Sep 17 2014

Get Involved to Make Medical Research a National Priority

medical researchIt’s your turn to give a shout-out for scientific discovery. The Rally for Medical Research Capitol Hill Day Thursday, Sept. 18, brings together almost 300 national organizations, including The Children’s Hospital of Philadelphia, in support of making funding for the National Institutes of Health (NIH) a national priority.

Programs like those at The Children’s Hospital of Philadelphia Research Institute need a reliable stream of revenue in order to conduct the long-term scientific projects that ultimately produce breakthrough treatments and cures for diseases.

Since 2003, the NIH budget has declined by more than 22 percent, or $6.1 billion, after adjusting for inflation, according to the Association of American Medical Colleges (AAMC), a rally day sponsor. The AAMC developed a set of advocacy materials to help the medical and research communities to urge Congress to pass the FY 2015 Labor, Health and Human Services, Education, and Related Agencies (Labor-HHS) spending bill and restore funding to NIH cut by sequestration in 2013. A draft of the bill provides $30.5 billion for NIH, a $606 million (2 percent) increase over FY 2014.

What can you do? Send a letter to members of Congress through the AAMC’s legislative action center telling you representatives that NIH is critical to the advancement of science and improving the health of people around the world. You can add a personal message about your research experience, what you hope to accomplish, or what inspires your research career.

Share tweets and posts encouraging your fellow scientists, medical trainees, graduate students/post docs to call Congress to action. Here’s an example:

Federal funding for medical research is the way we protect our nation’s health. Act now: #FinishtheJob

Support the AAMC’s Thunderclap campaign, which is a “crowdspeaking platform” that will post a message Thursday to the social media accounts of participants asking their friends and followers to also send a letter to Congress to pass the Labor-HHS bill. The AAMC hopes to generate thousands of letters in support of the federal investment in medical research. Get involved: The louder the thunder, the greater the impact.

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Sep 15 2014

Scholar Hope Grant Supports Neuroblastoma Research


©2014 Paul Crane, Crane Photography, Inc.

Pediatric oncology researchers at The Children’s Hospital of Philadelphia are driven to find new treatments for childhood cancer, and the Hyundai Hope On Wheels program is supporting their hard work by awarding a 2014 Scholar Hope grant to help fund investigations that focus on the aggressive form of neuroblastoma. Despite intense treatment, more than 50 percent of children with high-risk neuroblastoma die of their disease, accounting for 12 percent of pediatric cancer deaths.

Kristina Cole, MD, PhD, a CHOP attending physician and researcher with expertise in identifying therapeutic targets in pediatric cancer, received the Scholar Hope grant at a “Handprint Ceremony” in front of the hospital Sept. 11. Children from the oncology floor were invited to place their handprints in paint on a Hyundai car that is traveling across the country to build awareness of pediatric cancer research. Hyundai Motor America and its more than 820 U.S. Hyundai dealers have donated more than $86 million to pediatric cancer research in the U.S. through Hope On Wheels.

Each child’s handprint stands out as one of a kind, as does Dr. Cole’s novel research project which aims to demonstrate, for the first time, that a subset of patients with neuroblastoma could benefit from checkpoint inhibition and support further clinical development of new generation checkpoint inhibitors for pediatric solid tumors.

In previous work, Dr. Cole and colleagues have shown that neuroblastoma tumors rely on the DNA repair checkpoint protein kinase 1 (CHK1) to handle the cellular stress caused by the powerful MYCN oncogene that drives tumor growth. When CHK1 is inhibited, the neuroblastoma cells can no longer grow and die. Several clinical trials are underway based on the idea that if cancer cells are exposed to a CHK1 inhibitor, the protein will be unable to respond when the cell’s DNA is damaged by treatments such as chemotherapy.


©2014 Paul Crane, Crane Photography, Inc.

“This current research is unique because we’re trying to better understand which patients may benefit and why they may benefit,” Dr. Cole said. “We think that MYCN certainly has a very large role, but is it possible that other factors — like underlying defects in genes that mediate DNA damage — make certain patients even more likely to benefit from this treatment strategy.”

