Bench to Bedside

October 2014

Pioneering T-Cell Therapy Leads to Remarkable Remission Rate


A landmark new study published in the New England Journal of Medicine shows that 90 percent of leukemia patients treated with a groundbreaking form of cellular therapy achieved complete responses.

Led by The Children’s Hospital of Philadelphia’s Stephan M. Grupp, MD, PhD, the study is the latest to validate Dr. Grupp and colleagues’ work with CTL019 therapy, in which patients’ immune cells are engineered to multiply and fight against acute lymphoblastic leukemia (ALL) and other B cell cancers. The cells are designed to proliferate in patients’ bodies, continuing to fight and protect against cancer. Children’s Hospital’s Shannon Maude, MD, PhD, and the University of Pennsylvania’s Noelle Frey, MD, were the study’s co-first authors.

The most common form of leukemia found in children, ALL is largely curable, with a roughly 85 percent cure rate. However, the remaining 15 percent of ALL cases resist standard therapy. In conjunction with the Penn’s Carl H. June, MD, last year Dr. Grupp reported the results of early work that showed the promise of their immune therapy approach. In that study, also published in the New England Journal of Medicine, they showed two children with acute lymphoblastic leukemia achieved a complete response after being treated with an innovative cell therapy.

One of those patients was then 7-year-old Emily Whitehead, who was the subject of a media frenzy when the experimental therapy led to her dramatic recovery after she relapsed following conventional treatment. Since receiving the CTL019 therapy, Emily remains healthy and cancer-free.

In the recent New England Journal of Medicine paper, 30 children and adults were treated at Children’s Hospital and Penn with CTL019 therapy. Of those, 27 patients — 90 percent — experienced complete remissions, or a complete lack of detectable disease. Sustained remissions were seen in 67 percent of patients, and CTL019 cell proliferation was seen in 68 percent of patients.

Aside from the high percentage of complete remissions seen, the study’s findings are remarkable because many of the patients who took part had already experienced relapses or had treatment-refractory acute lymphoblastic leukemia. “Relapsed ALL is a considerable therapeutic challenge, particularly in patients who do not have a second complete remission or have a relapse after stem-cell transplantation,” the authors note. According to the study, of the 27 patients who had complete remissions, 19 remained in remission, some for as long as two years.

Advocacy organizations were quick to praise the CHOP-Penn team’s work. The Leukemia & Lymphoma Society (LLS), which has funded Dr. Grupp since 1992, called the work an “important advance.”

“This study comes almost exactly 70 years after Robert Roesler de Villiers, the son of the founders of LLS, died from ALL,” said the Leukemia & Lymphoma Society’s Louis J. DeGennaro, PhD. “At the time, the chance of surviving ALL was less than five percent of patients. Today nearly 90 percent of pediatric patients with ALL survive more than five years, and the findings announced today suggest that we may see even more patients surviving this blood cancer.”

“The patients who participated in these trials had relapsed as many as four times, including 60 percent whose cancers came back even after stem cell transplants,” said Dr. Grupp. “The durable responses we have observed with CTL019 therapy are unprecedented.”

To read more about CTL019 therapy, see The Children’s Hospital of Philadelphia’s page about the trial.

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International Study Pinpoints Childhood Epilepsy Genes


An international team of researchers recently identified gene mutations that can cause severe, difficult-to-treat forms of childhood epilepsy. Many of the mutations disrupt functioning in the synapse, the highly dynamic junction at which nerve cells communicate with one another.

“This research represents a paradigm shift in epilepsy research, giving us a new target on which to focus treatment strategies,” said pediatric neurologist Dennis Dlugos, MD, MSCE, director of the Pediatric Regional Epilepsy Program at The Children’s Hospital of Philadelphia, and one of the study’s co-authors. “There is tremendous potential for new drug development and personalized treatment strategies, which is our task for the years to come.”

Multiple researchers from the U.S. and Europe performed the research, the largest collaborative study to date focused on the genetic roots of severe epilepsies. The scientists reported their results recently in the American Journal of Human Genetics.

Two international research consortia collaborated on the study: the Epi4K/EPGP Consortium, funded by the National Institute of Neurological Disorders and Stroke (NINDS), and the European EuroEPINOMICS consortium. The genetic analysis was performed at Duke University’s Epi4K Sequencing, Biostatistics, and Bioinformatics Core, which is supported by the NINDS.

The current study added to the list of gene mutations previously reported to be associated with these severe epilepsy syndromes, called epileptic encephalopathies. The researchers sequenced the exomes (those portions of DNA that code for proteins) of 356 patients with severe childhood epilepsies, as well as their parents. The scientists looked for “de novo” mutations — those that arose in affected children, but not in their parents. In all, they identified 429 such de novo mutations.

In 12 percent of the children, these mutations were considered to unequivocally cause the child’s epilepsy. In addition to several known genes for childhood epilepsies, the study team found strong evidence for additional novel genes, many of which are involved in the function of the synapse.

