule chemokine receptor 4 agonist, has been shown to increase the mobilization of CD34+ cells
into the peripheral blood when given in combination with granulocyte colony–stimulating factor (G-CSF) and offers a potential treatment for
patients with NHL. Phase 3 studies showed that the combination of plerixafor plus G-CSF was safe, well tolerated, and the regimen mobilized
significantly higher numbers of stem cells than the G-CSF alone. Cells mobilized using G-CSF plus plerixafor are collected by apheresis and
used for autologous transplantation in patients with NHL. Plerixafor is administered by subcutaneous injection based on the patient’s body
weight (0.24 mg/kg). However, the weight-based dose may not be sufficient to obtain sufficient autologous cells for transplantation in lightweight patients. This phase 4 study compares a fixed and weight-based dose in lighter-weight patients to see if a fixed dose would be preferable
in this population.
For more information, call MEDULINE at 1-800-922-5250 or 843-792-2200 or visit the online edition at MUSChealth.com/progressnotes
19
Welcome
The Medical University of South Carolina Welcomes the Following New Physicians
Michael B. Lilly, M.D., Urologic Oncologist, to Co-lead Translational Research Program
at MUSC’s Hollings Cancer Center
I am pleased to announce that Michael B.
Lilly, M.D., a noted urologic oncologist
and translational cancer researcher, recently
assumed the position of Associate Director for
Translational Research at MUSC’s Hollings
Cancer Center.
Dr. Lilly brings to his new position a
wealth of experience in translational research.
He comes to MUSC from the University of
California, Irvine, where he served as the Vice
Michael B. Lilly, M.D.
Chief for Clinical Programs of the Division of
Hematology-Oncology and co-leader of the Translational Oncology
Program at the Chao Family Comprehensive Cancer Center. Prior to
that, he was Director of the Center for Molecular Biology and Gene
Therapy at Loma Linda School of Medicine, Loma Linda, CA.
Dr. Lilly, who is Board certified in internal medicine, hematology
and medical oncology, will be seeing patients with advanced prostate
cancer at MUSC. He will offer them the latest treatments, including
two new forms of hormone suppression, a novel chemotherapy drug
and the first vaccine developed to treat an established cancer.
The consummate physician-scientist, Dr. Lilly also has a robust
research program, focused primarily on prostate cancer, to complement
his clinical work. He has published more than 70 peer-reviewed articles
and served as primary investigator on almost 20 grants from both the
public (National Institutes of Health, Department of Defense) and
private sectors (biotechnology and pharmaceutical companies).
One line of his research focuses on PIM kinases, a group of enzymes
that transfer a phosphate from adenosine triphosphate to a protein and
in so doing change the function of that protein. Cells with high levels of
PIM kinases are almost certain to develop into cancerous cells. Interest
in PIM kinases as anticancer targets is growing because they foster
tumor initiation, are elevated in a number of tumor types (eg, prostate
cancer, lymphomas) and can lead to resistance to chemotherapy. Dr.
Lilly joins a number of other PIM investigators at Hollings Cancer
Center, including myself and Yubin Kang, M.D., who study this
family of protein kinases in prostate cancer and multiple myeloma,
respectively. With the recruitment of a PIM investigator of Dr. Lilly’s
stature, Hollings Cancer Center is positioning itself to be a national
center of research into this family of kinases. A goal of this cluster
of researchers will be progress toward an oral formulation of a small
molecule inhibitor of PIM kinases that could help prevent the PIMmediated development of cancer, shrink tumor size or guard against
chemotherapeutic resistance.
Dr. Lilly’s second main line of research is the development of an
antibody with the capacity to enter almost any type of cell; such an
antibody could be used as a delivery vehicle for anticancer compounds.
In other words, drugs targeting a specific cancer-promoting pathway
could be delivered into the cancer cells themselves, where their effect
would be more potent than when acting extracellularly. Although the
antibody would also deliver the drug to healthy cells, they would likely
be less negatively affected than the cancerous cells because they have
redundant pathways, meaning that another pathway could take the
place of the suppressed one. In contrast, cancers can be very dependent
initially on one or two pathways, a phenomenon known as oncogene
addiction, providing a window of opportunity when the cancer’s
progression can be slowed or halted by targeting those specific pathways.
As co-leader of the translational research program, Dr. Lilly will be
working to bring many early-phase clinical trials of novel therapeutic
agents (both small molecule and immunotherapeutic) to MUSC’s
Hollings Cancer Center. Indeed, he is already working on opening a
phase 1b/2a trial of a combination regimen of cabazitaxel plus Peregrine
Pharmaceuticals’ investigational monoclonal antibody bavituximab as
second-line chemotherapy for patients with castration-resistant prostate
cancer (NCT01335204). Cabazitaxel, a microtubule inhibitor, was
approved by the US Food and Drug Administration within the past
two years for the treatment of refractory prostate cancer. Bavituximab
is an antibody that disrupts tumor angiogenesis, thereby in essence
starving the tumor by interrupting its blood supply. Hollings Cancer
Center will be the national headquarters for this multicenter trial.