First, researchers will analyze large genomic datasets from hundreds of primary tumor samples to find any defects in DNA repair genes. Then, they will characterize how those mutations could make neuroblastoma tumors more sensitive than other tumor types to drugs that inhibit CHK1. Their third aim will be to do preclinical work in the laboratory with cell cultures and animal models to be able to justify a clinical trial of next generation checkpoint inhibitors in combination with traditional chemotherapy.

The researchers’ hypothesis that certain neuroblastoma tumors have increased dependency on the compensatory DNA repair pathway due to a possible defect in DNA repair genes is reminiscent of what has been described in breast cancer research, Dr. Cole said. Breast tumor cells with inherent DNA repair defects, such as mutations in BRCA1 or BRCA2, are sensitive to drugs that inhibit PARP, another protein that helps cancer cells repair DNA damage and survive. Tumor cells with normal BRCA proteins continue to grow.


©2014 Paul Crane, Crane Photography, Inc.

Dr. Cole is among 36 Scholar Hope two-year grant winners, who each received $250,000 for a total of $9 million in support. The ultimate goal of the Scholar Hope grant program is to find cures for childhood cancers once and for all, according to the program’s website.

“It is a great award that they’ve put together to support the work done by individuals from Children’s Oncology Group institutions all across the country who are investigating pediatric cancers,” Dr. Cole said. “They’ve been very generous to CHOP.”

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Sep 12 2014

Researchers Explore Girls’ Response to Breast Cancer Risk

breast cancerThis is the first generation where women are routinely tested for genetic mutations that may increase their risk for breast cancer. They are also increasingly aware of the implications of their cancer history and genetic testing results on their daughters.

Researchers at The Children’s Hospital of Philadelphia are collaborating with adult breast cancer specialists to find ways for girls from high-risk families to navigate the nuances of how growing up with this knowledge affects their well-being and health behaviors.

One in 8 women in the U.S. will develop invasive breast cancer during their lifetime, according to the American Cancer Society. It is estimated that 5 to 10 percent of breast cancer cases result directly from gene defects — usually a mutation in the BRCA1 and BRCA2 genes — inherited from a parent.

Yet little research has been completed that explores how adolescent girls understand and respond to learning about their familial breast cancer risk, and many pediatric practitioners are inexperienced in helping them to deal with a legacy of cancer. Lisa A. Schwartz, PhD, a psychologist in the Division of Oncology at CHOP, is involved with two studies that are addressing this knowledge gap: “Studies of Female Teens” (SOFT I and SOFT II) and “Lessons in Epidemiology and Genetics of Adult Cancer from Youth” (LEGACY Girls Study).

“We want to capitalize on this window of time during the transition to adulthood when health behaviors are being solidified, and provide guidance on how they value their health and how they fit health into their identity as it’s being developed,” Dr. Schwartz said.

She works closely on this research with co-principal investigators Angela R. Bradbury, MD, an assistant professor of medicine in the Division of Hematology-Oncology at the Perelman School of Medicine at the University of Pennsylvania, and Mary B. Daly, MD, PhD, at Fox Chase Cancer Center. Dr. Bradbury presented some of the SOFT II study’s findings in June at the annual meeting of the American Society of Clinical Oncology.

The study involved 320 girls with an average age of 15 years who were classified as either “high risk” or “population risk.” High-risk girls had a parent with a BRCA1/2 mutation or at least one first-degree or second-degree relative with a history of breast cancer. The results showed that high-risk girls were almost three times more likely to worry about breast cancer than population-risk girls, even when their mothers’ had no history of the disease. The study, which caught the attention of public media provider NewsWorks, also revealed that high-risk girls were significantly more likely to smoke cigarettes.

“We don’t know how to interpret that yet,” Dr. Schwartz said. “Is it because the anxiety is driving them to want to self-medicate, or is it because they have a fatalistic attitude that they’re going to get cancer anyway?”

The study team encouraged future research projects to evaluate outcomes of disclosure of genetic breast cancer risk to adolescents. Dr. Schwartz, Dr. Bradbury, and co-investigator Linda Patrick-Miller, associate director of the Center for Clinical Cancer Genetics at the University of Chicago, covered this emotionally charged topic in a presentation about sharing genetic information with offspring at the international conference Joining FORCEs Against Hereditary Cancer held in Philadelphia June 12-14.