Epilepsies are amongst the most common disorders of the central nervous system, affecting up to 3 million patients in the U.S. Up to one third of all epilepsies are resistant to treatment with antiepileptic medication and may be associated with other disabilities such as intellectual impairment and autism. Severe epilepsies are particularly devastating in children. In many patients with severe epilepsies, no cause for the seizures can be identified, but there is increasing evidence that genetic factors may play a causal role.

The research teams used a method called family-based exome sequencing, which looks at the part of the human genome that carries the blueprints for proteins. When comparing the sequence information in children with epilepsy with that of their parents, the researchers were able to identify the de novo changes that arose in the genomes of the affected children. While de novo changes are increasingly recognized as the genetic cause for severe seizure disorders, not all de novo changes are necessarily disease-causing.

“Everybody has one or two de novo mutations and it is our task to find those changes that cause disease,” said Children’s Hospital’s Ingo Helbig, MD. “We pulled out those genes that have more mutations in patients with epilepsy than you would expect by chance. These genes will hopefully tell us a bit more about the underlying disease mechanisms and how we can address them with new treatments.” As a member of the European EuroEPINOMICS consortium, Dr. Helbig was a co-initiator of the transatlantic collaboration that conducted the study. Dr. Helbig is also a member of the Genetics Commission of the International League Against Epilepsy.

The most surprising finding in the study by the international research group is a gene called DNM1, which was found to be mutated in five patients. The gene carries the code for dynamin-1, a structural protein that plays a role in shuttling small vesicles between the body of the neuron and the synapse. These vesicles are structures that contain neurotransmitters, chemical signals crucial to communication between nerve cells. When the researchers looked on a network level, they found that many of the genes that were found to be mutated in patients had a clear connection with the function of the synapse.

This research finding, says Dr. Dlugos, provides important information about the functional roles of the genes that were identified. “We knew that synaptic genes were important but not to this extent,” he added.

Advocacy groups applauded the study. Dr. Tracy Dixon-Salazar, associate research director at the non-profit Citizens United for Research in Epilepsy, and the mother of a child with severe genetic epilepsy, noted “It is exciting to see the big consortia put the genomic data of almost 400 patients together. This clearly highlights that by working together we can find new genes faster, helping us to explain what causes this often devastating disease in children.”

To learn more about The Children’s Hospital of Philadelphia’s epilepsy resources and research, see the Pediatric Regional Epilepsy Program website.

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Increases in Mitochondrial DNA Mutations Can Cause Shifts in Disease


Recent work by a mitochondrial medicine pioneer from The Children’s Hospital of Philadelphia details how subtle changes in mitochondrial function may cause a broad range of common metabolic and degenerative diseases. Mitochondria are tiny energy-producing structures within our cells that contain their own DNA. The research offers “key insights into understanding the underlying cause of metabolic and neurodegenerative disorders such as diabetes, Alzheimer, Parkinson and Huntington disease, as well as human aging,” said Children’s Hospital’s Douglas C. Wallace, PhD.

The new research, published in the Proceedings of the National Academy of Sciences (PNAS), shows that small changes in the ratio of mutant to normal mitochondrial DNA within the thousands of mitochondrial DNAs inside each cell can cause abrupt changes in the expression of numerous genes within the nuclear DNA. Furthermore, the different proportions of mutant mitochondrial DNA that result in altered nuclear gene expression correspond to the same proportions of mutations in mitochondrial DNA that are associated with diabetes and autism; brain, heart and muscle disease; or lethal infantile disease.

“By showing that subtle changes in the cellular proportion of the same mitochondrial DNA mutation can result in a wide range of different clinical manifestations, these findings challenge the traditional model that a single mutation causes a single disease,” said Dr. Wallace, director of CHOP Research’s Center for Mitochondrial and Epigenomic Medicine.

“The discrete changes in nuclear gene expression in response to small increases in mitochondrial DNA mutant level are analogous to the phase changes that result from adding heat to ice,” added Dr. Wallace. “As heat is added, the ice abruptly turns to water and with more heat, the water turns abruptly to steam.” Here a quantitative change (an increasing proportion of mitochondrial DNA mutation) results in a qualitative change (coordinate changes in nuclear gene expression together with discrete changes in clinical symptoms).

Existing in hundreds or thousands of copies outside the nucleus of every cell, mitochondria have their own DNA, distinct from the well-known DNA inside the cell nucleus. Although mitochondrial DNA (mtDNA) holds far fewer genes than nuclear DNA, mtDNA exchanges signals with nuclear DNA and participates in complicated networks of biochemical reactions essential to life.

The PNAS study builds on Dr. Wallace’s more than 40 years of investigating the mysteries of mitochondria. In 1988, he was the first investigator to demonstrate that mitochondrial DNA mutations can cause human disease. He has continued to build a body of research into mechanisms by which mutations in mtDNA contribute to both rare and common diseases by disrupting the body’s energy production. 