Dr. Lilly’s short-term goals as co-leader of the translational research
program are to increase Hollings Cancer Center’s portfolio of earlyphase trials for prostate and bladder cancer. He is also working with
information technology to establish a database that would better
characterize patients with prostate or bladder cancer seen at MUSC to
facilitate the design of clinical trials tailored to them. In the long term,
he would like to similarly expand the Hollings portfolio for additional
disease types.
We are fortunate to have a physician-scientist of Dr. Lilly’s caliber
join the MUSC faculty. I can’t think of anyone better to help foster
collaborations between laboratory scientists and clinicians and to
bring new opportunities for South Carolina patients to benefit from
innovative new anticancer treatments still in clinical trial.
Amit Agrawal, M.D. // Board Certification: Internal Medicine, Internal Medicine: Gastroenterology // Specialties: Gastroenterology & Hepatology // Special Interests: Esophageal motility and reflux disorders
// Medical School: Medical University of South Carolina // Residency: Medical University of South Carolina // Fellowship: Medical University of South Carolina
Amy Lee Bredlau, M.D. // Board Certification: Pediatrics // Specialties: Pediatric Hematology & Oncology // Special Interests: Neuro-oncology, Brain tumors in children, Diffuse intrinsic pontine glioma,
Medulloblastoma, Ependymoma, Optic glioma, Glioblastoma multiforme, Meningioma // Medical School: University of Nevada School of Medicine // Residency: University of California // Fellowship:
University of Rochester
Carolyn D. Britten, M.D. // Board Certification: Internal Medicine, Internal Medicine: Medical Oncology // Specialties: Hematology & Oncology //Special Interests: Gastrointestinal cancers // Medical School:
University of Toronto // Residency: University of Western Ontario // Fellowship: University of British Columbia, University of Texas Medical School at San Antonio
Stephen P. Kalhorn, M.D. // Specialty: Neurosurgery // Special Interests: Minimally invasive and complex spinal surgery, Spinal tumors, Spinal vascular malformations, Brain tumors , Endoscopic
surgery, Kyphoplasty, Adult spinal deformities // Medical School: Loyola University Chicago Stritch School of Medicine // Residency: New York University Medical Center // Fellowship: New York
University Medical Center
James R. Kiger, M.D., M.S. // Board Certification: Pediatrics // Specialty: Neonatology // Medical School: University of Pittsburgh School of Medicine // Residency: Medical University of South Carolina //
Fellowship: Medical University of South Carolina
J. Antonio Quiros, M.D. // Board Certification: Pediatrics // Specialty: Pediatric Gastroenterology // Special Interests: Pediatric gastroenterology and nutrition, Vitamin A, Inflammatory bowel disease,
Pancreatitis, Liver disease // Medical School: Escuela Autonoma de Ciencias Medicas // Residency: Case Western Reserve University // Fellowship: Children’s Hospital Los Angeles, Stanford University Hospital
Alicia S. Reams, M.D. // Specialty: Hospitalist // Special Interests: Care of the hospitalized patient // Medical School: Medical University of South Carolina // Residency: Medical University of South Carolina
Julie R. Ross, M.D. // Board Certification: Pediatrics // Specialty: Neonatology // Special Interests: Neonatal resuscitation // Medical School: Medical University of South Carolina // Residency: Vanderbilt
University // Fellowship: Medical University of South Carolina
Omar M. Shahateet, M.D. // Specialty: Hospitalist // Special interest: Care of the hospitalized patient // Medical School: Sindh Medical College // Residency: King Hussein Medical Center, Englewood Hospital
and Medical Center
Paul G. Thacker, Jr, M.D. // Board Certification: Diagnostic Radiology // Specialty: Radiology // Special Interests: Pediatric diagnostic radiology, Advanced pediatric cross-section imaging, Image-guided
procedures// Medical School: University of Mississippi School of Medicine // Residency: Mayo Clinic // Fellowship: Children’s Mercy Hospitals and Clinics
Katherine E. Twombley, M.D. // Board Certification: Pediatrics // Specialty: Pediatric Nephrology // Special Interest: Kidney transplant // Medical School: Medical University of South Carolina // Residency:
Miami Children’s Hospital // Fellowship: University of Texas Southwestern
David J. Walsh, M.D. // Board Certifications: Neurology-Special Qualifications, Child Neurology; Pediatrics // Specialties: Neurology, Pediatric Neurology // Special Interests: Epilepsy // Medical School:
Medical University of South Carolina // Residency: Medical University of South Carolina // Fellowship: Children’s Hospital Boston
Sincerely,
Andrew S. Kraft, M.D., Director
MUSC Hollings Cancer Center
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