Current National Comprehensive Cancer Network guidelines call for breast cancer surveillance for high-risk patients to begin with monthly self-exams at age 18, but semiannual clinical breast exams and annual mammograms are not recommended until age 25. Some contend that adolescents do not need to have immediate knowledge about their familial breast cancer risk since they do not undergo screening tests until adulthood. On the flip side, others advocate for disclosure in the teen years because young women can take steps to reduce their risks and practice healthy lifestyles as early as possible.

“Knowing your risk probably is a positive thing, but we’re not doing a good job of helping teens to manage that risk,” Dr. Schwartz said. “We don’t just want to leave these girls worrying and then turning to bad behaviors because they’re afraid that they have no choices. We can reframe this risk and help them to see that they can have control over their health.”

In light of the sensitive nature of their studies that recruited vulnerable adolescents, Dr. Schwartz participated with colleagues to implement an event monitoring committee to provide additional oversight of their research activities as a safeguard to identify any emotional, social, cultural, or economic issues that might develop. The study team published their framework and recommendations in the Journal of Adolescent Health for other investigators and institutional review boards to incorporate into future regulatory standards to improve the safety of behavioral and observational studies involving children and adolescents.

“When working with children and families, it’s important to really think through and identify any precautions that you can take in your research to protect them,” Dr. Schwartz said.

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Sep 08 2014

Study Aims to Reveal Novel Drivers of Allergic Disease

allergic disease

This strategy is an exciting alternative to current treatments for allergic disease that globally shut down immune function, Dr. Oliver said.

Chronic allergic disorders affect millions of individuals worldwide, and their frequency is increasing, especially in children and adults living in the U.S. Often, multiple allergic diseases, such as asthma, food allergies, atopic dermatitis, and some gastrointestinal disorders can occur in a single patient.

Investigators at The Children’s Hospital of Philadelphia are studying the underlying biological features that could be common from one allergic disease to another. In particular, they are interested in how two small adapter proteins, Ndfip1 and Ndfip2, activate enzymes called E3 ubiquitin ligases that could play an important role in preventing allergic disease.

“A small protein, ubiquitin, is the basis for the garbage disposal system of the cell,” explained Paula M. Oliver, PhD, in the Cell Pathology Division of CHOP and an associate professor of pathology and laboratory medicine at the University of Pennsylvania School of Medicine. “When ubiquitin is tagged to a protein, one of the outcomes can be degradation of that protein. So it is the cell’s way of removing unneeded proteins. When you don’t get rid of those proteins, you can get allergic disease.”

Dr. Oliver’s study team is using genetically engineered mice to study E3 ubiquitin ligase function. They previously have shown that mice in which a particular ligase — aptly named ITCH — cannot function, develop an allergic dermatitis-like phenotype that causes them to scratch. They also get inflammation of the lungs that is reminiscent of asthma and gastrointestinal disorders that have features similar to food allergies.

In Dr. Oliver’s current work that received funding in July from the National Institute of Allergy and Infectious Diseases, the investigators already have figured out how E3 ubiquitin ligases remain inactive in a closed, “off” position until Ndfip1 and Ndfip2 seem to open them up and turn them “on.”

“We took the next step in thinking that maybe there are some ways of forcing that to happen and turn on these enzymatic pathways in cells to prevent or treat allergic disease,” Dr. Oliver said.

This strategy is an exciting alternative to current treatments for allergic disease that globally shut down immune function, Dr. Oliver said. The new approach they are studying would disarm only the component of the immune system that drives allergic responses, while not affecting its ability to respond to viruses or pathogenic bacterial infections.

Over the next year, the study team will move toward developing therapeutic methods to regulate E3 ubiquitin ligase activation. They will design small penetrating peptides aimed at catalyzing the transfer of ubiquitin to a substrate protein in the cell. They also will work with a local company to create small molecule activators of the ligases, as a second possible approach.

“We are quite sure that there are other mechanisms that might control these things as well, so we’re continuing to understand exactly how this happens,” Dr. Oliver said. “We’re also trying to understand what the substrates are that need to be gotten rid of because that might tell us more about how allergic diseases start or which proteins are important in driving allergic diseases.”