Determining mtDNA Mutations’ Effects

In the current study, Dr. Wallace’s team investigated the impacts of steadily increasing levels of a pathogenic mutation in one particular base of mitochondrial DNA. Researchers already knew that if 10 to 30 percent of a person’s mitochondrial DNA has this mutation, a person has diabetes, and sometimes autism. Individuals with an mtDNA mutation level of 50 to 90 percent have other multisystem diseases, particularly MELAS syndrome, a severe condition which involves brain and muscle impairments. Above the 90 percent level, patients die in infancy.

In the current study, conducted in cultured human cells, Dr. Wallace and colleagues analyzed cells with different levels of this pathogenic mtDNA mutation to determine the effects on the gene expression of the cell. The researchers measured variations in cellular structure and function, nuclear gene expression, and production of different proteins.

“The mutations in mitochondria impair their ability to produce energy, and mitochondria transmit distress signals to the cell nucleus,” said Dr. Wallace. “But the nucleus can respond in only a limited number of ways.” Those responses may manifest themselves in discrete, profound consequences for patients.

Dr. Wallace argues that the medical significance of this research extends beyond the province of the relatively rare disorders typically classified as mitochondrial diseases. The gene expression profile — the pattern of gene activity seen at the level at which mtDNA mutations trigger brain disorders — parallels the profiles found in Alzheimer, Parkinson, and Huntington diseases.

“The findings in this study provide strong support for the concept that common metabolic diseases such as diabetes and obesity, heart and muscle diseases, and neurodegenerative diseases have underpinnings in energy deficiencies from malfunctioning mitochondria,” he said. “Thus this concept brings together a cluster of diseases previously considered to be separate from one another.”

Significantly, Dr. Wallace added that the research also pertains to aging. Because mitochondrial mutations accumulate as people age, mitochondrial energy production declines, with deleterious effects on the heart, the brain and on interrelated biological systems that sustain health and life.

Future investigations will examine how different diseases are associated with the sorts of abrupt phase changes his group found in the current cellular study, Dr. Wallace noted. Some of the cellular changes, signaling patterns and protein activity levels found in the current research might become useful biomarkers in disease studies and drug development. “For instance, a preclinical screen for potential drugs that could reverse gene expression profile changes of the mitochondrial DNA mutant cells could reveal new therapies,” he added.

Dr. Wallace’s current study reinforces the argument he has presented over the course of his career: that mitochondria play a central, largely under-recognized role in all common human diseases. He has long argued that a traditional biomedical approach focusing on anatomy and individual organs does not provide the insights generated from a systems biology, bioenergetics-focused approach.

Dr. Wallace’s paradigm-shifting hypotheses remain controversial in biomedicine. This latest study, he says, implies that the complexity of common diseases is rooted in the disconnect between continuous, linear changes in mtDNA mutations and the discontinuous, sudden phase changes in nuclear gene expression that result. Even as his overall arguments about the role of mitochondria contend for broader acceptance, the current findings may provide useful, versatile tools for understanding and treating disease.

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To Maintain Appropriate Antibiotic Use, Sustained Feedback Needed


A program that provides guidance to primary care physicians about appropriately prescribing antibiotics for children is effective, but its improvements wear off after regular auditing and feedback are discontinued.

“Our findings suggest that interventions with outpatient healthcare providers should include continued feedback to clinicians to remain effective,” said the study’s leader, Jeffrey S. Gerber, MD, PhD, an infectious diseases specialist at The Children’s Hospital of Philadelphia.

Dr. Gerber and colleagues recently published their research in the Journal of the American Medical Association and presented their findings at the infectious disease-focused IDWeek 2014 meeting in Philadelphia. In addition to Dr. Gerber, CHOP’s Theoklis Zaoutis, MD, MSCE, and Louis M. Bell, MD, chief of the Division of General Pediatrics, contributed to the study.

Because disease-causing microorganisms have been developing resistance to commonly used antibiotics, public health experts advocate more selective usage of those medications. The “antimicrobial stewardship” program in the current study included prospective audits of prescription patterns — evaluating prescriptions based on current prescribing guidelines for specific conditions issued by professional organizations. The program staff then provided personalized, private feedback reports to the practitioners, advising them whether their prescriptions followed current recommendations.

The study team analyzed electronic health records of 1.2 million office visits at 18 community-based primary care offices within the CHOP pediatric network, focusing on prescriptions for common bacterial respiratory infections in children. The researchers randomized the 18 practices into two groups — one receiving the intervention (an hour-long session of clinician education, followed by audit and feedback) and the other group receiving no intervention.

The researchers previously reported in June 2013 that inappropriate prescribing decreased significantly in the intervention group, from 26.8 percent to 14.3 percent, compared to a decrease from 28.4 percent to 22.6 percent in the control group.

Because the previous study covered a 12-month intervention period, the current study evaluated the durability of the effects. The team followed antibiotic prescription patterns for 18 months after the auditing and feedback ended.

Prescribing of broad-spectrum antibiotics, which according to guidelines are typically reserved as second-line treatments, increased over the extended time period, reverting to above-baseline levels. After adjusting the data set for the additional 18 months after intervention ended, the study team found inappropriate prescribing rose from 16.7 percent to 27.9 percent in the intervention group, and from 25.4 percent to 30.2 percent in controls.

“Our results suggest that audit and feedback were crucial parts of this intervention,” said Dr. Gerber, who added, “For the initial benefits of this program to persist, there needs to be continued, active feedback to the clinicians in primary care offices.”

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CIRP Research Improves Teen Driving Training, Assessment


A recent article in the Wall Street Journal on “one of the most dreaded rites of child-rearing — teaching a teenager to drive,” notes recent research on teen driving and training can help teens learn to be better drivers and so avoid accidents. The article touches on studies by Center for Injury Research and Prevention (CIRP) staff: one that examined a web-based intervention, and a more recent investigation of teen driving error frequency.

Though many parents do a good job of teaching the basics of driving — “steering, parking, and controlling the car” — the Wall Street Journal article notes that parents “are not so good, however, at teaching the skills young drivers need to actually avoid accidents, according to new research. Now, there are new techniques and even guides that have grown out of new scientific research into the parent-child dynamic in the car.”

Two studies cited by the Wall Street Journal article were led by CIRP experts. In August JAMA Pediatrics published a study authored by Jessica Mirman, PhD, that examined the effectiveness of the web-based Teen Driving Plan (TDP) tool in improving teen driving performance as measured by the Teen On-road Driving Assessment (tODA).

Along with CIRP’s Allison E. Curry, PhD, MPH, and Flaura K. Winston, MD, PhD, among others, Dr. Mirman measured the TDP’s effectiveness in increasing the quantity of practice and teens’ driving performance in 217 teen-parent dyads. The dyads were randomized to receive either the TDP or standard Pennsylvania driver manuals.

She found that the “dyads reported more practice in 5 of the 6 environments and at night and in bad weather compared with control dyads.” In addition, fewer teenagers who used the TDP had their tODA’s terminated for safety reasons than did the control group, who received PA manuals. The study’s “evidence suggest that the TDP improves supervised practice and the driving performance of prelicensed teenaged drivers,” the study author’s notes.

Indeed, as the Wall Street Journal article notes, one parent who participated in Dr. Mirman’s study says the TDP helped improved her driving lessons. “Having a game plan to work with, and to be accountable for, was better,” said Monica Pica.

The second study, led by Dennis Durbin, MD, MSCE, director of CHOP Research’s Office of Clinical and Translational Research, follows Dr. Mirman’s work by investigating driving errors made by teens during their learner’s permit period. This study, published in Accident Analysis & Prevention, used the tODA at 12 and 24 weeks of study to examine driving errors in teen and adult drivers.

Dr. Durbin and colleagues found that 55 percent of novice teen drivers committed “critical errors” at the 12-week tODA and 54 percent committed errors on the 24-week tODA. Only one experienced adult driver committed a critical error at 12 weeks and one at 24 weeks.

“In comparison to a group of experienced adult drivers, a substantially higher proportion of learner teens committed safety-relevant critical driving errors at both time points of assessment,” the authors note. The finding, they write, “suggest further research is needed to better understand how teens might effectively learn skills necessary for safe independent driving while they are still under supervised conditions.”

To read more, see the Wall Street Journal article, “Better Ways to Teach Teens to Drive.” And to learn more about the research being conducted at the Center for Injury Research and Prevention, see the CIRP website.

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Safety of Severe Asthma Care Outside the ICU Assessed


Clinicians at The Children’s Hospital of Philadelphia have extensive experience in treating children with acute asthma flares, partly due to the tremendous volume of patients with this respiratory condition who come from the urban community nearby. Asthma is one of the leading, serious, chronic illnesses among children in the U.S., and Philadelphia ranks among the top five worst asthma cities.

During an asthma exacerbation, a child’s lungs and airways overreact to a certain trigger. The airways’ lining swells, and muscles surrounding the airways constrict. As these air passages narrow and become clogged with mucus, the child’s breathing becomes difficult, as if trying to get air through a pinched straw.

About 2,700 patients are admitted for asthma in a given year at The Children’s Hospital of Philadelphia, accounting for 17 percent of the total admissions. When a child with a severe asthma flare arrives at the emergency room, clinicians initiate one hour of continuous aerosolized albuterol (CAA), a quick-acting beta-agonist bronchodilator, in addition to other therapies, to relieve the patient’s shortness of breath.

If the flare is very severe, clinicians will continue continuous medication delivery when the patient is admitted to the hospital, which in many hospitals occurs in the intensive care unit. Because asthma is such a prevalent pediatric condition, often a patient with severe asthma occupies an intensive care unit (ICU) bed that is in high demand.

Chén Kenyon, MD, an attending physician in the Division of General Pediatrics at CHOP, and colleagues, wanted to find out if these patients are treated safely and effectively with CAA in the non-ICU, inpatient setting, which may free up limited ICU beds for other high acuity patients and offer significant cost-savings. Unfortunately, no published scientific data existed to support this practice, so to begin to answer the question, they conducted a retrospective cohort analysis of electronic medical record data using the CHOP Data Warehouse.