In addition to receiving funding from the NIAID, Dr. Oliver’s work is supported by the American Asthma Foundation.

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Sep 04 2014

Award Set to Fund Opioid Withdrawal Investigation

opioidEvery year, approximately 350,000-400,000 infants are treated in a neonatal intensive care unit (NICU), according to a report put out by the Health Resources and Service Administration. Of those, between 50 and 80 percent become dependent on the opiates—such as the powerful analgesic morphine—they are prescribed for their pain. And per the Drug Enforcement Agency, morphine “has a high potential for abuse,” but is also “one of the most effective drugs known for the relief of severe pain and remains the standard against which new analgesics are measured.” This means that clinicians trying to manage their patients’ pain know the same treatments that ease their pain could lead to dependence and withdrawal later.

Currently, the “mainstay of pharmacologic management is gradual opioid weaning,” note the authors of a 2010 Pediatrics paper on opioids in children. Specifically, neonates are often weaned with methadone, pointed out The Children’s Hospital of Philadelphia’s Gordon A. Barr, PhD.

“There’s no good treatment,” for opioid dependence in infants, Dr. Barr said. “People have tried benzodiazepine, they’ve tried barbiturates, they’ve tried keeping the lights really low and dim and quiet—those environmental conditions help calm the baby, but they don’t slow the withdrawal process.” But the standard of care remains lowering the methadone dose gradually, he said.

Director of the Section of Acute and Chronic Pain Management in Children’s Hospital’s Department of Anesthesiology and Critical Care Medicine, Dr. Barr recently received a grant from the National Institute on Drug Abuse to examine the immune system’s role in opioid dependence during early development. Over the course of this two-year, exploratory R21 award, Dr. Barr plans to look “at whether modulation of immune function has the same consequences for opiate actions in infancy as it does in adults,” he said. “And if so, how?”

This project grows out recent “attention paid to he interactions of the immune system and brain function in general, and opiates and immune function and brain function in particular,” Dr. Barr noted. In addition to relieving pain, opiates are known to act as immunosuppressors, but how they do so in neonates remains poorly understood and understudied. There is a paucity of literature on opiate action during early development, Dr. Barr pointed out.

Preliminary research by Dr. Barr’s laboratory shows that activating the immune system during treatment actually worsens opioid withdrawal, and that doing so in very young neonates (mice younger than seven days old, or full-term human babies) has no effect. With this investigation, Dr. Barr will be specifically be looking at the immune receptor toll-like-receptor 4 (TLR4). Dr. Barr and his team’s hypothesis is that TLR4 in the nervous system is not functional in very young neonates, hence the lack of reaction observed when the immune system is activated during opioid treatment.

The investigators plan on evaluating a number of drugs, including some already approved for other uses and experimental drugs not yet on the market. Though pre-clinical, basic work, Dr. Barr’s hope with this project is that it will help inform clinical decisions in the future, and help to determine whether need exists for new drugs to be developed.

To read more about this study, see the August issue of CHOP Research’s Bench to Bedside . And to learn more about pain management, see the Department of Anesthesiology and Critical Care Medicine’s Pain Management Program.

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Sep 02 2014

Study Compares Lung Opening Strategies for Preterm Infants

infantWhen an infant is born, we usually think of the strenuous effort labor entails for the mother, but it also requires a fair amount of work on the baby’s part.

A newborn quickly has to adapt to breathing air, which calls for a large set of events to take place. In the fluid-filled environment of the uterus, the lung is essentially closed, and the infant has to expand the lung quickly, in order to take over the placenta’s business of putting oxygen into the bloodstream and getting rid of carbon dioxide.

That becomes a tricky thing to do for a baby who is born prematurely and extremely small — less than 1,000 grams — because the infant must have good muscle power to generate the high opening pressure required for its first breath to establish lung volume. This is where a research maneuver being studied by a multicenter, international clinical trial led by Haresh Kirpalani, BM, MSc, of The Children’s Hospital of Philadelphia, and Sarah J. Ratcliffe, PhD, of the University of Pennsylvania Perelman School of Medicine fits in.