“Using this unique resource, we are able to provide much more granularity than prior studies,” Dr. Kenyon said. “We can pinpoint physician orders and see at what point a particular therapy was ordered and when it was stopped.”

A clinical pathway in place for 18 years at CHOP helps clinicians to streamline and standardize asthma care. It includes a component that allows for CAA to be administered in the non-ICU, inpatient setting for patients with severe asthma who are assessed hourly by trained respiratory therapists and nurses. The researchers combed through physician orders for CAA of 1,300 children ages 2 to 18 treated under this protocol from July 2011 to June 2013. They compared the cohort to 1,700 patients who received intermittent albuterol only and assessed the two groups’ characteristics and rate of adverse outcomes. Results from the study appeared recently in Pediatrics.

“There seemed to be no difference in the prevalence of low potassium or cardiac arrhythmia, two side effects associated with beta-agonists in rare situations,” Dr. Kenyon said. “While patients who received continuous aerosolized albuterol had a higher rate of transfers to the ICU, there was no difference in the rate of intubation. Zero patients in the continuous aerosolized albuterol group were intubated. These findings support the safety – and efficacy – of continuous aerosolized albuterol delivery in the non-ICU setting.”

The researchers also determined that certain factors identified initially in the emergency room predicted which patients would go on to deteriorate clinically and require prolonged therapy.

These included comorbid pneumonia and administration of intravenous magnesium or subcutaneous terbutaline in the emergency room. Being acquainted with these characteristics may help clinicians in hospitals without a pediatric intensive care unit (PICU) in terms of recognition of patients at higher risk for clinical deterioration who may benefit from relocation to an institution that does have a PICU, Dr. Kenyon said.

While this retrospective study sets the stage for other hospitals to evaluate how CAA could fit within the context of their asthma protocols, Dr. Kenyon emphasized that CHOP’s success in CAA delivery outside the ICU is, at least in part, due to the support structure and care processes in place. For example, in addition to the standard nurse to patient ratio of 1 to 4 and robust expert respiratory therapy support, a critical assessment team assists front-line providers in the care of patients with severe asthma who have early signs of clinical deterioration.

“This is a first step,” Dr. Kenyon said. “There is still work to be done to figure out who the ideal cohort is for continuous therapy and what resources are necessary to make this practice safe and effective in a non-ICU setting outside of CHOP. But this study provides initial evidence for the safety and effectiveness for institutions that already are providing continuous aerosolized albuterol on their non-ICU units.”

Future studies could aim to reproduce a similar study on a multicenter level, Dr. Kenyon suggested. Researchers could perform further analysis of the data to reveal any potential cost savings that may be associated with centering CAA delivery for severe asthma cases outside the ICU. More evidence also is needed to determine the appropriate length of CAA administration, and if other modes of therapy could help to enhance patients’ recovery so that they spend less time in the hospital.

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Rescuing Mutation May Operate in Bone Marrow Failure


Bone marrow failure syndromes are rare disorders in which the bone marrow does not produce enough blood cells, increasing the risk for life-threatening bleeding, anemia, and infections. While children with these conditions usually will need bone marrow transplantation, a small percentage experience spontaneous remission.

Modern genomic approaches are allowing researchers at The Children’s Hospital of Philadelphia to discover how such remission cases occur, which potentially could lead to a novel approach that will transform the way these devastating conditions are understood and managed.

Their hypothesis is that natural mutations in stem cells or progenitor cells could “rescue” them and overcome the effects of inherited or acquired gene mutations linked to bone marrow failure.

They suggest that the process behind the correcting mutations is associated with clonal hematopoiesis. While clonal hematopoiesis typically is considered to be a black cloud because it is implicated in the series of genetic changes that lead to cancerous tumor development, this study suggests that clonal hematopoiesis could brighten the chances of recovery for patients with bone marrow failure syndromes.

“If the majority of blood cells are derived from a single stem cell, which is the mother cell of all blood cells, this is called clonal hematopoiesis,” explained Philip Mason, PhD, a senior scientist for CHOP’s Comprehensive Bone Marrow Failure Center (CBMFC). “Normal blood cell production is from many stem cells. We think that it is likely that a mutation takes place in a stem cell, or progenitor cell, which improves its ability to produce blood cells or even corrects the initial defect.”

Stem cells, or hematopoietic cells, develop in the spongy bone marrow and give rise to all blood cells. Progenitor cells are early descendants of stem cells that can differentiate to form one or more kinds of blood cells, such as red blood cells, platelets, or white blood cells. In bone marrow failure syndromes, the stem cells or progenitor cells are damaged and restrict blood production.

Rescuing mutations, in contrast, allow the stem cell to grow and divide, thus giving the mutated blood cells a growth advantage — sometimes to the extent that these mutated blood cells, all derived from a single stem cell, replace the entire blood cell production

Dr. Mason is principal investigator of a new study that focuses on an inherited bone marrow failure syndrome called Diamond Blackfan Anemia, which affects 5 to 7 infants per million births worldwide. The study team’s plan is to determine the DNA sequence in the blood cells from bone marrow of 20 study participants with Diamond Blackfan Anemia, and then compare it to the sequence of skin cells from the same participants. Along with experts from CHOP’s Center for Biomedical Informatics, the researchers will pinpoint the sequences that only appear in the bone marrow cells, which will help them to identify clones of cells that are likely to carry the characteristics of the rescuing mutations.