Previously, several large trials have looked at helping infants who weigh less than 1,000 grams to expand their lungs using a simple, low level continuous positive airway pressure, called CPAP, which is administered in the delivery room via a facemask at about 5 to 7 cmH2O. And while it’s been shown that CPAP can help the baby transition into a postnatal, oxygen-enriched environment satisfactorily, many of these babies end up requiring placement of an endotracheal tube in the windpipe that breathes for the baby. Intubation imposes an additional burden and risk of bronchopulmonary dysplasia, one of the main problems that face premature babies if they survive.

The research maneuver being tested in the Sustained Aeration of Infant Lungs Trial (SAIL) launched this summer will impose a higher peak inspiratory pressure of about 20 cmH20 and hold the breath for about 15 seconds immediately after birth to facilitate uniform lung aeration. Half the babies enrolled in the trial will receive the low level CPAP, and the other half will receive the research intervention delivered by a physician trained to implement the study protocol. A potential concern is that the higher pressure will increase the chance of air leaks, but so far the literature is not convincing that this is a problem, Dr. Kirpalani said.

“The results of the trial should enable us to take a near definitive look at the standard of care for resuscitation of these babies at delivery, and begin to give some guidance to the Neonatal Resuscitation Program as to whether sustained inflation is a useful strategy or not,” Dr. Kirpalani said.

The NRP is an educational program sponsored by the American Academy of Pediatrics and the American Heart Association to teach an evidence-based approach to resuscitation to multidisciplinary hospital staff who care for newborns at the time of delivery.

The SAIL research team expects over three years to enroll 600 infants with a gestational age of at least 23 weeks but less than 27 weeks who require resuscitation or respiratory intervention at birth. A particular challenge of this study is approaching parents during the stressful and uncertain time of preterm labor and gaining full parental consent to participate in the trial.

In a Pediatric Perspectives article published in the July issue of Pediatrics, Dr. Kirpalani and his neonatology colleagues at CHOP, Sara B. DeMauro, MD, and Barbara Schmidt, MD, MSc, and also at McMaster University, Canada, Janice Cairnie, RN, and Judy D’Ilario, RN, examined the importance of honesty, trust, and respect during consent discussions in neonatal clinical trials.

“We’ve always been of the mind that an ongoing dialogue after consent is extremely important to enable the parents to understand what the issues are and also to reinforce throughout the trial duration that we are conducting it largely because we do not know whether treatment A or treatment B is better,” Dr. Kirpalani said. “That gives parents multiple opportunities to revisit the informed consent question, allows them to voice their concerns, and understand their child’s potential benefits and risks. In a way, it should be like an ongoing part of the therapeutic relationship.”

The SAIL trial is supported by funding through the Eunice Kennedy Shriver National Institute of Child Health and Development.

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Aug 28 2014

Report on 100 Prenatal Surgeries for Spina Bifida Support it as New Standard of Care

spina bifidaReporting on 100 recent cases of fetal surgery for spina bifida, specialists from The Children’s Hospital of Philadelphia achieved results similar to those in a landmark clinical trial that established a new standard of care for prenatal repair of this birth defect.

The single-center study from the Center for Fetal Diagnosis and Treatment at CHOP represents the largest series reported since 2011 when the National Institutes of Health-sponsored Management of Myelomeningocele Study (MOMS) published its results in the New England Journal of Medicine.

Three years ago, the MOMS showed that fetal surgery led to decreased rates of shunting, which involves implanting a tube to drain excess fluid from the brain, at 12 months of age. Fetal surgery also reversed a life-threatening condition called Arnold Chiari 2 malformation, otherwise known as hindbrain herniation, and improved the children’s outcomes, including their ability to walk at 30 months of age.

“The MOMS trial presented very encouraging results and helped experts develop guidelines for optimal care, but there were questions about whether the benefits of this procedure could be reproduced outside the setting of a rigorous trial,” said Julie S. Moldenhauer, MD, a maternal-fetal medicine specialist at CHOP and lead author of the current paper in the journal Fetal Diagnosis and Therapy. “This study shows that an experienced program can achieve comparable results, and that we can modify our techniques to improve on the trial outcomes.”

CHOP’s center was one of the three fetal surgery programs that participated in the randomized MOMS trial, and has been performing fetal myelomeningocele (fMMC) repairs since 1998. In total, CHOP has performed more than 1,175 fetal surgeries for a range of birth defects, the largest number of any hospital in the world.

The current study draws on a cohort from all patients referred to CHOP for potential fMMC repair between January 2011 and March 2014. Of 587 total referrals, the program designated 139 to be candidates for the fetal surgery, and 100 mothers completed the surgery.

The current cohort had a decreased incidence of preterm premature rupture of membranes (PPROM) compared to the MOMS group; average operative times were significantly shorter; there were decreases in the incidence of pulmonary edema and the transfusion rate at the time of cesarean delivery. Also, early neonatal MRIs showed that 71 percent of the infants had no evidence of hindbrain herniation, in which part of the cerebellum (hindbrain) protrudes through the opening in the base of the skull into the spinal canal and obstructs the flow of cerebrospinal fluid, leading to a progressive hydrocephalus.

In addition, when compared to prenatal ultrasound evaluations of the anatomic level of the myelomeningocele, 55 percent of the newborns in the study had improved functional motor level, but the authors added that follow-up research will be needed to determine if this benefit persists in longer-term outcome studies.

For more details on the study, click here.

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Aug 26 2014

Investigators Excited to Receive CPCE Pilot Grant Awards


The spring 2014 award winners are Andrea Knight, MD, and Lori Kestenbaum, MD.

Medical research is a rewarding field to work in, but young investigators often find that while they have an abundance of bright ideas, scientific funding is not as plentiful. Any opportunity to get a research project off the ground is greatly appreciated, especially by the two Children’s Hospital of Philadelphia physicians who recently received 2014 Pilot Grant Awards from the Center for Pediatric Clinical Effectiveness (CPCE).

The purpose of the CPCE’s Pilot Grant Program is to promote and support fellows, junior faculty, and other CHOP researchers in conducting clinical effectiveness pilot research studies that will attract external support for large-scale studies. The CPCE accepts proposals twice a year, and promising projects undergo at least two rounds of reviews to determine that they fully meet the selection criteria. Candidates must be involved in research designed to produce evidence for what works best for treating, diagnosing, and preventing disease.

The spring 2014 award winners, Andrea Knight, MD, and Lori Kestenbaum, MD, are enthusiastic about launching their investigations.

Dr. Knight is an assistant professor in the Division of Pediatric Rheumatology at CHOP. Her research focus includes patient-centered outcomes and health services research in pediatric systemic lupus erythematosus (SLE), also known as lupus, an autoimmune disease that can affect multiple body systems. Her goal is to facilitate access to mental healthcare and improve health-related quality of life for children with SLE.

The pilot study aims to reveal key patient, caregiver, and provider-level factors that affect mental healthcare for pediatric SLE and mixed connective tissue disease patients (MCTD). The findings from this study will lay the groundwork for developing mental health screening and intervention options for pediatric patients with SLE/MCTD. Practitioners could use this knowledge to create a trusting environment that allows patients with chronic diseases to feel secure in expressing their mental health concerns and to more easily obtain appropriate mental healthcare.

“Ensuring that their mental health is adequately addressed is important because they have a lot of psychological stress dealing with their chronic conditions,” Dr. Knight said. “We want to gain some rich information from patients and their families about their mental health needs and any difficulties that they see to getting them addressed.”

The pilot grant will build on previous findings that Dr. Knight compiled as the principal investigator for a study evaluating the prevalence of depression and anxiety in pediatric SLE patients. She found that depression or anxiety affected about one-third of the patient cohort, but that mental health treatment rates in those with symptoms were low.

Over the next year, Dr. Knight and her study team will conduct patient-centered interviews with 30 participants that will aim to identify possible barriers to the mental health referral process. This experience also will allow Dr. Knight to expand her expertise to include more qualitative research processes.

“Surely, having funding toward a project is hard to capture these days, so it was very exciting to win the grant,” Dr. Knight said. “It also is exciting to know that the CPCE, policy lab, and CHOP as a whole are interested in this issue. I personally think that it is very important to my patients but also to chronic disease patients as a whole.”