Once this bioinformatics analysis is complete, the researchers will perform extensive validation using targeted deep sequencing methodology. This will help them to select candidate genes to be included in future functional studies to test if and how these mutations are capable of correcting the initial defect in ribosome synthesis seen in Diamond Blackfan Anemia that is responsible for the poor production of red cells.

If the study team finds clonal hematopoiesis due to mutations that increase blood cell survival or proliferation, they propose that similar mechanisms likely operate in all inherited bone marrow failure syndromes and possibly in the scenario of acquired aplastic anemia, although the mutations, genes, and pathways affected may differ. Dr. Mason also is a co-investigator of a larger study involving a multidisciplinary team of clinicians and researchers that focuses on 100 patients with acquired aplastic anemia. The lead principal investigator is Monica Bessler, MD, PhD, director of the CBMFC, a collaborative effort between CHOP and the Hospital of the University of Pennsylvania.

“While the study process is similar, it is more complicated because we don’t exactly know the causes of acquired aplastic anemia,” Dr. Mason said. “DNA sequencing and identifying the correcting mutations will help us to find out the disease’s origins, which may be different from patient to patient.”

Dr. Mason, who has investigated bone marrow failure diseases for 17 years, is enthusiastic about his involvement with both studies, which were awarded funding in August by the National Institute of Diabetes and Digestive and Kidney Diseases.

“This kind of study has only become possible in the last few years because of the technical advances in sequencing,” Dr. Mason said. “I’m excited by the possibility that it could work out and lead to better treatments for these patients.”

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Antibiotic Use in Infancy May Play Role in Obesity


While it is easy to blame the childhood obesity epidemic on too many french fries and video games, it is likely that multiple factors such as genetics and environment also contribute to excessive weight gain. A retrospective study based on data from The Children’s Hospital of Philadelphia’s electronic health records identified another significant risk factor that may influence how tendencies toward obesity develop during infancy.

Childhood obesity has more than doubled in children over the past 30 years, according to the Centers for Disease Control and Prevention. Many will remain obese into adulthood and be susceptible to heart disease, type 2 diabetes, stroke, several types of cancer, and osteoarthritis. Medical researchers at CHOP want to identify ways to intervene as early as possible, in order to avert the lifetime of medical, developmental, and social problems associated with obesity.

They were intrigued by the emerging idea that the microbial population that begins to colonize in infants’ intestines shortly after birth, known as the microbiome, plays an important role in establishing energy metabolism. Previous studies have shown that antibiotic exposure influences the microbiome’s diversity and composition.

“As pediatricians, we’re interested in whether there is anything happening early in life that resets this ‘thermostat’ and has a long-term effect on how your body regulates its weight,” said L. Charles Bailey, MD, PhD, lead author of the study that appeared online Sept. 29 in JAMA Pediatrics. “The thought is that the microbiome may be critically dependent on what is going on during infancy.”

Dr. Bailey and colleagues observed an increased risk of obesity with greater antibiotic use, particularly for children with four or more exposures to broad-spectrum antibiotics in early childhood. The study team analyzed electronic health records from 2001 to 2013 of 64,580 children with annual visits at ages 0 to 23 months, as well as one or more visits at ages 24 to 59 months within the network of primary care practices affiliated with CHOP. They assessed the relationships between antibiotic prescription and related diagnoses before age 24 months and the development of obesity in the following three years.

“What this study is showing is that we can detect a connection between the antibiotics that you may have received as an infant and what your weight is going to look like later in childhood,” Dr. Bailey said, adding that it is important to note that the study does not directly examine cause and effect.

The investigators saw the association with broad-spectrum drugs, but they reported no significant association between obesity and narrow-spectrum drugs. For this study, they classified first-line therapy for common pediatric infections, such as penicillin and amoxicillin, as narrow-spectrum. They considered broad-spectrum antibiotics to include those recommended in current guidelines as second-line therapy.

“What we think we’re seeing here with these associations is that the more we choose to use narrow-spectrum antibiotics, the less likely it may be that we’re doing something that will affect a patient’s risk of obesity later on,” Dr. Bailey said.

One of the study’s advantages is that the researchers capitalized on CHOP’s wealth of information captured during regular medical care for a large group of patients without compromising individuals’ privacy. While the study did not assess children’s activity levels, dietary habits, family structure, or socioeconomics, the researchers’ conclusions were similar to those from a previous study that evaluated those factors and also found a connection between antibiotics in early childhood and higher risk of obesity.

Future investigations are needed involving multiple large pediatric health systems that will take a broader look at several populations and how adopting guidelines that accentuate the use of narrow-spectrum antibiotics might affect patients’ risk of obesity, Dr. Bailey said.  In addition to supporting this type of research locally, CHOP is also a key contributor to networks such as PEDSnet that link many children’s hospitals to make more effective clinical research possible.