The second recipient of the award, Dr. Kestenbaum, is a fellow in Pediatric Infectious Diseases at CHOP. Her research is focused in two areas: understanding vaccine hesitancy to increase vaccine acceptance and modifying antibiotic prescribing practices for common childhood illnesses to reduce antibiotic overuse.

The pilot study will investigate antibiotic prescription practices and efficacy in patients with community-acquired pneumonia (CAP). CAP is the leading cause of mortality for children beyond the neonatal period worldwide, and current guidelines recommend amoxicillin as first line treatment to target the most common causes of CAP. Despite these guidelines, the most commonly prescribed antibiotics are macrolides, a class of antibiotics that does not appropriately treat the most common causes of bacterial pneumonia.

“The [study] design takes advantage of CHOP’s practice-based research network, which is an invaluable resource in the fact that it links together 31 primary care practices, multiple different regions, socioeconomic classes, and is all united under one electronic health record,” Dr. Kestenbaum noted.

The study will entail a thorough analysis of a dataset from the ambulatory EHR system in order to pinpoint patient and provider characteristics that are likely to influence antibiotic prescribing choices in the outpatient setting. Afterward, Dr. Kestenbaum will manually review additional data to compare how treatment regimens with amoxicillin vs. macrolides are associated with patients’ outcomes.

“This study will look at what drives providers to make treatment decisions,” Dr. Kestenbaum said. “Is it something about the patient, is it something about the provider, or is there another factor that drives providers to make treatment decisions that are not in our national guidelines?”

Dr. Kestenbaum expects that results of this comparative effectiveness pilot study will help to support future guideline development and implementation to ensure appropriate antibiotic prescribing practices for the management of CAP.

“The opportunity to have a pilot grant is really exciting,” Dr. Kestenbaum said. “It allows me to collect preliminary data to support future study proposals. The support of the CPCE for those of us who are just starting out is incredibly helpful.”

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Aug 22 2014

Award Will Support Novel Hemophilia Therapy Investigation


Dr. Ivanciu’s research deals with the blood coagulation response, and in particular the coagulation factor IX (FIX).

The Children’s Hospital of Philadelphia’s Lacramioara Ivanciu, PhD, was one of five investigators who recently received funding through the Bayer Hemophilia Awards Program (BHAP). A “unique initiative dedicated to supporting innovative research and educational initiatives that benefit people with hemophilia,” the BHAP is administered by Bayer Healthcare, a subsidiary of the German pharmaceutical giant Bayer AG, and awards grants to hemophilia investigators and professionals.

An investigator in the Children’s Hospital’s Division of Hematology, Dr. Ivanciu’s research is focused on the design of novel bypass agents for the treatment of hemophilia. An inherited bleeding disorder, hemophilia is a lifelong disease that can require chronic management According to the CDC, each year in the U.S. approximately 400 babies with hemophilia are born.

Dr. Ivanciu’s research deals with the blood coagulation response, and in particular the coagulation factor IX (FIX). A key part of the coagulation system, FIX deficiency results in Hemophilia B, which is most often treated by replacement FIX therapy. However, FIX replacement therapy requires multiple injections and high doses, as FIX has a short half-life.

“My research focus on bioengineering coagulation factor IX as a potential alternative strategy for hemophilia B therapy,” said Dr. Ivanciu. “The novel FIX variants are expected to have prolonged half-life and efficacy and thus, be more efficient at lower doses. This could greatly benefit the patients with hemophilia by reducing the therapeutic dose, an important goal in the replacement therapy,” said Dr. Ivanciu.

In addition, Dr. Ivanciu recently co-authored a paper published in Blood examining recombinant activated human Factor VII, and was the first author another paper also published in Blood that focused on two other coagulation factors, factor Xa and factor Va.

Saying she was “very pleased” to receive the BHAP Early Careeer Investigator award, Dr. Ivanciu noted that its support will allow her “to advance the understanding of bleeding disorders by developing and applying new systems models and therapeutics to these problems.”

“I am in a unique position to make meaningful contribution to the field and possibly advance new therapies for the treatment of hemophilia,” she added.