Researchers also are looking at ways the microbial communities living in infants’ intestines are swayed by dietary and environmental factors. The Children’s Hospital of Philadelphia’s Healthy Weight Program has a study underway that is following the changes of the microbiota of infants through the first year of life to see if it correlates with weight gain. As part of the study, they will track any babies who are prescribed antibiotics, in order to identify fluctuations in their microbial profiles.

Such research projects will add up to help give clinicians practical guidance on how to address the complexities of obesity.

“Treating obesity is going to be a matter of finding the collection of things that together have a major effect, even though each alone has only a small effect,” Dr. Bailey said. “Part of what we are exploring in this study is one of those factors that we can possibly modify in the way we take care of kids and make it better.”

Christopher Forrest, MD, PhD; Peixin Zhang, PhD; Thomas M. Richards, MS; Alice Livshits, BS; and Patricia DeRusso, MD, MS, contributed to the article published in JAMA Pediatrics. The American Beverage Foundation for a Healthy America provided an unrestricted donation to support this Healthy Weight Program research study.

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Research Funding Shortfalls Require Personal Response


The Children’s Hospital of Philadelphia’s Peter M. Grollman, vice president of CHOP’s Office of Government Affairs, Community Relations, and Advocacy recently penned a powerful editorial on arguing that tepid government support for medical researchers demands a personal response from voters.

“You, too, may be counting on a cure some day. That’s why it’s personal,” Grollman notes.

Children’s Hospital’s Office of Government Affairs, Community Relations, and Advocacy works “to support the Hospital, the Research Institute, and the entire CHOP health network in its goals of excellent patient care, innovative research and quality professional education.” To further CHOP’s mission of improving the health of children everywhere, the Office partners with community members, advocates on behalf of pediatric medical research, and develops relationships with members of government.

Grollman’s editorial — in which he notes family struggles with Parkinson’s disease, cancer, and Lou Gehrig’s Disease — comes at a time when support for the NIH (which funds most medical research in the United States) has flattened. Though the agency’s funding may seem impressive — in the 2015 budget the agency is allotted $30.2 billion — that number is misleading. Adjusted for inflation, the 2015 budget is about $100 million lower than the 2002 level.

Despite clear evidence showing that robust federal support for biomedical research leads to findings that can improve the health of patients in unexpected ways, government support for medical research continues to be lukewarm. “Research conducted in CHOP’s labs has discovered cures for certain types of congenital blindness and childhood leukemia,” Grollman notes, adding that such “great news should invigorate our government leaders to invest even more in the NIH.”

However, the reaction to success stories like those seen at CHOP “appears to be just the opposite: complacency. To date, the response to the empirical evidence in creating medical breakthroughs has been nothing short of unacceptable,” Grollman writes. “According to a 2013 Congressional Research Service report, after adjusting for inflation, funding for the NIH decreased 22 percent over the past decade.”

Therefore, Grollman calls on voters to make the issue personal.

“When funding for medical research is diminished, we are all impacted. We must respond. We need to move the discussion from our homes to the halls of government, where the personal interests and futures of Americans have been discussed and considered for generations,” he says.

To read more, see Grollman’s editorial on If you’re interested in contacting members of Congress and want to find your representatives and senators, see this tool from OpenCongress.

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Children’s Hospital Researchers Honored


Four researchers from The Children’s Hospital of Philadelphia were recently honored with awards from the Perelman School of Medicine at the University of Pennsylvania. The 2014 Penn Medicine Awards of Excellence recognize faculty who exemplify the highest values of innovation, commitment to service, leadership, dedication to patient care, and scholarship and teaching.

The following investigators were honored:

“The contributions of these clinicians and scientists exemplify the outstanding quality of patient care, mentoring, research, and teaching of our world-class faculty,” J. Larry Jameson, MD, PhD, executive vice president of the University of Pennsylvania Health System and dean of Penn’s School of Medicine, stated in an announcement of the awards. “I am extremely proud to honor these faculty for their achievements.”

The awardees shared their reactions to this outstanding accomplishment and described some of the projects that demonstrate their drive, dedication, and professionalism. Congratulations to all of the winners!

Dr. Blobel is a hematology researcher in the Department of Pediatrics at The Children’s Hospital of Philadelphia:  “The award recognizes the highly productive people in our group who have carried out all the work and made the lab into what it is today.

“In recent years what we consider to be our breakthroughs are related to two major areas of investigation. One involves the study of higher order chromatin architecture and the development of reagents to alter it with an eye on therapeutic uses. In particular, we have developed an approach that might be suitable as a strategy to treat sickle cell anemia.

“The other involves studies into epigenetic ‘memory’ as it pertains to cell division. During mitosis our chromatin undergoes massive changes in the way it is organized, and virtually all genes are silenced, and it is believed that specific mechanisms are in place that ensure that the correct gene expression patterns are restored upon exit from mitosis. We think that such mechanisms help cells to maintain their identity and differentiation state. Our lab has gained insights into this question and in the process developed tools that are useful to investigators pursuing similar questions.”

Dr. Miller is a psychologist and director of research for the Division of Adolescent Medicine at The Children’s Hospital of Philadelphia: “I am so gratified to work at CHOP and Penn, with such a rich array of collaborators doing interesting and innovative work. My research on child and adolescent decision-making has depended on the support of multiple clinical programs and principal investigators at CHOP, as well as an effective and talented research staff. The overall goal of my work is to identify the ways in which children and adolescents can be involved in decision making about their own health, to enhance their sense of control and facilitate effective decision making as they mature.”

Dr. Liu is a pediatric neuro-ophthalmologist and faculty member of the Ophthalmology Division at The Children’s Hospital of Philadelphia, and a Professor of Neurology and Ophthalmology at Penn: “I have to admit that I was humbled by the Lindback Award. Looking at some of the comments about my teaching, I didn’t realize that I had had such a positive influence as a teacher. To follow in the footsteps of other highly acclaimed, great teachers is really quite an honor — one that I never really expected.”

Dr. Marsh is an assistant professor of neurology and pediatrics at The Children’s Hospital of Philadelphia:  “I am thrilled to have been awarded the Leonard Berwick teaching award. I work hard to infuse my clinical teaching with the basic science fundamentals that are important for all students and residents to remember during their clinical training. In my role as a physician scientist, I study the basic physiological mechanisms underlying a disease, infantile spasms, that I diagnosis and treat in children. Hence, in my day-to-day work, I attempt to merge the science and clinical realms and instill this approach to the students I teach. I find my work, going from basic mechanisms to the patient, very fulfilling and one of the most rewarding parts of my job.”

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Core Seeks to Ease Recruitment Process


As the saying goes, it takes a village: without patients who believe in the promise that clinical research offers, medical studies can be doomed to fail. While every investigation is the product of hard work by teams of researchers, fellows, laboratory assistants, and coordinators, it is those patients who are willing to take part in a study that are key to its success. But at times finding and recruiting study participants can be an uphill battle.

The Children’s Hospital of Philadelphia Research Institute’s new Recruitment Enhancement Core (REC) hopes to smooth the recruitment process for busy investigators and their teams. The REC works to make investigators’ lives easier by offering assistance with recruitment plans, creating marketing and promotional materials, and giving them access to a registry of potential recruits.

Led by Chris Gantz, the REC falls under CHOP Research Institute’s Clinical Research Support Office. All told, Gantz has almost a decade of experience at Children’s Hospital and the University of Pennsylvania, and has been working to support clinical research since 2002. Gantz has a background in neuroscience as well as an MBA from Drexel University’s Lebow College of Business, and he has developed relationships with research project stakeholders, overhauled and improved recruitment plans, and managed research teams.

The idea for the REC dates to approximately 2007 when Gantz, who was then working as a research coordinator, had a lunchroom conversation with a colleague about difficulties they were both having with recruiting. After two years at Penn — where he built a recruitment team — Gantz formally proposed establishing a CHOP research core devoted to recruitment, eventually joining the Clinical Research Support Office. Though the REC is a new program, he hopes to grow its staff, and has been working with one of the 2014 Research Administration Fellows, Sarah Tash, PhD.

Much of the REC’s work draws on Gantz’s clinical research experience and marketing background. For example, the REC works with investigators to create recruitment letter content and appearance — including even the envelopes the letters come in — all with the goal of making sure letters are actually opened once they’re sent out. Likewise, Gantz has been working to create a centralized, accessible space in the Hospital where recruitment flyers would be displayed.

“We are trying leverage some best practices that we’ve learned about marketing to participants,” Gantz said.

The REC has also been working to create a version of CHOP Research Institute’s Clinical Research Finder tool for the Hospital’s website, and building a participant registry in part by encouraging investigators to ask their patients if they might be interested in taking part in future clinical research projects. Indeed, according to a study by the Center for Information & Study on Clinical Research Participation, 95 percent of “study volunteers say that they would consider participating in another clinical research study in the future.”

To that end, the REC has been working to establish the Research Participant Registry (RPR). A comprehensive database of potential participants that will be populated with existing study participants referred by study teams and members of the public who opt in. “The majority of individuals participating in studies would participate again, the problem is that we haven’t always been asking,” said Gantz, adding, “over time we hope build a robust registry of people interested in participating in research.”

The REC has also been working with the Penn to identify opportunities for collaboration, and recently spoke at a panel made up of Penn and CHOP research personnel to discuss ways to enhance recruitment across both institutions. In addition, the REC has a number of community engagement activities planned, Gantz said, such as having investigators visit schools to raise awareness of CHOP and how integral participants are to clinical research.

Overall, the goal of the REC is to help reduce the burden recruitment can create, thereby saving study teams’ time and resources, Gantz said.

For more information about the Recruitment Enhancement Core, see the CRSO website, or contact Chris Gantz directly at

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Produced by The Children’s Hospital of Philadelphia Research Institute.

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