“BHAP, now in its twelfth year, continues to attract high-quality applicants who are committed to answering important scientific and medical questions. Through our support of their research, this year’s winners will contribute to a better understanding of hemophilia and bleeding disorders and ways to improve treatment and optimize patient outcomes,” said Bayer Healthcare’s Prasad Mathew, MD.

For more information hematology research and care at The Children’s Hospital of Philadelphia, see the Division of Hematology’s website.

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Aug 20 2014

New Study Focuses on Nasal Steroids as OSA Treatment

nasal_steroidsRemoving a child’s tonsils and adenoids, or adenotonsillectomy, currently is the primary therapy for childhood obstructive sleep apnea syndrome (OSAS), but many parents remain wary about surgery and would welcome an alternative approach. Researchers from the Sleep Center at The Children’s Hospital of Philadelphia are set to launch the “Steroids for Pediatric Research in Kids (SPARK)” trial in September that will investigate the use of nasal corticosteroids as a possible treatment for OSAS.

OSAS is extremely common, according to Carole L. Marcus, MBBCh, director of CHOP’s Sleep Center. It is seen in 2 to 4 percent of children, but she maintains that it is greatly underdiagnosed. Usually, a blockage from enlarged tonsils or adenoids cause obstruction in breathing, called apneas and hypopneas, that repeatedly disrupt a child’s sleep. If OSAS is left untreated, it can result in significant complications, ranging from behavioral problems and sleepiness in mild-to-moderate cases, and cognitive abnormalities, high blood pressure, and growth disturbances in more severe cases.

One of the lessons that Dr. Marcus learned from being a co-investigator of the Childhood Adenotonsillectomy Study for Children With OSAS (CHAT Study) — a large, randomized, multicenter control study that compared the effectiveness of surgery vs. watchful waiting for OSAS — was that better treatments and more therapeutic choices for families are needed. While adenotonsillectomy is relatively safe, about 3 percent of children will have significant hemorrhage postoperatively, and other complications can occur.

“Most families were hoping to hold off on surgery because they were scared,” Dr. Marcus said.

Over the past few years, several small, short-term studies have reported on nasal steroids as an alternative treatment for pediatric OSAS. They showed overall benefit for mild OSAS cases but did not study more severe cases; in addition, the results demonstrated tremendous individual variability. The American Academy of Pediatrics clinical practice guidelines for the diagnosis and management of OSAS issued in 2012, which Dr. Marcus chaired, included nasal steroids as a treatment option, but there was not enough evidence to give a strong recommendation.

Dr. Marcus and colleagues are launching the SPARK study to increase knowledge about the effect of nasal steroids and to identify which subgroups of patients with OSAS are most likely to benefit. For example, the research team will determine if children with asthma and/or atopy respond better to nasal steroids. Another subgroup they will focus on is African-American children because strong data from CHAT and other studies have shown that they have more severe OSAS and do not respond as well to surgery. Sophisticated genetic tests included in the SPARK study will help the investigators to further characterize responders vs. non-responders.

The double-blind, randomized control trial also will assess nasal steroids’ duration of action and possible side effects, which for a small minority of children include growth problems, ocular abnormalities, and adrenal suppression.

“Does the disease recur if you stop nasal steroids?” Dr. Marcus asked. “Is it cured forever? Do you keep doing sleep studies? If kids are on the steroids long-term, are you likely to see complications?”

In order to answer those questions, the study is designed to randomize children to receive either nasal steroids or placebo for three months. After three months, those in the nasal steroid arm of the study will be re-randomized to either ongoing steroids or placebo for another nine months.

The multidisciplinary study team will include investigators from general pediatrics and several specialty areas including sleep medicine, endocrinology, ophthalmology, allergy, and otolaryngology. They aim to recruit about 300 patients, with a goal of randomizing 156 participants, from these diverse practice settings.

“I’m hoping we’ll find a nonsurgical alternative for some children but that it also will lead to more personalized medicine,” Dr. Marcus said. “One treatment does not fit all.”

The National Heart, Lung, and Blood Institute is funding the research project.

For more information on the SPARK study, contact research coordinator Ruth Bradford.

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